Deafness, Congenital, With Onychodystrophy, Autosomal Dominant

A number sign (#) is used with this entry because of evidence that autosomal dominant congenital deafness with onychodystrophy (DDOD) is caused by heterozygous mutation in the ATP6V1B2 gene (606939) on chromosome 8p21.

Description

The DDOD syndrome is characterized by autosomal dominant inheritance of congenital deafness and onychodystrophy. Conical, hypoplastic teeth is also a feature (Robinson et al., 1962).

See also DOOR syndrome (220500), an autosomal recessive disorder, which includes congenital deafness, onychodystrophy, osteodystrophy, and mental retardation.

Clinical Features

Robinson et al. (1962) presented the pedigree of 17 persons in 3 generations with 5 affected. The propositus was a 15-year-old girl with fissured small dystrophic nails, coniform teeth with selective tooth agenesis, and syndactylism of the toes of the right foot with union of the first and second toes, and the third with the fourth toe. She had severe sensorineural hearing loss and had attended a school for the deaf. One brother was normal while another brother and a sister and their mother had similar nail and dental defects. All affected members had a high frequency hearing loss together with a 70 db low frequency loss in the propositus. The maternal grandmother of the propositus was thought to have a similar syndrome but was not available for study. The authors found elevation of electrolyte concentrations in sweat, suggesting this was a characteristic hidrotic form of ectodermal dysplasia with delayed primary and secondary dentition, misshapen and missing teeth, and dystrophic small nails. The hidrotic nature of the ectodermal dysplasia distinguishes this condition from that described under deafness with anhidrotic ectodermal dysplasia (125050).

Goodman et al. (1969) observed a mother and son with sensorineural deafness and onychodystrophy. The mother's right thumb was triphalangic, and the left thumb was biphalangic with a rudimentary third phalanx that appeared to be fused with the middle phalanx.

Moghadam and Statten (1972) observed triphalangeal thumbs with hypoplastic terminal phalanges, absent or hypoplastic fingernails, and deafness in mother and son of Filipino extraction. The authors noted that Feinmesser and Zelig (1961) reported 2 sisters with congenital deafness and onychodystrophy. However, the parents were consanguineous, suggesting autosomal recessive inheritance. Despite autosomal recessive inheritance, James et al. (2007) concluded that the family of Feinmesser and Zelig (1961) did not have DOOR syndrome since they lacked mental retardation.

Kondoh et al. (1999) reported a girl, her mother, and her maternal grandfather with DDOD syndrome. The proband, an infant, had congenital hearing loss and hypoplastic nails or absence of nails. The mother was noted to have sensorineural deafness at age 1 year, had no toenails, hypoplastic fingernails, and coniform or small permanent teeth. The maternal grandfather had congenital deafness, conical teeth with oligodontia, and dystrophic nails. His mother was reportedly similarly affected. Kondoh et al. (1999) noted the similarities to the family reported by Robinson et al. (1962). White and Fahey (2011) suggested that the family reported by Robinson et al. (1962) may have had a distinct disorder with oligodontia as a feature.

White and Fahey (2011) reported a 3-generation family in which 3 individuals had DDOD. The proband was a 28-year-old man with profound sensorineural hearing loss and abnormal hands and feet. He had mild brachydactyly of the hands, finger-like thumbs that were not triphalangeal, and small and dysplastic nails of the thumbs and fifth fingers; the fingertips of these digits were bulbous. The feet showed hypoplastic nails on both great toes and absent nails on the second to fifth toes. Hand radiographs showed a short distal phalanx of the fifth digits, and foot radiographs showed absence of the terminal phalanx of toes two through five and a pyramidal-shaped distal phalanx of the great toes. He had some mild facial features, including deep-set eyes with mild hypotelorism and midface hypoplasia. The remainder of the examination was normal with no abnormalities of skin, teeth, or hair. The patient's father reportedly had deafness and a similar appearance of the hands and feet. One of the proband's daughters, who died suddenly at age 2 months, had sensorineural deafness, absent nails on the thumbs and fifth fingers with bulbous fingertips, and hypoplastic or absent toenails. She also had cutis aplasia on the vertex of the scalp.

Yuan et al. (2014) studied 3 unrelated Chinese probands who had been diagnosed with congenital deafness and onychodystrophy. All 3 were reported to display an identical phenotype, including severe congenital sensorineural hearing loss, absence of nails, and aplasia of the middle phalanx of the fifth finger. None had inner ear malformation or intellectual disability; successful language rehabilitation following unilateral cochlear implantation confirmed their normal mental development. The clinical information reported for these 3 patients was limited, and medical history was obtained by questionnaire.

Menendez et al. (2017) studied a 12-year-old Guatemalan boy who at birth was noted to have bilateral digital anomalies of the hands and feet. Audiologic testing at age 1 year revealed profound bilateral sensorineural hearing impairment. Examination at age 12 years showed high forehead with dolichocephaly, bilateral triphalangeal thumbs without nails, hypoplastic fingernails on the second through fifth digits, and flat feet with absent toenails. He did not exhibit gingival hyperplasia, hypertrichosis, organomegaly, or joint hyperextensibility. His parents and 2 sibs were healthy. (Tekin (2017) noted that figure 2 in the article by Menendez et al. (2017) incorrectly indicates that the Guatemalan family was consanguineous.)

Inheritance

The transmission pattern of DDOD syndrome in the families reported by Robinson et al. (1962), Kondoh et al. (1999), and White and Fahey (2011) was consistent with autosomal dominant inheritance.

Molecular Genetics

By whole-exome sequencing in 2 unrelated Chinese pedigrees with congenital deafness, anonychia, and aplasia of the middle phalanx of the fifth finger, Yuan et al. (2014) identified heterozygosity for the same de novo nonsense mutation in the ATP6V1B2 gene (R506X; 606939.0001) in both probands. Sanger sequencing of ATP6V1B2 in a third Chinese DDOD family revealed a de novo R506X mutation in that proband as well. The mutation, which segregated with disease in all 3 families, was not found in 1,053 ethnically matched controls with normal hearing.

By whole-exome sequencing in a 12-year-old Guatemalan boy with DDOD, Menendez et al. (2017) identified heterozygosity for the R506X mutation in ATP6V1B2. The mutation was not found in his unaffected parents or sibs; it appeared to have arisen de novo, although paternity testing was not performed.