Multiple Synostoses Syndrome 3

A number sign (#) is used with this entry because of evidence that multiple synostoses syndrome-3 (SYNS3) is caused by heterozygous mutation in the FGF9 gene (600921) on chromosome 13q12.

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

Clinical Features

Wu et al. (2009) described 12 affected individuals from a 5-generation Chinese family segregating autosomal dominant multiple synostoses syndrome, with fusions of proximal interphalangeal, carpal-tarsal, and humeroradial joints. Hearing, stature, and intelligence were normal in all affected individuals. Only mild semidislocation or cubital valgus at elbow joints or limitation of finger joint flexion was found in 4 patients aged 11 years or below, suggesting that the phenotype is age dependent.

Rodriguez-Zabala et al. (2017) reported an affected Spanish father and son. The son was noted to have premature closure of the sagittal suture at age 2 months, and examination showed dolichocephaly, mild proptosis, and normal palate. At age 5 he exhibited broad thumbs and halluces, but did not show any clinically relevant joint limitations or osseous fusions. His father had been investigated in childhood for premature closure of cranial sutures, likely sagittal based on cranial shape, and also had broad thumbs and cleft palate. Examination revealed normal stature, dolichocephaly, proptosis, radially deviated broad thumbs with congenital fixed contractures of the interphalangeal joints, cutaneous syndactyly of toes, and broad medially deviated halluces. He also had joint movement limitation of the carpal, tarsal, and interphalangeal joints of the toes as well as vertebral lumbar joints, which he stated was progressively worsening. X-rays revealed osseous fusion of the affected joints.

Mapping

Wu et al. (2009) performed linkage analysis in a 5-generation Chinese family segregating autosomal dominant multiple synostoses syndrome, but found no linkage to known loci on chromosomes 17q22 and 20q11.2. A genomewide screen identified a single locus on chromosome 13q11-q12 that cosegregated with the disease (maximum 2-point lod score of 3.7 at D12S1236). Fine mapping and haplotype analysis narrowed the critical interval to 8.6 Mb between D13S175 and D13S221, a region containing 22 candidate genes.

Molecular Genetics

In a 5-generation Chinese family with autosomal dominant multiple synostoses syndrome mapping to chromosome 13q11-q12, Wu et al. (2009) identified a heterozygous missense mutation in the candidate FGF9 gene (S99N; 600921.0001) that segregated with disease and was not found in 250 unrelated ethnically matched controls.

In a Spanish father and son with multiple synostoses syndrome, Rodriguez-Zabala et al. (2017) analyzed a skeletal dysplasia-targeted gene panel and identified heterozygosity for a missense mutation in the FGF9 gene (R62G; 600921.0002) that segregated with disease in the family and was not found in 150 Spanish controls or in the gnomAD database. The mutation appeared to have arisen de novo in the father, as it was not detected in the biologically confirmed unaffected paternal grandparents.