ORPHA: 3237; DO: 0081319;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 13q12.11 | Multiple synostoses syndrome 3 | 612961 | Autosomal dominant | 3 | FGF9 | 600921 |
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).
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.
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.
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.
Tang et al. (2017) found that both heterozygous and homozygous knockin mice with the S99N mutation (600921.0001) in Fgf9 displayed a SYNS3-like phenotype, with curly tails and partially or fully fused multiple joints. Observation of joint morphology at different stages of limb development revealed that joint synostosis in homozygous Fgf9 S99N knockin mice was caused by failure of interzone formation with excess chondrogenesis. Fgf9 inhibited mesenchymal cell differentiation into chondrocytes through downregulation of Sox6 (607257) and Sox9 (608160) in wildtype mice, but the S99N mutation attenuated the inhibitory effect in mutant mice. Fgf9 also maintained Gdf5 (601146) expression in elbow and knee joints during development of wildtype mice, but the S99N mutation abolished Gdf5 expression in the prospective elbow and knee joint regions. In addition, the S99N mutation lowered the affinity of Fgf9 to its receptors by changing its conformation, leading to reduced Fgf9 signaling in the presumed joint regions of limbs.
Rodriguez-Zabala, M., Aza-Carmona, M., Rivera-Pedroza, C. I., Belinchon, A., Guerrero-Zapata, I., Barraza-Garcia, J., Vallespin, E., Lu, M., del Pozo, A., Glucksman, M. J., Santos-Simarro, F., Heath, K. E. FGF9 mutation causes craniosynostosis along with multiple synostoses. Hum. Mutat. 38: 1471-1476, 2017. [PubMed: 28730625] [Full Text: https://doi.org/10.1002/humu.23292]
Tang, L., Wu, X., Zhang, H., Lu, S., Wu, M., Shen, C., Chen, X., Wang, Y., Wang, W., Shen, Y., Gu, M., Ding, X., Jin, X., Fei, J., Wang, Z. A point mutation in Fgf9 impedes joint interzone formation leading to multiple synostoses syndrome. Hum. Molec. Genet. 26: 1280-1293, 2017. [PubMed: 28169396] [Full Text: https://doi.org/10.1093/hmg/ddx029]
Wu, X., Gu, M., Huang, L., Liu, X., Zhang, H., Ding, X., Xu, J., Cui, B., Wang, L., Lu, S, Chen, X., Zhang, H., Huang, W., Yuan, W., Yang, J., Gu, Q., Fei, J., Chen, Z., Yuan, Z., Wang, Z. Multiple synostoses syndrome is due to a missense mutation in exon 2 of FGF9 gene. Am. J. Hum. Genet. 85: 53-63, 2009. [PubMed: 19589401] [Full Text: https://doi.org/10.1016/j.ajhg.2009.06.007]