Alternative titles; symbols
SNOMEDCT: 702351004; ORPHA: 3275; DO: 0090116;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3p14.3 | Spondylocarpotarsal synostosis syndrome | 272460 | Autosomal recessive | 3 | FLNB | 603381 |
A number sign (#) is used with this entry because of evidence that spondylocarpotarsal synostosis syndrome (SCT) is caused by homozygous or compound heterozygous mutation in the gene encoding filamin B (FLNB; 603381) on chromosome 3p14.
Spondylocarpotarsal synostosis syndrome (SCT) is characterized by disproportionate short stature and spinal deformity. Clinical features include clubfeet, facial dysmorphism, dental enamel hypoplasia, cleft palate, joint laxity, and conductive hearing loss. Characteristic radiologic findings include block vertebrae and carpal and tarsal fusion. Delay in ossification of the epiphyses of carpal bones and epiphyseal dysplasia of the femur have been observed (Salian et al., 2018).
Spondylocarpotarsal fusions in association with contractures and pterygia (see CPSKF1A, 178110 and CPSKF1B, 618649) can be caused by mutation in the MYH3 gene (160720).
Wiles et al. (1992) used the designation congenital synspondylism for a form of congenital familial extensive vertebral anomalies (CFEVA). They suggested that this represents an entity separate from spondylocostal dysplasia (SCD; 122600) and spondylothoracic dysplasia (STD; 277300). They reported 2 brothers and an unrelated Australian girl who had an unusual constellation of vertebral fusions without rib anomalies as well as carpal coalition. By analogy to symphalangism (185800), they chose the designation synspondylism. The 2 brothers had Lebanese parents born in the same district of Lebanon but not known to be consanguineous. The Australian girl was later found to have a mutation in the MYH3 gene (see CPSKF1A, 178110).
Two sibs with apparently the same disorder were reported by Langer and Moe (1975) and by Akbarnia and Moe (1978). Scoliosis was a more impressive feature than in the case of the Lebanese brothers reported by Wiles et al. (1992). Akbarnia and Moe (1978) referred to the condition as 'familial congenital scoliosis with unilateral unsegmented bar.' Their patients were an Iranian brother and sister whose parents were first cousins. Both showed right thoracic lordoscoliosis with failure of segmentation on the left from the third to the eleventh thoracic vertebra. Both had clubfeet as well as partial coalition of the carpal bones.
Ventruto and Catani (1986) described 2 Italian brothers, aged 16 and 8 years, who had 8 normal sibs and whose gypsy parents were first cousins. The unilateral unsegmented fusion bar was on the left in the older brother and on the right in the younger brother. Ventruto and Catani (1986) were impressed by the presence of joint laxity, congenital inguinal hernias, clubfoot, and peculiar facies (hypertelorism, short nasal septum, and broad bridge and tip of the nose).
Langer et al. (1994) reported 6 additional patients, 2 of them sibs. They used the term spondylocarpotarsal synostosis syndrome, with or without unilateral unsegmented bar, because carpal synostosis, usually capitate-hamate and lunate-triquetrum, was a feature and tarsal synostoses were present in all patients in whom the feet had been radiographed. The patients were of short stature, with disproportionately short trunk. The feet were flat. Cleft palate and sensorineural or mixed hearing loss were variable manifestations. Wiles et al. (1992) gave a useful review of several types of congenital familial extensive vertebral anomalies, including the costovertebral segmentation defect with mesomelia (COVESDEM syndrome; 268310).
Coelho et al. (1998) described 3 patients (2 of them sibs born to first-cousin parents) with spondylocarpotarsal synostosis syndrome. Sensorineural deafness was found in 2 of the 3 patients. Of 18 reported patients, including these 3, 10 were sib pairs from 5 families, with first-cousin consanguinity of parents in 3.
Seaver and Boyd (2000) reported a sporadic case, which they stated brought the number of well-documented cases of spondylocarpotarsal synostosis to 19 and was the first case documenting cervical spine instability. The 5-year-old girl had hypoplasia of C1 and odontoid and subluxation of C2 on C3.
Steiner et al. (2000) reported a Brazilian family with spondylocarpotarsal synostosis. The parents were first cousins and had 10 children, 5 of whom were affected. The 3 described in the report had short-trunk dwarfism of postnatal onset, scoliosis, unsegmented thoracic vertebrae with unilateral bar, and carpal bone fusion. Lens opacities, rarefaction of retinal pigmentation, and narrowing of retinal vessels were seen in 2 patients. These ocular manifestations may be coincidental or represent previously undescribed findings in this condition.
Mitter et al. (2008) described a 5-year-old German boy, born of first-cousin parents, with spondylocarpotarsal synostosis and a mutation in the FLNB gene (603381.0013). In addition to the typical findings of this disorder, he demonstrated ossification delay of multiple epiphyses (especially delayed carpal bone age) and bilateral proximal femoral epiphyseal dysplasia. Similar radiographic findings were described in another boy with spondylocarpotarsal synostosis reported by Honeywell et al. (2002).
Brunetti-Pierri et al. (2008) reported an Italian girl, born of consanguineous parents, with spondylocarpotarsal synostosis syndrome due to a homozygous FLNB mutation (603381.0014). She had short stature, scoliosis, short trunk, delayed bone age, vertebral fusions, and capitate-hamate fusion. She did not have facial dysmorphic features. Growth hormone (GH) deficiency was documented, but there was no response to GH administration. MRI did not show any abnormality of the hypothalamo-pituitary area, but there was platybasia and basilar impression, stenosis of the foramen magnum, but no signs of medullary compression at the cervicomedullary junction. A younger brother, who was heterozygous for the mutation, had short stature and transient GH deficiency.
Salian et al. (2018) described 4 males and 6 females from 7 families with SCT due to FLNB mutations. All of the patients, who ranged in age from 7 months to 15 years, had disproportionate short stature (-2.4 to -9.5 SD). Variable features included short neck (6/10), pectus carinatum (5/10), and mild facial dysmorphisms such as coarse face and frontal bossing (2/10). Radiologic features included contiguous vertebral fusion, most commonly T5-T7. Cervical or lumbar fusion was noted in 4 patients. Scoliosis was observed in 9 patients, lumbar lordosis in 2 patients, and crowding of the ribs in 9 patients. Capitate-hamate fusion was noted in 9 patients, lunate-triquetrum fusion in 3 patients, and tarsal fusion in 5 patients. Salian et al. (2018) noted strong intrafamilial variability in at least 1 family.
Autosomal recessive inheritance of spondylocarpotarsal synostosis syndrome was confirmed by the finding of homozygous or compound heterozygous mutations in the FLNB gene (603381) in patients with the disorder.
In a study of 4 families with spondylocarpotarsal synostosis syndrome, 3 of which were consanguineous, Steiner et al. (2004) used linkage analysis to establish that the disease gene is located on chromosome 3p14. A common region of homozygosity was found between markers D3S3724 and D3S1300 on 3p, defining a physical interval of approximately 4 million bp.
In 4 unrelated SCT families, Krakow et al. (2004) found that affected individuals were either homozygous or compound heterozygous for nonsense mutations in the FLNB gene (603381.0001-603381.0003). In all 4 families, the segregation of the mutations was compatible with autosomal recessive inheritance. The premature stop codons were all located within the repeat domain of filamin B, and Krakow et al. (2004) concluded that SCT results from the absence or truncation of filamin B.
In a 5-year-old by with SCT, Mitter et al. (2008) identified homozygosity for a nonsense mutation in the FLNB gene (603381.0013).
In an Italian girl, born of consanguineous parents, with SCT, Brunetti-Pierri et al. (2008) identified a homozygous nonsense mutation in the FLNB gene (603381.0014).
In affected members of 7 families with SCT, Salian et al. (2018) identified 2 nonsense and 5 frameshift variants in the FLNB gene (see, e.g., 603381.0016), all in homozygous state.
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Salian, S., Shukla, A., Shah, H., Bhat, S. N., Bhat, V. R., Nampoothiri, S., Shenoy, R., Phadke, S. R., Hariharan, S. V., Girisha, K. M. Seven additional families with spondylocarpotarsal synostosis syndrome with novel biallelic deleterious variants in FLNB. Clin. Genet. 94: 159-164, 2018. [PubMed: 29566257] [Full Text: https://doi.org/10.1111/cge.13252]
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Steiner, C. E., Torriani, M., Norato, D. Y. J., Marques-de-Faria, A. P. Spondylocarpotarsal synostosis with ocular findings. Am. J. Med. Genet. 91: 131-134, 2000. [PubMed: 10748412]
Steiner, C., Ehtesham, N., Taylor, K. D., Sebald, E., Cantor, R., King, L. M., Guo, X., Hang, T., Hu, M. S., Cui, J.-R., Friedman, B., Norato, D., Allanson, J., Honeywell, C., Mettler, G., Field, F., Lachman, R., Cohn, D. H., Krakow, D. A locus for spondylocarpotarsal synostosis syndrome at chromosome 3p14. J. Med. Genet. 41: 266-269, 2004. [PubMed: 15060099] [Full Text: https://doi.org/10.1136/jmg.2003.012252]
Ventruto, V., Catani, L. Progressive scoliosis by unilateral unsegmented fusion bar, foot deformity, joint laxity, congenital inguinal herniae, peculiar face. Am. J. Med. Genet. 25: 429-432, 1986. [PubMed: 3789006] [Full Text: https://doi.org/10.1002/ajmg.1320250304]
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