Ichthyosis, Congenital, Autosomal Recessive 2

A number sign (#) is used with this entry because of evidence that autosomal recessive congenital ichthyosis-2 (ARCI2) is caused by homozygous or compound heterozygous mutation in the ALOX12B gene (603741) on chromosome 17p13.

Description

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders of keratinization characterized primarily by abnormal skin scaling over the whole body. These disorders are limited to skin, with approximately two-thirds of patients presenting severe symptoms. The main skin phenotypes are lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur (summary by Fischer, 2009). Neither histopathologic findings nor ultrastructural features clearly distinguish between NCIE and LI. In addition, mutations in several genes have been shown to cause both lamellar and nonbullous ichthyosiform erythrodermal phenotypes (Akiyama et al., 2003). At the First Ichthyosis Consensus Conference in Soreze in 2009, the term 'autosomal recessive congenital ichthyosis' (ARCI) was designated to encompass LI, NCIE, and harlequin ichthyosis (ARCI4B; 242500) (Oji et al., 2010).

NCIE is characterized by prominent erythroderma and fine white, superficial, semiadherent scales. Most patients present with collodion membrane at birth and have palmoplantar keratoderma, often with painful fissures, digital contractures, and loss of pulp volume. In half of the cases, a nail dystrophy including ridging, subungual hyperkeratosis, or hypoplasia has been described. Ectropion, eclabium, scalp involvement, and loss of eyebrows and lashes seem to be more frequent in NCIE than in lamellar ichthyosis (summary by Fischer et al., 2000). In LI, the scales are large, adherent, dark, and pigmented with no skin erythema. Overlapping phenotypes may depend on the age of the patient and the region of the body. The terminal differentiation of the epidermis is perturbed in both forms, leading to a reduced barrier function and defects of lipid composition in the stratum corneum (summary by Lefevre et al., 2006).

In later life, the skin in ARCI may have scales that cover the entire body surface, including the flexural folds, and the scales are highly variable in size and color. Erythema may be very mild and almost invisible. Some affected persons exhibit scarring alopecia, and many have secondary anhidrosis (summary by Eckl et al., 2005).

For a discussion of genetic heterogeneity of autosomal recessive congenital ichthyosis, see ARCI1 (242300).

Clinical Features

Jobard et al. (2002) studied 6 consanguineous families (3 Turkish, 2 North African, 1 French) with congenital ichthyosis mapping to chromosome 17p. All affected individuals were born as collodion babies, and all had features consistent with nonbullous ichthyosiform erythroderma. A 3-year-old boy from 1 of the Turkish families presented mild ichthyosiform erythroderma, with fine white desquamation over the entire body and palmoplantar keratoderma. A 12-year-old girl from an unrelated Turkish family had fine white scaling on her face, neck, trunk, and flexor surfaces, but larger and darker polygonal scales on the buttocks and extensor surfaces of her arms and legs. She also had an ectropion, an eclabium, severe palmoplantar keratoderma, mild diffuse alopecia, and thin nails.

Self-Healing Collodion Baby

Harting et al. (2008) reported 2 male infants born with collodion membrane who had dramatic improvement of the skin in the first few weeks of life and then developed very mild nonbullous congenital ichthyosiform erythroderma. The first was a Hispanic boy who was born with a hyperkeratotic, fissured, and tight parchment-like membrane, as well as bilateral ectropion, eclabium and fixed open mouth, and low-set dysplastic ears. He had hypoplastic fingers, toes, and nails, and his movements were reduced due to tight skin over his extremities. At day 3 of life, application of topical emollients resulted in dramatic improvement, and at 8 weeks of age, his skin was completely normal except for minimal residual erythema and scant fine white scales on his trunk and extremities; at 3 months, only a small pink plaque was visible on his back with minimal scale. Histologic examination of the collodion membrane showed nonspecific findings typical of many forms of ichthyosis: a thickened stratum corneum with hyperkeratosis, acanthosis, and mild hypergranulosis. Electron microscopy revealed a cornified cell envelope like that seen in harlequin ichthyosis (HI; see 242500), suggesting that cornified cell envelope is not a specific diagnostic feature of HI. The other boy had a thick glossy encasement with areas of fissuring and associated eclabium; the membrane was shed by 2 weeks of age, leaving behind mildly xerotic but mostly normal-appearing skin. Later in infancy, he developed a fine, generalized, mild scaling consistent with an extremely mild NCIE with pruritic areas of erythema and scaling accentuated in flexural creases consistent with atopic eczema, and he also manifested hyperlinear palms and infraorbital folds.

Vahlquist et al. (2010) studied 11 Swedish and 4 Danish patients with autosomal recessive congenital ichthyosis of the 'self-healing' type, all of whom were born with a variably thick collodion membrane, with ectropion present in 8 cases. The membrane was spontaneously shed after 2 to 4 weeks, exposing almost normal-appearing skin. Examination at 2 years to 37 years of age, however, revealed that all of the patients had varying degrees of mild ichthyosis, consisting of scaling in the armpits, acral hyperkeratosis and keratoderma, coarse scales on the scalp, and fine scaling around the neck, together with xerotic extremities and red cheeks that stung with exposure to salt water. All but 1 of the patients exhibited moderate to severe anhidrosis. Vahlquist et al. (2010) proposed the term 'self-improving collodion ichthyosis' (SICI) as a better designation for this phenotype.

Mapping

In 56 consanguineous families with congenital ichthyosis in which all known ARCI loci except chromosome 17p13.1 had been excluded, Jobard et al. (2002) analyzed 6 microsatellites and identified 6 kindreds from the Mediterranean basin with linkage to 17p13.1. Further genotyping in those 6 families revealed a homozygous interval between D17S960 and D17S1858 in all patients. The maximum pairwise lod score (theta = 0) for the marker D17S1844 was 6.63 and the multipoint lod score at the same locus was 10.04. Linkage disequilibrium analysis reduced the interval size to approximately 600 kb between D17S1812 and D17S1805, a segment containing 2 genes from the LOX family, ALOX12B (603741) and ALOXE3 (607206).

Molecular Genetics

In affected individuals from 3 consanguineous families with congenital ichthyosis mapping to chromosome 17p13.1, one of North African origin and 2 of Turkish origin, Jobard et al. (2002) identified homozygosity for a 1-bp deletion and 2 missense mutations in the ALOX12B gene (603741.0001-603741.0003). In another 3 families with ARCI mapping to 17p13.1 (ARCI3; 606545), they identified homozygosity for mutations in the ALOXE3 gene (607206). Jobard et al. (2002) hypothesized that the product of 1 of these enzymes might be the substrate of the other, and thus function in the same metabolic pathway. Yu et al. (2003) demonstrated that ALOXE3 functions as an epoxy alcohol synthase using the product of ALOX12B as the preferred substrate. providing strong biochemical evidence for functional linkage of the ALOX12B and ALOXE3 proteins. The 2 genes are coexpressed in tissues, and mutation in either can cause ichthyosis, indicating a functional relationship.

Eckl et al. (2005) analyzed the ALOX12B and ALOXE3 genes in 143 families of Indo-European and Arab origins with autosomal recessive congenital ichthyosis that were negative for mutation in the TGM1 gene (190195), and identified 11 different point mutations in the ALOX12B gene (see, e.g., 603741.0004-603741.0006) and 5 in the ALOXE3 gene (see, e.g., 607206.0002 and 607206.0004-607206.0006) in 17 families. All of the mutations cosegregated with disease in the respective families, and none was found in 150 ethnically matched controls. Eckl et al. (2005) concluded that approximately 10% of ARCI patients carry mutations in one of the LOX genes.

Lesueur et al. (2007) analyzed the ALOX12B and ALOXE3 genes in 20 patients from 11 families with ARCI mapping to chromosome 17p13, and identified homozygosity or compound heterozygosity for mutations in the ALOX12B gene in 6 families, including a Turkish patient who exhibited a lamellar phenotype (603471.0007). No disease-causing mutations were identified in patients from 5 families, in whom the candidate gene ALOX15B (603697) was analyzed as well, indicating that other genes on chromosome 17p13 may be involved in this disease.

In 2 infants who had ARCI consisting of self-healing collodion membrane followed by mild nonbullous congenital ichthyosiform erythroderma, who were both negative for mutation in the TGM1 gene, Harting et al. (2008) identified compound heterozygosity for mutations in the ALOX12B gene (603741.0008-603741.0011).

In 15 Scandinavian patients with ARCI of the self-healing collodion baby type, Vahlquist et al. (2010) analyzed 7 ARCI-related genes and identified homozygosity or compound heterozygosity for mutations in the ALOX12B gene in 8 patients (see, e.g., 603741.0012 and 603741.0013), in the ALOXE3 gene in 3 patients (see, e.g., 607206.0008), and in the TGM1 gene in 1 patient. No mutations were identified in the 3 remaining patients.

Genetic Heterogeneity

Eckl et al. (2009) studied 250 unrelated patients representing the entire phenotypic spectrum of ARCI, including 15 patients from families previously studied by Eckl et al. (2005), and found that mutations in TGM1 accounted for 38% of the cases, whereas mutations in the ALOX12B (603741) and ALOXE3 (607206) genes each represented 6.8% of the cases.

Genotype/Phenotype Correlations

Eckl et al. (2005) performed detailed clinical characterization of affected individuals from 17 ARCI families with mutations in the ALOX12B or ALOXE3 genes and concluded that LOX mutations lead to typical but mild ARCI phenotypes, with fine white scales and moderate erythema. Most patients were born with collodion membranes. Palmoplantar keratoderma was a rare finding, and was only mild when present. Eckl et al. (2005) noted that the self-healing course can also be associated with LOX mutations, and there was improvement of ichthyosis in early childhood in some cases.

Eckl et al. (2009) assessed in detail 21 ARCI patients from 19 families in whom mutations in ALOX12B and ALOXE3 had been found, including some of the families previously studied by Eckl et al. (2005). Neonates born with collodion membrane often showed a mild to moderate manifestation compared with other types of congenital ichthyosis. Ectropion or eclabium, mostly mild, was only present in one-third of cases. Children and adults showed a generalized scaling with mild to moderate erythema; scales were mostly whitish to light brown, discrete to moderate in adherence, and small in size. More than half of the patients (13 of 19) showed a striking palmoplantar hyperlinearity with or without mild keratoderma. In contrast to ichthyosis vulgaris (146700), patients showed a mild keratotic lichenification that also included the elbow or popliteal fossa and the dorsa of the extremities. Heat intolerance because of reduced sweating ability (hypohidrosis) was present in almost all patients. Eckl et al. (2009) noted that erythema was significantly more pronounced in patients with ALOX12B mutations than in those with ALOXE3 mutations. In addition, all ALOX12B patients showed mild hyperkeratosis of palms and soles with accentuated palmoplantar creases, whereas keratoderma was absent in 9 of 12 patients with ALOXE3 mutations, and the other 3 patients showed only very discrete palmar or plantar keratosis.