Metacarpal 4-5 Fusion

A number sign (#) is used with this entry because of evidence that metacarpal 4-5 fusion (MF4) is caused by mutation in the FGF16 gene (300827) on chromosome Xq21.

Clinical Features

Orel (1928) and Holmes et al. (1972) described fusion of the fourth and fifth metacarpals as an X-linked recessive trait. Other reports are more consistent with autosomal dominant inheritance (e.g., Habighorst and Albers, 1965). The families of Lerch (1948) and of Habighorst and Albers (1965) suggested autosomal dominant inheritance because of affected females and male-to-male transmission. Anneren and Amilon (1994) described this malformation in 5 males in 4 generations of a family. The carrier females were normal by clinical and radiologic examination.

Holmes et al. (1972) excluded linkage of the disorder in their family to the colorblindness locus on Xq28. An X-linked form of split-hand/foot malformation (SHFM2; 313350) has been mapped to Xq26. The possibility of allelism of X-linked ectrodactyly and X-linked metacarpal fusion should be investigated.

Lonardo et al. (2004) described a 4-generation family with isolated fusion of the fourth and fifth metacarpals. They noted that only males were affected and that there were no instances of male-to-male transmission, consistent with X-linked recessive transmission.

Jamsheer et al. (2013) described a 12-year-old Polish boy in whom ulnar deviation of both fifth fingers was noted at birth. He was also found to have right-sided inguinal hernia and hydrocele of testis. Radiography showed fusion of the fourth and fifth metacarpals and shortening of the fifth metacarpal bones. On examination at 12 years of age, he had normal stature, with bilateral shortening of the fifth rays of the hands as well as minimal syndactyly of toes 2-3. He had a triangular face, with upslanted palpebral fissures and a thin upper lip, but no additional dysmorphic features were noted. Intellectual development was normal, although he had attention deficit-hyperactivity disorder. He had 2 younger brothers who were clinically and radiologically normal. Jamsheer et al. (2013) also studied a German boy with isolated bilateral metacarpal 4-5 fusion with shortening of the fifth metacarpals.

Jones et al. (2014) reported 2 half brothers from a Caucasian British family who had metacarpal 4-5 fusion. The 23-year-old half brother had bilateral ulnar deviation of the fifth fingers at birth, which caused difficulty in writing and in fine motor movements; he underwent surgery to reduce the deviation of the left fifth finger. He also had bilateral high-arched feet, large first toes, swelling of the dorsum of both feet, sandal gap, and flexion deformity of the first metatarsophalangeal joints. His 6-year-old half brother had unilateral ulnar deviation of the right fifth finger at birth, and also had very large first toes.

Molecular Genetics

In a 12-year-old Polish boy with metacarpal 4-5 fusion who was negative for mutation in the NOG (602991), GDF5 (601146), and HOXD13 (142989) genes, Jamsheer et al. (2013) performed whole-exome sequencing and identified a nonsense mutation in the FGF16 gene (R179X; 300827.0001). The mutation was present in heterozygosity in his clinically and radiologically unaffected mother, but was not found in his unaffected brothers. Sequencing of the FGF16 gene in a German boy with typical metacarpal 4-5 fusion revealed another nonsense mutation (S157X; 300827.0002); his parents were unavailable for study.

In 2 half brothers with metacarpal 4-5 fusion, Jones et al. (2014) identified a 19-bp duplication in the FGF16 gene (300827.0003) that was also present in heterozygosity in their unaffected mother. The authors noted that the more extensive involvement of the feet in the older half brother suggested that modifier genes might be important in the phenotypic expression.