SNOMEDCT: 1286834000; ORPHA: 642085; DO: 0112200;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p13.2 | Spondyloepimetaphyseal dysplasia with joint laxity, type 3 | 618395 | Autosomal recessive | 3 | EXOC6B | 607880 |
A number sign (#) is used with this entry because of evidence that spondyloepimetaphyseal dysplasia with joint laxity-3 (SEMDJL3) is caused by homozygous mutation in the EXOC6B gene (607880) on chromosome 2p13.
Spondyloepimetaphyseal dysplasia with joint laxity-3 (SEMDJL3) is characterized by multiple joint dislocations at birth, severe joint laxity, scoliosis, gracile metacarpals and metatarsals, delayed bone age, and poorly ossified carpal and tarsal bones (Girisha et al., 2016).
For a discussion of genetic heterogeneity of SEMD with joint laxity, see SEMDJL1 (271640).
Spranger et al. (2006) described 5 patients with a 'leptodactylic' form of SEMD, including 2 sisters (patients 2 and 3) who were later found to have a mutation in the EXOC6B gene (see MOLECULAR GENETICS). Both sisters were born with bilateral hip and patellar dislocations. Examination at ages 12 and 9.5 years, respectively, showed similar findings. Both patients used wheelchairs for mobility and were obese, and both had round faces with a high nasal bridge and mild myopia. The girls were short, with heights in the 5th centile, and showed restricted mobility of most large joints, mild kyphoscoliosis, and genua valga. Fingers were long and slender, with distal tapering and hypermobile joints. The older sister had normal intellectual development, whereas the younger sister exhibited mild learning difficulties.
Girisha et al. (2016) reported 2 brothers, aged 20 and 14 years, from a consanguineous family, who had severe short stature and were born with dislocations of hip and knee joints and severe joint laxity. Walking was delayed due to the joint problems. Both patients exhibited left lower thoracic scoliosis and short neck. X-rays showed spondyloepimetaphyseal dysplasia, with severely dysplastic epiphyses at the proximal humerus and femur. Mild platyspondyly, scoliosis, and narrow interpedicular distance were present, as well as bilateral dislocation of hip and knee joints and patellae. The proximal carpal bones showed absent ossification with overall short carpus, whereas distal carpal bones showed delayed ossification, irregularity, and poor morphology. Metacarpals and metatarsals were slender (leptodactylic). Radial and ulnar metaphyses were cupped with short sclerotic striations, and distal epiphyses were flattened with distal ulnar hypoplasia. Mild osteopenia was observed. The radial heads were dislocated and there was pes planus. Girisha et al. (2016) noted phenotypic overlap with SEMDJL1 and SEMDJL2 (603546).
Spondylometaphyseal dysplasia with joint laxity type 3 is an autosomal recessive disorder (Girisha et al., 2016; Campos-Xavier et al., 2018).
In 2 brothers with SEMD and multiple joint dislocations who were negative for mutation in skeletal dysplasia-associated genes, Girisha et al. (2016) performed whole-exome sequencing and identified homozygosity for a nonsense mutation in the EXOC6B gene (Y302X; 607880.0001), for which their unaffected first-cousin parents were heterozygous.
In 2 sisters with SEMD and multiple joint dislocations, originally reported by Spranger et al. (2006), who were negative for mutation in the KIF22 gene (603213), Campos-Xavier et al. (2018) identified homozygosity for an approximately 220-kb deletion within the EXOC6B gene (607880.0002).
Campos-Xavier, B., Rogers, R. C., Niel-Butschi, F., Ferreira, C., Unger, S., Spranger, J., Superti-Furga, A. Confirmation of spondylo-epi-metaphyseal dysplasia with joint laxity, EXOC6B type. (Letter) Am. J. Med. Genet. 176A: 2934-2935, 2018. [PubMed: 30284759] [Full Text: https://doi.org/10.1002/ajmg.a.40631]
Girisha, K. M., Kortum, F., Shah, H., Alawi, M., Dalal, A., Bhavani, G. S., Kutsche, K. A novel multiple joint dislocation syndrome associated with a homozygous nonsense variant in the EXOC6B gene. Europ. J. Hum. Genet. 24: 1206-1210, 2016. [PubMed: 26669664] [Full Text: https://doi.org/10.1038/ejhg.2015.261]
Spranger, J., Lebel, R. R., Rogers, R. C. Spondyloepimetaphyseal dysplasia, leptodactylic type: variability, familial cases and differential diagnosis. Proc. Greenwood Genet. Center 25: 15-25, 2006.