Spondyloocular Syndrome

A number sign (#) is used with this entry because of evidence that spondyloocular syndrome (SOS) is caused by homozygous mutation in the XYLT2 gene (608125) on chromosome 17q21.

Clinical Features

Schmidt et al. (2001) described a consanguineous family from northern Iraq in which 6 of 7 sibs were affected by spondyloocular syndrome. Clinical features included cataract, loss of vision due to retinal detachment, facial dysmorphism, facial hypotonia, normal height with disproportionate short trunk, immobile spine with thoracic kyphosis, and reduced lumbar lordosis. The index patient showed a dense cataract and complete retinal detachment in the right eye; in the left eye, the lens nucleus was absent but there was no retinal detachment. Radiologic examination revealed generalized moderate osteoporosis, marked platyspondyly, and advanced bone age.

Munns et al. (2015) reported 3 patients from 2 unrelated families with an SOS-like phenotype, including bone fragility, hearing impairment, cardiac septal defects, and learning difficulties. The first family was of European Australian descent and was nonconsanguineous, but endogamy was considered likely due to the geographic isolation of the parents' region of origin. After sustaining a femoral fracture at 18 months of age, the proband was found to have multiple vertebral compression fractures with generalized vertebral flattening. Physical examination revealed low posterior hairline, short webbed neck, posteriorly rotated and low-set ears, shield chest, undescended left testis, long fingers and toes, and overriding second and third toes. Bone mineral density (BMD) was low, and he began receiving intravenous pamidronate infusions; however, new vertebral compression fractures occurred despite therapy. Echocardiography revealed an atrial septal defect, repaired at 8 years of age, as well as mitral valve prolapse and dysplastic aortic valve. Abdominal ultrasound showed bilateral mild to moderately dilated distal ureters, but normal appearance of kidneys. The proband was diagnosed with mild to moderate sensorineural hearing loss at 9 years of age, and required hearing aids. Ophthalmologic examination showed amblyopia and nystagmus, and at age 11 he developed spontaneous left retinal detachment that resulted in loss of vision in that eye. At 13 years of age, posterior subcapsular cataracts were noted. By 14 years of age, he had sustained 5 more long bone fractures and had noticeable pectus carinatum with inferior depression; he was fully ambulant but had an unsteady gait due to muscle weakness and poor vision. The proband's younger brother had a very similar clinical course, with vertebral flattening and compression fractures detected before 1 year of age. Despite intravenous pamidronate treatment, he developed new compression fractures, and examination at 11 years of age showed bilateral femoral deformities as well as fractures. In addition, he had cardiac findings, sensorineural hearing loss, and urinary tract findings identical to those of his brother. Both sibs also exhibited mild learning difficulties. Munns et al. (2015) also studied an unrelated 19-year-old man, born of first-cousin parents, who sustained 3 femur fractures by 3.5 years of age. Examination at 3.75 years of age showed short stature, multiple vertebral compression fractures, mild left hemiplegia with spasticity in the left lower extremity, and low BMD. Despite treatment with pamidronate and bisphosphonate, he sustained a total of 10 lower extremity fractures and was never able to walk independently, being wheelchair-dependent at 19 years of age. Other features included hearing deficit noted at 10 years of age for which hearing aids were required, bilateral cataracts that were removed at 12 years of age, and unilateral retinal detachment at age 15. He had no apparent learning difficulties. Munns et al. (2015) noted that the skeletal phenotype in these patients resembled that of the sibship described by Schmidt et al. (2001).

Molecular Genetics

In 2 sibs with spondyloocular syndrome, Munns et al. (2015) performed whole-exome sequencing; analysis of the data excluded mutation in 10 genes associated with Noonan syndrome (163950) and 11 genes known to be associated with osteogenesis imperfecta. Both affected sibs were homozygous for a 1-bp duplication in the XYLT2 gene (608125.0002), located within an approximately 23-Mb shared region of homozygosity on chromosome 17. The mutation, which segregated with disease in the family, was not found in an in-house exome database or in the 1000 Genomes Project, dbSNP (build 132), Exome Variant Server, or ExAC databases. In an unrelated man with SOS, Munns et al. (2015) sequenced the XYLT2 gene and identified homozygosity for a 1-bp deletion (608125.0003) that was present in heterozygosity in his unaffected first-cousin parents.

Exclusion Studies

Rudolph et al. (2003) excluded several candidate genes, including 3 collagen genes and the PAX6 gene (607108), as the cause of the disorder in the family reported by Schmidt et al. (2001). They also excluded linkage to the critical interval for the osteoporosis-pseudoglioma syndrome (259770).