Ichthyosis, Congenital, Autosomal Recessive 10

A number sign (#) is used with this entry because of evidence that autosomal recessive congenital ichthyosis-10 (ARCI10) is caused by homozygous or compound heterozygous mutation in the PNPLA1 gene (612121) on chromosome 6p21.

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

Grall et al. (2012) studied 6 affected individuals from 2 families segregating autosomal recessive congenital ichthyosis-10. All were born as collodion babies and later developed generalized ichthyosis, with mild to moderate fine grayish-white scales and moderate erythroderma and palmoplantar keratoderma. Histopathology of affected skin presented a thicker cornified layer, pronounced desquamation of upper loosely packed scales, and hypergranulosis with increased amounts of keratohyalin. Conspicuous regularly spaced small holes were visible in the granular layer. Electron microscopy showed more than 40 layers of cornified lamellae, consisting partly of loose content but otherwise mostly homogeneous, with some lipid droplets, membrane structures, and increased amounts of melanosomal remnants but only a few remnants of cholesterol crystals. In the transition to the living epidermal layers, there were many transit cells and numerous vesicular structures within the cells of the granular layer, corresponding to the holes observed by light microscopy.

Fachal et al. (2014) reported 3 members of a consanguineous Galician family (family 13) with ARCI10. The proband was a 39-year-old woman who was born as a collodion baby. Her skin had generalized small white scales, with underlying erythroderma and palmoplantar hyperlinearity but without keratoderma. Her nails were not affected. She had mild facial lesions and thick adherent scales on the scalp, but no eclabium, ectropion, or alopecia. The patient complained of severe heat intolerance. She had 2 affected brothers.

Ahmad et al. (2016) reported 3 consanguineous Pakistani families segregating ARCI10. Affected members shared the common characteristic features of generalized fine, dry, dark brown scaling of the body with abnormal sweating and hyperthermia. They had mild erythroderma and hyperkeratosis. Ectropion, eclabium, and alopecia were not observed.

Boyden et al. (2017) reported 14 families with ARCI10. The phenotypes were highly variable, even among patients with the same PNPLA1 mutations. Seven of 19 patients presented with a collodion membrane at birth, and 8 showed generalized erythema and scaling. Mature phenotypes included a fine or plate-lake scale, and erythema ranged from minimal to severe. The presence and degree of ectropion and palmoplantar keratoderma were variable but were absent or mild in most patients.

Molecular Genetics

From a cohort of 46 consanguineous ARCI families that had undergone genomewide linkage analysis and in which no causative mutation had been found in genes known to have a role in ARCI, Grall et al. (2012) selected 10 families in which affected individuals showed a homozygous haplotype in the 6p21 region containing the candidate gene PNPLA1. Sequencing identified 2 distinct PNPLA1 mutations in 2 of the families: 3 affected sibs from an Algerian family were homozygous for a nonsense mutation (E131X; 612121.0001), and 3 affected children from a Moroccan family were homozygous for a missense mutation (A59V; 612121.0002). The mutations segregated with disease in each family and were not found in a panel of 384 control DNA samples.

In affected members of a Galician family (family 13) with ARCI, Fachal et al. (2014) identified homozygosity for a missense mutation (A34T; 612121.0003) in the PNPLA1 gene. The mutation was found by sequencing of the PNPLA1 gene after mutation in 5 other candidate genes had been excluded. The mutation segregated with the disorder in the family.

By exome and Sanger sequencing in 3 consanguineous families segregating ARCI linked to chromosome 6p22-p21, Ahmad et al. (2016) identified homozygosity for a missense mutation (D34E; 612121.0004) in the PNPLA1 gene. The mutation segregated with the phenotype in each family and was not found in the ExAC database, in 94 unrelated Pakistani control samples, or in 215 in-house exome sequences from unrelated Pakistani control individuals.

Using multiplex targeted next-generation sequencing of 42 genes known to cause disorders of keratinization or whole-exome sequencing in 732 kindreds with ichthyosis, Boyden et al. (2017) identified 14 unrelated probands who were compound heterozygous or homozygous for mutations in the PNPLA1 gene. The mutations segregated with disease in all of the kindreds, of which 5 were consanguineous. Affected members of 2 families with presumably autosomal dominant inheritance, one of which was previously reported by Toribio et al. (1986) as having autosomal dominant inheritance, were found to have compound heterozygous or homozygous mutations in the PNPLA1 gene (see 612121.0003 and 612121.0005-612121.0006). A total of 16 different PNPLA1 mutations were found, including 2 that result in early termination, 1 splice-site mutation, and 13 missense substitutions at conserved residues. All missense mutations were within the more highly conserved N-terminal portion of the protein, and all but 2 were within the patatin domain. Two of the missense mutations were distal to the patatin domain, suggesting that residues outside the canonical enzymatic region may be important to protein function.

Animal Model

In golden retriever dogs with hereditary nonepidermolytic retention ichthyosis, Grall et al. (2012) identified homozygosity for a truncating mutation within the highly conserved C-terminal region of PNPLA1. Histopathology showed compact orthokeratotic epidermal hyperkeratosis composed of many layers of completely keratinized epidermal cells and pronounced acanthosis in the epidermis. Cytoplasmic vacuolic structures were visible on semi-thin sections in keratinocytes from the subgranular layers. Ultrastructural analysis showed regular groups of electron-lucent polyclonal clefts within lamellae of the cornified layer, corresponding to remnants of cholesterol crystals. In keratinocytes of the granular layer, irregular accumulations of abnormal membranous and vesicular material were seen, suggesting a degenerative process of intracellular membrane trafficking. These areas corresponded to the perinuclear vacuolic regions observed with hematoxylin-eosin staining.