Answering a century old riddle: brachydactyly type A1

Abstract

In 1903, Farabee analyzed the heredity of the human digital malformation, brachydactyly, the first recorded disorder of the autosomal dominant Mendelian trait. In 1951, Bell classified this type of brachydactyly as type A1 (BDA1). Over 100 cases from different ethnic groups have so far been reported. However, the real breakthrough in identifying the cause of BDA1 has only taken place in the last few years with the progress of the mapping and identification of one of the genes responsible for this disorder, thus providing an answer for a century old riddle. In this article, we attempt to review the current state of knowledge on the genetic features of BDA1 with its century-old history and signalling pathway of IHH, and also discuss genotype-phenotype correlation not only of BDA1, but also of all types of brachydactyly.

Non‐metric variation of the middle phalanges of the human toes (II–V): long/short types and their evolutionary significance

“…Short middle phalanges evoke the aspect observed in some types of brachydactyly (or brachymesophalangy), which is an exceptional congenital defect in the human hand (Haws & McKusick, ; Temtamy & McKusick, ; Buyse, ; McKusick, ; Gao & He, ). In brachydactyly type A, the shortening is confined mainly to the middle phalanges; in type A1 (Farabee type), it affects the middle phalanges of all digits that are rudimentary and sometimes fused with the distal phalanges; in type A2, the shortening is restricted to the second digital ray (finger and toe); in type A3, to the fifth digit.…”

“…Unlike proximal and distal phalanges, the middle ones seem to lack any identifiable nutrient foramina, and it is likely that small periosteal vessels were entirely responsible for the blood supply (Mysorekar & Nandedkar, 1979); further studies would be interesting in order to ascertain if it is the case both in types L and S. This mode of reduction of the toes, concerning the middle phalanges, is particularly original: it is indeed never observed in other primates in which the reduction of the digital rays (digits/toes), when it exists, primarily affects the distal phalanges that regress and even disappear (Jouffroy & Lessertisseur, 1977). Short middle phalanges evoke the aspect observed in some types of brachydactyly (or brachymesophalangy), which is an exceptional congenital defect in the human hand (Haws & McKusick, 1963;Temtamy & McKusick, 1978;Buyse, 1990;McKusick, 1990;Gao & He, 2004). In brachydactyly type A, the shortening is confined mainly to the middle phalanges; in type A1 (Farabee type), it affects the middle phalanges of all digits that are rudimentary and sometimes fused with the distal phalanges; in type A2, the shortening is restricted to the second digital ray (finger and toe); in type A3, to the fifth digit.…”

Missense mutations in IHH impair Indian Hedgehog signaling in C3H10T1/2 cells: Implications for brachydactyly type A1, and new targets for Hedgehog signaling

“…However, it was only recently that IHH was identified as a locus for BDA1 [17]. So far, heterozygous missense mutations in IHH have been identified in BDA1 patients [15,16] and homozygous missense mutations in patients with Acrocapitofemoral Dysplasia [32].…”

The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla

“…Brachydactyly type A1 (BDA1) is characterized by absent or shortened middle phalanges5. Five missense substitutions in human Indian hedgehog (Ihh) that cause BDA1 (E95K, E95G, D100N, D100E, and E131K) affect residues that directly coordinate calcium (Fig.…”