Keratitis-Ichthyosis-Deafness Syndrome, Autosomal Dominant

A number sign (#) is used with this entry because autosomal dominant KID syndrome is caused by heterozygous mutation in the connexin-26 gene (GJB2; 121011) on chromosome 13q.

Vohwinkel syndrome (124500) is an allelic disorder involving congenital deafness with keratopachydermia and constrictions of fingers and toes. Another similar disorder caused by mutation in GJB2 is palmoplantar keratoderma with deafness (148350).

See 242150 for a possible autosomal recessive form of KID syndrome.

Clinical Features

Grob et al. (1987) described KID syndrome in a father and daughter. In the father the disorder was complicated by fatal skin cancer. A second instance of familial occurrence was described by Nazzaro et al. (1990) in a mother and daughter. The mother had progressive corneal opacification that required repeated bilateral corneal grafts, which were unsuccessful. Langer et al. (1990) reported 3 patients who had the characteristic hyperkeratotic skin lesions and neurosensory hearing defects. Two had ophthalmologic manifestations.

Corneal epithelial defects, scarring, and neovascularization ('keratitis') cause progressive decline of visual acuity and may eventually lead to blindness. Congenital sensorineural hearing loss is generally severe and bilateral, although unilateral or moderate hearing impairment has been observed (Szymko-Bennett et al., 2002). Increased susceptibility to mucocutaneous infections is common and sometimes fatal in the neonatal period. Squamous cell carcinoma of the skin and oral mucosa is a rare but serious complication that can shorten life expectancy.

Messmer et al. (2005) described the ocular manifestations in 3 patients with molecularly confirmed KID syndrome. The manifestations included loss of eyebrows and lashes, thickened and keratinized eyelids, trichiasis, recurrent corneal epithelial defects, superficial and deep corneal stromal vascularization with scarring, keratoconjunctivitis sicca, and in 1 patient, limbal insufficiency. Visual acuity ranged from normal to severe visual loss.

Nyquist et al. (2007) described 2 young adults with KID syndrome who developed malignant proliferating pilar tumors of the scalp. The first was a 32-year-old African American woman who had progressive, severe hidradenitis of the groin and dissecting cellulitis of the scalp, both recalcitrant to aggressive treatment with antibiotics and isotretinoin. Moderately differentiated squamous cell carcinoma was found in the area of the hidradenitis at 28 years of age and treated with surgical resection and adjuvant radiation and chemotherapy. Three years later, she underwent resection of a primary malignant proliferating pilar tumor of the scalp, with metastases found in 3 of 25 lymph nodes examined. The second patient was a 24-year-old man of mixed Japanese and African American background who developed an ulcerated scalp nodule at age 19 that appeared to be squamous cell carcinoma on biopsy. Histopathologic examination of multiple enlarging scalp nodules that developed over the next 6 months revealed a spectrum of disease from pilar cysts to proliferating pilar tumors, with some areas showing fully transformed malignant changes with an infiltrating pattern of growth. The patient continued to develop multiple masses of the scalp, which were treated with intralesional methotrexate, but he ultimately required subtotal full-thickness scalp resection; he later developed metastases to the lungs and the base of the skull and cavernous sinus, and despite whole brain radiation and systemic chemotherapy, died of his disease.

Nomenclature

Skinner et al. (1981) proposed that the term KID syndrome be used for an entity that falls under the general heading of congenital ectodermal defects.

Inheritance

Richard et al. (2002) confirmed autosomal dominant inheritance of a form of KID syndrome.

Langer et al. (1990) suggested spontaneous mutation as the basis of the disorder. Wilson et al. (1991) presented evidence for an autosomal dominant form of the KID syndrome as well as a recessive form (242150) that is associated with progressive cirrhosis and mental retardation. It seems likely that the patient of Senter et al. (1978) had the autosomal dominant form of the disease, whereas the patient reported by Desmons et al. (1971) had the recessive form. A low incidence of affected sibs in reported cases and 2 sibships of 9 with only 1 affected member (Beare et al., 1972; Cram et al., 1979) support the existence of a dominant form. Familial occurrence was reported by Grob et al. (1987), Nazzaro et al. (1990), and Kone-Paut et al. (1998), among others.

Sbidian et al. (2010) reported an African family in which the lethal form of KID syndrome occurred in 2 dizygotic twins and in their brother, all of whom carried the G45E mutation in the GJB2 gene (121011.0033). The father was completely unaffected, whereas the mother showed palmoplantar keratoderma. Neither parent carried the mutation in the blood, and the mutation was absent from a skin biopsy from the mother, suggesting germline mosaicism. The 3 sibs inherited the same maternal GJB2 allele, which was also found prenatally in a fourth affected sib.

Diagnosis

Prenatal Diagnosis

Sbidian et al. (2010) reported prenatal diagnosis of the lethal form of KID syndrome by chorionic villus biopsy with detection of the G45E mutation in the GJB2 gene in a family with recurrence of the disorder in 3 older sibs. The 3 older sibs presented at birth with dysmorphic features, including scaphocephaly, asymmetrical ears, almond-shaped eyes, short nose and philtrum, anteverted nostrils, thin upper lip, hypertrophic gums, short and large fingers, and single palmar crease. All had ichthyosiform erythrodermal skin, painful bathing-trunk pachydermia, palmoplantar keratoderma, dystrophic nails, complete atrichia with keratosis pilaris, and congenital absence of the foreskin. One patient also had edema and dyskeratotic laryngeal mucosa. All showed failure to thrive, suggesting a digestive disorder. Skin biopsies from 2 patients showed compact orthokeratotic hyperkeratosis associated with epidermal hyperplasia and acanthosis, with decreased or absent granular layer. In 1 patient, biopsy showed acanthosis and swollen keratinocytes. All died of infection by age 5 months.

Population Genetics

Caceres-Rios et al. (1996) stated that approximately 70 cases, most of them sporadic, had been reported.

Molecular Genetics

Van Steensel et al. (2002) reported the detection of a connexin-26 mutation in a patient with sporadic KID syndrome. They sequenced connexin genes that are known or expected to be involved in skin disorders sometimes accompanied by deafness: GJB2, GJB6 (604418), GJB3 (603324), GJB5 (604493), GJB4 (605425), and GJA4 (121012). An asp50-to-asn mutation in connexin-26 (D50N; 121011.0020), the only mutation found, was not present in either parent or in 164 control chromosomes, suggesting that is not a polymorphism.

Richard et al. (2002) provided compelling evidence that KID is caused by heterozygous missense mutations in the connexin-26 gene. In each of 10 patients with this syndrome, they identified a point mutation leading to substitution of conserved residues in the cytoplasmic amino terminus or first extracellular domain of CX26. One of these mutations was detected in 6 unrelated sporadic case subjects and also segregated in 1 family with vertical transmission of KID (121011.0020). This result indicated the presence of a common, recurrent mutation and established its autosomal dominant nature. They found that mutant CX26 was incapable of inducing intercellular coupling in vitro, which indicated its functional impairment. Decreased host defense and increased carcinogenic potential in KID illustrated that gap junction communication plays not only a crucial role in epithelial homeostasis and differentiation but also in immune response and epidermal carcinogenesis.

Sonoda et al. (2004) reported the ocular findings, clinical course, and treatment regimen for 2 Japanese patients with KID syndrome. One patient was found to have an asp50-to-tyr mutation in the GJB2 gene (D50Y; 121011.0027); the other had no pathologic mutation in the GJB2 gene.

A fatal course of KID syndrome in the first year of life, due to severe infections of the skin lesions and septicemia, was reported in at least 5 patients (Gilliam and Williams, 2002). In 3 Austrian patients with KID syndrome, Janecke et al. (2005) identified the D50N mutation in the GJB2 gene. In an Austrian patient with the fatal form of KID syndrome, they identified a gly45-to-glu mutation in the GJB2 gene (G45E; 121011.0033) and a common polymorphism in the GJB3 gene (a 798C-T transition). Janecke et al. (2005) noted that the G45E mutation had not previously been reported in Caucasian patients; however, it was the third most common GJB2 mutation in Japanese patients with autosomal recessive nonsyndromic hearing loss, occurring 16% of disease alleles (Ohtsuka et al., 2003). Janecke et al. (2005) stated that their findings suggested different modes of action of the same GJB2 mutation that are dependent on genetic background and that this hypothesis was substantiated by their observation of a variable clinical course in patients harboring the D50N mutation.

Nyquist et al. (2007) analyzed the GJB2 gene in 2 young adults with KID syndrome who developed malignant proliferating pilar tumors of the scalp and identified heterozygosity for the common D50N mutation in a 32-year-old African American woman. In a 24-year-old man of mixed Japanese and African American background, they identified homozygosity for a glu114-to-gly change and heterozygosity for a val27-to-ile change in the GJB2 gene, both of which are known polymorphisms in Asian individuals; no mutation was found in the GJB3, GJB4, GJB5, or GJB6 genes.

Titeux et al. (2009) reported a Portuguese boy with KID syndrome who was heterozygous for the known D50N mutation in the GJB2 gene (121011.0020). His mother, who had bilateral hyperkeratotic hyperpigmented linear cutaneous lesions on the chest, shoulders, and back along Blaschko lines, consistent with type 1 segmental manifestations (see 113800 and Happle, 1997), was found to be mosaic for the mutation. The boy also had nystagmus, generalized hypotonia, and spastic tetraparesia, and MRI revealed hypoplasia of the cerebellar vermis; Titeux et al. (2009) stated that cerebellar and neuromuscular defects had been reported previously in only a few cases of KID syndrome (Caceres-Rios et al., 1996).