Keratitis-Ichthyosis-Deafness Syndrome, Autosomal Dominant
In 6 unrelated sporadic patients with keratitis-ichthyosis-deafness syndrome (KIDAD; 148210) and in 1 family with vertical transmission of KID, Richard et al. (2002) identified a 148G-A transition in the GJB2 gene, resulting in an asp50-to-asn (D50N) substitution. This mutation occurred in the highly conserved first extracellular loop of CX26, which is crucial for voltage gating and connexon-connexon interactions. The presence of this mutation in 7 unrelated probands of varying ethnic origins but not in any unaffected parents or sibs strongly suggested to Richard et al. (2002) that D50N arose de novo in each family and is a common mutation in KID.
Alvarez et al. (2003) found the same mutation in a sporadic case of KID syndrome in Spain.
Janecke et al. (2005) identified the D50N mutation in heterozygous state in 3 Austrian patients with KID syndrome and remarked on the variable phenotype. Two of the cases were mother and daughter. The mother had 'eczema' since the age of 6 weeks. Mild to moderate bilateral sensorineural hearing loss was diagnosed at 5 years of age. Photophobia due to keratitis became apparent at 24 years of age. Recurrent corneal epithelial erosions and ulcerations as well as trichiatic lashes resulted in corneal scarring and vascularization with moderate visual loss. She developed sensory neuropathy of the fingers and hands that was attributed to the hyperkeratosis and also had recurrent axillary and anal fistula. The 13-year-old daughter was known to have 'eczema' since the first weeks of life and episodes of cutaneous candida infections. She had diffuse hyperkeratosis mostly affecting the extremities and the external ears. Mild to moderate bilateral sensorineural hearing loss was diagnosed at 4 years of age. Ophthalmologic examination at age 13 years was unremarkable. She had normal growth and psychomotor development. The third patient had the D50N mutation on a de novo basis. Transient cardiomyopathy and persistent ductus arteriosus were diagnosed in the neonatal period. Profound sensorineural hearing loss was diagnosed at 6 months of age. At that time, sparse and depigmented hair, as well as photophobia, were apparent. Palmoplantar hyperkeratosis and joint contractures of the elbows and ankles were noted at 2 years of age. From the age of 5 years, severe involvement of cornea occurred, with reduction of visual acuity to finger counting by age 12 years. By that age hearing loss had progressed to right-sided deafness, and contractures as well as decreased sensibility due to hyperkeratotic plaques affected most joints. Janecke et al. (2005) pointed out the strikingly wide variation in severity of the phenotype associated with the D50N mutation as an indication of the influence of genetic background. The mutation was not present in more than 500 individuals who were screened for recessive deafness mutations or in 96 healthy controls of Austrian origin.
Nyquist et al. (2007) identified heterozygosity for the D50N mutation in a 32-year-old African American woman with KID syndrome, severe hidradenitis of the groin, and dissecting cellulitis of the scalp. She developed moderately differentiated squamous cell carcinoma in the area of the hidradenitis at 28 years of age, and 3 years later was found to have a primary malignant proliferating pilar tumor of the scalp, with metastases in 3 of 25 lymph nodes examined.
Titeux et al. (2009) reported a Portuguese boy with KID syndrome who was heterozygous for the D50N mutation. The mutation was 'barely detectable' in DNA from a lesional skin biopsy from his mother, who had segmental manifestations of disease, with bilateral hyperkeratotic hyperpigmented linear cutaneous lesions on the chest, shoulders, and back along Blaschko lines. Allele-specific amplification showed a difference in signal intensity between the proband and his mother, consistent with maternal mosaicism for the mutation.
Hystrix-like Ichthyosis with Deafness
Van Geel et al. (2002) identified the D50N mutation in a patient with hystrix-like ichthyosis-deafness (HID) syndrome (602540).
