Ichthyosis, Congenital, Autosomal Recessive 5

A number sign (#) is used with this entry because of evidence that autosomal recessive congenital ichthyosis-5 (ARCI5) can be caused by homozygous mutation in the CYP4F22 gene (611495) on chromosome 19p13.

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

Virolainen et al. (2000) reported a Finnish family in which all affected members displayed a nonlamellar, nonerythrodermic ichthyosis phenotype not directly resembling either classic lamellar ichthyosiform or classic erythrodermic congenital ichthyosiform erythroderma. Scales in the skin were fine and white, and neither erythroderma nor ectropion were present. Scaling was more prominent in the knees, ankles, and ears. Palms and soles appeared to be hyperlinear (excessively creased). Three patients were born as collodion babies, whereas 2 others were ichthyotic at birth. On histologic examination, the granular layer was present in all patients, excluding clear-cut ichthyosis vulgaris (146700). The family originated from a Finnish subisolate, the archipelago of Larsmo on the coast of Ostrobothnia.

Lefevre et al. (2006) studied 12 consanguineous families with autosomal recessive congenital ichthyosis (ARCI). All families originated from Mediterranean countries, including 9 from Algeria, 1 from France, 1 from Italy, and 1 from Lebanon. Most patients were not born as collodion babies, but presented with erythrodermal skin. After birth they developed whitish, grayish scaling in the periumbilical region, lower part of the body, and buttocks. Hyperlinearity of the palms and soles similar to that found in ichthyosis vulgaris was observed in all patients, and all had scales on the scalp, which sometimes had a squamous pityriasiform appearance. Light microscopy of skin biopsies revealed typical histopathologic features of ichthyosis, including hyperkeratosis or more extensive orthokeratosis, mild thickening of the stratum corneum and moderate acanthosis and parakeratosis. A normal or slightly prominent granular layer and a mild dermal perivascular lymphocytic infiltrate with dilation of dermal capillaries were observed.

Lugassy et al. (2008) reported a large consanguineous Israeli Druze family in which 4 affected individuals were born with collodion membrane and subsequently displayed severe erythroderma, generalized scaling, and palmoplantar keratoderma. The disease course was complicated in most cases by multiple episodes of sepsis and hypernatremic dehydration, as well as 1 instance of transient acute renal failure.

Mapping

In a genomewide scan of large consanguineous families of different origins with ARCI of the lamellar form, Fischer et al. (2000) identified a locus on chromosome 19 in 6 families, obtaining a maximum multipoint lod score of 11.25 at D19S566. Homozygosity was demonstrated by haplotype analysis for a considerable number of microsatellite markers from the pericentric region of chromosome 19p12-q12.

Virolainen et al. (2000) performed a genomewide scan, with 370 highly polymorphic microsatellite markers, on 5 affected individuals from a Finnish family with nonlamellar, nonerythrodermic ARCI. The only evidence for linkage emerged from markers in a 6.0-cM region on 19p13.2-p13.1. The maximum 2-point lod score was 7.33 with locus D19S252, and a multipoint likelihood calculation gave a maximum location score of 5.2. The affected individuals shared 2 compound core haplotypes, suggesting compound heterozygosity. Virolainen et al. (2000) stated that this was the first locus for a nonlamellar, nonerythrodermic form of ARCI.

By linkage analysis of 12 consanguineous Mediterranean families with lamellar ARCI, Lefevre et al. (2006) mapped the disease locus to a 3.06-Mb interval on chromosome 19 (lod = 15.83 at D19S930, theta = 0.0). They noted that their interval was nearly identical to a 3.5-Mb interval identified by Virolainen et al. (2000) in a large Finnish family with a nonlamellar, nonerythrodermic form of ARCI.

Using microsatellite marker panels spanning the major ARCI chromosomal loci to type DNA samples from members of a large consanguineous Israeli Druze family with ARCI, Lugassy et al. (2008) identified a homozygous haplotype at the 19p13 locus in all 4 affected individuals.

Molecular Genetics

In 12 consanguineous Mediterranean families with lamellar ARCI, Lefevre et al. (2006) identified 7 different mutations in the CYP4F22 gene (see, e.g., 611495.0001-611495.0004).

In 4 affected individuals from a large consanguineous Israeli Druze family with ARCI, Lugassy et al. (2008) identified homozygosity for a nonsense mutation in the CYP4F22 gene (W521X; 611495.0005).