In the classification of the brachydactylies, the analysis by Bell (1951) proved highly useful. The type A brachydactylies of Bell have the shortening confined mainly to the middle phalanges. In the A1 type, the middle phalanges of all ... In the classification of the brachydactylies, the analysis by Bell (1951) proved highly useful. The type A brachydactylies of Bell have the shortening confined mainly to the middle phalanges. In the A1 type, the middle phalanges of all the digits are rudimentary or fused with the terminal phalanges. The proximal phalanges of the thumbs and big toes are short. - Genetic Heterogeneity of Brachydactyly Type A1 Another locus for this phenotype, designated BDA1B (607004), has been mapped to chromosome 5. A third form of BDA1, BDA1C (615072), is caused by mutation in the GDF5 gene (601146) on chromosome 20q11.
This trait has the distinction of being the first in man to be interpreted in mendelian dominant terms, by Farabee (1903). Haws and McKusick (1963) followed up on Farabee's family. The subjects were short of stature. Type A1 ... This trait has the distinction of being the first in man to be interpreted in mendelian dominant terms, by Farabee (1903). Haws and McKusick (1963) followed up on Farabee's family. The subjects were short of stature. Type A1 brachydactyly was present in the women of 3 successive generations, who also had ankylosis of the thumbs, which was not accompanied by synostosis on x-ray, and mental retardation (Piussan et al., 1983); see 188201. Stiff thumbs also occur with the C.S. Lewis type of symphalangism (185650). Drinkwater (1908, 1912, 1914) performed a comprehensive study of families with BDA1 and concluded that the shortness of the phalanges was attributable to absence of the epiphyses, short shaft of the bone, and premature closure of the epiphyses, when present. He noted that affected individuals tended to be of shorter stature in adulthood.
Studying 2 families with multiple affected members, Mastrobattista et al. (1995) excluded the following candidate genes: HOXD (see 142980), MSX1 (142983), MSX2 (123101), FGF1 (131220), and FGF2 (134920). Affected members of 1 of the families reported by Mastrobattista ... Studying 2 families with multiple affected members, Mastrobattista et al. (1995) excluded the following candidate genes: HOXD (see 142980), MSX1 (142983), MSX2 (123101), FGF1 (131220), and FGF2 (134920). Affected members of 1 of the families reported by Mastrobattista et al. (1995) were found by Kirkpatrick et al. (2003) to have a mutation in the Indian hedgehog gene (600726.0007). The family was of Mexican descent. Gao et al. (2001) identified 3 heterozygous missense mutations in the region encoding the amino-terminal signaling domain of Indian hedgehog (600726.0001-600726.0003) in all affected members of 3 large, unrelated Chinese families. The 3 mutant amino acids, which are conserved across diverse vertebrates and invertebrates, are thought to be adjacent on the surface of IHH. McCready et al. (2002) studied descendants of the first and third brachydactylous families reported by Drinkwater (1908, 1914) and showed that although they were not known to be related, they shared a common mutation within the IHH gene (D100N; 600726.0004). The family reported by Farabee (1903) and the first kindred reported by Drinkwater (1908) had been thought to be related, but no connection between the families could be established by Haws and McKusick (1963). McCready et al. (2005) identified the D100N mutation of the IHH gene in descendants of the family described by Farabee (1903). Using 16 markers spanning the IHH locus, they identified a common haplotype between this family and the 2 kindreds studied by Drinkwater (1908, 1914) and McCready et al. (2002), suggesting a common founder. In affected members of a 5-generation Chinese family with brachydactyly type A1, Liu et al. (2006) identified a heterozygous mutation in the IHH gene (600726.0008). Radiographic analysis of affected individuals showed unaffected proximal phalanges of the thumb and no apparent anomalies of the feet. In affected members of a large 4-generation Chinese family with brachydactyly, Zhu et al. (2007) identified heterozygosity for the D100N mutation of the IHH gene and demonstrated a haplotype different than the previously published Farabee-Drinkwater common haplotype (McCready et al., 2005), suggesting that the mutation arose independently in this family. The hands of the affected family members were broad, and there was shortening of all digits; x-ray examination revealed that the defects were mainly confined to the middle phalanges and metacarpals. In affected members of a Dutch family with mild brachydactyly type A1, Lodder et al. (2008) identified a heterozygous deletion in the IHH gene (600276.0009), resulting in an in-frame deletion of residue glu95, which was predicted to be located on the edge of a groove important for the interaction between IHH and PTCH1 (601309). Lodder et al. (2008) noted that this was the first reported deletion in the IHH gene, but that this residue has been reported to be affected in other patients with the disorder (see, e.g., G95K; 600726.0001).