Fibular Hypoplasia And Complex Brachydactyly

A number sign (#) is used with this entry because of evidence that fibular hypoplasia and complex brachydactyly is caused by homozygous or compound heterozygous mutation in the GDF5 gene (601146) on chromosome 20q11.

Clinical Features

Fibular hypoplasia and complex brachydactyly was probably first described by Du Pan (1924), who reported the isolated case of a boy with a complex type of brachydactyly associated with bilateral absence of the fibula. The same disorder was described by Grebe (1955) in a brother and sister from a first-cousin marriage. The sibs had shortening of various metacarpals, small carpals, trapezoid middle phalanx of the index finger, with radial deviation, almost complete absence of the fibula bilaterally, and tibiotarsal dislocation (Volkmann deformity). The toes were short and laterally deviated.

Kohn et al. (1989) reported 3 sibs with short-limb dwarfism associated with bilateral absence of fibulae and severe abnormalities of all digits. There was also hypoplasia of the distal ulna leading to bowing of the radius. Hypoplasia or absence of proximal and middle phalanges resulted in deformed 'nubbin-like' fingers and toes similar to those seen in Grebe syndrome (200700). However, shortness of the limbs was much less marked than in the latter condition.

Ahmad et al. (1990) described a highly inbred Pakistani kindred with at least 9 affected persons, providing strong support for autosomal recessive inheritance. The average inbreeding coefficient for the affected persons was significantly greater than that for unaffected persons in the pedigree, and consanguineous loops could account for all affected persons being homozygous for the same abnormal allele.

Szczaluba et al. (2005) reported a Polish mother and daughter with Du Pan syndrome. The daughter showed symmetric shortening of the extremities, unequal brachydactyly with the thumbs most severely affected, equinovalgus deformity with medial displacement of the tibia at the ankle joint, absence of the fibulae, and small but well-formed nails. Psychomotor development was normal. The mother had mesomelic shortening of the extremities, brachydactyly, partial syndactyly of the fingers, equinovalgus deformity, and severe hypoplasia/dysplasia of the fibulae and short tubular bones.

Douzgou et al. (2008) reported a 20-month-old boy with complex brachydactyly and mild proximal fibular hypoplasia. Hand plain films showed delayed ossification of the phalanges, apparently absent middle phalanges, hypoplastic metacarpals, and absent metacarpals and proximal phalanges of the first rays. There was also mild proximal hypoplasia of the fibula, without valgus deformity of the knee, instability of the proximal tibiofibular articulation, or anomalies of the femur. These findings supported a less severe involvement of the middle lower limb skeleton. Molecular analysis identified compound heterozygosity for 2 mutations in the GDF5 gene (601146.0018; 601146.0019). The father, who was heterozygous for 1 of the mutations, had features consistent with brachymesophalangy on radiographic studies of the hand.

Molecular Genetics

Because of similarities to the Hunter-Thompson (201250) and Grebe (200700) types of acromesomelic chondrodysplasia, Faiyaz-Ul-Haque et al. (2002) examined genomic DNA from a Pakistani family with Du Pan syndrome for mutations in the GDF5 gene and identified homozygosity for a missense mutation (601146.0005).

In a mother and daughter with Du Pan syndrome, Szczaluba et al. (2005) identified heterozygosity for 3 mutations on the same allele of the GDF5 gene (601146.0012). The authors postulated that the 3 mutations had a synergistic cis-acting dominant-negative effect on gene expression, resulting in autosomal dominant inheritance of the disorder in this family.