Osteopetrosis, Autosomal Recessive 8

A number sign (#) is used with this entry because of evidence that autosomal recessive osteopetrosis-8 (OPTB8) is caused by homozygous mutation in the SNX10 gene (614780) on chromosome 7p15.

For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive osteopetrosis, see OPTB1 (259700).

Clinical Features

Aker et al. (2012) studied 4 affected children from 2 consanguineous Palestinian families with osteopetrosis (OPT). All 4 patients had older relatives with OPT, and were suspected of having OPT at 1 to 4 months of age because of macrocephaly or failure to thrive due to feeding problems caused by upper airway issues. Examination revealed age-appropriate neurocognitive development, increased head circumference, broad open fontanel, frontal bossing, and hepatosplenomegaly. Hearing was normal, but vision was impaired due to the presence of severe optic nerve atrophy, although the retinas were intact. Laboratory investigation revealed anemia, thrombocytopenia, and high lactate dehydrogenase (LDH). Radiography showed dense bones with no distinction between outer and inner plates due to extensive encroachment of cortical bone into the medullary space. Brain CT disclosed narrowed optic and auditory canals with sclerosis of the semicircular canals; the ethmoid and mastoid air cells and sphenoid sinuses were fully ossified. Two of the patients underwent bone marrow transplantation at ages 10 months and 19 months, respectively, and at follow-up had normal growth and development. One patient died at 32 months of age.

Megarbane et al. (2013) reported an Iraqi boy, born to consanguineous parents, who had macrocephaly, anemia, and splenomegaly at 4 months of age. At age 1 year, a brain MRI revealed external hydrocephalus and corpus callosum hypoplasia. His older brother, who was blind since 3 years of age, died at age 5 years with hydrocephalus, splenomegaly, and anemia. A 7-year-old paternal cousin, also born of consanguineous parents, was reported to display similar clinical features and to be blind and deaf. At 2 years of age, the proband developed vomiting, sleepiness, gaze palsy, crossed eyes and uncontrolled eye movements, difficulty in feeding, irritability, and loss of coordination with gait disturbances. Examination revealed macrocephaly, triangular face, open anterior fontanel, prominent forehead and occiput, protuberant eyes, strabismus, small chin, and joint hyperlaxity. Anemia and leukopenia were noted. CT scan showed brain atrophy with subarachnoid dilation and mild increase in ventricular volume, compatible with external hydrocephalus, and thinning of the corpus callosum. Abdominal ultrasound showed an enlarged spleen. Skeletal radiographs demonstrated increased density of long bones with defective modeling, metaphyseal undermodeling (Erlenmeyer flask-like appearance), transverse alternating bands of greater and lesser density in tubular bones, short femoral neck, increased width of the ribs, anteriorly notched vertebral bodies of the thoracolumbar spine, and bone-in-bone appearance. Ventriculoperitoneal shunt relieved the signs of hydrocephalus. Ophthalmologic examination was normal, but vision started to regress 6 months later; at 5 years of age, he was almost blind and required twice-monthly transfusions.

Mapping

In 3 affected children from a large consanguineous Palestinian family segregating autosomal recessive osteopetrosis, Aker et al. (2012) identified a single shared genomic stretch on chromosome 7 (chr7:11.46-26.60 Mb, NCBI36). A 10-year-old Palestinian boy with osteopetrosis from an unrelated consanguineous family had a partly overlapping homozygous region on chromosome 7 (chr7:25.38-34.26 Mb). Within the common 1.22-Mb interval, all 4 patients shared an identical haplotype over the 128 encompassed SNP markers (rs2391129-rs1029561).

Molecular Genetics

In affected children from 2 unrelated consanguineous Palestinian families segregating autosomal recessive osteopetrosis (OPT) mapping to chromosome 7p15, Aker et al. (2012) sequenced 5 candidate genes and identified homozygosity for a missense mutation in the SNX10 gene (R51Q; 614780.0001) that segregated with disease in both families. Screening of additional unrelated OPT patients identified another consanguineous Palestinian family in which 2 affected sisters also carried the mutation. Screening of 211 ethnically matched controls revealed 1 carrier of the R51Q mutation.

In a 5-year-old Iraqi boy with osteopetrosis, born of consanguineous parents and negative for mutation in 6 known osteopetrosis-associated genes, Megarbane et al. (2013) sequenced the candidate gene SNX10 and identified homozygosity for a nonsense mutation (R16X; 614780.0002). The mutation was present in heterozygosity in his unaffected parents and healthy sister.