Ichthyosis, Congenital, Autosomal Recessive 4a

A number sign (#) is used with this entry because of evidence that autosomal recessive congenital ichthyosis-4A (ARCI4A) is caused by homozygous or compound heterozygous mutation in the ABCA12 gene (607800) on chromosome 2q35.

Mutation in the ABCA12 gene can also cause a severe, often-fatal form of congenital ichthyosis, so-called harlequin ichthyosis (ARCI4B; 242500).

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 general phenotypic description and discussion of genetic heterogeneity of autosomal recessive congenital ichthyosis, see ARCI1 (242300).

Clinical Features

Parmentier et al. (1996) studied 8 affected individuals from 3 consanguineous Moroccan families with congenital ichthyosis. All patients fulfilled diagnostic criteria for the lamellar form of ichthyosis: collodion baby phenotype at birth, generalized ichthyosis with involvement of the large folds, palmoplantar keratoderma, and absence of skin erythema. No major phenotypic differences were found between the families, although mild variability was observed within families regarding the extent of scaling and the consequent mechanical ectropion. None of the patients displayed extracutaneous manifestations such as spastic paraplegia, neuritis, or hepatosplenomegaly, which may occur in ichthyosis-associated disorders such as Sjogren-Larsson syndrome (270200), Refsum syndrome (266500), and Dorfman-Chanarin syndrome (275630).

Mapping

By genomewide linkage analysis with polymorphic microsatellite markers in 3 consanguineous Moroccan families with congenital ichthyosis, Parmentier et al. (1996) obtained a maximum 2-point lod score of 7.60 at theta = 0 with D2S137 on chromosome 2q33-q35.

Parmentier et al. (1999) presented a physical map that encompassed the ICR2B locus, including the mapping of new microsatellite markers. Based on this new map, genotyping 4 additional families from Morocco and Algeria with autosomal recessive congenital ichthyosis highly suggested a reduction in size of the candidate interval. The final interval was covered by a single YAC which was 2.2 Mb long.

Molecular Genetics

Lefevre et al. (2003) studied 9 families with ARCI mapping to chromosome 2q33-q35, including 2 Moroccan families originally studied by Parmentier et al. (1996) and 2 Moroccan and 2 Algerian families previously studied by Parmentier et al. (1999), as well as 2 more families from Algeria and 1 from Mali. Analysis of the candidate gene ABCA12 revealed homozygosity or compound heterozygosity for 5 different missense mutations (607800.0001-607800.0005). All of the patients were born as collodion babies, and all presented generalized lamellar ichthyosis with large adherent dark pigmented scales, with ectropion and palmoplantar keratoderma, except for 1 patient with a milder form of ichthyosis who also exhibited nail involvement (607800.0005). None of the patients presented erythema or syndromic features.

Genotype/Phenotype Correlations

Akiyama (2010) reviewed mutations in the ABCA12 gene and stated that a total of 56 mutations had been reported in 66 ARCI families, including 48 with harlequin ichthyosis (HI), 10 with lamellar ichthyosis (LI), and 8 with ichthyosis of the congenital ichthyosiform erythroderma (CIE) type. Most of the mutations in HI patients were truncating mutations, and homozygosity or compound heterozygosity for truncating mutations in ABCA12 always resulted in the HI phenotype. In CIE families, at least 1 mutation on each allele was typically a missense mutation, and combinations of missense mutations in the first ATP-binding cassette of ABCA12 caused the LI phenotype.