It is the most common form of ichthyosis in northern European populations, with a prevalence of 1 in 80 in English patient cohorts.10 IV is characterized, in most cases, by a relatively late presentation, a few months after birth. Patients exhibit a fine, whitish scaling, and, although it is most prominent on the extensor surface of the extremities, it is not uncommon for the entire body surface to be affected. Occasionally, patients have larger, lighter brown scales on the extensor areas of the extremities, especially the lower ones. Another characteristic feature of IV is palmar hyperlinearity, a finding known as filaggrin palm11 (Fig. 2). Palmoplantar keratoderma is a much less common finding.12 Additionally, many patients suffer from itching, and scratching leads to very expressive whitish linear lesions. Although IV is frequently associated with atopic dermatitis, only half of the patients with this inflammatory disease associate pathogenic variants in FLG.13 IV is caused by semi-dominant pathogenic variants in FLG14—a gene encoding the filaggrin protein—the major protein inside corneocytes. Of note, there are 2 more rarer forms of ichthyosis that also affect filaggrin metabolism, caused by recessive pathogenic variants in CASP1415 and dominant pathogenic variants in ASPRV1.16 While the first form exhibits a phenotype similar to IV, the second one, exceptionally, exhibits a phenotype similar to lamellar ichthyosis—see below—but with palmar hyperlinearity and no collodion membrane at birth.16

Figure 2.

Ichthyosis vulgaris. Palmar hyperlinearity (filaggrin palms) in a patient with a pathogenic variant in FLG.

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RXLI affects only men (with a prevalence of 1 in 5000)17 as it is caused by deletions of the steroid sulfatase gene (STS), located in a distal region of the short arm of the X chromosome that does not undergo inactivation.18 Although women are carriers of the disease and transmit it, they only manifest it in the rare cases in which the gene deletion occurs in both chromosomes.19 RXLI is characterized by the presence of dark brown polygonal scales on the extensor surfaces of the extremities (Fig. 3). Although the size of the scales is variable, they tend to be larger on the extensor surfaces of the lower extremities. Involvement of the flexures is variable and probably depends on the severity of desquamation being present in the most clinically expressive subjects. Desquamation affects the scalp, neck, and retroauricular region, giving a false appearance of insufficient hygiene to some of these patients. Palms and soles are usually spared. As with IV, many patients with RXLI are born with a normal skin and manifest the disease after the first few months of life, yet they still some have some sort of presentation at birth similar to yet much milder than a collodion membrane. The deficit in STS function prevents desulfation of cholesterol sulfate in the epidermis, hindering adequate desquamation of the horny layer. It also prevents desulfation of dehydroepiandrosterone sulfate, hindering cervical maturation during labor, causing prolonged second stage of labor in carrier women, which can help confirm clinical suspicion.20 Although RXLI is considered a non-syndromic ichthyosis, 30%-40% of patients present with attention deficit hyperactivity disorder, so it is very likely that some steroid metabolized by the STS enzyme plays a role as a neurotransmitter.21

Figure 3.

X-linked recessive ichthyosis. Typical dark polygonal scaling on the lower extremity.

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IV and RXLI may have a similar appearance in the more symptomatic IV cases. Family history screening—involvement of maternal grandfather or mother's siblings—normal appearance of palms and soles and sparing of flexures in most patients with RXLI may help differentiate the 2 entities. The confluence of pathogenic variants in FLG and STS in some patients may significantly increase the expressiveness of desquamation in RXLI patients and facilitate association of palmoplantar hyperlinearity.22

ARCI alludes to its inheritance pattern, has a very low prevalence, estimated to be between 7.2 and 16.2 affected per 106 inhabitants both in Spain23 and other regions.24,25 Unlike ichthyoses in the previous group, ARCIs debut at birth. The most typical form of presentation is called collodion baby, which is characterized by a shiny and smooth transparent glue-like membrane that covers the entire body and, in most severe cases, causes ectropion (eversion of the eyelids) and eclabium (eversion of the lips). The collodion membrane is shed within the first few weeks of life, progressing into a phenotypic presentation of variable severity, with varying degrees of erythema and different desquamation morphology. Accordingly, 5 different clinical forms are distinguished and detailed below. In cases where no collodion membrane is seen, neonates present with erythroderma and varying degrees of hyperkeratosis and desquamation. In most cases, the affected genes are involved in the metabolism of ceramides,8 a lipid component of the intercellular matrix that prevents transepidermal water loss (Fig. 4) (Table 3). Although there is no exact geno-phenotypic correlation, patients with pathogenic variants in TGM1 associate alopecia, ectropion, and neonatal presentation as a collodion baby with a significantly higher frequency than the other genes.8

Figure 4.

Ceramide synthesis pathway in the epidermis. These reactions involve the union of a sphingoid base (blue) and a fatty acid (green) to form acylceramide, which can be released as a free lipid (yellow) or bound to proteins (orange). Mutations in the genes depicted cause non-syndromic (black) or syndromic (red) ichthyosis.

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Source: Modified from “Ichthyosis,” C. Gutiérrez-Cerrajero et al.9

According to the current classification of ichthyoses,8 there are 5 clinical forms of ARCI, including:

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  Lamellar ichthyosis: characterized by a moderate-to-severe degree of erythema and desquamation in large lamellae of somewhat darker tone than the patient's skin, i.e. light brown in light phototypes and dark brown in darker phototypes. Although this large sheet-like desquamation affects the entire body, it is more evident on the lower extremities and the frontal region of the face (Fig. 5). Many patients also present ectropion and a thick adherent scalp desquamation that may precede an almost total cicatricial alopecia.26 Palmoplantar involvement also presents a laminar aspect, with areas of diffuse thickening and a smooth surface (Fig. 6). Alterations in nail morphology are not a rare finding, such as incurvation of the nail plate, linear areas of leukonychia and increased extension of the lunula.

  
  

  Figure 5.

  Autosomal recessive congenital ichthyosis. Lamellar desquamation in a patient with the dark phototype TGM1 variant.

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  Figure 6.

  Autosomal recessive congenital ichthyosis. Plantar involvement in a patient with a TGM1 variant. The surface is thickened, smooth, shiny, and occasionally fissured.

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  Congenital ichthyosiform erythroderma: together with lamellar ichthyosis, it is a classic phenotype of ARCI. Patients present with erythroderma of variable intensity and generalized desquamation with smaller scales than in the lamellar forms (Fig. 7). The scalp is usually less thick and adherent than in the lamellar forms. Characteristically, patients exhibit skin thickening of the dorsum of the hands and feet and a relative loss of elasticity of the skin of the fingers that determines a certain retraction of the fingers and a phenomenon of pseudoleukonychia when stretching them since cutaneous bed is exsanguinated (Fig. 8). Additionally, many patients also present a true leukonychia of probable post-inflammatory origin. Palmoplantar involvement determines a thickening of the palms and soles of leather-like appearance without true hyperkeratosis (Fig. 9). Many patients also exhibit, additionally, a striking facial reddening of the cheeks regardless of the severity of involvement of the rest of the body surface.

  
  

  Figure 7.

  Autosomal recessive congenital ichthyosis. Fine scaling and moderate erythroderma are observed in a patient with an ABCA12 variant, demonstrating the phenotypic variability of this genetic variant.

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  Figure 8.

  Autosomal recessive congenital ichthyosis. Patient with a pathogenic variant in TGM1. Pseudoleukonychia. Note how the loss of elasticity of the skin of the hands causes the nail bed to become vascularized when the patient attempts to stretch his fingers.

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  Figure 9.

  ARCI. Palmar involvement in a patient with a variant in the ALOX12B gene. Note the thickened, shiny, and scaly appearance of the palm without the yellowish hue seen in other palmar keratodermas.

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  Harlequin ichthyosis is the severe form of ARCI. It is so named because infants are born with rigid, thickened skin with extensive and deep linear fissures reminiscent of harlequin costumes. The rigidity of the skin integument is such that it restricts respiratory movements and sucking ability, endangering the child's life. Similarly, patients exhibit severe ectropion, eclabium, and severe limitation of the mobility of the fingers, which are enclosed by the corneous shell. This phenotype progresses weeks later to a severe form of congenital ichthyosiform erythroderma which, among other, associates symptoms, alopecia of the scalp, eyebrows and eyelashes, ectropion, anomalies of the auricular pavilions, joint deformities, and permanent mobility limitations27 (Fig. 10). It is due to recessive pathogenic variants that cause complete loss of function of ABCA12,27 with slightly less severe phenotypes in patients with 2 different heterozygous pathogenic variants.28

  
  

  Figure 10.

  ARCI. Patient with harlequin ichthyosis due to a pathogenic variant in the ABCA12 gene presenting with severe auricle deformity and scarring alopecia on the scalp.

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  Self-improving collodion baby: this is a clinical variant in which the collodion membrane progresses, regardless of its severity, to a mild ARCI phenotype. Although the expressivity of ichthyosis is very faint in some areas such as the trunk and proximal extremities, patients usually present with facial erythema, skin thickening on elbows, knees, and dorsum of hands and feet (Fig. 11), as well as palmoplantar thickening similar in appearance to that described in congenital ichthyosiform erythroderma. Phenotypic progression to self-improving forms is not predictable, which makes prognostic information of collodion infants within the first few days of life difficult to obtain. In fact, it is due to recessive pathogenic variants in ALOX12B,29ALOXE3,30CYP4F2231 or TGM1,32 genes that can also determine a much more important clinical involvement and therefore even an immediate molecular diagnosis cannot predict progression.

  
  

  Figure 11.

  ARCI. Thickening of the skin on the back of the hands in a patient with self-improving ichthyosis due to the TGM1 variant. The trunk and the rest of the upper extremities appear almost normal.

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  Acral self-improving collodion baby is an exceptional clinical form in which the collodion membrane only affects the distal part of the extremities. It is due to recessive pathogenic variants in TGM1.33

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  Bathing suit ichthyosis is an ARCI variant in which patients are born with a collodion membrane and progress to a lamellar ichthyosis phenotype of variable expressivity that only affects the trunk and scalp. It is an exceptional form initially described in the North African population34 and it is due to recessive pathogenic variants in TGM135 that generate a thermosensitive protein that loses activity in warmer areas of the body.

They receive the name keratinopathic ichthyoses because they are caused by pathogenic variants in genes encoding keratins, have a very low prevalence, estimated at 1.1 per million.24 Different clinical forms are distinguished according to the inheritance pattern and phenotypic features.

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  Autosomal dominant keratinopathic ichthyosis: the most common form of keratinopathic ichthyosis. Its main characteristic is intercellular separation, which is why it is also called epidermolytic ichthyosis. Patients are born with erythroderma, blisters, and erosions so extensive that differential diagnosis with epidermolysis bullosa can be difficult to establish. As the weeks go by, patients suffer from less erosions and a diffuse hyperkeratosis grows, which will eventually become more accentuated on the flexor surfaces of the large folds and, later, on elbows and knees. Patients exhibit throughout their lives a variable degree of erythema and skin fragility that makes them prone to erosions with minimal trauma (Fig. 12). This group of ichthyoses is caused by dominant variants in KRT136 or KRT10.36 Those caused by variants in KRT1 commonly present palmoplantar keratoderma (Fig. 13), usually absent in those associated with pathogenic variants in KRT10, since in palmoplantar skin KRT9 can partially rescue the phenotype of a loss of KRT10.36

  
  

  Figure 12.

  Epidermolytic keratinopathic ichthyosis due to a pathogenic variant in the KRT10 gene. Generalized involvement is observed with extensive areas of thickening in the upper and lower extremities and areas of skin fragility in the pretibial and lateral regions of the feet. The involvement stops at the palmoplantar border and spares the palms and soles.

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  Figure 13.

  Epidermolytic keratinopathic ichthyosis due to a pathogenic variant in the KRT1 gene. Diffuse palmar thickening and involvement of the lower extremity are observed, with evident areas of cutaneous fragility.

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  Autosomal recessive keratinopathic ichthyosis: clinically very similar to the above. It is caused by pathogenic recessive variants in KRT10.37 Its prevalence is much lower than the dominant forms.

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  Annular keratinopathic ichthyosis: a special subtype in which patients are born with an appearance similar to that of other keratinopathic ichthyoses, but subsequently progress to a less severe clinical form in which. In addition to diffuse hyperkeratosis at the level of the large folds, transient annular lesions with superficial desquamation are observed38 (Fig. 14). It is caused by dominant pathogenic variants in KRT139 or KRT10.40

  
  

  Figure 14.

  Annular epidermolytic keratinopathic ichthyosis due to a variant in the KRT10 gene. An annular lesion with superficial peripheral desquamation typical of certain KRT10 variants that result in this peculiar clinical form is observed.

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  Superficial keratinopathic ichthyosis shows a milder phenotype than the 2 previous ones and does not present erythroderma at birth. It is characterized by mild-to-moderate diffuse hyperkeratosis showing predilection for articular surfaces. There may be focal detachment of the hyperkeratosis, a phenomenon called “mauserung” or “molting” in the international literature (Fig. 15). It is caused by dominant pathogenic variants in KRT2.41 This keratin is expressed in superficial layers of the stratum corneum and probably for this reason the clinical manifestation and the phenomena of epidermolysis and focal detachment of hyperkeratosis are less expressive vs cases related to pathogenic variants in KRT1 and KRT10.

  
  

  Figure 15.

  Superficial epidermolytic keratinopathic ichthyosis due to a KRT2 variant, where patchy superficial detachment of the epidermis (“flaking”) is observed.

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  Mosaic keratinopathic ichthyoses are characterized by hyperkeratotic lesions of Blaschkoid distribution whose extent is variable, ranging from a few centimeters (epidermolytic nevus) to hemicorporal, uni or bilateral involvement. They are due to postzygotic pathogenic variants in KRT1,42KRT10,43 or KRT2,44 in which the disease-causing mutation only affects some epidermal progenitors. The area of affected skin varies depending on the timing of mutation, the earlier the mutation occurs, the more extensive it is. In cases where the mosaic affects the gonads, the disease can be transmitted to the patient's children as generalized keratinopathic ichthyosis.

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  Keratinopathic ichthyosis with reversion patches (in confetti): a particular type of non-epidermolytic keratinopathic ichthyosis in which there is no epidermolysis and therefore the typical histological findings of intercellular separation are not observed. Clinically, patients present with severe ichthyosiform erythroderma and variable palmoplantar involvement. At school age, small lenticular areas of healthy skin begin to be observed on the trunk, which increase in number and size with age (Fig. 16). Patients may also present ectropion, scalp alopecia, nail changes, hypertrichosis, and abnormal gait, among other symptoms.45 It is caused by dominant variants in KRT1046 or, much less frequently, in KRT1, whose reversions appear in adulthood.47 Healthy skin patches are caused by loss of heterozygosity of the mutated allele due to mitotic recombination events whose triggering factor is unknown, but is thought to be related to aberrant import of mutated keratins to the nucleus.45

  
  

  Figure 16.

  Non-epidermolytic keratinopathic ichthyosis with reverse mosaicism due to KRT10 variant. Note the lenticular lesions resembling normal skin on the anterior trunk.

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  Other non-syndromic ichthyoses are shown in Table 3. Although they are very rare, some have prominent clinical data that may facilitate diagnosis, such as superficial desquamation and underlying erythema in peeling skin syndromes (Fig. 17) or cribriform keratoderma produced by loricrin variants (Fig. 18).

  
  

  Figure 17.

  Skin exfoliation syndrome due to a pathogenetic variant in CDSN. The patient presents with diffuse erythema with patchy areas of superficial exfoliation.

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  Figure 18.

  Loricrin keratoderma. Diffuse plantar involvement in an affected individual, showing small, cribriform depressions.

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