Multiple Synostoses Syndrome 4

A number sign (#) is used with this entry because of evidence that multiple synostoses syndrome-4 (SYNS4) is caused by heterozygous mutation in the GDF6 gene (601147) on chromosome 8q22.

Description

Multiple synostoses syndrome-4 is characterized by fusion of carpal and tarsal bones, as well as conductive hearing loss (Terhal et al., 2018).

For a general phenotypic description and a discussion of genetic heterogeneity of multiple synostoses syndrome, see SYNS1 (186500).

Clinical Features

Wang et al. (2016) reported a large 6-generation Chinese family in which 46 members experienced joint fusions of variable severity. All affected individuals had congenital bilateral foot deformities with diminished ankle flexion, resulting in debilitating pain and difficulty with ambulation. Computed tomography 3D bone reconstructions revealed that the joints between nearly all the tarsal bones were completely absent, and there was fusion of all the tarsometatarsal joints except for the cuboid-fifth metatarsal joint. Although the patients' hands appeared normal, x-rays showed variable carpal bone fusion. In addition, affected individuals exhibited progressive conductive deafness after 40 years of age.

Terhal et al. (2018) studied 5 of the 10 affected members of a 4-generation family segregating autosomal dominant multiple synostoses syndrome resulting in tarsal and carpal bone fusions and variable hearing loss. All exhibited broad forefeet with overlapping toes and flat arches, with x-rays showing variable fusion of carpal and tarsal bones; several patients also had brachydactyly and fifth-finger clinodactyly. Cervical spine x-rays were normal in 2 patients, whereas a third patient, 65 years of age, showed degenerative changes in uncovertebral joints and intervertebral joints C5 to C7, with decrease in joint space. Of 10 affected family members, 5 had hearing loss due to otosclerosis, 1 of whom was diagnosed at age 6 years with stapes fixation. Eye examination was performed in 3 patients and was normal, except for mild Fuchs dystrophy in the oldest patient (age 65).

Molecular Genetics

In a large 6-generation Chinese family with multiple synostoses syndrome, negative for mutation in known SYNS-associated genes, Wang et al. (2016) performed whole-exome sequencing and identified heterozygosity for a missense mutation in the GDF6 gene (Y444N; 601147.0010) that segregated fully with disease and was not found in ethnically matched controls or in public variant databases. Functional analysis indicated that the Y444N substitution represents a gain-of-function mutation.

In a 4-generation family with multiple synostoses syndrome, negative for mutation in 2 known SYNS-associated genes, Terhal et al. (2018) sequenced the candidate gene GDF6 and identified heterozygosity for a missense mutation (S429R; 601147.0011) that segregated with disease and was not found in public variant databases.