Although it was originally thought that LI and CIE were different entities, there have been reports of patients with intermediate clinical manifestations and both conditions can be caused by mutations in the same gene.15,16 In addition, patients with the same mutation, even within the same family, can develop different phenotypes.12,15

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 (Fig. 1A). Hypohidrosis, severe heat intolerance, and nail dystrophy are frequently observed in both LI and CIE.17–19 Patients with LI usually have more severe clinical manifestations than those with CIE. They have large platelike scales, often of a dark color, covering the whole body surface area. Erythroderma is either absent or minimal. Such patients usually have ectropion and, at times, eclabium, hypoplasia of joint and nasal cartilage, scarring alopecia, especially at the edge of the scalp, and palmoplantar keratoderma (Fig. 1B and C). CIE is characterized by the presence of erythroderma and fine whitish scaling (Fig. 2). Some patients have marked erythema and generalized scaling. The scales can be large and dark colored, particularly on the extensor surfaces of the legs. In less severe cases, erythema is mild and the scaling is fine.

Figure 1.

Clinical features of lamellar ichthyosis. A, Brownish lamellar desquamation. B, Marked plantar hyperkeratosis. C, Scarring alopecia of the scalp.

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Figure 2.

Patient with congenital ichthyosiform erythroderma and mutations in the ALOXE3 gene. Mild erythema and generalized whitish furfuraceous desquamation can be seen.

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Histopathologic changes do not provide a diagnosis. In LI, massive orthokeratotic hyperkeratosis is observed, usually with twice the extension as in CIE. The epidermis is acanthotic and occasionally takes on a psoriasis-like appearance. The cell proliferation rate is normal or slightly elevated.17–19 Patients with CIE have less marked hyperkeratosis, with focal or extensive parakeratosis, a normal or thickened granular layer, and more pronounced acanthosis. The epidermal turnover is increased.17–19

Although a close correlation between molecular, clinical, and ultrastructural findings has so far not been found, electron microscopy may nevertheless be useful for ruling out other forms of ichthyosis and for guiding genetic analyses in some cases. Four types of congenital ichthyosis have been described (Table 2).

Congenital ichthyosis type 1 is characterized by the absence of ultrastructural markers for ichthyosis types 2, 3, and 4. Therefore, diagnosis is usually only made when the other types have been excluded. The most frequent finding is the presence of lipid droplets or rings in the stratum corneum (Fig. 3A).20 These lipid droplets are not a constant feature or specific to this particular type as they are not present in all cases,20 and they may be present in other types of ichthyosis.21,22 Clinically, most patients present with manifestations of CIE.12,20 One-third of patients have mutations in the TGM1 gene.16 This ultrastructural type has also been identified in association with mutations in the ALOX12B gene.23,24

Figure 3.

Electron microscope images. A, Congenital ichthyosis type 1, showing lipid droplets in the stratum corneum and absence of ultrastructural markers of the other types of ichthyosis. B, Congenital ichthyosis type 2, characterized by the presence of cholesterol clefts (arrow) in corneocytes.

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Congenital ichthyosis type 2 is characterized by cholesterol clefts in the stratum corneum (Fig. 3B).21 Such clefts are a constant finding in this type of ichthyosis, and can be detected in different biopsies in the same patient; treatment with oral retinoids has no impact on these clefts.12,25 Electron-dense aggregates have also been observed on corneocytes in some patients with deficient TGase 1 activity.26–28 Clinically, most patients present with severe manifestations of CIE.12 This ultrastructural type is strongly associated with mutations in the TGM1 gene.12,16

Congenital ichthyosis type 3 is characterized by lamellar membranous structures in the stratum granulosum and/or stratum corneum. These structures are arranged in strips around an empty space close to the nucleus.22,29–31 The clinical manifestations in this type are different to the others; onset of ichthyosis is variable, desquamation and erythema may be patchy or generalized, and the flexures in particular are affected. Mutations in the NIPAL4 gene are responsible for 93% of ichthyoses type 3.32

Characteristically, in congenital ichthyosis type 4, some cells in the stratum granulosum and stratum corneum are filled with trilamellar membrane packages.33 These findings are pathognomic for ichthyosis prematurity syndrome, a condition currently considered as a syndromic form of ichthyosis.34,35

In genetic terms, the ARCIs are very heterogeneous. The TGM1 gene is associated with most cases, but mutations in 5 other genes (ALOX12B, ALOXE3, NIPAL4, CYP4F22, and ABCA12) have been reported. Fischer et al.36 studied 520 families with ARCI and identified mutations in at least 1 of these genes in 78% of cases (TGM1 in 32%, NIPAL4 in 16%, ALOX12B in 12%, CYP4F22 in 8%, ALOXE3 in 5%, and ABCA12 in 5%). In another study of 250 patients with ARCI of different origins, 38% had TGM1 mutations, 6.8% had ALOXE3 mutations, and 6.8% had ALOX12B mutations.37 In Galicia, we identified mutations in the TGM1, ALOX12B, ALOXE3, NIPAL4, and CYP4F22 genes in 75% of the families studied, but the distribution of mutations was different.14 The TGM1 gene was mutated in 68.7% of the cases while the ALOXE3 gene was mutated in just 1 patient. We did not detect mutations in any of the other 3 genes studied.

The TGM1 gene is located on chromosome 14q11.2 and has 15 exons (GenBank NM-000359.2). It encodes the TGase 1 enzyme, which is one of the 3 TGase enzymes found in the epidermis.38 This enzyme participates in the formation of the cornified envelope by catalyzing calcium-dependent cross-linking of several proteins such as involucrin, loricrin, and proline-rich proteins.39,40 It also catalyzes binding of ¿-hydroxyceramides in the outer layer of the cornified envelope with proteins in the inner layer.41,42 In patients with TGM1 mutations, the cornified envelope is missing and TGase 1 activity is reduced or nonexistent.43–47

Since 1995, when this gene was identified as responsible for some cases of ARCI,48–50 more than 110 mutations have been reported in patients of different origins. Mutations in TGM1 are the most common cause of ARCI.36,37 This mutation has been found in 55% of cases in the United States and in 84% of cases in Norway.12,51 The most frequent mutation is c.877-2A>G, which has been found in 34% of the mutated alleles reported to date.52 The high frequency of this mutation in countries such as the United States and Norway is due to a founder effect.12,53 The second most frequent mutation is p.Arg142His. This and similar mutations have been reported in countries such as Egypt, Germany, Finland, and the United States,15,49–51,54–56 and it would seem that these are hotspot mutations.57 The p.Arg307Trp mutation is frequent in the Japanese population.5 In Galicia, the p.Arg760X, c.1223_1227delACACA and c.984+1G>A mutations in TGM1 were identified in 81.82% of the families with mutations in this gene, suggesting a founder effect.14 Confirmation of this hypothesis was obtained by haplotype study (work as yet unpublished).

TGM1 mutations are responsible for most cases of LI15,27,44,46,56,58–63 and for a small percentage of cases of CIE.43,47,64,65 Such mutations can also give rise to other forms of ARCI such as SHCB, acral SHCB, and bathing suit ichthyosis.

Many studies have attempted to demonstrate genotype-phenotype associations between mutations in TGM1 and ultrastructural or clinical findings, but no significant correlation has been observed to date.15,16,53 In general, patients with mutations in the TGM1 gene are more severely affected than those without such mutations. In a study of 83 patients with ARCI in Sweden and Estonia, the presence of ectropion and collodion baby was associated with TGM1 mutations, while a higher rate of erythema was observed in patients without mutations in this gene.66 Another study showed that the type of scaling is the main difference between carriers and noncarriers of TGM1 mutations, on finding that all patients with mutations in this gene had lamellar scaling whereas 80% of those without TGM1 mutations had fine scaling.14 In addition, it has been seen that truncating mutations are more frequently associated with hypohidrosis and sweating disorders than missense mutations.51 In the north American population, a model based on the presence of certain clinical characteristics predicts that patients who are born as collodion babies and have ocular disorders and/or alopecia are 4 times more likely to have TGM1 mutations.51

The ALOXE3 and ALOX12B genes are located on chromosome 17p13.1.67 They have a similar structure with 15 exons that encode the epidermal LOXs eLOX-3 and 12R-LOX.68,69 The fact that they are predominantly expressed in the suprabasal layers of the epidermis supports their role in advanced phases of epidermal differentiation, with participation in the processing of lamellar bodies.24,70 These enzymes act on adjacent steps in the hepoxilin pathway (Fig. 4). 12R-LOX transforms arachidonic acid to 12R-hydroxyeicosatetraenoic acid while eLOX-3 converts this product into an epoxyalcohol isomer69,71 of the hepoxilin A3 family.72 The hepoxilin product is unstable and is hydrolyzed in cells to a specific trihydroxy derivative (trioxilin). Although the exact role of the products of the hepoxilin pathway is not known, 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.

Figure 4.

Schematic diagram of the hepoxilin pathway, showing the participation of the ALOXE3, ALOX12B, NIPAL4, and CYP4F22 genes. Mutations in these genes are responsible for some types of ARCI. HPETE indicates hydroperoxyeicosatetraenoic acid.

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The ALOX12B and ALOXE3 genes were first identified in 2002.73,74 Since then, more than 30 mutations in the ALOX12B gene23,24,37,75–77 and approximately 10 in the ALOXE3 gene37,74,75 have been reported. These mutations are responsible for 14% to 17% of ARCIs36,37 and 72.2% of SHCBs.23,78,79 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 mutations75,80 and by using animal models that reproduced the ichthyosiform phenotype seen in humans.81–83 Both genes are responsible for a similar percentage of ARCI cases. However, the range of different mutations in the ALOXE3 gene is limited, due to the predominance of 2 mutations, p.Arg234X and p.Pro630Leu, which seem to correspond to hotspots.37,74,75

The patients with mutations in the ALOXE3 and ALOX12B genes usually show a CIE phenotype.74,75,77 The severity of scaling is mild or moderate, and the scales have a whitish or light brown color. Erythema may also be present. As many as 76% of the patients are born as collodion babies and 88% have sweating disorders.37 Patients with mutations in the ALOX12B gene show more limited, whitish desquamation compared with carriers of mutations in the ALOXE3 gene. In these cases, the scales are brownish and adherent. The presence of erythema, palmoplantar hyperkeratosis, and accentuation of the palmoplantar folds are also associated with ALOX12B mutations.37

The NIPAL4 gene, also known as the ichthyin gene, is located on chromosome 5q33. It has 6 exons that encode a protein with several transmembrane domains of unknown function.84 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.84 It would thus be implicated in the formation of lamellar bodies or in their transport towards the extracellular space.32 In support of this are 2 observations. First, in 93% of the cases, mutations in this gene are associated with an ultrastructural pattern of congenital ichthyosis type 3, characterized by abnormalities in the lamellar bodies and the presence of elongated perinuclear membranes in the stratum granulosum.32 Second, NIPAL4 is expressed essentially in the stratum granulosum of the epidermis, where the lamellar bodies are present.85

Since the discovery of the NIPAL4 gene in 2004,84 only 9 mutations have been reported in patients from Mediterranean countries (Algeria, Turkey, and Syria),84 Scandinavian countries,32 Pakistan,85 the Faroe Islands,32 and South America.84

The clinical spectrum of patients with mutations in this gene is broad, even among members of the same family. Between 3.7%32 and 60%84 are born as collodion babies. When the collodion membrane disappears, most patients develop the manifestations of CIE, with fine whitish scales on an erythematous base on the face and trunk and larger, brownish scales on the neck, buttocks, and legs.84 Marked xerosis, generalized brownish reticular hyperkeratotic plaques that appear accentuated in the skin folds, and facial dyschromia may be present.32,85 In addition, palmoplantar keratoderma is a frequent finding along with occasional finger contractures and curved finger nails. Some studies have reported findings more typical of LI.32,85 The presence of signs and symptoms of atopic dermatitis has been reported in some patients, although mutations in the FLG gene were not detected in any of these cases.85

The FLJ39501 or CYP4F22 gene is located on chromosome 19p13.12.86 It has 12 exons87 and encodes a P450 cytochrome, family 4, subfamily F, polypeptide 2, homolog of leukotriene B4- ω-hydroxylase (CYP4F2). The reaction catalyzed by the product of FLJ39501 in the skin and the substrates of that reaction may be deduced by analogy with its known homologs CYP4F2 and CYP4F3.88 It has been hypothesized that CYP4F2 and CYP4F3 participate in the hepoxilin pathway by catalyzing the conversion of trioxilin A3 to 20-hydroxy-(R)trioxilin A387 and that the end product of this pathway, 20-carboxy-trioxilin A3, may have a key biological regulatory effect in the skin.89

To date, only 8 mutations of this gene have been reported in 12 consanguineous families from Mediterranean countries87 and in 1 family of Israeli origin.62

In the families reported by Lefèvre et al.,87 most patients had a CIE phenotype at birth and this subsequently progressed to LI. Patients were usually born with marked erythroderma, although without any collodion membrane. As they got older, they developed generalized whitish-grey scaling, which was more marked in the periumbilical region, on the buttocks, and on the lower part of the body. Hyperlinearity of the palms and soles and desquamation on the scalp, at times of pityriasiform type, were frequent.87 In another family, the 3 members affected were born as collidion babies and developed intense erythroderma, generalized desquamation, and palmoplantar keratoderma.62

In 2003, the ABCA12 gene was reported to be responsible for some cases of LI and was mapped to chromosome 2q34.4 It was subsequently confirmed that mutations in this gene were also responsible for HI.2,3ABCA12 encodes 53 exons, and belongs to a family of ABC transporters, which bind adenosine triphosphate while also facilitating the transport of several molecules across the cell membrane.90 The members of the ABCA subfamily are all implicated in lipid transport.91 Deficient ABCA12 function causes lipid transport disorders in lamellar bodies and so lead to a decrease in intercellular lipid levels in the stratum corneum.3Ultrastructural studies have shown that ABCA12 is located in lamellar bodies associated with glycosylceramides.91ABCA12 mutations have been associated with disorders in the distribution and transport of glycosylceramides and with decreased levels of hydroxyceramides, one of the main components in the lipid barrier in the intercellular spaces.3,6,92,93 The massive hyperkeratosis that occurs in these patients could be a compensatory response to a deficient lipid barrier.94 It might also be due to the lack of desquamation of the corneocytes,93 which could be caused by defects in the transport of certain proteases, such as callicrein 5 and cathepsin D, resulting from disorders in the lamellar bodies.95 Murine models and in vitro studies suggest that ABCA12 mutations also have an effect on epidermal differentiation.95–97

To date, more than 50 mutations have been reported in the ABCA12 gene in patients with ARCI from Africa, Europe, Pakistan, and Japan. The most frequent mutations are p.Val244SerfsTer28,2,98,99 identified in Pakistani and Indian populations, and p.Asn1380Ser,4 identified in African families. In both case, these may be founding mutations.

The extent of the ABCA12 mutations is related to phenotype, with mutations associated with complete loss of function leading to the HI phenotype.2,3,98–102 By contrast, in LI and CIE, most mutations are missense, and have a less severe effect on protein function.4–6,103 The mutations underlying the LI phenotype seem to be concentrated in the first adenosine triphosphate binding cassette region.4 Clinically, patients with CIE and mutations in the ABCA12 gene have medium-size scales that are somewhat larger than those usually observed in patients with this phenotype.

Although collodion baby affects the whole body, cases confined to the acral regions have been reported. In 1952, Finlay et al.120 reported a case of collodion membrane that affected only the hands and feet and that followed a self-healing course. Recently, a new case of acral SHCB has been reported in association with mutations of the TGM1 gene.8 It is not known why these lesions are restricted to acral regions, although factors associated with site-dependent regulation of enzyme activity may be in operation.8

The primary aim of treatment in ichthyosis is to eliminate scaling and reduce xerosis without causing excessive irritation (Table 3). Before deciding on treatment, aspects such as age and sex of the patient, type and severity of the disease, and extent and site of the lesions should be taken into consideration.128

Daily bathing is recommended for patients with ARCI to mechanically eliminate scales and traces of moisturizer. This is easier if the patient is immersed in water for 15 to 30minutes. Some authors recommend adding sodium bicarbonate to the bath to denaturalize the keratins and make the water alkaline, and so facilitate elimination of the scales.129 Other products that can be added include wheat starch, corn starch, or rice starch. Bathing oils are not appropriate as they may lead to occlusion with subsequent risk of bacterial proliferation and worsening of thermoregulation.

Moisturizers and topical keratolytic agents are usually the first therapeutic option. They improve skin barrier function and facilitate desquamation. Mild local adverse effects, such as transient pruritus, irritation, or stinging sensation may occur.

Sodium chloride, urea, vitamin E acetate, glycerol, and petroleum jelly can be used as moisturizers and lubricants. In patients with thick scaling and marked hyperkeratosis, 1 or more keratolytic agents, such as α-hydroxy acids (lactic and glycolic acid),130 salicylic acid, N-acetylcystein,131–133 urea (>5%),134 and propylene glycol, can be added. Modulators of keratinocyte differentiation are also used. These include topical retinoids (tretinoin, adapalene, tazarotene),135,136 calcipotriol,137 and dexpanthenol.Topical retinoids often cause irritation and small, very painful fissures.137 Moreover, there is a risk of absorption and teratogenicity in fertile women if they are used too extensively.138 To enhance the effectiveness of keratolytics and moisturizers, occlusive dressing may be applied in specific areas refractory to treatment.139 An additive or synergistic effect can also be attained by combining 2 or more keratolytic agents or moisturizers.140–142 Treatment should be optimized for each individual, given the highly variable nature of the condition and skin sensitivity and differences in response to each treatment. The optimization process can be helped by treating one side of the body differently to the other to enable comparisons. 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. In addition, the risk of percutaneous absorption of topical products such as urea, salicylic acid, and lactic acid is greater.143–145

Oral retinoids have keratolytic effects that help eliminate scales and prevent excessive hyperkeratosis. Both isotretinoin and aromatic retinoids (acitretin and etretinate) have proved effective in the treatment of ARCIs.128,146,147 Acitretin at a dose of 0.5 to 1mg/kg/d is the most widely used drug, especially in patients with LI.148 Patients with CIE may have a more complete response and at lower doses.

The main adverse effects are mucocutaneous disorders, teratogenicity, musculoskeletal disorders, and abnormal lipid profile and transaminase elevation.149–152 With regards to teratogenicity, in the case of etretinate and acitretin, the drugs should be avoided during pregnancy and patients should avoid becoming pregnant for 3 years after discontinuation of treatment.151 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.128

Treatment monitoring should include a laboratory work-up with a liver function test and lipid profile before starting treatment, then at 1 month and every 3 months after starting treatment. In fertile women, 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 (in the case of acitretin). When prolonged treatment is required with retinoids, growth and bone development should be monitored. Some authors suggest performing a bone study before treatment followed by a yearly examination.151 Recent guidelines do not recommend performing routine radiography because of the possible harmful effects.152 Instead, selective radiographic studies are recommended in patients who have atypical bone pain.152

An alternative to systemic retinoid treatment is the use of drugs known as retinoic acid metabolism blocking agents, which increase the endogenous levels of retinoic acid. One such drug is liarozole, which has been granted orphan status for the treatment of LI, CIE, and HI by the European Medicines Agency and the US Food and Drug Administration.153–155 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.154

In patients with ectropion, the application of artificial tears and eye lubricants and moisturizing the skin of the face and the cheeks in particular can reduce palpebral retraction. Surgical correction is a valid option in severe cases, but this usually has to be repeated a few years later. Hydrotherapy may be beneficial.156 Patients should be advised to avoid strenuous physical activity when the ambient temperature is high, given that hypohidrosis carries with it the risk of heat stroke and convulsions. Oral retinoids can improve thermoregulation.157 Physiotherapy is important for preventing flexion contracture, particularly in the case of HI. Regular cleansing of the external auditory canal by an ear-throat-nose specialist can prevent scales from accumulating and so prevent hearing loss.