Ichthyosis, Congenital, Autosomal Recessive 8

A number sign (#) is used with this entry because of evidence that this late-onset form of autosomal recessive congenital ichthyosis (ARCI8) can be caused by homozygous mutation in the LIPN gene (613924) on chromosome 10q23.

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

Clinical Features

Israeli et al. (2011) studied a consanguineous Arab Muslim pedigree in which the index patient, whose skin appeared normal at birth, developed widespread ichthyosis at 5 years of age. At 14 years of age, the entire surface of her skin was covered with fine whitish scales, whereas her face was slightly erythematous. Photographs of her legs demonstrated 'diffuse lamellar ichthyosis.' Skin biopsy revealed hyperkeratosis and acanthosis without epidermolytic changes or intracytoplasmic vacuoles. Six additional family members were similarly affected, including a brother, paternal aunt and uncle, and 3 cousins. Her first-cousin parents and 3 sibs were unaffected.

Mapping

In a consanguineous Arab Muslim pedigree segregating an autosomal recessive late-onset autosomal recessive congenital ichthyosis of the lamellar type, Israeli et al. (2011) performed homozygosity mapping and identified 5 regions of homozygosity greater than 2 Mb in size. Fine mapping using microsatellite typing suggested linkage to chromosome 10q23 and excluded all other candidate loci. Recombination events narrowed the critical region to a 10.8-Mb interval bound by markers D10S1174 and D10S520.

Molecular Genetics

In a consanguineous Arab Muslim pedigree with late-onset ARCI of the lamellar type mapping to chromosome 10q23, Israeli et al. (2011) sequenced 28 candidate genes and identified homozygosity for a 2-bp deletion in the LIPN gene (613924.0001) that segregated with disease in the family.