Stapes Ankylosis With Broad Thumbs And Toes

A number sign (#) is used with this entry because of evidence that stapes ankylosis with broad thumbs and toes is caused by heterozygous mutation in the NOG gene (602991) on chromosome 17q22.

Mutations in the NOG gene can also cause symphalangism and synostosis syndromes.

Clinical Features

Teunissen and Cremers (1990) reported a family with 5 males in 3 generations who were affected with what appeared to be a 'new' autosomal dominant syndrome. There were several instances of male-to-male transmission. All 5 patients had ankylosis of stapes, hyperopia, broad thumbs, broad first toes, and syndactyly. In most, stapedial ankylosis was bilateral, leading to a 40 to 60 dB conductive hearing loss. There was bilateral syndactyly of the second and third toe in at least 1. Fused cervical vertebrae were seen in 2 of the 5 patients. Carpal and tarsal fusion and symphalangism were not found.

Milunsky et al. (1999) described a family with a syndrome that the authors considered to be the same as the autosomal dominant syndrome described by Teunissen and Cremers (1990). A mother and daughter had stapes ankylosis, hyperopia, and short broad thumbs; hyperopia and short broad thumbs were present in the mother's generation and in the mother's brother and their mother. Their paternal grandfather had short broad thumbs. Neither the mother nor the daughter had symphalangism, however, possibly distinguishing this syndrome from the proximal symphalangism syndrome (SYM1; 185800) and from the facioaudiosymphalangism syndrome described by Hilhorst-Hofstee et al. (1997). The mother and daughter did have cylindrical noses and hypoplasia of the alae nasi.

Hirshoren et al. (2008) reported a 22-year-old woman of Jewish Ashkenazi origin with bilateral stapes ankylosis, hyperopia, broad thumbs, symphalangism of the second, fourth, and fifth fingers, cutaneous syndactyly of the second and third fingers, hypoplastic nails of the second, fourth, and fifth fingers, and shortened second and fifth fingers; she could not reach her ears to use a hearing aid due to limited elbow pronation/supination and flexion, and mobility of her hips and knees was limited as well. The proband also had bilateral small 'feathery' opacities of the lens, primarily in the cortical regions. Her father had a more severe phenotype, with hypoplastic nails and brachytelephalangia of multiple fingers and toes. Pedigree analysis revealed 7 family members with hearing loss and skeletal anomalies segregating in an autosomal dominant fashion. Hirshoren et al. (2008) stated that the constellation of findings in the proband best fitted a diagnosis of Teunissen-Cremers syndrome, although she had brachydactyly type B (see BDB2, 611377) and symphalangism (see SYNS1, 186500).

Molecular Genetics

Brown et al. (2002) identified heterozygous mutations in the NOG gene (602991.0001-602991.0002) in 2 families with autosomal dominant stapes ankylosis with broad thumbs and toes, hyperopia, and skeletal anomalies but without symphalangism. The first family, of Italian descent, had conductive hearing loss that was inherited as an autosomal dominant with complete penetrance. Each affected individual was thought to have had nonsyndromic otosclerosis. The second family was that reported by Milunsky et al. (1999).

In a 22-year-old woman of Jewish Ashkenazi origin diagnosed with Teunissen-Cremers syndrome, Hirshoren et al. (2008) identified a missense mutation in the NOG gene (602991.0012) that had previously been found in patients with proximal symphalangism (185800) and brachydactyly, type B2 (611377). The authors noted that although the proband's lens opacities had not previously been reported in Teunissen-Cremers syndrome, the noggin/BMP pathway had been shown to play an important role in the chick and mouse ocular development (see Trousse et al. (2001) and Furuta and Hogan (1998), respectively).