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and congenital ichthyosiform erythroderma &#40;CIE&#41;&#46; In the new classification&#44; harlequin ichthyosis &#40;HI&#41; was added to this group<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> because inactivating mutations in the <span class="elsevierStyleItalic">ABCA12</span> gene have been identified as responsible for this disorder&#44;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3</span></a> while nonsense mutations in the same gene may give rise to the LI<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> or CIE<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;6</span></a> phenotype&#46; Other less common variants included in the group of ARCIs are self-healing collodion baby &#40;SHCB&#41;&#44; acral SHCB&#44; and bathing suit ichthyosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#8211;9</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">Only limited data are available on the epidemiology of ARCIs&#46; In the United States&#44; a prevalence at birth of 1 per 100 000 population for LI and of 1 per 200 000 population for CIE has been estimated&#46; Other studies have reported a combined prevalence for LI and CIE of 1 per 200 000 to 300 000 population&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;11</span></a> In some countries such as Norway&#44; the estimated prevalence is greater &#40;1 per 91 000&#41; due to founder mutations&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> The finding of 1 or several recurrent mutations in a population may be because the mutation occurred at a given point in history and was then passed from generation to generation &#40;founder mutation&#41; or because the region of the genome where the mutation is found has a DNA sequence susceptible to mutation &#40;mutation hotspot&#41;&#46; In Spain&#44; the estimated prevalence of ARCI is 1 per 138 000 in the general population and 1 per 61 700 among children under 10 years of age&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> In certain regions of Spain&#44; the prevalence might be even higher&#46; On the Galician coast&#44; for example&#44; a prevalence of 1 per 33 000 was reported&#44; due also to a founder effect&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Lamellar Ichthyosis and Congenital Ichthyosiform Erythroderma</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Clinical Characteristics</span><p id="par0015" class="elsevierStylePara elsevierViewall">Although it was originally thought that LI and CIE were different entities&#44; there have been reports of patients with intermediate clinical manifestations and both conditions can be caused by mutations in the same gene&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;16</span></a> In addition&#44; patients with the same mutation&#44; even within the same family&#44; can develop different phenotypes&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;15</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Most patients are born enveloped in a collodion membrane that progressively disappears during the first weeks of life and is replaced by the definitive phenotype &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A&#41;&#46; Hypohidrosis&#44; severe heat intolerance&#44; and nail dystrophy are frequently observed in both LI and CIE&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#8211;19</span></a> Patients with LI usually have more severe clinical manifestations than those with CIE&#46; They have large platelike scales&#44; often of a dark color&#44; covering the whole body surface area&#46; Erythroderma is either absent or minimal&#46; Such patients usually have ectropion and&#44; at times&#44; eclabium&#44; hypoplasia of joint and nasal cartilage&#44; scarring alopecia&#44; especially at the edge of the scalp&#44; and palmoplantar keratoderma &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>B and C&#41;&#46; CIE is characterized by the presence of erythroderma and fine whitish scaling &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Some patients have marked erythema and generalized scaling&#46; The scales can be large and dark colored&#44; particularly on the extensor surfaces of the legs&#46; In less severe cases&#44; erythema is mild and the scaling is fine&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Histopathology</span><p id="par0025" class="elsevierStylePara elsevierViewall">Histopathologic changes do not provide a diagnosis&#46; In LI&#44; massive orthokeratotic hyperkeratosis is observed&#44; usually with twice the extension as in CIE&#46; The epidermis is acanthotic and occasionally takes on a psoriasis-like appearance&#46; The cell proliferation rate is normal or slightly elevated&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#8211;19</span></a> Patients with CIE have less marked hyperkeratosis&#44; with focal or extensive parakeratosis&#44; a normal or thickened granular layer&#44; and more pronounced acanthosis&#46; The epidermal turnover is increased&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#8211;19</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Ultrastructure</span><p id="par0030" class="elsevierStylePara elsevierViewall">Although a close correlation between molecular&#44; clinical&#44; and ultrastructural findings has so far not been found&#44; electron microscopy may nevertheless be useful for ruling out other forms of ichthyosis and for guiding genetic analyses in some cases&#46; Four types of congenital ichthyosis have been described &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Congenital Ichthyosis Type 1</span><p id="par0035" class="elsevierStylePara elsevierViewall">Congenital ichthyosis type 1 is characterized by the absence of ultrastructural markers for ichthyosis types 2&#44; 3&#44; and 4&#46; Therefore&#44; diagnosis is usually only made when the other types have been excluded&#46; The most frequent finding is the presence of lipid droplets or rings in the stratum corneum &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>A&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> These lipid droplets are not a constant feature or specific to this particular type as they are not present in all cases&#44;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> and they may be present in other types of ichthyosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#44;22</span></a> Clinically&#44; most patients present with manifestations of CIE&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;20</span></a> One-third of patients have mutations in the <span class="elsevierStyleItalic">TGM1</span> gene&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> This ultrastructural type has also been identified in association with mutations in the <span class="elsevierStyleItalic">ALOX12B</span> gene&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;24</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Congenital Ichthyosis Type 2</span><p id="par0040" class="elsevierStylePara elsevierViewall">Congenital ichthyosis type 2 is characterized by cholesterol clefts in the stratum corneum &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>B&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> Such clefts are a constant finding in this type of ichthyosis&#44; and can be detected in different biopsies in the same patient&#59; treatment with oral retinoids has no impact on these clefts&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;25</span></a> Electron-dense aggregates have also been observed on corneocytes in some patients with deficient TGase 1 activity&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#8211;28</span></a> Clinically&#44; most patients present with severe manifestations of CIE&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> This ultrastructural type is strongly associated with mutations in the <span class="elsevierStyleItalic">TGM1</span> gene&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;16</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Congenital Ichthyosis Type 3</span><p id="par0045" class="elsevierStylePara elsevierViewall">Congenital ichthyosis type 3 is characterized by lamellar membranous structures in the stratum granulosum and&#47;or stratum corneum&#46; These structures are arranged in strips around an empty space close to the nucleus&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;29&#8211;31</span></a> The clinical manifestations in this type are different to the others&#59; onset of ichthyosis is variable&#44; desquamation and erythema may be patchy or generalized&#44; and the flexures in particular are affected&#46; Mutations in the <span class="elsevierStyleItalic">NIPAL4</span> gene are responsible for 93&#37; of ichthyoses type 3&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Congenital Ichthyosis Type 4</span><p id="par0050" class="elsevierStylePara elsevierViewall">Characteristically&#44; in congenital ichthyosis type 4&#44; some cells in the stratum granulosum and stratum corneum are filled with trilamellar membrane packages&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> These findings are pathognomic for ichthyosis prematurity syndrome&#44; a condition currently considered as a syndromic form of ichthyosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34&#44;35</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Molecular Studies</span><p id="par0055" class="elsevierStylePara elsevierViewall">In genetic terms&#44; the ARCIs are very heterogeneous&#46; The <span class="elsevierStyleItalic">TGM1</span> gene is associated with most cases&#44; but mutations in 5 other genes &#40;<span class="elsevierStyleItalic">ALOX12B</span>&#44; <span class="elsevierStyleItalic">ALOXE3</span>&#44; <span class="elsevierStyleItalic">NIPAL4</span>&#44; <span class="elsevierStyleItalic">CYP4F22</span>&#44; and <span class="elsevierStyleItalic">ABCA12</span>&#41; have been reported&#46; Fischer et al&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> studied 520 families with ARCI and identified mutations in at least 1 of these genes in 78&#37; of cases &#40;<span class="elsevierStyleItalic">TGM1</span> in 32&#37;&#44; <span class="elsevierStyleItalic">NIPAL4</span> in 16&#37;&#44; <span class="elsevierStyleItalic">ALOX12B</span> in 12&#37;&#44; <span class="elsevierStyleItalic">CYP4F22</span> in 8&#37;&#44; <span class="elsevierStyleItalic">ALOXE3</span> in 5&#37;&#44; and <span class="elsevierStyleItalic">ABCA12</span> in 5&#37;&#41;&#46; In another study of 250 patients with ARCI of different origins&#44; 38&#37; had <span class="elsevierStyleItalic">TGM1</span> mutations&#44; 6&#46;8&#37; had <span class="elsevierStyleItalic">ALOXE3</span> mutations&#44; and 6&#46;8&#37; had <span class="elsevierStyleItalic">ALOX12B</span> mutations&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> In Galicia&#44; we identified mutations in the <span class="elsevierStyleItalic">TGM1</span>&#44; <span class="elsevierStyleItalic">ALOX12B</span>&#44; <span class="elsevierStyleItalic">ALOXE3</span>&#44; <span class="elsevierStyleItalic">NIPAL4</span>&#44; and <span class="elsevierStyleItalic">CYP4F22</span> genes in 75&#37; of the families studied&#44; but the distribution of mutations was different&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> The <span class="elsevierStyleItalic">TGM1</span> gene was mutated in 68&#46;7&#37; of the cases while the <span class="elsevierStyleItalic">ALOXE3</span> gene was mutated in just 1 patient&#46; We did not detect mutations in any of the other 3 genes studied&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">TGM1</span><p id="par0060" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">TGM1</span> gene is located on chromosome 14q11&#46;2 and has 15 exons &#40;GenBank NM-000359&#46;2&#41;&#46; It encodes the TGase 1 enzyme&#44; which is one of the 3 TGase enzymes found in the epidermis&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> This enzyme participates in the formation of the cornified envelope by catalyzing calcium-dependent cross-linking of several proteins such as involucrin&#44; loricrin&#44; and proline-rich proteins&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">39&#44;40</span></a> It also catalyzes binding of ¿-hydroxyceramides in the outer layer of the cornified envelope with proteins in the inner layer&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">41&#44;42</span></a> In patients with <span class="elsevierStyleItalic">TGM1</span> mutations&#44; the cornified envelope is missing and TGase 1 activity is reduced or nonexistent&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">43&#8211;47</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Since 1995&#44; when this gene was identified as responsible for some cases of ARCI&#44;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">48&#8211;50</span></a> more than 110 mutations have been reported in patients of different origins&#46; Mutations in <span class="elsevierStyleItalic">TGM1</span> are the most common cause of ARCI&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36&#44;37</span></a> This mutation has been found in 55&#37; of cases in the United States and in 84&#37; of cases in Norway&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;51</span></a> The most frequent mutation is c&#46;877-2A<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>G&#44; which has been found in 34&#37; of the mutated alleles reported to date&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> The high frequency of this mutation in countries such as the United States and Norway is due to a founder effect&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;53</span></a> The second most frequent mutation is p&#46;Arg142His&#46; This and similar mutations have been reported in countries such as Egypt&#44; Germany&#44; Finland&#44; and the United States&#44;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;49&#8211;51&#44;54&#8211;56</span></a> and it would seem that these are hotspot mutations&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a> The p&#46;Arg307Trp mutation is frequent in the Japanese population&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> In Galicia&#44; the p&#46;Arg760X&#44; c&#46;1223&#95;1227delACACA and c&#46;984<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1G<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>A mutations in <span class="elsevierStyleItalic">TGM1</span> were identified in 81&#46;82&#37; of the families with mutations in this gene&#44; suggesting a founder effect&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> Confirmation of this hypothesis was obtained by haplotype study &#40;work as yet unpublished&#41;&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">TGM1</span> mutations are responsible for most cases of LI<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;27&#44;44&#44;46&#44;56&#44;58&#8211;63</span></a> and for a small percentage of cases of CIE&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">43&#44;47&#44;64&#44;65</span></a> Such mutations can also give rise to other forms of ARCI such as SHCB&#44; acral SHCB&#44; and bathing suit ichthyosis&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Many studies have attempted to demonstrate genotype-phenotype associations between mutations in <span class="elsevierStyleItalic">TGM1</span> and ultrastructural or clinical findings&#44; but no significant correlation has been observed to date&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;16&#44;53</span></a> In general&#44; patients with mutations in the <span class="elsevierStyleItalic">TGM1</span> gene are more severely affected than those without such mutations&#46; In a study of 83 patients with ARCI in Sweden and Estonia&#44; the presence of ectropion and collodion baby was associated with <span class="elsevierStyleItalic">TGM1</span> mutations&#44; while a higher rate of erythema was observed in patients without mutations in this gene&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a> Another study showed that the type of scaling is the main difference between carriers and noncarriers of <span class="elsevierStyleItalic">TGM1</span> mutations&#44; on finding that all patients with mutations in this gene had lamellar scaling whereas 80&#37; of those without <span class="elsevierStyleItalic">TGM1</span> mutations had fine scaling&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> In addition&#44; it has been seen that truncating mutations are more frequently associated with hypohidrosis and sweating disorders than missense mutations&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> In the north American population&#44; a model based on the presence of certain clinical characteristics predicts that patients who are born as collodion babies and have ocular disorders and&#47;or alopecia are 4 times more likely to have <span class="elsevierStyleItalic">TGM1</span> mutations&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">ALOXE3 <span class="elsevierStyleItalic">and</span> ALOX12B</span><p id="par0080" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">ALOXE3</span> and <span class="elsevierStyleItalic">ALOX12B</span> genes are located on chromosome 17p13&#46;1&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a> They have a similar structure with 15 exons that encode the epidermal LOXs eLOX-3 and 12R-LOX&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">68&#44;69</span></a> The fact that they are predominantly expressed in the suprabasal layers of the epidermis supports their role in advanced phases of epidermal differentiation&#44; with participation in the processing of lamellar bodies&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#44;70</span></a> These enzymes act on adjacent steps in the hepoxilin pathway &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46; 12R-LOX transforms arachidonic acid to 12R-hydroxyeicosatetraenoic acid while eLOX-3 converts this product into an epoxyalcohol isomer<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">69&#44;71</span></a> of the hepoxilin A<span class="elsevierStyleInf">3</span> family&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">72</span></a> The hepoxilin product is unstable and is hydrolyzed in cells to a specific trihydroxy derivative &#40;trioxilin&#41;&#46; Although the exact role of the products of the hepoxilin pathway is not known&#44; it has been speculated that they may participate in the formation of intercellular lipids of the stratum corneum or act as signals for inducing keratinocyte differentiation&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">ALOX12B</span> and <span class="elsevierStyleItalic">ALOXE3</span> genes were first identified in 2002&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">73&#44;74</span></a> Since then&#44; more than 30 mutations in the <span class="elsevierStyleItalic">ALOX12B</span> gene<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;24&#44;37&#44;75&#8211;77</span></a> and approximately 10 in the <span class="elsevierStyleItalic">ALOXE3</span> gene<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;74&#44;75</span></a> have been reported&#46; These mutations are responsible for 14&#37; to 17&#37; of ARCIs<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36&#44;37</span></a> and 72&#46;2&#37; of SHCBs&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;78&#44;79</span></a> The causative relationship between these mutations and phenotype was confirmed by demonstrating that the catalytic activity of the epidermal LOX was totally abolished in patients with these mutations<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">75&#44;80</span></a> and by using animal models that reproduced the ichthyosiform phenotype seen in humans&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">81&#8211;83</span></a> Both genes are responsible for a similar percentage of ARCI cases&#46; However&#44; the range of different mutations in the <span class="elsevierStyleItalic">ALOXE3</span> gene is limited&#44; due to the predominance of 2 mutations&#44; p&#46;Arg234X and p&#46;Pro630Leu&#44; which seem to correspond to hotspots&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;74&#44;75</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">The patients with mutations in the <span class="elsevierStyleItalic">ALOXE3</span> and <span class="elsevierStyleItalic">ALOX12B</span> genes usually show a CIE phenotype&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">74&#44;75&#44;77</span></a> The severity of scaling is mild or moderate&#44; and the scales have a whitish or light brown color&#46; Erythema may also be present&#46; As many as 76&#37; of the patients are born as collodion babies and 88&#37; have sweating disorders&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> Patients with mutations in the <span class="elsevierStyleItalic">ALOX12B</span> gene show more limited&#44; whitish desquamation compared with carriers of mutations in the <span class="elsevierStyleItalic">ALOXE3</span> gene&#46; In these cases&#44; the scales are brownish and adherent&#46; The presence of erythema&#44; palmoplantar hyperkeratosis&#44; and accentuation of the palmoplantar folds are also associated with <span class="elsevierStyleItalic">ALOX12B</span> mutations&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Ichthyin&#47;NIPAL4</span><p id="par0095" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">NIPAL4</span> gene&#44; also known as the <span class="elsevierStyleItalic">ichthyin</span> gene&#44; is located on chromosome 5q33&#46; It has 6 exons that encode a protein with several transmembrane domains of unknown function&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">84</span></a> It has been hypothesized that the protein product participates in the same metabolic pathway as LOX and may act as a receptor for trioxilins A3 and B3 or for other metabolites of the hepoxilin metabolic pathway&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">84</span></a> It would thus be implicated in the formation of lamellar bodies or in their transport towards the extracellular space&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> In support of this are 2 observations&#46; First&#44; in 93&#37; of the cases&#44; mutations in this gene are associated with an ultrastructural pattern of congenital ichthyosis type 3&#44; characterized by abnormalities in the lamellar bodies and the presence of elongated perinuclear membranes in the stratum granulosum&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> Second&#44; <span class="elsevierStyleItalic">NIPAL4</span> is expressed essentially in the stratum granulosum of the epidermis&#44; where the lamellar bodies are present&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">85</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Since the discovery of the <span class="elsevierStyleItalic">NIPAL4</span> gene in 2004&#44;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">84</span></a> only 9 mutations have been reported in patients from Mediterranean countries &#40;Algeria&#44; Turkey&#44; and Syria&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">84</span></a> Scandinavian countries&#44;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> Pakistan&#44;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">85</span></a> the Faroe Islands&#44;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> and South America&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">84</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">The clinical spectrum of patients with mutations in this gene is broad&#44; even among members of the same family&#46; Between 3&#46;7&#37;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> and 60&#37;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">84</span></a> are born as collodion babies&#46; When the collodion membrane disappears&#44; most patients develop the manifestations of CIE&#44; with fine whitish scales on an erythematous base on the face and trunk and larger&#44; brownish scales on the neck&#44; buttocks&#44; and legs&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">84</span></a> Marked xerosis&#44; generalized brownish reticular hyperkeratotic plaques that appear accentuated in the skin folds&#44; and facial dyschromia may be present&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;85</span></a> In addition&#44; palmoplantar keratoderma is a frequent finding along with occasional finger contractures and curved finger nails&#46; Some studies have reported findings more typical of LI&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;85</span></a> The presence of signs and symptoms of atopic dermatitis has been reported in some patients&#44; although mutations in the <span class="elsevierStyleItalic">FLG</span> gene were not detected in any of these cases&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">85</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">CYP4F22</span><p id="par0110" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">FLJ39501</span> or <span class="elsevierStyleItalic">CYP4F22</span> gene is located on chromosome 19p13&#46;12&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">86</span></a> It has 12 exons<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">87</span></a> and encodes a P450 cytochrome&#44; family 4&#44; subfamily F&#44; polypeptide 2&#44; homolog of leukotriene B4- &#969;-hydroxylase &#40;CYP4F2&#41;&#46; The reaction catalyzed by the product of <span class="elsevierStyleItalic">FLJ39501</span> in the skin and the substrates of that reaction may be deduced by analogy with its known homologs CYP4F2 and CYP4F3&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">88</span></a> It has been hypothesized that CYP4F2 and CYP4F3 participate in the hepoxilin pathway by catalyzing the conversion of trioxilin A3 to 20-hydroxy-&#40;R&#41;trioxilin A3<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">87</span></a> and that the end product of this pathway&#44; 20-carboxy-trioxilin A3&#44; may have a key biological regulatory effect in the skin&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">89</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">To date&#44; only 8 mutations of this gene have been reported in 12 consanguineous families from Mediterranean countries<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">87</span></a> and in 1 family of Israeli origin&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">In the families reported by Lef&#232;vre et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">87</span></a> most patients had a CIE phenotype at birth and this subsequently progressed to LI&#46; Patients were usually born with marked erythroderma&#44; although without any collodion membrane&#46; As they got older&#44; they developed generalized whitish-grey scaling&#44; which was more marked in the periumbilical region&#44; on the buttocks&#44; and on the lower part of the body&#46; Hyperlinearity of the palms and soles and desquamation on the scalp&#44; at times of pityriasiform type&#44; were frequent&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">87</span></a> In another family&#44; the 3 members affected were born as collidion babies and developed intense erythroderma&#44; generalized desquamation&#44; and palmoplantar keratoderma&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">ABCA12</span><p id="par0125" class="elsevierStylePara elsevierViewall">In 2003&#44; the <span class="elsevierStyleItalic">ABCA12</span> gene was reported to be responsible for some cases of LI and was mapped to chromosome 2q34&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> It was subsequently confirmed that mutations in this gene were also responsible for HI&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3</span></a><span class="elsevierStyleItalic">ABCA12</span> encodes 53 exons&#44; and belongs to a family of ABC transporters&#44; which bind adenosine triphosphate while also facilitating the transport of several molecules across the cell membrane&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">90</span></a> The members of the ABCA subfamily are all implicated in lipid transport&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">91</span></a> Deficient ABCA12 function causes lipid transport disorders in lamellar bodies and so lead to a decrease in intercellular lipid levels in the stratum corneum&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>Ultrastructural studies have shown that ABCA12 is located in lamellar bodies associated with glycosylceramides&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">91</span></a><span class="elsevierStyleItalic">ABCA12</span> mutations have been associated with disorders in the distribution and transport of glycosylceramides and with decreased levels of hydroxyceramides&#44; one of the main components in the lipid barrier in the intercellular spaces&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;6&#44;92&#44;93</span></a> The massive hyperkeratosis that occurs in these patients could be a compensatory response to a deficient lipid barrier&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">94</span></a> It might also be due to the lack of desquamation of the corneocytes&#44;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">93</span></a> which could be caused by defects in the transport of certain proteases&#44; such as callicrein 5 and cathepsin D&#44; resulting from disorders in the lamellar bodies&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">95</span></a> Murine models and in vitro studies suggest that <span class="elsevierStyleItalic">ABCA12</span> mutations also have an effect on epidermal differentiation&#46;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">95&#8211;97</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">To date&#44; more than 50 mutations have been reported in the <span class="elsevierStyleItalic">ABCA12</span> gene in patients with ARCI from Africa&#44; Europe&#44; Pakistan&#44; and Japan&#46; The most frequent mutations are p&#46;Val244SerfsTer28&#44;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;98&#44;99</span></a> identified in Pakistani and Indian populations&#44; and p&#46;Asn1380Ser&#44;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> identified in African families&#46; In both case&#44; these may be founding mutations&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">The extent of the <span class="elsevierStyleItalic">ABCA12</span> mutations is related to phenotype&#44; with mutations associated with complete loss of function leading to the HI phenotype&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3&#44;98&#8211;102</span></a> By contrast&#44; in LI and CIE&#44; most mutations are missense&#44; and have a less severe effect on protein function&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#8211;6&#44;103</span></a> The mutations underlying the LI phenotype seem to be concentrated in the first adenosine triphosphate binding cassette region&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Clinically&#44; patients with CIE and mutations in the <span class="elsevierStyleItalic">ABCA12</span> gene have medium-size scales that are somewhat larger than those usually observed in patients with this phenotype&#46;</p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Harlequin Ichthyosis</span><p id="par0140" class="elsevierStylePara elsevierViewall">HI or harlequin fetus is a severe and usually fatal form of ichthyosis&#46; The children are usually premature with extensive shiny hyperkeratotic plaques&#44; separated by deep fissures&#44; that cover the entire integument and form geometric patterns reminiscent of clothing worn by harlequins&#44; thereby giving the condition its name&#46; Skin tightness leads to marked eversion of the eyelids and lips&#44; rudimentary development of joint and nasal cartilage and&#44; occasionally&#44; microcephaly&#46; The children rarely have eyelashes or eyebrows&#44; although the hair on the scalp may be conserved&#46; The hands and feet are swollen and edematous&#44; and often covered by a glove-like layer&#46; They may have finger contractures&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">For such patients&#44; the risk of dying during the neonatal period is very high&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">104</span></a> Pulmonary ventilation is compromised&#59; transepidermal water loss leads to dehydration&#44; hydroelectric imbalance&#44; and thermal instability&#59; and the risk of infections is increased&#46; Facial tightness and eclabium hinder sucking and therefore feeding&#44; with the corresponding worsening of dehydration&#46; Neonates with this condition rarely lived longer a few weeks&#46; In recent years&#44; however&#44; the chances of long-term survival have increased notably&#44; essentially due to administration of systemic retinoids and progress in intensive neonatal care&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">105</span></a> In a recent study&#44; 83&#37; of the patients treated with oral retinoids survived compared to 24&#37; of untreated patients&#46; Most of the deaths occurred in the first 3 days of life&#44; but treatment was not started until after this in many of the survivors&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">104</span></a> This would suggests that many of these early deaths would have occurred regardless of retinoid treatment&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">The children who survive the neonatal period generally develop severe CIE&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">106</span></a> The nature and location of mutations in the <span class="elsevierStyleItalic">ABCA12</span> gene and the extent of transporter function loss may determine prognosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;92&#44;107</span></a> Patients who conserve a certain degree of protein activity&#44; albeit minimal&#44; may have a better chance of surviving&#46; Carriers of homozygous mutations have a higher mortality rate&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">104</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">The main histologic characteristic of HI is the presence of an extremely thick and compact orthokeratotic stratum corneum&#46; The hair follicles and sweat ducts have prominent hyperkeratotic plugs<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">107&#44;108</span></a> and have abnormal or absent lamellar bodies&#44; lipid inclusions&#44; or remnants of organelles or nuclei in the corneocytes&#44; and absence of intercellular lipids in the ultrastructural study&#46;<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">108&#44;109</span></a> The hair follicles show a marked concentration of keratotic material&#44; which is a diagnostic feature of HI used for prenatal diagnosis&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">To date&#44; the rate of detection of mutations in the <span class="elsevierStyleItalic">ABCA12</span> gene in patients with HI is close to 100&#37;&#44; and so this would appear to be a genetically homogeneous condition&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Collodion Baby and Self-healing Collodion Baby</span><p id="par0165" class="elsevierStylePara elsevierViewall">Collodion babies are usually born prematurely and perinatal morbidity and mortality are increased&#46; At birth&#44; the neonate is covered by a shiny taught transparent membrane reminiscent of cellophane wrapping &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>&#41;&#46; The babies have ectropion&#44; eclabium&#44; and hypoplasia of the nasal and joint cartilage&#46; Sucking and pulmonary ventilation may be hindered<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">110</span></a> and transepidermal loss of water and the risk of infections are increased&#46;<a class="elsevierStyleCrossRefs" href="#bib0550"><span class="elsevierStyleSup">110&#44;111</span></a></p><elsevierMultimedia ident="fig0025"></elsevierMultimedia><p id="par0170" class="elsevierStylePara elsevierViewall">Collodion baby is the usual presentation for HI and CIE&#46; Autosomal dominant LI&#44;<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">112&#44;113</span></a> Sj&#246;gren-Larsson syndrome&#44;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">110</span></a> trichothyodystrophy&#44;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">114</span></a> juvenile Gaucher disease&#44;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">110</span></a> neutral lipid storage disease&#44; Conradi-H&#252;nermann-Happle syndrome&#44; Hays-Wells syndrome&#44; and ectodermal dysplasia<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">115</span></a> may also occasionally present as collodion baby&#46; The membrane disappears spontaneously in 10&#37; to 24&#37; of neonates&#44; to give way to completely normal skin&#46;<a class="elsevierStyleCrossRefs" href="#bib0550"><span class="elsevierStyleSup">110&#44;116</span></a> In the past&#44; these cases were described as LI of the newborn&#44;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">117</span></a> but they are not referred to as SHCB&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">118</span></a> Some authors have suggested the term <span class="elsevierStyleItalic">self-improving collodion ichthyosis</span> because many of these patients&#44; when reexamined later in childhood or as adults&#44; have a variable degree of anhidrosis and heat intolerance and mild signs of ichthyosis&#44; such as xerosis and fine desquamation&#44; particularly in the axillae and neck&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">78</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Neither optical microscopy nor ultrastructural investigations of collodion baby are specific&#46; It is therefore preferable to delay the skin biopsy until the definitive phenotype has developed&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Mutations in the <span class="elsevierStyleItalic">TGM1</span>&#44;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#44;119</span></a><span class="elsevierStyleItalic">ALOXE3</span>&#44;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">78</span></a> and <span class="elsevierStyleItalic">ALOX12B</span><a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;78&#44;79</span></a> genes have been identified in patients with SHCB&#46; <span class="elsevierStyleItalic">ALOX12B</span> mutations are the most common&#46; In a series of 15 Scandinavian patients with SHCB&#44; 67&#37; had mutations in the <span class="elsevierStyleItalic">ALOX12B</span> gene&#44; 25&#37; in the <span class="elsevierStyleItalic">ALOXE3</span> gene&#44; and 8&#46;3&#37; in the <span class="elsevierStyleItalic">TGM1</span> gene&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">78</span></a> Mutations were not found in some patients&#44; and so other genes are also likely to be implicated&#46; There has been speculation that these mutations reduce enzymatic activity in the uterus but not after birth&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> In the uterus&#44; where the hydrostatic pressure is high&#44; chelation by water converts the mutated enzyme into an inactive conformation&#46; After birth&#44; when the pressure decreases&#44; the enzyme returns to its active form and its activity increases sufficiently to maintain a normal or minimally affected phenotype&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Acral Self-healing Collodion Baby</span><p id="par0185" class="elsevierStylePara elsevierViewall">Although collodion baby affects the whole body&#44; cases confined to the acral regions have been reported&#46; In 1952&#44; Finlay et al&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">120</span></a> reported a case of collodion membrane that affected only the hands and feet and that followed a self-healing course&#46; Recently&#44; a new case of acral SHCB has been reported in association with mutations of the <span class="elsevierStyleItalic">TGM1</span> gene&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> It is not known why these lesions are restricted to acral regions&#44; although factors associated with site-dependent regulation of enzyme activity may be in operation&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p></span></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Bathing Suit Ichthyosis</span><p id="par0190" class="elsevierStylePara elsevierViewall">Bathing suit ichthyosis was first reported as an independent ARCI variant in 2005 although cases of ichthyosis with a peculiar distribution had been reported previously&#46;<a class="elsevierStyleCrossRefs" href="#bib0605"><span class="elsevierStyleSup">121&#8211;123</span></a> It has been detected mainly in patients of South African origin&#44;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> although it has also been reported in individuals from Europe and Mediterranean countries&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">124</span></a> At birth&#44; patients have a generalized collodion membrane which then sheds to leave the characteristic distribution of scaling&#46; The trunk&#44; proximal region of the arms&#44; including the axillae&#44; the neck&#44; and the scalp are generally affected&#44; while the central part of the face&#44; the limbs&#44; and the adrenal region are usually spared&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> The scales are large&#44; lamellar&#44; and dark in color&#46; Finer desquamation may occur in the popliteal and antecubital fossae&#46;<a class="elsevierStyleCrossRefs" href="#bib0620"><span class="elsevierStyleSup">124&#44;125</span></a> The palms of the hands and soles of the feet have mild diffuse hyperkeratosis whereas the backs of the hands and feet show no involvement&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">Histopathologic study of affected skin shows marked hyperkeratosis without parakeratosis&#44; normal granular layers&#44; mild or moderate acanthosis&#44; and a mild lymphocytic infiltrate in the upper dermis&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Electron microscopy observations are consistent with congenital ichthyosis type 2 in most cases&#46; Uninvolved skin does not show any abnormal findings&#46;<a class="elsevierStyleCrossRefs" href="#bib0620"><span class="elsevierStyleSup">124&#44;125</span></a> In healthy skin&#44; TGase 1 activity is slightly reduced and usually localized in pericellular areas&#46; In involved skin&#44; enzymatic activity is residual and abnormally located in the cytoplasm&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">124</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">Mutations have been detected in the <span class="elsevierStyleItalic">TGM1</span> gene in all patients with bathing suit ichthyosis studied to date&#46;<a class="elsevierStyleCrossRefs" href="#bib0595"><span class="elsevierStyleSup">119&#44;124&#8211;126</span></a> The most common mutation is p&#46;Arg315Leu&#44; which has been identified in most South African patients and could be a founding mutation&#46; Oji et al&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">124</span></a> suggested that skin temperature might play a role in the development of these manifestations&#46; Using digital thermography&#44; the authors showed a strong correlation between body temperature and desquamation&#44; with the hottest areas of the body being the ones most affected&#46; Aufenvenne et al&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">127</span></a> showed a decrease in optimum temperature for TGase 1 activity in patients with bathing suit ichthyosis&#46; This decrease was not observed in healthy controls or in patients with generalized LI&#46; This decrease in temperature would explain the phenotype of these patients&#46; The optimum temperature is 37<span class="elsevierStyleHsp" style=""></span>&#176;C for the normal enzyme but 31<span class="elsevierStyleHsp" style=""></span>&#176;C for the mutated enzyme&#46;</p><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Treatment</span><p id="par0205" class="elsevierStylePara elsevierViewall">The primary aim of treatment in ichthyosis is to eliminate scaling and reduce xerosis without causing excessive irritation &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; Before deciding on treatment&#44; aspects such as age and sex of the patient&#44; type and severity of the disease&#44; and extent and site of the lesions should be taken into consideration&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">128</span></a></p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Bathing and Mechanical Elimination of Scales</span><p id="par0210" class="elsevierStylePara elsevierViewall">Daily bathing is recommended for patients with ARCI to mechanically eliminate scales and traces of moisturizer&#46; This is easier if the patient is immersed in water for 15 to 30<span class="elsevierStyleHsp" style=""></span>minutes&#46; Some authors recommend adding sodium bicarbonate to the bath to denaturalize the keratins and make the water alkaline&#44; and so facilitate elimination of the scales&#46;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">129</span></a> Other products that can be added include wheat starch&#44; corn starch&#44; or rice starch&#46; Bathing oils are not appropriate as they may lead to occlusion with subsequent risk of bacterial proliferation and worsening of thermoregulation&#46;</p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Topical Treatment</span><p id="par0215" class="elsevierStylePara elsevierViewall">Moisturizers and topical keratolytic agents are usually the first therapeutic option&#46; They improve skin barrier function and facilitate desquamation&#46; Mild local adverse effects&#44; such as transient pruritus&#44; irritation&#44; or stinging sensation may occur&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">Sodium chloride&#44; urea&#44; vitamin E acetate&#44; glycerol&#44; and petroleum jelly can be used as moisturizers and lubricants&#46; In patients with thick scaling and marked hyperkeratosis&#44; 1 or more keratolytic agents&#44; such as &#945;-hydroxy acids &#40;lactic and glycolic acid&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">130</span></a> salicylic acid&#44; N-acetylcystein&#44;<a class="elsevierStyleCrossRefs" href="#bib0655"><span class="elsevierStyleSup">131&#8211;133</span></a> urea &#40;&#62;<span class="elsevierStyleHsp" style=""></span>5&#37;&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">134</span></a> and propylene glycol&#44; can be added&#46; Modulators of keratinocyte differentiation are also used&#46; These include topical retinoids &#40;tretinoin&#44; adapalene&#44; tazarotene&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0675"><span class="elsevierStyleSup">135&#44;136</span></a> calcipotriol&#44;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">137</span></a> and dexpanthenol&#46;Topical retinoids often cause irritation and small&#44; very painful fissures&#46;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">137</span></a> Moreover&#44; there is a risk of absorption and teratogenicity in fertile women if they are used too extensively&#46;<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">138</span></a> To enhance the effectiveness of keratolytics and moisturizers&#44; occlusive dressing may be applied in specific areas refractory to treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">139</span></a> An additive or synergistic effect can also be attained by combining 2 or more keratolytic agents or moisturizers&#46;<a class="elsevierStyleCrossRefs" href="#bib0700"><span class="elsevierStyleSup">140&#8211;142</span></a> Treatment should be optimized for each individual&#44; given the highly variable nature of the condition and skin sensitivity and differences in response to each treatment&#46; The optimization process can be helped by treating one side of the body differently to the other to enable comparisons&#46; Neonates and small children should be treated with a vehicle without any active substances as the skin is very fine and sensitive and most keratolytics are not tolerated&#46; In addition&#44; the risk of percutaneous absorption of topical products such as urea&#44; salicylic acid&#44; and lactic acid is greater&#46;<a class="elsevierStyleCrossRefs" href="#bib0715"><span class="elsevierStyleSup">143&#8211;145</span></a></p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Systemic Treatment</span><p id="par0225" class="elsevierStylePara elsevierViewall">Oral retinoids have keratolytic effects that help eliminate scales and prevent excessive hyperkeratosis&#46; Both isotretinoin and aromatic retinoids &#40;acitretin and etretinate&#41; have proved effective in the treatment of ARCIs&#46;<a class="elsevierStyleCrossRefs" href="#bib0640"><span class="elsevierStyleSup">128&#44;146&#44;147</span></a> Acitretin at a dose of 0&#46;5 to 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d is the most widely used drug&#44; especially in patients with LI&#46;<a class="elsevierStyleCrossRef" href="#bib0740"><span class="elsevierStyleSup">148</span></a> Patients with CIE may have a more complete response and at lower doses&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">The main adverse effects are mucocutaneous disorders&#44; teratogenicity&#44; musculoskeletal disorders&#44; and abnormal lipid profile and transaminase elevation&#46;<a class="elsevierStyleCrossRefs" href="#bib0745"><span class="elsevierStyleSup">149&#8211;152</span></a> With regards to teratogenicity&#44; in the case of etretinate and acitretin&#44; the drugs should be avoided during pregnancy and patients should avoid becoming pregnant for 3 years after discontinuation of treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0755"><span class="elsevierStyleSup">151</span></a> Isotretinoin has a shorter half-life and is completely eliminated from the organism after 1 month and so may be the preferred option in women who wish to become pregnant&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">128</span></a></p><p id="par0235" class="elsevierStylePara elsevierViewall">Treatment monitoring should include a laboratory work-up with a liver function test and lipid profile before starting treatment&#44; then at 1 month and every 3 months after starting treatment&#46; In fertile women&#44; a pregnancy test should be performed in the 2 weeks before starting treatment and an effective contraceptive measure should be used from 4 weeks before treatment until 3 years afterwards &#40;in the case of acitretin&#41;&#46; When prolonged treatment is required with retinoids&#44; growth and bone development should be monitored&#46; Some authors suggest performing a bone study before treatment followed by a yearly examination&#46;<a class="elsevierStyleCrossRef" href="#bib0755"><span class="elsevierStyleSup">151</span></a> Recent guidelines do not recommend performing routine radiography because of the possible harmful effects&#46;<a class="elsevierStyleCrossRef" href="#bib0760"><span class="elsevierStyleSup">152</span></a> Instead&#44; selective radiographic studies are recommended in patients who have atypical bone pain&#46;<a class="elsevierStyleCrossRef" href="#bib0760"><span class="elsevierStyleSup">152</span></a></p><p id="par0240" class="elsevierStylePara elsevierViewall">An alternative to systemic retinoid treatment is the use of drugs known as retinoic acid metabolism blocking agents&#44; which increase the endogenous levels of retinoic acid&#46; One such drug is liarozole&#44; which has been granted orphan status for the treatment of LI&#44; CIE&#44; and HI by the European Medicines Agency and the US Food and Drug Administration&#46;<a class="elsevierStyleCrossRefs" href="#bib0765"><span class="elsevierStyleSup">153&#8211;155</span></a> This drug has been shown to be more effective than acitretin in clinical trials and it is also better tolerated and has a better pharmacokinetic profile&#46;<a class="elsevierStyleCrossRef" href="#bib0770"><span class="elsevierStyleSup">154</span></a></p></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Other Medical Care</span><p id="par0245" class="elsevierStylePara elsevierViewall">In patients with ectropion&#44; the application of artificial tears and eye lubricants and moisturizing the skin of the face and the cheeks in particular can reduce palpebral retraction&#46; Surgical correction is a valid option in severe cases&#44; but this usually has to be repeated a few years later&#46; Hydrotherapy may be beneficial&#46;<a class="elsevierStyleCrossRef" href="#bib0780"><span class="elsevierStyleSup">156</span></a> Patients should be advised to avoid strenuous physical activity when the ambient temperature is high&#44; given that hypohidrosis carries with it the risk of heat stroke and convulsions&#46; Oral retinoids can improve thermoregulation&#46;<a class="elsevierStyleCrossRef" href="#bib0785"><span class="elsevierStyleSup">157</span></a> Physiotherapy is important for preventing flexion contracture&#44; particularly in the case of HI&#46; Regular cleansing of the external auditory canal by an ear-throat-nose specialist can prevent scales from accumulating and so prevent hearing loss&#46;</p></span></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Genetic Counseling and Prenatal Diagnosis</span><p id="par0250" class="elsevierStylePara elsevierViewall">When a patient is diagnosed with ichthyosis&#44; he or she should be offered appropriate genetic counseling in which the nature of the disorder&#44; the transmission mode&#44; and the risk of future manifestations in the family are explained&#46; Prenatal diagnosis can indicate whether the fetus is affected and&#44; if this is the case&#44; psychological preparation of the family can be offered and problems anticipated during pregnancy and birth&#46; The parents can be given the option of an abortion if no treatment is available&#46; In addition&#44; should gene therapy for these conditions become available in the future&#44; prenatal diagnosis would enable application of this therapy as early as possible&#46;</p><p id="par0255" class="elsevierStylePara elsevierViewall">For more than 20 years&#44; prenatal diagnosis was performed by taking a biopsy sample of fetal skin and studying it by optical microscopy&#44; electron microscopy&#44; or immunohistochemistry&#46;<a class="elsevierStyleCrossRefs" href="#bib0790"><span class="elsevierStyleSup">158&#44;159</span></a> This invasive procedure could only be performed in the late phases of pregnancy&#44; between weeks 15 and 23 of gestation&#44; and was associated with a 1&#37; to 3&#37; risk of losing the fetus&#46;<a class="elsevierStyleCrossRefs" href="#bib0800"><span class="elsevierStyleSup">160&#44;161</span></a> The identification of the molecular mechanisms of hereditary skin disorders has enabled a much earlier diagnosis based on genetic techniques&#46;<a class="elsevierStyleCrossRefs" href="#bib0510"><span class="elsevierStyleSup">102&#44;162&#8211;164</span></a> Fetal DNA is obtained by amniocentesis performed between weeks 15 and 20 or by chorionic villus sampling between weeks 10 and 12&#46; The risk of fetal loss with these techniques is less than between 0&#46;5&#37; and 1&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0825"><span class="elsevierStyleSup">165</span></a> Other noninvasive methods in development are analysis of fetal cell DNA and free fetal DNA in maternal circulation<a class="elsevierStyleCrossRef" href="#bib0830"><span class="elsevierStyleSup">166</span></a> as well as the use of 3-dimensional ultrasound&#46;<a class="elsevierStyleCrossRefs" href="#bib0835"><span class="elsevierStyleSup">167&#44;168</span></a></p><p id="par0260" class="elsevierStylePara elsevierViewall">Preimplantation genetic diagnosis could also be possible in in vitro fertilization techniques&#44; such that only fertilized eggs free of the mutation are implanted in the uterus&#44; thereby avoiding the need for abortion in most cases&#46;<a class="elsevierStyleCrossRef" href="#bib0845"><span class="elsevierStyleSup">169</span></a></p></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Future Strategies for Genetic Treatment of Ichthyosis</span><p id="par0265" class="elsevierStylePara elsevierViewall">Although important progress has been made in the genetic diagnosis of ichthyosis&#44; new strategies are also being pursued for these diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0850"><span class="elsevierStyleSup">170</span></a> The skin is the most accessible organ for gene transfer therapies&#44; and so such techniques are minimally invasive&#46;<a class="elsevierStyleCrossRef" href="#bib0855"><span class="elsevierStyleSup">171</span></a> However&#44; the skin also has unique immunologic characteristics that do not favor long-term expression of a transgenic product&#46;<a class="elsevierStyleCrossRef" href="#bib0860"><span class="elsevierStyleSup">172</span></a> In LI&#44; a process of ex vivo gene transfer managed to restore normal <span class="elsevierStyleItalic">TGM1</span> expression and correct the phenotype of skin transplanted on the back of immunosuppressed mice&#46;<a class="elsevierStyleCrossRefs" href="#bib0865"><span class="elsevierStyleSup">173&#44;174</span></a> Recently&#44; the phenotype of cultured keratinocytes from patients with HI due to mutations in the <span class="elsevierStyleItalic">ABCA12</span> gene has also been recovered&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Conflicts of Interest</span><p id="par0270" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
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        0 => array:2 [
          "identificador" => "xres104065"
          "titulo" => "Abstract"
        ]
        1 => array:2 [
          "identificador" => "xpalclavsec91631"
          "titulo" => "Keywords"
        ]
        2 => array:2 [
          "identificador" => "xres104066"
          "titulo" => "Resumen"
        ]
        3 => array:2 [
          "identificador" => "xpalclavsec91629"
          "titulo" => "Palabras clave"
        ]
        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        5 => array:3 [
          "identificador" => "sec0010"
          "titulo" => "Lamellar Ichthyosis and Congenital Ichthyosiform Erythroderma"
          "secciones" => array:13 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Clinical Characteristics"
            ]
            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Histopathology"
            ]
            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Ultrastructure"
            ]
            3 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Congenital Ichthyosis Type 1"
            ]
            4 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Congenital Ichthyosis Type 2"
            ]
            5 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Congenital Ichthyosis Type 3"
            ]
            6 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Congenital Ichthyosis Type 4"
            ]
            7 => array:2 [
              "identificador" => "sec0050"
              "titulo" => "Molecular Studies"
            ]
            8 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "TGM1"
            ]
            9 => array:2 [
              "identificador" => "sec0060"
              "titulo" => "ALOXE3 and ALOX12B"
            ]
            10 => array:2 [
              "identificador" => "sec0065"
              "titulo" => "Ichthyin&#47;NIPAL4"
            ]
            11 => array:2 [
              "identificador" => "sec0070"
              "titulo" => "CYP4F22"
            ]
            12 => array:2 [
              "identificador" => "sec0075"
              "titulo" => "ABCA12"
            ]
          ]
        ]
        6 => array:2 [
          "identificador" => "sec0080"
          "titulo" => "Harlequin Ichthyosis"
        ]
        7 => array:3 [
          "identificador" => "sec0085"
          "titulo" => "Collodion Baby and Self-healing Collodion Baby"
          "secciones" => array:1 [
            0 => array:2 [
              "identificador" => "sec0090"
              "titulo" => "Acral Self-healing Collodion Baby"
            ]
          ]
        ]
        8 => array:3 [
          "identificador" => "sec0095"
          "titulo" => "Bathing Suit Ichthyosis"
          "secciones" => array:5 [
            0 => array:2 [
              "identificador" => "sec0100"
              "titulo" => "Treatment"
            ]
            1 => array:2 [
              "identificador" => "sec0105"
              "titulo" => "Bathing and Mechanical Elimination of Scales"
            ]
            2 => array:2 [
              "identificador" => "sec0110"
              "titulo" => "Topical Treatment"
            ]
            3 => array:2 [
              "identificador" => "sec0115"
              "titulo" => "Systemic Treatment"
            ]
            4 => array:2 [
              "identificador" => "sec0120"
              "titulo" => "Other Medical Care"
            ]
          ]
        ]
        9 => array:2 [
          "identificador" => "sec0125"
          "titulo" => "Genetic Counseling and Prenatal Diagnosis"
        ]
        10 => array:2 [
          "identificador" => "sec0130"
          "titulo" => "Future Strategies for Genetic Treatment of Ichthyosis"
        ]
        11 => array:2 [
          "identificador" => "sec0135"
          "titulo" => "Conflicts of Interest"
        ]
        12 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2011-09-13"
    "fechaAceptado" => "2011-11-13"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec91631"
          "palabras" => array:5 [
            0 => "Ichthyosis"
            1 => "Autosomal recessive congenital ichthyosis"
            2 => "ARCI"
            3 => "<span class="elsevierStyleItalic">TGM1</span>"
            4 => "<span class="elsevierStyleItalic">ALOXE3</span>"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec91629"
          "palabras" => array:5 [
            0 => "Ictiosis"
            1 => "Ictiosis cong&#233;nita autos&#243;mica recesiva"
            2 => "ICAR"
            3 => "<span class="elsevierStyleItalic">TGM1</span>"
            4 => "<span class="elsevierStyleItalic">ALOXE3</span>"
          ]
        ]
      ]
    ]
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    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The term <span class="elsevierStyleItalic">autosomal recessive congenital ichthyosis</span> &#40;ARCI&#41; refers to a group of rare disorders of keratinization classified as nonsyndromic forms of ichthyosis&#46; This group was traditionally divided into lamellar ichthyosis &#40;LI&#41; and congenital ichthyosiform erythroderma &#40;CIE&#41; but today it also includes harlequin ichthyosis&#44; self-healing collodion baby&#44; acral self-healing collodion baby&#44; and bathing suit ichthyosis&#46;</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">The combined prevalence of LI and CIE has been estimated at 1 case per 138 000 to 300 000 population&#46; In some countries or regions&#44; such as Norway and the coast of Galicia&#44; the prevalence may be higher due to founder effects&#46; ARCI is genetically highly heterogeneous and has been associated with 6 genes to date&#58; <span class="elsevierStyleItalic">TGM1</span>&#44; <span class="elsevierStyleItalic">ALOXE3</span>&#44; <span class="elsevierStyleItalic">ALOX12B</span>&#44; <span class="elsevierStyleItalic">NIPAL4</span>&#44; <span class="elsevierStyleItalic">CYP4F22</span>&#44; and <span class="elsevierStyleItalic">ABCA12</span>&#46; In this article&#44; we review the current knowledge on ARCI&#44; with a focus on clinical&#44; histological&#44; ultrastructural&#44; genetic&#44; molecular&#44; and treatment-related aspects&#46;</p>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Las ictiosis cong&#233;nitas autos&#243;micas recesivas &#40;ICAR&#41; son trastornos infrecuentes de la queratinizaci&#243;n que se engloban en las formas no sindr&#243;micas de ictiosis&#46; Cl&#225;sicamente se distingu&#237;an en este grupo la ictiosis laminar &#40;IL&#41; y la eritrodermia ictiosiforme cong&#233;nita &#40;EIC&#41;&#46; Actualmente se incluyen tambi&#233;n la ictiosis arlequ&#237;n&#44; el beb&#233; colodi&#243;n autorresolutivo&#44; el beb&#233; colodi&#243;n autorresolutivo acral y la ictiosis en traje de ba&#241;o&#46;</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Se ha estimado una prevalencia conjunta para IL y EIC de 1&#58;138&#46;000-1&#58;300&#46;000&#46; En algunos pa&#237;ses o regiones&#44; como Noruega y la costa gallega&#44; la prevalencia podr&#237;a ser mayor debido a la existencia de efectos fundadores&#46; Desde el punto de vista gen&#233;tico son muy heterog&#233;neas&#46; Seis genes se han asociado a estas entidades&#58; <span class="elsevierStyleItalic">TGM1</span>&#44; <span class="elsevierStyleItalic">ALOXE3</span>&#44; <span class="elsevierStyleItalic">ALOX12B</span>&#44; <span class="elsevierStyleItalic">NIPAL4</span>&#44; <span class="elsevierStyleItalic">CYP4F22</span> y <span class="elsevierStyleItalic">ABCA12</span>&#46; En este trabajo se pretenden revisar los conocimientos actuales en el campo de las ICAR&#44; incluyendo aspectos cl&#237;nicos&#44; histol&#243;gicos&#44; ultraestructurales&#44; gen&#233;tico-moleculares y de tratamiento&#46;</p>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Rodr&#237;guez-Pazos L&#44; et al&#46; Ictiosis cong&#233;nitas autos&#243;micas recesivas&#46; Actas Dermosifiliogr&#46; 2013&#59;104&#58;270&#8211;84&#46;</p>"
      ]
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        "descripcion" => array:1 [
          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Clinical features of lamellar ichthyosis&#46; A&#44; Brownish lamellar desquamation&#46; B&#44; Marked plantar hyperkeratosis&#46; C&#44; Scarring alopecia of the scalp&#46;</p>"
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Patient with congenital ichthyosiform erythroderma and mutations in the <span class="elsevierStyleItalic">ALOXE3</span> gene&#46; Mild erythema and generalized whitish furfuraceous desquamation can be seen&#46;</p>"
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Electron microscope images&#46; A&#44; Congenital ichthyosis type 1&#44; showing lipid droplets in the stratum corneum and absence of ultrastructural markers of the other types of ichthyosis&#46; B&#44; Congenital ichthyosis type 2&#44; characterized by the presence of cholesterol clefts &#40;arrow&#41; in corneocytes&#46;</p>"
        ]
      ]
      3 => array:7 [
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        "etiqueta" => "Figure 4"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Schematic diagram of the hepoxilin pathway&#44; showing the participation of the <span class="elsevierStyleItalic">ALOXE3&#44; ALOX12B&#44; NIPAL4</span>&#44; and <span class="elsevierStyleItalic">CYP4F22</span> genes&#46; Mutations in these genes are responsible for some types of ARCI&#46; HPETE indicates hydroperoxyeicosatetraenoic acid&#46;</p>"
        ]
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        "etiqueta" => "Figure 5"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Collodion baby that subsequently progressed to a lamellar ichthyosis phenotype&#46;</p>"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Abbreviations&#58;</span> ARC&#44; arthrogryposis&#8211;renal dysfunction&#8211;cholestasis&#59; ARCI&#44; autosomal recessive congenital ichthyosis&#59; CEDNIK&#44; cerebral dysgenesis&#44; neuropathy&#44; ichthyosis&#44; and palmoplantar keratoderma&#59; KID&#44; keratitis ichthyosis deafness&#59; KLICK&#44; keratosis linearis with ichthyosis congenital and sclerosing keratoderma&#59; MEDNIK&#44; mental retardation&#44; enteropathy&#44; deafness&#44; peripheral neuropathy&#44; ichthyosis&#44; keratoderma&#46;</p>"
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                  \t\t\t\t">Syndromic Forms&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Common Ichthyoses</span><span class="elsevierStyleHsp" style=""></span>Ichthyosis vulgaris<span class="elsevierStyleHsp" style=""></span>Recessive x-linked ichthyosis &#40;nonsyndromic&#41;<span class="elsevierStyleBold">ARCI</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Major forms</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Harlequin ichthyosis<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Lamellar ichthyosis<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Congenital ichthyosiform erythroderma<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Minor forms</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Self-healing collodion baby<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Acral self-healing collodion baby<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Bathing suit ichthyosis<span class="elsevierStyleBold">Keratinopathic Ichthyoses</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Major forms</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Epidermolytic ichthyosis<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Superficial epidermolytic ichthyosis<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Minor forms</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Annular epidermolytic ichthyosis<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Curth-Macklin ichthyosis<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Autosomal recessive epidermolytic ichthyosis<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Epidermolytic nevus<span class="elsevierStyleBold">Other Forms</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Loricrin keratoderma</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Erythrokeratodermia variabilis</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Peeling skin syndrome</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Congenital reticular ichthyosiform erythroderma</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">KLICK syndrome</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Syndromic X-linked Ichthyosis</span>Recessive x-linked ichthyosis &#40;syndromic&#41;Ichthyosis follicularis&#44; alopecia&#44; and photophobia &#40;IFAP&#41; syndromeConradi-H&#252;nermann-Happle syndrome &#40;chondrodysplasia punctata type 2&#41;<span class="elsevierStyleBold">Syndromic Autosomal Ichthyosis</span><span class="elsevierStyleItalic">Skin disorders</span>Netherton syndromeIchthyosis-hypotrichosis syndromeIchthyosis-sclerosing cholangitis syndromeTrichothiodystrophy<span class="elsevierStyleItalic">Neurologic disorders</span>Sj&#246;gren-Larsson syndromeRefsum diseaseMEDNIK syndrome<span class="elsevierStyleItalic">Fatal disease course</span>Gaucher disease&#44; type 2Multiple sulfatase deficiencyCEDNIK syndromeARC syndrome<span class="elsevierStyleItalic">Other associated signs</span>KID syndromeChanarin-Dorfman syndromeIchthyosis prematurity syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab185615.png"
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Consensus Classification Based on the Clinical Features of Ichthyosis<span class="elsevierStyleSup">1</span>&#46;</p>"
        ]
      ]
      6 => array:7 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Abbreviations&#58;</span> CIE&#44; congenital ichthyosiform erythroderma&#59; LI&#44; lamellar ichthyosis&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Type&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Main Feature&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Other Features&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Mutations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Clinical Manifestations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Absense of ultrastructural markers of ichthyosis types 2&#44; 3&#44; and 4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lipid droplets or rings in the stratum corneum &#40;most frequent&#41;Small keratohyalin granulesVesicular or lobular membrane coating granules&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">TGM1</span> &#40;33&#46;3&#37;&#41;<span class="elsevierStyleItalic">ALOX12B</span> &#40;2 cases&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CIE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cholesterol clefts in the stratum corneum&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Absence or thinning of cornified envelopeSmall keratohyalin granulesLipid droplets&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">TGM1</span> &#40;89-100&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Laminated membraneous structures in the stratum granulosum and&#47;or stratum corneum&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Abnormal membrane coating granulesLipid dropletsFoci of prominent juxtanuclear vacuoles in the granular layer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">NIPAL4</span> &#40;93&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CIE &#40;most frequent&#41;LI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Trilamellar membrane packets that fill some cells in the stratum granulosum and&#47;or stratum corneum&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Abnormal membrane coating granules&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">FTAP4</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ichthyosis prematurity syndrome &#40;100&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Ultrastructural Classification of Congenital Ichthyoses&#46;</p>"
        ]
      ]
      7 => array:7 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Therapeutic strategy for the autosomal recessive congenital ichthyoses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bathing and mechanical elimination of scales&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bathing with sodium bicarbonate or wheat starch&#44; corn starch&#44; or rice starch&#59; mechanical removal of the scales &#40;1 or 2 times a day&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Topical treatment &#40;sequential&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Urea-containing moisturizersKeratinolytics with propylene glycolCombined keratinolytics &#40;propylene glycol&#44; &#945;-hydroxy acids&#44; or urea&#41;Keratinolytics combined with salicylic acidTopical retinoidsIn neonates and small children&#44; apply a vehicle without active ingredients&#46; Avoid urea&#44; salicylic acid&#44; and lactic acid due to the risk of systemic absorption&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Oral treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Oral retinoids &#40;acitretin or isotretinoin&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Other measures&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Follow-up of ectropion by the ophthalmologistRegular cleansing of the outer ear by the ear-throat-nose specialistPhysiotherapy to prevent contractures&#46;Avoidance of strenuous activities in a high ambient temperatureHydrotherapy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Therapeutic Strategy in Autosomal Recessive Congenital Ichthyoses&#46;</p>"
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    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:174 [
            0 => array:3 [
              "identificador" => "bib0005"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Revised nomenclature and classification of inherited ichthyoses&#58; results of the First Ichthyosis Consensus Conference in Sor&#232;ze 2009"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaad.2009.11.020"
                      "Revista" => array:7 [ …7]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0010"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mutations in ABCA12 underlie the severe congenital skin disease harlequin ichthyosis"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1086/429844"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0015"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mutations in lipid transporter ABCA12 in harlequin ichthyosis and functional recovery by corrective gene transfer"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1172/JCI24834"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0020"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mutations in the transporter ABCA12 are associated with lamellar ichthyosis type 2"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/hmg/ddg235"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0025"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "ABCA12 is a major causative gene for non-bullous congenital ichthyosiform erythroderma"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/jid.2009.23"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0030"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Novel ABCA12 mutations identified in two cases of non-bullous congenital ichthyosiform erythroderma associated with multiple skin malignant neoplasia"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/sj.jid.5700885"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0035"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Self-healing collodion baby&#58;a dynamic phenotype explained by a particular transglutaminase-1 mutation"
                      "autores" => array:1 [ …1]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1046/j.1523-1747.2003.12032.x"
                      "Revista" => array:6 [ …6]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0040"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
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                      "titulo" => "Autosomal Recessive Congenital ichthyosis"
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                    0 => array:1 [
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                    0 => array:1 [
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                      "titulo" => "Self-healing collodion membrane and mild nonbullous congenital ichthyosiform erythroderma due to 2 novel mutations in the ALOX12B gene"
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                      "titulo" => "Partially disturbed lamellar granule secretion in mild congenital ichthyosiform erythroderma with ALOX12B mutations"
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                    0 => array:2 [
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "New observations on the fine structure of lamellar ichthyosis and the effect of treatment with etretinate"
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                  "host" => array:1 [
                    0 => array:1 [
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Lamellar ichthyosis with a novel homozygous C-terminal mutation in the transglutaminase-1 gene"
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                    0 => array:2 [
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                      "titulo" => "Analyses of the transglutaminase 1 gene mutation and ultrastructural characteristics in a Japanese patient with lamellar ichthyosis"
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                    0 => array:1 [
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                0 => array:2 [
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                      "titulo" => "Defective stratum corneum and early neonatal death in mice lacking the gene for transglutaminase 1 &#40;keratinocyte transglutaminase&#41;"
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                      "titulo" => "Ichthyosis with laminated membrane structures"
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                    0 => array:1 [
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                    0 => array:2 [
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                0 => array:2 [
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                    0 => array:1 [
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                      "titulo" => "Autosomal recessive congenital ichthyosis"
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                      "doi" => "10.1038/emm.1999.2"
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                    0 => array:1 [
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                      "titulo" => "Genetic and immunohistochemical detection of mutations inactivating the keratinocyte transglutaminase in patients with lamellar ichthyosis"
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                    0 => array:1 [
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                      "titulo" => "Novel mutations of TGM1 in a child with congenital ichthyosiform erythroderma"
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                      "titulo" => "The hepoxilin connection in the epidermis"
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                    0 => array:1 [
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Review
Autosomal Recessive Congenital Ichthyosis
Ictiosis congénitas autosómicas recesivas
L. Rodríguez-Pazosa,
Autor para correspondencia
ladrizos@hotmail.com

Corresponding author.
, M. Ginartea, A. Vegab, J. Toribioa
a Departamento de Dermatología, Complejo Hospitalario Universitario, Facultad de Medicina, Santiago de Compostela, Spain
b Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica-USC, CIBERER, IDIS, Santiago de Compostela, Spain
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Clinical features of lamellar ichthyosis&#46; A&#44; Brownish lamellar desquamation&#46; B&#44; Marked plantar hyperkeratosis&#46; C&#44; Scarring alopecia of the scalp&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The latest consensus classification of ichthyosis differentiates between 2 main forms&#58; the nonsyndromic forms&#44; which present with skin manifestations only&#44; and the syndromic forms&#44; which present with manifestations in other organs as well &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Among the nonsyndromic forms&#44; 4 groups are identified&#58; common ichthyoses&#44; autosomal recessive congenital ichthyoses &#40;ARCIs&#41;&#44; keratinopathic ichthyoses&#44; and other less common ichthyoses&#46;Traditionally&#44; the group of ARCIs was divided into 2 disorders&#44; lamellar ichthyosis &#40;LI&#41; and congenital ichthyosiform erythroderma &#40;CIE&#41;&#46; In the new classification&#44; harlequin ichthyosis &#40;HI&#41; was added to this group<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> because inactivating mutations in the <span class="elsevierStyleItalic">ABCA12</span> gene have been identified as responsible for this disorder&#44;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3</span></a> while nonsense mutations in the same gene may give rise to the LI<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> or CIE<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;6</span></a> phenotype&#46; Other less common variants included in the group of ARCIs are self-healing collodion baby &#40;SHCB&#41;&#44; acral SHCB&#44; and bathing suit ichthyosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#8211;9</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">Only limited data are available on the epidemiology of ARCIs&#46; In the United States&#44; a prevalence at birth of 1 per 100 000 population for LI and of 1 per 200 000 population for CIE has been estimated&#46; Other studies have reported a combined prevalence for LI and CIE of 1 per 200 000 to 300 000 population&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;11</span></a> In some countries such as Norway&#44; the estimated prevalence is greater &#40;1 per 91 000&#41; due to founder mutations&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> The finding of 1 or several recurrent mutations in a population may be because the mutation occurred at a given point in history and was then passed from generation to generation &#40;founder mutation&#41; or because the region of the genome where the mutation is found has a DNA sequence susceptible to mutation &#40;mutation hotspot&#41;&#46; In Spain&#44; the estimated prevalence of ARCI is 1 per 138 000 in the general population and 1 per 61 700 among children under 10 years of age&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> In certain regions of Spain&#44; the prevalence might be even higher&#46; On the Galician coast&#44; for example&#44; a prevalence of 1 per 33 000 was reported&#44; due also to a founder effect&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Lamellar Ichthyosis and Congenital Ichthyosiform Erythroderma</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Clinical Characteristics</span><p id="par0015" class="elsevierStylePara elsevierViewall">Although it was originally thought that LI and CIE were different entities&#44; there have been reports of patients with intermediate clinical manifestations and both conditions can be caused by mutations in the same gene&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;16</span></a> In addition&#44; patients with the same mutation&#44; even within the same family&#44; can develop different phenotypes&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;15</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Most patients are born enveloped in a collodion membrane that progressively disappears during the first weeks of life and is replaced by the definitive phenotype &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A&#41;&#46; Hypohidrosis&#44; severe heat intolerance&#44; and nail dystrophy are frequently observed in both LI and CIE&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#8211;19</span></a> Patients with LI usually have more severe clinical manifestations than those with CIE&#46; They have large platelike scales&#44; often of a dark color&#44; covering the whole body surface area&#46; Erythroderma is either absent or minimal&#46; Such patients usually have ectropion and&#44; at times&#44; eclabium&#44; hypoplasia of joint and nasal cartilage&#44; scarring alopecia&#44; especially at the edge of the scalp&#44; and palmoplantar keratoderma &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>B and C&#41;&#46; CIE is characterized by the presence of erythroderma and fine whitish scaling &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Some patients have marked erythema and generalized scaling&#46; The scales can be large and dark colored&#44; particularly on the extensor surfaces of the legs&#46; In less severe cases&#44; erythema is mild and the scaling is fine&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Histopathology</span><p id="par0025" class="elsevierStylePara elsevierViewall">Histopathologic changes do not provide a diagnosis&#46; In LI&#44; massive orthokeratotic hyperkeratosis is observed&#44; usually with twice the extension as in CIE&#46; The epidermis is acanthotic and occasionally takes on a psoriasis-like appearance&#46; The cell proliferation rate is normal or slightly elevated&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#8211;19</span></a> Patients with CIE have less marked hyperkeratosis&#44; with focal or extensive parakeratosis&#44; a normal or thickened granular layer&#44; and more pronounced acanthosis&#46; The epidermal turnover is increased&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#8211;19</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Ultrastructure</span><p id="par0030" class="elsevierStylePara elsevierViewall">Although a close correlation between molecular&#44; clinical&#44; and ultrastructural findings has so far not been found&#44; electron microscopy may nevertheless be useful for ruling out other forms of ichthyosis and for guiding genetic analyses in some cases&#46; Four types of congenital ichthyosis have been described &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Congenital Ichthyosis Type 1</span><p id="par0035" class="elsevierStylePara elsevierViewall">Congenital ichthyosis type 1 is characterized by the absence of ultrastructural markers for ichthyosis types 2&#44; 3&#44; and 4&#46; Therefore&#44; diagnosis is usually only made when the other types have been excluded&#46; The most frequent finding is the presence of lipid droplets or rings in the stratum corneum &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>A&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> These lipid droplets are not a constant feature or specific to this particular type as they are not present in all cases&#44;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> and they may be present in other types of ichthyosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#44;22</span></a> Clinically&#44; most patients present with manifestations of CIE&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;20</span></a> One-third of patients have mutations in the <span class="elsevierStyleItalic">TGM1</span> gene&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> This ultrastructural type has also been identified in association with mutations in the <span class="elsevierStyleItalic">ALOX12B</span> gene&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;24</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Congenital Ichthyosis Type 2</span><p id="par0040" class="elsevierStylePara elsevierViewall">Congenital ichthyosis type 2 is characterized by cholesterol clefts in the stratum corneum &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>B&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> Such clefts are a constant finding in this type of ichthyosis&#44; and can be detected in different biopsies in the same patient&#59; treatment with oral retinoids has no impact on these clefts&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;25</span></a> Electron-dense aggregates have also been observed on corneocytes in some patients with deficient TGase 1 activity&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#8211;28</span></a> Clinically&#44; most patients present with severe manifestations of CIE&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> This ultrastructural type is strongly associated with mutations in the <span class="elsevierStyleItalic">TGM1</span> gene&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;16</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Congenital Ichthyosis Type 3</span><p id="par0045" class="elsevierStylePara elsevierViewall">Congenital ichthyosis type 3 is characterized by lamellar membranous structures in the stratum granulosum and&#47;or stratum corneum&#46; These structures are arranged in strips around an empty space close to the nucleus&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;29&#8211;31</span></a> The clinical manifestations in this type are different to the others&#59; onset of ichthyosis is variable&#44; desquamation and erythema may be patchy or generalized&#44; and the flexures in particular are affected&#46; Mutations in the <span class="elsevierStyleItalic">NIPAL4</span> gene are responsible for 93&#37; of ichthyoses type 3&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Congenital Ichthyosis Type 4</span><p id="par0050" class="elsevierStylePara elsevierViewall">Characteristically&#44; in congenital ichthyosis type 4&#44; some cells in the stratum granulosum and stratum corneum are filled with trilamellar membrane packages&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> These findings are pathognomic for ichthyosis prematurity syndrome&#44; a condition currently considered as a syndromic form of ichthyosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34&#44;35</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Molecular Studies</span><p id="par0055" class="elsevierStylePara elsevierViewall">In genetic terms&#44; the ARCIs are very heterogeneous&#46; The <span class="elsevierStyleItalic">TGM1</span> gene is associated with most cases&#44; but mutations in 5 other genes &#40;<span class="elsevierStyleItalic">ALOX12B</span>&#44; <span class="elsevierStyleItalic">ALOXE3</span>&#44; <span class="elsevierStyleItalic">NIPAL4</span>&#44; <span class="elsevierStyleItalic">CYP4F22</span>&#44; and <span class="elsevierStyleItalic">ABCA12</span>&#41; have been reported&#46; Fischer et al&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> studied 520 families with ARCI and identified mutations in at least 1 of these genes in 78&#37; of cases &#40;<span class="elsevierStyleItalic">TGM1</span> in 32&#37;&#44; <span class="elsevierStyleItalic">NIPAL4</span> in 16&#37;&#44; <span class="elsevierStyleItalic">ALOX12B</span> in 12&#37;&#44; <span class="elsevierStyleItalic">CYP4F22</span> in 8&#37;&#44; <span class="elsevierStyleItalic">ALOXE3</span> in 5&#37;&#44; and <span class="elsevierStyleItalic">ABCA12</span> in 5&#37;&#41;&#46; In another study of 250 patients with ARCI of different origins&#44; 38&#37; had <span class="elsevierStyleItalic">TGM1</span> mutations&#44; 6&#46;8&#37; had <span class="elsevierStyleItalic">ALOXE3</span> mutations&#44; and 6&#46;8&#37; had <span class="elsevierStyleItalic">ALOX12B</span> mutations&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> In Galicia&#44; we identified mutations in the <span class="elsevierStyleItalic">TGM1</span>&#44; <span class="elsevierStyleItalic">ALOX12B</span>&#44; <span class="elsevierStyleItalic">ALOXE3</span>&#44; <span class="elsevierStyleItalic">NIPAL4</span>&#44; and <span class="elsevierStyleItalic">CYP4F22</span> genes in 75&#37; of the families studied&#44; but the distribution of mutations was different&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> The <span class="elsevierStyleItalic">TGM1</span> gene was mutated in 68&#46;7&#37; of the cases while the <span class="elsevierStyleItalic">ALOXE3</span> gene was mutated in just 1 patient&#46; We did not detect mutations in any of the other 3 genes studied&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">TGM1</span><p id="par0060" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">TGM1</span> gene is located on chromosome 14q11&#46;2 and has 15 exons &#40;GenBank NM-000359&#46;2&#41;&#46; It encodes the TGase 1 enzyme&#44; which is one of the 3 TGase enzymes found in the epidermis&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> This enzyme participates in the formation of the cornified envelope by catalyzing calcium-dependent cross-linking of several proteins such as involucrin&#44; loricrin&#44; and proline-rich proteins&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">39&#44;40</span></a> It also catalyzes binding of ¿-hydroxyceramides in the outer layer of the cornified envelope with proteins in the inner layer&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">41&#44;42</span></a> In patients with <span class="elsevierStyleItalic">TGM1</span> mutations&#44; the cornified envelope is missing and TGase 1 activity is reduced or nonexistent&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">43&#8211;47</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Since 1995&#44; when this gene was identified as responsible for some cases of ARCI&#44;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">48&#8211;50</span></a> more than 110 mutations have been reported in patients of different origins&#46; Mutations in <span class="elsevierStyleItalic">TGM1</span> are the most common cause of ARCI&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36&#44;37</span></a> This mutation has been found in 55&#37; of cases in the United States and in 84&#37; of cases in Norway&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;51</span></a> The most frequent mutation is c&#46;877-2A<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>G&#44; which has been found in 34&#37; of the mutated alleles reported to date&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> The high frequency of this mutation in countries such as the United States and Norway is due to a founder effect&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;53</span></a> The second most frequent mutation is p&#46;Arg142His&#46; This and similar mutations have been reported in countries such as Egypt&#44; Germany&#44; Finland&#44; and the United States&#44;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;49&#8211;51&#44;54&#8211;56</span></a> and it would seem that these are hotspot mutations&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a> The p&#46;Arg307Trp mutation is frequent in the Japanese population&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> In Galicia&#44; the p&#46;Arg760X&#44; c&#46;1223&#95;1227delACACA and c&#46;984<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1G<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>A mutations in <span class="elsevierStyleItalic">TGM1</span> were identified in 81&#46;82&#37; of the families with mutations in this gene&#44; suggesting a founder effect&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> Confirmation of this hypothesis was obtained by haplotype study &#40;work as yet unpublished&#41;&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">TGM1</span> mutations are responsible for most cases of LI<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;27&#44;44&#44;46&#44;56&#44;58&#8211;63</span></a> and for a small percentage of cases of CIE&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">43&#44;47&#44;64&#44;65</span></a> Such mutations can also give rise to other forms of ARCI such as SHCB&#44; acral SHCB&#44; and bathing suit ichthyosis&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Many studies have attempted to demonstrate genotype-phenotype associations between mutations in <span class="elsevierStyleItalic">TGM1</span> and ultrastructural or clinical findings&#44; but no significant correlation has been observed to date&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;16&#44;53</span></a> In general&#44; patients with mutations in the <span class="elsevierStyleItalic">TGM1</span> gene are more severely affected than those without such mutations&#46; In a study of 83 patients with ARCI in Sweden and Estonia&#44; the presence of ectropion and collodion baby was associated with <span class="elsevierStyleItalic">TGM1</span> mutations&#44; while a higher rate of erythema was observed in patients without mutations in this gene&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a> Another study showed that the type of scaling is the main difference between carriers and noncarriers of <span class="elsevierStyleItalic">TGM1</span> mutations&#44; on finding that all patients with mutations in this gene had lamellar scaling whereas 80&#37; of those without <span class="elsevierStyleItalic">TGM1</span> mutations had fine scaling&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> In addition&#44; it has been seen that truncating mutations are more frequently associated with hypohidrosis and sweating disorders than missense mutations&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> In the north American population&#44; a model based on the presence of certain clinical characteristics predicts that patients who are born as collodion babies and have ocular disorders and&#47;or alopecia are 4 times more likely to have <span class="elsevierStyleItalic">TGM1</span> mutations&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">ALOXE3 <span class="elsevierStyleItalic">and</span> ALOX12B</span><p id="par0080" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">ALOXE3</span> and <span class="elsevierStyleItalic">ALOX12B</span> genes are located on chromosome 17p13&#46;1&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a> They have a similar structure with 15 exons that encode the epidermal LOXs eLOX-3 and 12R-LOX&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">68&#44;69</span></a> The fact that they are predominantly expressed in the suprabasal layers of the epidermis supports their role in advanced phases of epidermal differentiation&#44; with participation in the processing of lamellar bodies&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#44;70</span></a> These enzymes act on adjacent steps in the hepoxilin pathway &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46; 12R-LOX transforms arachidonic acid to 12R-hydroxyeicosatetraenoic acid while eLOX-3 converts this product into an epoxyalcohol isomer<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">69&#44;71</span></a> of the hepoxilin A<span class="elsevierStyleInf">3</span> family&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">72</span></a> The hepoxilin product is unstable and is hydrolyzed in cells to a specific trihydroxy derivative &#40;trioxilin&#41;&#46; Although the exact role of the products of the hepoxilin pathway is not known&#44; it has been speculated that they may participate in the formation of intercellular lipids of the stratum corneum or act as signals for inducing keratinocyte differentiation&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">ALOX12B</span> and <span class="elsevierStyleItalic">ALOXE3</span> genes were first identified in 2002&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">73&#44;74</span></a> Since then&#44; more than 30 mutations in the <span class="elsevierStyleItalic">ALOX12B</span> gene<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;24&#44;37&#44;75&#8211;77</span></a> and approximately 10 in the <span class="elsevierStyleItalic">ALOXE3</span> gene<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;74&#44;75</span></a> have been reported&#46; These mutations are responsible for 14&#37; to 17&#37; of ARCIs<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36&#44;37</span></a> and 72&#46;2&#37; of SHCBs&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;78&#44;79</span></a> The causative relationship between these mutations and phenotype was confirmed by demonstrating that the catalytic activity of the epidermal LOX was totally abolished in patients with these mutations<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">75&#44;80</span></a> and by using animal models that reproduced the ichthyosiform phenotype seen in humans&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">81&#8211;83</span></a> Both genes are responsible for a similar percentage of ARCI cases&#46; However&#44; the range of different mutations in the <span class="elsevierStyleItalic">ALOXE3</span> gene is limited&#44; due to the predominance of 2 mutations&#44; p&#46;Arg234X and p&#46;Pro630Leu&#44; which seem to correspond to hotspots&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;74&#44;75</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">The patients with mutations in the <span class="elsevierStyleItalic">ALOXE3</span> and <span class="elsevierStyleItalic">ALOX12B</span> genes usually show a CIE phenotype&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">74&#44;75&#44;77</span></a> The severity of scaling is mild or moderate&#44; and the scales have a whitish or light brown color&#46; Erythema may also be present&#46; As many as 76&#37; of the patients are born as collodion babies and 88&#37; have sweating disorders&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> Patients with mutations in the <span class="elsevierStyleItalic">ALOX12B</span> gene show more limited&#44; whitish desquamation compared with carriers of mutations in the <span class="elsevierStyleItalic">ALOXE3</span> gene&#46; In these cases&#44; the scales are brownish and adherent&#46; The presence of erythema&#44; palmoplantar hyperkeratosis&#44; and accentuation of the palmoplantar folds are also associated with <span class="elsevierStyleItalic">ALOX12B</span> mutations&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Ichthyin&#47;NIPAL4</span><p id="par0095" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">NIPAL4</span> gene&#44; also known as the <span class="elsevierStyleItalic">ichthyin</span> gene&#44; is located on chromosome 5q33&#46; It has 6 exons that encode a protein with several transmembrane domains of unknown function&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">84</span></a> It has been hypothesized that the protein product participates in the same metabolic pathway as LOX and may act as a receptor for trioxilins A3 and B3 or for other metabolites of the hepoxilin metabolic pathway&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">84</span></a> It would thus be implicated in the formation of lamellar bodies or in their transport towards the extracellular space&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> In support of this are 2 observations&#46; First&#44; in 93&#37; of the cases&#44; mutations in this gene are associated with an ultrastructural pattern of congenital ichthyosis type 3&#44; characterized by abnormalities in the lamellar bodies and the presence of elongated perinuclear membranes in the stratum granulosum&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> Second&#44; <span class="elsevierStyleItalic">NIPAL4</span> is expressed essentially in the stratum granulosum of the epidermis&#44; where the lamellar bodies are present&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">85</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Since the discovery of the <span class="elsevierStyleItalic">NIPAL4</span> gene in 2004&#44;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">84</span></a> only 9 mutations have been reported in patients from Mediterranean countries &#40;Algeria&#44; Turkey&#44; and Syria&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">84</span></a> Scandinavian countries&#44;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> Pakistan&#44;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">85</span></a> the Faroe Islands&#44;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> and South America&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">84</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">The clinical spectrum of patients with mutations in this gene is broad&#44; even among members of the same family&#46; Between 3&#46;7&#37;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> and 60&#37;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">84</span></a> are born as collodion babies&#46; When the collodion membrane disappears&#44; most patients develop the manifestations of CIE&#44; with fine whitish scales on an erythematous base on the face and trunk and larger&#44; brownish scales on the neck&#44; buttocks&#44; and legs&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">84</span></a> Marked xerosis&#44; generalized brownish reticular hyperkeratotic plaques that appear accentuated in the skin folds&#44; and facial dyschromia may be present&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;85</span></a> In addition&#44; palmoplantar keratoderma is a frequent finding along with occasional finger contractures and curved finger nails&#46; Some studies have reported findings more typical of LI&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;85</span></a> The presence of signs and symptoms of atopic dermatitis has been reported in some patients&#44; although mutations in the <span class="elsevierStyleItalic">FLG</span> gene were not detected in any of these cases&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">85</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">CYP4F22</span><p id="par0110" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">FLJ39501</span> or <span class="elsevierStyleItalic">CYP4F22</span> gene is located on chromosome 19p13&#46;12&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">86</span></a> It has 12 exons<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">87</span></a> and encodes a P450 cytochrome&#44; family 4&#44; subfamily F&#44; polypeptide 2&#44; homolog of leukotriene B4- &#969;-hydroxylase &#40;CYP4F2&#41;&#46; The reaction catalyzed by the product of <span class="elsevierStyleItalic">FLJ39501</span> in the skin and the substrates of that reaction may be deduced by analogy with its known homologs CYP4F2 and CYP4F3&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">88</span></a> It has been hypothesized that CYP4F2 and CYP4F3 participate in the hepoxilin pathway by catalyzing the conversion of trioxilin A3 to 20-hydroxy-&#40;R&#41;trioxilin A3<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">87</span></a> and that the end product of this pathway&#44; 20-carboxy-trioxilin A3&#44; may have a key biological regulatory effect in the skin&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">89</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">To date&#44; only 8 mutations of this gene have been reported in 12 consanguineous families from Mediterranean countries<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">87</span></a> and in 1 family of Israeli origin&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">In the families reported by Lef&#232;vre et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">87</span></a> most patients had a CIE phenotype at birth and this subsequently progressed to LI&#46; Patients were usually born with marked erythroderma&#44; although without any collodion membrane&#46; As they got older&#44; they developed generalized whitish-grey scaling&#44; which was more marked in the periumbilical region&#44; on the buttocks&#44; and on the lower part of the body&#46; Hyperlinearity of the palms and soles and desquamation on the scalp&#44; at times of pityriasiform type&#44; were frequent&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">87</span></a> In another family&#44; the 3 members affected were born as collidion babies and developed intense erythroderma&#44; generalized desquamation&#44; and palmoplantar keratoderma&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">ABCA12</span><p id="par0125" class="elsevierStylePara elsevierViewall">In 2003&#44; the <span class="elsevierStyleItalic">ABCA12</span> gene was reported to be responsible for some cases of LI and was mapped to chromosome 2q34&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> It was subsequently confirmed that mutations in this gene were also responsible for HI&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3</span></a><span class="elsevierStyleItalic">ABCA12</span> encodes 53 exons&#44; and belongs to a family of ABC transporters&#44; which bind adenosine triphosphate while also facilitating the transport of several molecules across the cell membrane&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">90</span></a> The members of the ABCA subfamily are all implicated in lipid transport&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">91</span></a> Deficient ABCA12 function causes lipid transport disorders in lamellar bodies and so lead to a decrease in intercellular lipid levels in the stratum corneum&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>Ultrastructural studies have shown that ABCA12 is located in lamellar bodies associated with glycosylceramides&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">91</span></a><span class="elsevierStyleItalic">ABCA12</span> mutations have been associated with disorders in the distribution and transport of glycosylceramides and with decreased levels of hydroxyceramides&#44; one of the main components in the lipid barrier in the intercellular spaces&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;6&#44;92&#44;93</span></a> The massive hyperkeratosis that occurs in these patients could be a compensatory response to a deficient lipid barrier&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">94</span></a> It might also be due to the lack of desquamation of the corneocytes&#44;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">93</span></a> which could be caused by defects in the transport of certain proteases&#44; such as callicrein 5 and cathepsin D&#44; resulting from disorders in the lamellar bodies&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">95</span></a> Murine models and in vitro studies suggest that <span class="elsevierStyleItalic">ABCA12</span> mutations also have an effect on epidermal differentiation&#46;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">95&#8211;97</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">To date&#44; more than 50 mutations have been reported in the <span class="elsevierStyleItalic">ABCA12</span> gene in patients with ARCI from Africa&#44; Europe&#44; Pakistan&#44; and Japan&#46; The most frequent mutations are p&#46;Val244SerfsTer28&#44;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;98&#44;99</span></a> identified in Pakistani and Indian populations&#44; and p&#46;Asn1380Ser&#44;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> identified in African families&#46; In both case&#44; these may be founding mutations&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">The extent of the <span class="elsevierStyleItalic">ABCA12</span> mutations is related to phenotype&#44; with mutations associated with complete loss of function leading to the HI phenotype&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3&#44;98&#8211;102</span></a> By contrast&#44; in LI and CIE&#44; most mutations are missense&#44; and have a less severe effect on protein function&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#8211;6&#44;103</span></a> The mutations underlying the LI phenotype seem to be concentrated in the first adenosine triphosphate binding cassette region&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Clinically&#44; patients with CIE and mutations in the <span class="elsevierStyleItalic">ABCA12</span> gene have medium-size scales that are somewhat larger than those usually observed in patients with this phenotype&#46;</p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Harlequin Ichthyosis</span><p id="par0140" class="elsevierStylePara elsevierViewall">HI or harlequin fetus is a severe and usually fatal form of ichthyosis&#46; The children are usually premature with extensive shiny hyperkeratotic plaques&#44; separated by deep fissures&#44; that cover the entire integument and form geometric patterns reminiscent of clothing worn by harlequins&#44; thereby giving the condition its name&#46; Skin tightness leads to marked eversion of the eyelids and lips&#44; rudimentary development of joint and nasal cartilage and&#44; occasionally&#44; microcephaly&#46; The children rarely have eyelashes or eyebrows&#44; although the hair on the scalp may be conserved&#46; The hands and feet are swollen and edematous&#44; and often covered by a glove-like layer&#46; They may have finger contractures&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">For such patients&#44; the risk of dying during the neonatal period is very high&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">104</span></a> Pulmonary ventilation is compromised&#59; transepidermal water loss leads to dehydration&#44; hydroelectric imbalance&#44; and thermal instability&#59; and the risk of infections is increased&#46; Facial tightness and eclabium hinder sucking and therefore feeding&#44; with the corresponding worsening of dehydration&#46; Neonates with this condition rarely lived longer a few weeks&#46; In recent years&#44; however&#44; the chances of long-term survival have increased notably&#44; essentially due to administration of systemic retinoids and progress in intensive neonatal care&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">105</span></a> In a recent study&#44; 83&#37; of the patients treated with oral retinoids survived compared to 24&#37; of untreated patients&#46; Most of the deaths occurred in the first 3 days of life&#44; but treatment was not started until after this in many of the survivors&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">104</span></a> This would suggests that many of these early deaths would have occurred regardless of retinoid treatment&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">The children who survive the neonatal period generally develop severe CIE&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">106</span></a> The nature and location of mutations in the <span class="elsevierStyleItalic">ABCA12</span> gene and the extent of transporter function loss may determine prognosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;92&#44;107</span></a> Patients who conserve a certain degree of protein activity&#44; albeit minimal&#44; may have a better chance of surviving&#46; Carriers of homozygous mutations have a higher mortality rate&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">104</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">The main histologic characteristic of HI is the presence of an extremely thick and compact orthokeratotic stratum corneum&#46; The hair follicles and sweat ducts have prominent hyperkeratotic plugs<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">107&#44;108</span></a> and have abnormal or absent lamellar bodies&#44; lipid inclusions&#44; or remnants of organelles or nuclei in the corneocytes&#44; and absence of intercellular lipids in the ultrastructural study&#46;<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">108&#44;109</span></a> The hair follicles show a marked concentration of keratotic material&#44; which is a diagnostic feature of HI used for prenatal diagnosis&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">To date&#44; the rate of detection of mutations in the <span class="elsevierStyleItalic">ABCA12</span> gene in patients with HI is close to 100&#37;&#44; and so this would appear to be a genetically homogeneous condition&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Collodion Baby and Self-healing Collodion Baby</span><p id="par0165" class="elsevierStylePara elsevierViewall">Collodion babies are usually born prematurely and perinatal morbidity and mortality are increased&#46; At birth&#44; the neonate is covered by a shiny taught transparent membrane reminiscent of cellophane wrapping &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>&#41;&#46; The babies have ectropion&#44; eclabium&#44; and hypoplasia of the nasal and joint cartilage&#46; Sucking and pulmonary ventilation may be hindered<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">110</span></a> and transepidermal loss of water and the risk of infections are increased&#46;<a class="elsevierStyleCrossRefs" href="#bib0550"><span class="elsevierStyleSup">110&#44;111</span></a></p><elsevierMultimedia ident="fig0025"></elsevierMultimedia><p id="par0170" class="elsevierStylePara elsevierViewall">Collodion baby is the usual presentation for HI and CIE&#46; Autosomal dominant LI&#44;<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">112&#44;113</span></a> Sj&#246;gren-Larsson syndrome&#44;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">110</span></a> trichothyodystrophy&#44;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">114</span></a> juvenile Gaucher disease&#44;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">110</span></a> neutral lipid storage disease&#44; Conradi-H&#252;nermann-Happle syndrome&#44; Hays-Wells syndrome&#44; and ectodermal dysplasia<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">115</span></a> may also occasionally present as collodion baby&#46; The membrane disappears spontaneously in 10&#37; to 24&#37; of neonates&#44; to give way to completely normal skin&#46;<a class="elsevierStyleCrossRefs" href="#bib0550"><span class="elsevierStyleSup">110&#44;116</span></a> In the past&#44; these cases were described as LI of the newborn&#44;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">117</span></a> but they are not referred to as SHCB&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">118</span></a> Some authors have suggested the term <span class="elsevierStyleItalic">self-improving collodion ichthyosis</span> because many of these patients&#44; when reexamined later in childhood or as adults&#44; have a variable degree of anhidrosis and heat intolerance and mild signs of ichthyosis&#44; such as xerosis and fine desquamation&#44; particularly in the axillae and neck&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">78</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Neither optical microscopy nor ultrastructural investigations of collodion baby are specific&#46; It is therefore preferable to delay the skin biopsy until the definitive phenotype has developed&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Mutations in the <span class="elsevierStyleItalic">TGM1</span>&#44;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#44;119</span></a><span class="elsevierStyleItalic">ALOXE3</span>&#44;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">78</span></a> and <span class="elsevierStyleItalic">ALOX12B</span><a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;78&#44;79</span></a> genes have been identified in patients with SHCB&#46; <span class="elsevierStyleItalic">ALOX12B</span> mutations are the most common&#46; In a series of 15 Scandinavian patients with SHCB&#44; 67&#37; had mutations in the <span class="elsevierStyleItalic">ALOX12B</span> gene&#44; 25&#37; in the <span class="elsevierStyleItalic">ALOXE3</span> gene&#44; and 8&#46;3&#37; in the <span class="elsevierStyleItalic">TGM1</span> gene&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">78</span></a> Mutations were not found in some patients&#44; and so other genes are also likely to be implicated&#46; There has been speculation that these mutations reduce enzymatic activity in the uterus but not after birth&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> In the uterus&#44; where the hydrostatic pressure is high&#44; chelation by water converts the mutated enzyme into an inactive conformation&#46; After birth&#44; when the pressure decreases&#44; the enzyme returns to its active form and its activity increases sufficiently to maintain a normal or minimally affected phenotype&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Acral Self-healing Collodion Baby</span><p id="par0185" class="elsevierStylePara elsevierViewall">Although collodion baby affects the whole body&#44; cases confined to the acral regions have been reported&#46; In 1952&#44; Finlay et al&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">120</span></a> reported a case of collodion membrane that affected only the hands and feet and that followed a self-healing course&#46; Recently&#44; a new case of acral SHCB has been reported in association with mutations of the <span class="elsevierStyleItalic">TGM1</span> gene&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> It is not known why these lesions are restricted to acral regions&#44; although factors associated with site-dependent regulation of enzyme activity may be in operation&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p></span></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Bathing Suit Ichthyosis</span><p id="par0190" class="elsevierStylePara elsevierViewall">Bathing suit ichthyosis was first reported as an independent ARCI variant in 2005 although cases of ichthyosis with a peculiar distribution had been reported previously&#46;<a class="elsevierStyleCrossRefs" href="#bib0605"><span class="elsevierStyleSup">121&#8211;123</span></a> It has been detected mainly in patients of South African origin&#44;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> although it has also been reported in individuals from Europe and Mediterranean countries&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">124</span></a> At birth&#44; patients have a generalized collodion membrane which then sheds to leave the characteristic distribution of scaling&#46; The trunk&#44; proximal region of the arms&#44; including the axillae&#44; the neck&#44; and the scalp are generally affected&#44; while the central part of the face&#44; the limbs&#44; and the adrenal region are usually spared&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> The scales are large&#44; lamellar&#44; and dark in color&#46; Finer desquamation may occur in the popliteal and antecubital fossae&#46;<a class="elsevierStyleCrossRefs" href="#bib0620"><span class="elsevierStyleSup">124&#44;125</span></a> The palms of the hands and soles of the feet have mild diffuse hyperkeratosis whereas the backs of the hands and feet show no involvement&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">Histopathologic study of affected skin shows marked hyperkeratosis without parakeratosis&#44; normal granular layers&#44; mild or moderate acanthosis&#44; and a mild lymphocytic infiltrate in the upper dermis&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Electron microscopy observations are consistent with congenital ichthyosis type 2 in most cases&#46; Uninvolved skin does not show any abnormal findings&#46;<a class="elsevierStyleCrossRefs" href="#bib0620"><span class="elsevierStyleSup">124&#44;125</span></a> In healthy skin&#44; TGase 1 activity is slightly reduced and usually localized in pericellular areas&#46; In involved skin&#44; enzymatic activity is residual and abnormally located in the cytoplasm&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">124</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">Mutations have been detected in the <span class="elsevierStyleItalic">TGM1</span> gene in all patients with bathing suit ichthyosis studied to date&#46;<a class="elsevierStyleCrossRefs" href="#bib0595"><span class="elsevierStyleSup">119&#44;124&#8211;126</span></a> The most common mutation is p&#46;Arg315Leu&#44; which has been identified in most South African patients and could be a founding mutation&#46; Oji et al&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">124</span></a> suggested that skin temperature might play a role in the development of these manifestations&#46; Using digital thermography&#44; the authors showed a strong correlation between body temperature and desquamation&#44; with the hottest areas of the body being the ones most affected&#46; Aufenvenne et al&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">127</span></a> showed a decrease in optimum temperature for TGase 1 activity in patients with bathing suit ichthyosis&#46; This decrease was not observed in healthy controls or in patients with generalized LI&#46; This decrease in temperature would explain the phenotype of these patients&#46; The optimum temperature is 37<span class="elsevierStyleHsp" style=""></span>&#176;C for the normal enzyme but 31<span class="elsevierStyleHsp" style=""></span>&#176;C for the mutated enzyme&#46;</p><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Treatment</span><p id="par0205" class="elsevierStylePara elsevierViewall">The primary aim of treatment in ichthyosis is to eliminate scaling and reduce xerosis without causing excessive irritation &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; Before deciding on treatment&#44; aspects such as age and sex of the patient&#44; type and severity of the disease&#44; and extent and site of the lesions should be taken into consideration&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">128</span></a></p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Bathing and Mechanical Elimination of Scales</span><p id="par0210" class="elsevierStylePara elsevierViewall">Daily bathing is recommended for patients with ARCI to mechanically eliminate scales and traces of moisturizer&#46; This is easier if the patient is immersed in water for 15 to 30<span class="elsevierStyleHsp" style=""></span>minutes&#46; Some authors recommend adding sodium bicarbonate to the bath to denaturalize the keratins and make the water alkaline&#44; and so facilitate elimination of the scales&#46;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">129</span></a> Other products that can be added include wheat starch&#44; corn starch&#44; or rice starch&#46; Bathing oils are not appropriate as they may lead to occlusion with subsequent risk of bacterial proliferation and worsening of thermoregulation&#46;</p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Topical Treatment</span><p id="par0215" class="elsevierStylePara elsevierViewall">Moisturizers and topical keratolytic agents are usually the first therapeutic option&#46; They improve skin barrier function and facilitate desquamation&#46; Mild local adverse effects&#44; such as transient pruritus&#44; irritation&#44; or stinging sensation may occur&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">Sodium chloride&#44; urea&#44; vitamin E acetate&#44; glycerol&#44; and petroleum jelly can be used as moisturizers and lubricants&#46; In patients with thick scaling and marked hyperkeratosis&#44; 1 or more keratolytic agents&#44; such as &#945;-hydroxy acids &#40;lactic and glycolic acid&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">130</span></a> salicylic acid&#44; N-acetylcystein&#44;<a class="elsevierStyleCrossRefs" href="#bib0655"><span class="elsevierStyleSup">131&#8211;133</span></a> urea &#40;&#62;<span class="elsevierStyleHsp" style=""></span>5&#37;&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">134</span></a> and propylene glycol&#44; can be added&#46; Modulators of keratinocyte differentiation are also used&#46; These include topical retinoids &#40;tretinoin&#44; adapalene&#44; tazarotene&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0675"><span class="elsevierStyleSup">135&#44;136</span></a> calcipotriol&#44;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">137</span></a> and dexpanthenol&#46;Topical retinoids often cause irritation and small&#44; very painful fissures&#46;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">137</span></a> Moreover&#44; there is a risk of absorption and teratogenicity in fertile women if they are used too extensively&#46;<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">138</span></a> To enhance the effectiveness of keratolytics and moisturizers&#44; occlusive dressing may be applied in specific areas refractory to treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">139</span></a> An additive or synergistic effect can also be attained by combining 2 or more keratolytic agents or moisturizers&#46;<a class="elsevierStyleCrossRefs" href="#bib0700"><span class="elsevierStyleSup">140&#8211;142</span></a> Treatment should be optimized for each individual&#44; given the highly variable nature of the condition and skin sensitivity and differences in response to each treatment&#46; The optimization process can be helped by treating one side of the body differently to the other to enable comparisons&#46; Neonates and small children should be treated with a vehicle without any active substances as the skin is very fine and sensitive and most keratolytics are not tolerated&#46; In addition&#44; the risk of percutaneous absorption of topical products such as urea&#44; salicylic acid&#44; and lactic acid is greater&#46;<a class="elsevierStyleCrossRefs" href="#bib0715"><span class="elsevierStyleSup">143&#8211;145</span></a></p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Systemic Treatment</span><p id="par0225" class="elsevierStylePara elsevierViewall">Oral retinoids have keratolytic effects that help eliminate scales and prevent excessive hyperkeratosis&#46; Both isotretinoin and aromatic retinoids &#40;acitretin and etretinate&#41; have proved effective in the treatment of ARCIs&#46;<a class="elsevierStyleCrossRefs" href="#bib0640"><span class="elsevierStyleSup">128&#44;146&#44;147</span></a> Acitretin at a dose of 0&#46;5 to 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d is the most widely used drug&#44; especially in patients with LI&#46;<a class="elsevierStyleCrossRef" href="#bib0740"><span class="elsevierStyleSup">148</span></a> Patients with CIE may have a more complete response and at lower doses&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">The main adverse effects are mucocutaneous disorders&#44; teratogenicity&#44; musculoskeletal disorders&#44; and abnormal lipid profile and transaminase elevation&#46;<a class="elsevierStyleCrossRefs" href="#bib0745"><span class="elsevierStyleSup">149&#8211;152</span></a> With regards to teratogenicity&#44; in the case of etretinate and acitretin&#44; the drugs should be avoided during pregnancy and patients should avoid becoming pregnant for 3 years after discontinuation of treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0755"><span class="elsevierStyleSup">151</span></a> Isotretinoin has a shorter half-life and is completely eliminated from the organism after 1 month and so may be the preferred option in women who wish to become pregnant&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">128</span></a></p><p id="par0235" class="elsevierStylePara elsevierViewall">Treatment monitoring should include a laboratory work-up with a liver function test and lipid profile before starting treatment&#44; then at 1 month and every 3 months after starting treatment&#46; In fertile women&#44; a pregnancy test should be performed in the 2 weeks before starting treatment and an effective contraceptive measure should be used from 4 weeks before treatment until 3 years afterwards &#40;in the case of acitretin&#41;&#46; When prolonged treatment is required with retinoids&#44; growth and bone development should be monitored&#46; Some authors suggest performing a bone study before treatment followed by a yearly examination&#46;<a class="elsevierStyleCrossRef" href="#bib0755"><span class="elsevierStyleSup">151</span></a> Recent guidelines do not recommend performing routine radiography because of the possible harmful effects&#46;<a class="elsevierStyleCrossRef" href="#bib0760"><span class="elsevierStyleSup">152</span></a> Instead&#44; selective radiographic studies are recommended in patients who have atypical bone pain&#46;<a class="elsevierStyleCrossRef" href="#bib0760"><span class="elsevierStyleSup">152</span></a></p><p id="par0240" class="elsevierStylePara elsevierViewall">An alternative to systemic retinoid treatment is the use of drugs known as retinoic acid metabolism blocking agents&#44; which increase the endogenous levels of retinoic acid&#46; One such drug is liarozole&#44; which has been granted orphan status for the treatment of LI&#44; CIE&#44; and HI by the European Medicines Agency and the US Food and Drug Administration&#46;<a class="elsevierStyleCrossRefs" href="#bib0765"><span class="elsevierStyleSup">153&#8211;155</span></a> This drug has been shown to be more effective than acitretin in clinical trials and it is also better tolerated and has a better pharmacokinetic profile&#46;<a class="elsevierStyleCrossRef" href="#bib0770"><span class="elsevierStyleSup">154</span></a></p></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Other Medical Care</span><p id="par0245" class="elsevierStylePara elsevierViewall">In patients with ectropion&#44; the application of artificial tears and eye lubricants and moisturizing the skin of the face and the cheeks in particular can reduce palpebral retraction&#46; Surgical correction is a valid option in severe cases&#44; but this usually has to be repeated a few years later&#46; Hydrotherapy may be beneficial&#46;<a class="elsevierStyleCrossRef" href="#bib0780"><span class="elsevierStyleSup">156</span></a> Patients should be advised to avoid strenuous physical activity when the ambient temperature is high&#44; given that hypohidrosis carries with it the risk of heat stroke and convulsions&#46; Oral retinoids can improve thermoregulation&#46;<a class="elsevierStyleCrossRef" href="#bib0785"><span class="elsevierStyleSup">157</span></a> Physiotherapy is important for preventing flexion contracture&#44; particularly in the case of HI&#46; Regular cleansing of the external auditory canal by an ear-throat-nose specialist can prevent scales from accumulating and so prevent hearing loss&#46;</p></span></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Genetic Counseling and Prenatal Diagnosis</span><p id="par0250" class="elsevierStylePara elsevierViewall">When a patient is diagnosed with ichthyosis&#44; he or she should be offered appropriate genetic counseling in which the nature of the disorder&#44; the transmission mode&#44; and the risk of future manifestations in the family are explained&#46; Prenatal diagnosis can indicate whether the fetus is affected and&#44; if this is the case&#44; psychological preparation of the family can be offered and problems anticipated during pregnancy and birth&#46; The parents can be given the option of an abortion if no treatment is available&#46; In addition&#44; should gene therapy for these conditions become available in the future&#44; prenatal diagnosis would enable application of this therapy as early as possible&#46;</p><p id="par0255" class="elsevierStylePara elsevierViewall">For more than 20 years&#44; prenatal diagnosis was performed by taking a biopsy sample of fetal skin and studying it by optical microscopy&#44; electron microscopy&#44; or immunohistochemistry&#46;<a class="elsevierStyleCrossRefs" href="#bib0790"><span class="elsevierStyleSup">158&#44;159</span></a> This invasive procedure could only be performed in the late phases of pregnancy&#44; between weeks 15 and 23 of gestation&#44; and was associated with a 1&#37; to 3&#37; risk of losing the fetus&#46;<a class="elsevierStyleCrossRefs" href="#bib0800"><span class="elsevierStyleSup">160&#44;161</span></a> The identification of the molecular mechanisms of hereditary skin disorders has enabled a much earlier diagnosis based on genetic techniques&#46;<a class="elsevierStyleCrossRefs" href="#bib0510"><span class="elsevierStyleSup">102&#44;162&#8211;164</span></a> Fetal DNA is obtained by amniocentesis performed between weeks 15 and 20 or by chorionic villus sampling between weeks 10 and 12&#46; The risk of fetal loss with these techniques is less than between 0&#46;5&#37; and 1&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0825"><span class="elsevierStyleSup">165</span></a> Other noninvasive methods in development are analysis of fetal cell DNA and free fetal DNA in maternal circulation<a class="elsevierStyleCrossRef" href="#bib0830"><span class="elsevierStyleSup">166</span></a> as well as the use of 3-dimensional ultrasound&#46;<a class="elsevierStyleCrossRefs" href="#bib0835"><span class="elsevierStyleSup">167&#44;168</span></a></p><p id="par0260" class="elsevierStylePara elsevierViewall">Preimplantation genetic diagnosis could also be possible in in vitro fertilization techniques&#44; such that only fertilized eggs free of the mutation are implanted in the uterus&#44; thereby avoiding the need for abortion in most cases&#46;<a class="elsevierStyleCrossRef" href="#bib0845"><span class="elsevierStyleSup">169</span></a></p></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Future Strategies for Genetic Treatment of Ichthyosis</span><p id="par0265" class="elsevierStylePara elsevierViewall">Although important progress has been made in the genetic diagnosis of ichthyosis&#44; new strategies are also being pursued for these diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0850"><span class="elsevierStyleSup">170</span></a> The skin is the most accessible organ for gene transfer therapies&#44; and so such techniques are minimally invasive&#46;<a class="elsevierStyleCrossRef" href="#bib0855"><span class="elsevierStyleSup">171</span></a> However&#44; the skin also has unique immunologic characteristics that do not favor long-term expression of a transgenic product&#46;<a class="elsevierStyleCrossRef" href="#bib0860"><span class="elsevierStyleSup">172</span></a> In LI&#44; a process of ex vivo gene transfer managed to restore normal <span class="elsevierStyleItalic">TGM1</span> expression and correct the phenotype of skin transplanted on the back of immunosuppressed mice&#46;<a class="elsevierStyleCrossRefs" href="#bib0865"><span class="elsevierStyleSup">173&#44;174</span></a> Recently&#44; the phenotype of cultured keratinocytes from patients with HI due to mutations in the <span class="elsevierStyleItalic">ABCA12</span> gene has also been recovered&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Conflicts of Interest</span><p id="par0270" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "titulo" => "Introduction"
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          "identificador" => "sec0010"
          "titulo" => "Lamellar Ichthyosis and Congenital Ichthyosiform Erythroderma"
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              "identificador" => "sec0015"
              "titulo" => "Clinical Characteristics"
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              "titulo" => "Histopathology"
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              "titulo" => "Ultrastructure"
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              "titulo" => "Congenital Ichthyosis Type 1"
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              "titulo" => "Congenital Ichthyosis Type 2"
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              "titulo" => "Congenital Ichthyosis Type 3"
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              "titulo" => "Congenital Ichthyosis Type 4"
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              "titulo" => "ALOXE3 and ALOX12B"
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              "titulo" => "Ichthyin&#47;NIPAL4"
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          "titulo" => "Harlequin Ichthyosis"
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              "titulo" => "Acral Self-healing Collodion Baby"
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    "fechaAceptado" => "2011-11-13"
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            1 => "Autosomal recessive congenital ichthyosis"
            2 => "ARCI"
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      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The term <span class="elsevierStyleItalic">autosomal recessive congenital ichthyosis</span> &#40;ARCI&#41; refers to a group of rare disorders of keratinization classified as nonsyndromic forms of ichthyosis&#46; This group was traditionally divided into lamellar ichthyosis &#40;LI&#41; and congenital ichthyosiform erythroderma &#40;CIE&#41; but today it also includes harlequin ichthyosis&#44; self-healing collodion baby&#44; acral self-healing collodion baby&#44; and bathing suit ichthyosis&#46;</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">The combined prevalence of LI and CIE has been estimated at 1 case per 138 000 to 300 000 population&#46; In some countries or regions&#44; such as Norway and the coast of Galicia&#44; the prevalence may be higher due to founder effects&#46; ARCI is genetically highly heterogeneous and has been associated with 6 genes to date&#58; <span class="elsevierStyleItalic">TGM1</span>&#44; <span class="elsevierStyleItalic">ALOXE3</span>&#44; <span class="elsevierStyleItalic">ALOX12B</span>&#44; <span class="elsevierStyleItalic">NIPAL4</span>&#44; <span class="elsevierStyleItalic">CYP4F22</span>&#44; and <span class="elsevierStyleItalic">ABCA12</span>&#46; In this article&#44; we review the current knowledge on ARCI&#44; with a focus on clinical&#44; histological&#44; ultrastructural&#44; genetic&#44; molecular&#44; and treatment-related aspects&#46;</p>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Las ictiosis cong&#233;nitas autos&#243;micas recesivas &#40;ICAR&#41; son trastornos infrecuentes de la queratinizaci&#243;n que se engloban en las formas no sindr&#243;micas de ictiosis&#46; Cl&#225;sicamente se distingu&#237;an en este grupo la ictiosis laminar &#40;IL&#41; y la eritrodermia ictiosiforme cong&#233;nita &#40;EIC&#41;&#46; Actualmente se incluyen tambi&#233;n la ictiosis arlequ&#237;n&#44; el beb&#233; colodi&#243;n autorresolutivo&#44; el beb&#233; colodi&#243;n autorresolutivo acral y la ictiosis en traje de ba&#241;o&#46;</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Se ha estimado una prevalencia conjunta para IL y EIC de 1&#58;138&#46;000-1&#58;300&#46;000&#46; En algunos pa&#237;ses o regiones&#44; como Noruega y la costa gallega&#44; la prevalencia podr&#237;a ser mayor debido a la existencia de efectos fundadores&#46; Desde el punto de vista gen&#233;tico son muy heterog&#233;neas&#46; Seis genes se han asociado a estas entidades&#58; <span class="elsevierStyleItalic">TGM1</span>&#44; <span class="elsevierStyleItalic">ALOXE3</span>&#44; <span class="elsevierStyleItalic">ALOX12B</span>&#44; <span class="elsevierStyleItalic">NIPAL4</span>&#44; <span class="elsevierStyleItalic">CYP4F22</span> y <span class="elsevierStyleItalic">ABCA12</span>&#46; En este trabajo se pretenden revisar los conocimientos actuales en el campo de las ICAR&#44; incluyendo aspectos cl&#237;nicos&#44; histol&#243;gicos&#44; ultraestructurales&#44; gen&#233;tico-moleculares y de tratamiento&#46;</p>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Rodr&#237;guez-Pazos L&#44; et al&#46; Ictiosis cong&#233;nitas autos&#243;micas recesivas&#46; Actas Dermosifiliogr&#46; 2013&#59;104&#58;270&#8211;84&#46;</p>"
      ]
    ]
    "multimedia" => array:8 [
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        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Clinical features of lamellar ichthyosis&#46; A&#44; Brownish lamellar desquamation&#46; B&#44; Marked plantar hyperkeratosis&#46; C&#44; Scarring alopecia of the scalp&#46;</p>"
        ]
      ]
      1 => array:7 [
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Patient with congenital ichthyosiform erythroderma and mutations in the <span class="elsevierStyleItalic">ALOXE3</span> gene&#46; Mild erythema and generalized whitish furfuraceous desquamation can be seen&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "fig0015"
        "etiqueta" => "Figure 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Electron microscope images&#46; A&#44; Congenital ichthyosis type 1&#44; showing lipid droplets in the stratum corneum and absence of ultrastructural markers of the other types of ichthyosis&#46; B&#44; Congenital ichthyosis type 2&#44; characterized by the presence of cholesterol clefts &#40;arrow&#41; in corneocytes&#46;</p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "fig0020"
        "etiqueta" => "Figure 4"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Schematic diagram of the hepoxilin pathway&#44; showing the participation of the <span class="elsevierStyleItalic">ALOXE3&#44; ALOX12B&#44; NIPAL4</span>&#44; and <span class="elsevierStyleItalic">CYP4F22</span> genes&#46; Mutations in these genes are responsible for some types of ARCI&#46; HPETE indicates hydroperoxyeicosatetraenoic acid&#46;</p>"
        ]
      ]
      4 => array:7 [
        "identificador" => "fig0025"
        "etiqueta" => "Figure 5"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
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        "figura" => array:1 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Collodion baby that subsequently progressed to a lamellar ichthyosis phenotype&#46;</p>"
        ]
      ]
      5 => array:7 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Abbreviations&#58;</span> ARC&#44; arthrogryposis&#8211;renal dysfunction&#8211;cholestasis&#59; ARCI&#44; autosomal recessive congenital ichthyosis&#59; CEDNIK&#44; cerebral dysgenesis&#44; neuropathy&#44; ichthyosis&#44; and palmoplantar keratoderma&#59; KID&#44; keratitis ichthyosis deafness&#59; KLICK&#44; keratosis linearis with ichthyosis congenital and sclerosing keratoderma&#59; MEDNIK&#44; mental retardation&#44; enteropathy&#44; deafness&#44; peripheral neuropathy&#44; ichthyosis&#44; keratoderma&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nonsyndromic Forms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Syndromic Forms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Common Ichthyoses</span><span class="elsevierStyleHsp" style=""></span>Ichthyosis vulgaris<span class="elsevierStyleHsp" style=""></span>Recessive x-linked ichthyosis &#40;nonsyndromic&#41;<span class="elsevierStyleBold">ARCI</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Major forms</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Harlequin ichthyosis<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Lamellar ichthyosis<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Congenital ichthyosiform erythroderma<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Minor forms</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Self-healing collodion baby<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Acral self-healing collodion baby<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Bathing suit ichthyosis<span class="elsevierStyleBold">Keratinopathic Ichthyoses</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Major forms</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Epidermolytic ichthyosis<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Superficial epidermolytic ichthyosis<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Minor forms</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Annular epidermolytic ichthyosis<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Curth-Macklin ichthyosis<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Autosomal recessive epidermolytic ichthyosis<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Epidermolytic nevus<span class="elsevierStyleBold">Other Forms</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Loricrin keratoderma</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Erythrokeratodermia variabilis</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Peeling skin syndrome</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Congenital reticular ichthyosiform erythroderma</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">KLICK syndrome</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Syndromic X-linked Ichthyosis</span>Recessive x-linked ichthyosis &#40;syndromic&#41;Ichthyosis follicularis&#44; alopecia&#44; and photophobia &#40;IFAP&#41; syndromeConradi-H&#252;nermann-Happle syndrome &#40;chondrodysplasia punctata type 2&#41;<span class="elsevierStyleBold">Syndromic Autosomal Ichthyosis</span><span class="elsevierStyleItalic">Skin disorders</span>Netherton syndromeIchthyosis-hypotrichosis syndromeIchthyosis-sclerosing cholangitis syndromeTrichothiodystrophy<span class="elsevierStyleItalic">Neurologic disorders</span>Sj&#246;gren-Larsson syndromeRefsum diseaseMEDNIK syndrome<span class="elsevierStyleItalic">Fatal disease course</span>Gaucher disease&#44; type 2Multiple sulfatase deficiencyCEDNIK syndromeARC syndrome<span class="elsevierStyleItalic">Other associated signs</span>KID syndromeChanarin-Dorfman syndromeIchthyosis prematurity syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab185615.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Consensus Classification Based on the Clinical Features of Ichthyosis<span class="elsevierStyleSup">1</span>&#46;</p>"
        ]
      ]
      6 => array:7 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Abbreviations&#58;</span> CIE&#44; congenital ichthyosiform erythroderma&#59; LI&#44; lamellar ichthyosis&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Type&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Main Feature&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Other Features&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Mutations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Clinical Manifestations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Absense of ultrastructural markers of ichthyosis types 2&#44; 3&#44; and 4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lipid droplets or rings in the stratum corneum &#40;most frequent&#41;Small keratohyalin granulesVesicular or lobular membrane coating granules&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">TGM1</span> &#40;33&#46;3&#37;&#41;<span class="elsevierStyleItalic">ALOX12B</span> &#40;2 cases&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CIE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cholesterol clefts in the stratum corneum&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Absence or thinning of cornified envelopeSmall keratohyalin granulesLipid droplets&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">TGM1</span> &#40;89-100&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Laminated membraneous structures in the stratum granulosum and&#47;or stratum corneum&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Abnormal membrane coating granulesLipid dropletsFoci of prominent juxtanuclear vacuoles in the granular layer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">NIPAL4</span> &#40;93&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CIE &#40;most frequent&#41;LI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Trilamellar membrane packets that fill some cells in the stratum granulosum and&#47;or stratum corneum&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Abnormal membrane coating granules&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">FTAP4</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ichthyosis prematurity syndrome &#40;100&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Ultrastructural Classification of Congenital Ichthyoses&#46;</p>"
        ]
      ]
      7 => array:7 [
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        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
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                  \t\t\t\t" style="border-bottom: 2px solid black">Therapeutic strategy for the autosomal recessive congenital ichthyoses&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Bathing and mechanical elimination of scales&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Bathing with sodium bicarbonate or wheat starch&#44; corn starch&#44; or rice starch&#59; mechanical removal of the scales &#40;1 or 2 times a day&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Topical treatment &#40;sequential&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Urea-containing moisturizersKeratinolytics with propylene glycolCombined keratinolytics &#40;propylene glycol&#44; &#945;-hydroxy acids&#44; or urea&#41;Keratinolytics combined with salicylic acidTopical retinoidsIn neonates and small children&#44; apply a vehicle without active ingredients&#46; Avoid urea&#44; salicylic acid&#44; and lactic acid due to the risk of systemic absorption&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Oral retinoids &#40;acitretin or isotretinoin&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Follow-up of ectropion by the ophthalmologistRegular cleansing of the outer ear by the ear-throat-nose specialistPhysiotherapy to prevent contractures&#46;Avoidance of strenuous activities in a high ambient temperatureHydrotherapy&nbsp;\t\t\t\t\t\t\n
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                    0 => array:1 [
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                      "titulo" => "Autosomal recessive congenital ichthyosis"
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                    0 => array:2 [
                      "doi" => "10.1038/jid.2009.57"
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                    0 => array:1 [
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                      "titulo" => "Bricks and mortar of the epidermal barrier"
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                    0 => array:2 [
                      "doi" => "10.1038/emm.1999.2"
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              "identificador" => "bib0210"
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                    0 => array:2 [
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                0 => array:2 [
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                      "titulo" => "Consequences of seven novel mutations on the expression and structure of keratinocyte transglutaminase"
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                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [ …6]
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                0 => array:2 [
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                      "titulo" => "Genetic and immunohistochemical detection of mutations inactivating the keratinocyte transglutaminase in patients with lamellar ichthyosis"
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                    0 => array:1 [
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                      "titulo" => "In vitro and rapid in situ transglutaminase assays for congenital ichthyoses--a comparative study"
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                    0 => array:2 [
                      "doi" => "10.1046/j.1523-1747.1998.00132.x"
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                ]
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                      "titulo" => "A novel homozygous mutation 371delA in TGM1 leads to a classic lamellar ichthyosis phenotype"
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                    0 => array:1 [
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                    0 => array:2 [
                      "doi" => "10.1007/s00403-005-0591-7"
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                      "titulo" => "Linkage of autosomal recessive lamellar ichthyosis to chromosome 14q"
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                  "host" => array:1 [
                    0 => array:1 [
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                      "titulo" => "Mutations in the gene for transglutaminase 1 in autosomal recessive lamellar ichthyosis"
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                    0 => array:2 [
                      "doi" => "10.1038/ng0395-279"
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                    0 => array:1 [
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                0 => array:2 [
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                      "titulo" => "Novel transglutaminase-1 mutations and genotype-phenotype investigations of 104 patients with autosomal recessive congenital ichthyosis in the USA"
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                    0 => array:2 [
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                      "titulo" => "Mutations in transglutaminase 1 gene in autosomal recessive congenital ichthyosis in Egyptian families"
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                  "host" => array:1 [
                    0 => array:1 [
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                      "titulo" => "Diagnosis of autosomal recessive lamellar ichthyosis with mutations in the TGM1 gene"
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                    0 => array:1 [
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                0 => array:2 [
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                    0 => array:2 [
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                      "titulo" => "Identification of mutations in the transglutaminase 1 gene in lamellar ichthyosis"
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                  "host" => array:1 [
                    0 => array:1 [
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                      "titulo" => "Role of Sp1 response element in transcription of the human transglutaminase 1 gene"
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                      "titulo" => "Novel mutations of TGM1 in a child with congenital ichthyosiform erythroderma"
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                    0 => array:1 [
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                0 => array:2 [
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                    0 => array:2 [
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                    0 => array:2 [
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                  "host" => array:1 [
                    0 => array:1 [
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                      "titulo" => "The lipoxygenase gene ALOXE3 implicated in skin differentiation encodes a hydroperoxide isomerase"
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                    0 => array:2 [
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