Spondylocostal Dysostosis 4, Autosomal Recessive

A number sign (#) is used with this entry because spondylocostal dysostosis-4 (SCDO4) is caused by homozygous or compound heterozygous mutation in the HES7 gene (608059) on chromosome 17p13.

For a general phenotypic description and a discussion of genetic heterogeneity of spondylocostal dysostosis (SCDO), see SCDO1 (277300).

Clinical Features

Sparrow et al. (2008) described a consanguineous family of Caucasian Mediterranean origin in which the proband was diagnosed prenatally with hydrocephalus and myelomeningocele, and at birth was found to have a bell-shaped, symmetric, and shortened thorax, lumbosacral myelomeningocele, ectopic and stenotic anus, and talipes. Radiologic examination showed shortening of the spine, with multiple and contiguous vertebral segmentation defects involving all spinal regions, but mainly the thoracic spine. The ribs had very crowded origins on the left side, and were irregularly aligned with variable points of fusion along their length on the right side. Neurogenic bladder was present, and cerebral CT scan showed Chiari II malformation. The unaffected parents were second cousins, and the proband had 2 healthy sibs.

Sparrow et al. (2010) reported a nonconsanguineous Italian family in which a sister and brother had spondylocostal dysostosis. Newborn radiographs of the sister showed multiple segmentation anomalies and rib fusions: there were 11 pairs of ribs bilaterally, with lateral fusion of the right first through fourth ribs, and posterior fusion of the left fifth and sixth ribs. She had a short trunk and short stature, and during the first year of life, her span was greater than her length. MRI at 21 years of age showed multiple segmentation anomalies in the cervical spine with butterfly and hemivertebrae; the arch of C1 was fused to C2 anteriorly, and some spinous processes were fused. Superior displacement of the odontoid process was seen, and the junction of the medulla and cervical spinal cord was angulated anteriorly. Magnetic resonance angiography showed a dominant right vertebral artery with hypoplasia of the left vertebral artery, which did not communicate with the basilar artery. At 23 years of age, pulmonary function testing revealed a forced vital capacity (FVC) and forced expiratory volume over 1 second (FEV1) that were decreased to almost one-half of predicted values; functional vital capacity was decreased in proportion to total lung capacity, consistent with a moderate restrictive ventilatory defect. Newborn radiographs in the affected brother showed 8 ribs bilaterally with costal fusions on the right, and multiple hemivertebrae with apparent block fusion of L2 to L3. By 13 years of age, he had developed prominent pectus excavatum, with stiffness in the trunk and neck, thoracic hypokyphosis, and lumbar hypolordosis. MRI at age 15 years showed multiple segmentation anomalies in the cervical and thoracic region, and magnetic resonance angiography demonstrated a hypoplastic left vertebral artery with absence of both posterior communicating arteries.

Sparrow et al. (2013) described 7 patients from 3 families, including a large consanguineous Arab family, with features consistent with spondylocostal dysostosis-4. Dextrocardia with situs inversus was seen in 3 of the 7 patients, suggesting randomization of left-right patterning. Neural tube defects were seen in 2 patients (one had spina bifida occulta and the other had thoracic myelomeningocele and Chiari II malformation) and were thought most likely to be secondary to failure of vertebral function. Patients were found to have a homozygous frameshift mutation in HES7 (see MOLECULAR GENETICS). Sparrow et al. (2013) suggested that HES7 mutations are associated with defects in laterality and in vertebral and neural tube formation.

Mapping

In a consanguineous family of Caucasian Mediterranean origin with spondylocostal dysostosis (SCDO), in which mutation in 3 genes known to cause recessive SCDO had been excluded (see SCDO1, 277300), Sparrow et al. (2008) performed autozygosity mapping and identified a 10.1-Mb region of homozygosity on chromosome 17 between SNPs rs8064630 and rs9893391 that was present in the proband but absent from parents and unaffected sibs.

Molecular Genetics

In the proband of a consanguineous family of Caucasian Mediterranean origin with spondylocostal dysostosis mapping to chromosome 17p13, Sparrow et al. (2008) sequenced 2 candidate genes and identified homozygosity for a missense mutation in 1 of them, HES7 (608059.0001). The parents and 1 unaffected sib who were heterozygous for the mutation had heights in the normal range and radiography of the spine and ribs showed normal anatomy.

In a brother and sister with SCDO from a nonconsanguineous Italian family, Sparrow et al. (2010) sequenced the 4 genes known to cause SCDO and identified compound heterozygosity for missense mutations in the HES7 gene (608059.0002 and 608059.0003). Sparrow et al. (2010) noted that in addition to the vertebral defects characteristic of SCDO, both affected individuals manifested defects of the vertebral arteries in the neck that had not previously been described in SCDO patients; they suggested that this finding might be unique to HES7-related SCDO.

In 7 patients from 3 families with SCDO, Sparrow et al. (2013) identified a homozygous frameshift mutation in the HES7 gene (608059.0004) that resulted in significant reduction of HES7 protein function. Four patients were from a consanguineous Arab family and the other patients were from 2 additional families from the same geographic area. Three patients also had dextrocardia with situs inversus and 2 patients also had neural tube defects.