Ichthyosis, Congenital, Autosomal Recessive 11

A number sign (#) is used with this entry because of evidence that autosomal recessive congenital ichthyosis-11 (ARCI11) is caused by homozygous mutation in the ST14 gene (606797), which encodes type II transmembrane serine protease matriptase, on chromosome 11q24.

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 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

Lestringant et al. (1998) reported the cases of 5 Emirati sibs (3 girls and 2 boys), aged 4 to 18 years, with normal stature, diffuse congenital ichthyosis, patchy follicular atrophoderma, generalized and diffuse nonscarring hypotrichosis, and marked hypohidrosis. Ichthyosis was present at birth; there were no babies collodion babies. The scaling was diffuse and involved the great flexures and scalp, but spared the face, elbows, knees, hands, and feet. The follicular atrophoderma, also present at birth, involved pronounced follicular pitting on the dorsal aspects of the wrists, hands, and first phalanges of the fingers. In all patients, there were ill-defined pits on facial skin, giving a vermiculate or 'orange peel' appearance. On the dorsum of the wrists and around the elbows and knees there was a zone where ichthyosis progressively transformed into follicular atrophoderma. Sweating was assessed only clinically, with very few droplets present in the eyebrows and on the nose. Steroid sulfatase activity was normal. Electron microscopic studies of ichthyotic skin showed no specific abnormality. The first-cousin parents were of Bedouin ancestry and had normal stature, normal sweating, and no skin or hair lesions. Lestringant et al. (1998) noted that follicular atrophoderma, which is a rare anomaly observed mainly as a feature of the X-linked dominant form of chondrodysplasia punctata (302960) and in the X-linked dominant Bazex syndrome (301845), had not previously been reported in association with diffuse ichthyosis; they concluded that the disorder in this family represented a new autosomal recessive genodermatosis.

Tursen et al. (2002) reported an isolated case, a 17-year-old Turkish girl from a consanguineous family who exhibited ichthyosis, hypotrichosis, and follicular atrophoderma. Ichthyosis was present at birth, and she had almost no scalp hair until 4 months of age; she stated that her scalp hair had improved and straightened with age. Examination revealed diffuse ichthyosiform scaling sparing the major flexures and face; the ichthyotic skin was hypohidrotic, but the axillae, palms, and soles sweated normally. Follicular atrophoderma was observed on the backs of her hands. She had diffuse and patchy nonscarring hypotrichosis with a receding anterior hairline. Her hair, which the authors characterized as 'woolly,' was light brown, coarse, curly, and unruly, in contrast to the straight black hair of family members. Eyelashes and particularly eyebrows were sparse. Hair microscopy was normal apart from curling, and skin biopsy of ichthyotic skin showed orthokeratosis with focal hypogranulosis; electron microscopy showed normal tonofilaments. There was no family history of similar skin problems; her parents and paternal grandparents were first cousins.

Basel-Vanagaite et al. (2007) described a consanguineous Israeli Arab family with autosomal recessive ichthyosis with hypotrichosis. Among the offspring of first-cousin parents, 3 sibs were affected and 5 unaffected. Ichthyosis and abnormal hair were present at birth. Two of the affected sibs had a vernix-like layer covering the entire body, which was progressively shed during the first month of life. Hypotrichosis was generalized and diffuse. Scaling was diffuse, including on the scalp, but the face was unaffected. The hair of all patients appeared curly, sparse, fragile, brittle, dry, and lusterless, and showed slow growth. Light microscopy and scanning electron microscopy of hair obtained from affected sibs disclosed a number of abnormalities, including dysplastic hair, pili torti, pili bifurcati, and central pili mono-bifurcati. Over time, scalp hair growth and appearance improved, and the scalp hair darkened with age. Follicular atrophoderma was not seen and sweating was normal. All 3 affected sibs had photophobia and 1 had corneal opacities. Another had pingueculum from 11 years of age. In addition, 2 of the 3 affected sibs had abnormal dentition, with notching/pitting in 1 and conical primary teeth in the other. Four of the 8 sibs had Hirschsprung disease; however, only 1 of these 4 had ichthyosis.

Avrahami et al. (2008) reported a 2.5-year-old Turkish girl with congenital ichthyosis, light brown, curly, sparse hair, and generalized hypotrichosis with sparse body hair, eyebrows, and eyelashes. She did not have photophobia or corneal opacities, but did have blepharitis. Her nails, teeth, and sweating were normal. The phenotype of this patient closely resembled that of the family reported by Basel-Vanagaite et al. (2007), but was less severe.

Alef et al. (2009) restudied the Emirati Bedouin family originally reported by Lestringant et al. (1998), noting that the hypotrichosis appeared to improve with age. At the time of first examination, the younger sibs had sparse, unruly, and lusterless hair on the scalp, with bald patches and a receding anterior hairline, whereas the 2 oldest sibs had nearly normal scalp hair with only a receding hairline. Similarly, eyebrows that were at first wiry and limited to the most medial part, progressively straightened and extended outward, and eyelashes, initially sparse and limited to the upper eyelids, progressively grew on the lower lids. Facial and body hair were absent in the 3 younger sibs, whereas the 2 oldest had exhibited some lip and armpit hair. Examination 8 years after initial presentation in the 2 affected brothers showed fully developed pingueculum and photophobia in the 19-year-old, who also had normal-appearing scalp hair, whereas the 22-year-old had marked photophobia and corneal opacities, and had developed ichthyosis in place of prior follicular atrophoderma on the dorsum of his right hand and his knees. Histopathology of skin biopsies from 1 of the Emirati Bedouin patients and from the Turkish woman originally reported by Tursen et al. (2002) showed an epidermis of normal thickness with regular differentiation of keratinocytes in the spinous layer. The granular layer was thinned, and the stratum corneum showed orthohyperkeratosis. The hair follicle epithelium was thinned, and hair infundibulum showed hyperkeratosis and a very thin stratum granulosum. Electron microscopy confirmed the very thin stratum granulosum, and the lower lamellae of the stratum corneum appeared only loosely connected laterally and contained deposits that appeared to be lamellar bodies. Alef et al. (2009) noted that the ultrastructural findings were similar in patients from both families.

Mapping

By homozygosity mapping in a consanguineous Israeli Arab family segregating autosomal recessive congenital ichthyosis with hypotrichosis, Basel-Vanagaite et al. (2007) mapped the disorder to chromosome 11q24.3-q25, in a region containing 22 known or predicted genes.

Alef et al. (2009) performed genomewide microsatellite analysis in 5 affected and 3 unaffected sibs from a large Emirati Bedouin pedigree with ichthyosis, follicular atrophoderma, and hypotrichosis, originally described by Lestringant et al. (1998), and obtained maximum 2-point lod scores of 3.6 and 3.4 at D11S910 and D2S1363, respectively. Analysis of a Turkish pedigree with a similar phenotype, previously reported by Tursen et al. (2002), was only compatible with linkage to the region on chromosome 11. Refined mapping confirmed the locus with a combined lod score of 4.0 at D11S4131 and D11S910. Haplotype analysis defined an approximately 10.9-cM (4.1-Mb) candidate interval on chromosome 11q24, between markers D11S4150 and M11TA01.

Molecular Genetics

By sequencing candidate genes in a consanguineous Israeli Arab family with autosomal recessive congenital ichthyosis with hypotrichosis mapping to chromosome 11q24.3-q25, Basel-Vanagaite et al. (2007) identified homozygosity for a missense mutation in the ST14 gene (G827R; 606797.0001) that segregated with disease and was not found in 434 Arab control chromosomes.

In a 2.5-year-old Turkish girl with ARCI and hypotrichosis, Avrahami et al. (2008) identified a homozygous mutation in the ST14 gene (M1I; 606797.0002).

In a large Emirati Bedouin pedigree and a Turkish woman with ARCI, hypotrichosis, and follicular atrophoderma mapping to chromosome 11q24, originally described by Lestringant et al. (1998) and Tursen et al. (2002), respectively, Alef et al. (2009) analyzed the candidate gene ST14 and identified homozygosity for a splice site mutation (606797.0003) and a 1-bp deletion (606797.0004).