Split-Hand/foot Malformation 1 With Sensorineural Hearing Loss, Autosomal Recessive

A number sign (#) is used with this entry because of evidence that autosomal recessive split-hand/foot malformation-1 with sensorineural hearing loss (SHFM1D) is caused by homozygous mutation in the DLX5 gene (600028) on chromosome 7q21. One such family has been reported.

For a general phenotypic description and a discussion of genetic heterogeneity of split-hand/foot malformation, see SHFM1 (183600).

Clinical Features

Shamseldin et al. (2012) reported a consanguineous Yemeni family in which 2 daughters had split-hand/foot malformation as well as hearing impairment. The proband was a 6-year-old girl who had severe short stature but normal weight and head circumference, in whom development had been normal except for delayed walking due to the lower limb defects. Mild synophrys and low anterior hairline were noted. She had near-full dorsalization of the palms, tapered fingers, and cylindrical nails, as well as asymmetric short and severely deformed legs and feet. There was restriction of flexion at all metacarpophalangeal and interphalangeal joints as well as mild scoliosis. Audiometric examination showed moderate hearing impairment on the right and severe impairment on the left. Skeletal survey revealed hypoplasia of the lower third of the right tibia with rotation of the fibula, malpositioned left tibia and fibula, medially placed distal end of the fibula, subluxation of the superior tibiofibular and ankle joints, and a deviated fifth distal phalanx. Her 4-year-old sister, who also had hearing loss, had mild frontal bossing, high frontal hair line, and a severe asymmetric claw-like deformity. Her right hand had an elongated abducted thumb, wide fused ring and middle fingers, and an absent index finger, whereas her left hand had a deep middle cleft, elongated ring finger, and clinodactyly of the fifth finger. Her back and lower limbs appeared normal. An affected older sister had died at 7 years of age, but the cause of death was unknown; in addition, 2 great-aunts and 1 great-uncle were reportedly affected.

Molecular Genetics

In 2 affected sisters from a consanguineous Yemeni family with split-hand/foot malformation and hearing loss, who had no detectable chromosomal aberration, Shamseldin et al. (2012) performed exome sequencing with autozygome overlap and found 6 variants present in the sisters' shared autozygome, only 1 of which was predicted to be pathogenic: a missense mutation in the DLX5 gene (Q178P; 600028.0001) that segregated with the disorder and was not found in 192 ethnically matched controls or the Exome Variant Server.