Sclerosteosis

Sclerosteosis is a rare skeletal dysplasia which is characterised by progressive bone thickening and sclerosis of the skeleton (especially the skull and the mandible) (1,2).

• mainly seen in Afrikaners of Dutch descent in South Africa, but isolated individuals or families in several other countries (Spain, Brazil, USA, Germany, Japan and Senegal) have also been reported (2,3)

It is inherited as an autosomal recessive disease.

• loss of function mutations in the SOST genes (located on chromosome 17q12-21) which encodes for the protein sclerostin is responsible for the progressive bone overgrowth
• in the Afrikaners population, the estimated carrier rate of the determinant gene is around 1 in 100 individuals

Sclerostin secreted by osteocytes inhibits osteoblastogenesis and bone formation. Hence in patients with sclerostin deficiency, there is an increase in bone mass due to increased bone formation that is not associated with increased bone resorption (1).

The clinical picture is similar to van Buchem disease with the major difference between the two conditions being gigantism and the hand abnormalities which are present in sclerosteosis but never in van Buchem disease. Some of the clinical features include:

• severe facial distortion - a very thick calvarium with macrocephaly and an enlarged mandible
• tall stature sometimes even gigantism
• hand malformations - syndactylyl of the digits, radial deviation of the terminal phalanges, dysplastic or absent nails
• severe headaches may be present due to raised intracranial pressure
• narrowing of cranial foramina may cause recurrent facial-nerve palsy, deafness, and optic atrophy (4,5)

Heterozygos carriers are clinically normal (although age-related radiographic evidence of calvarial thickening may be seen in some) (1).

There are no reports of fractures in these patient groups (1). Skeletal deformities are not seen at birth but become noticeable at around 5 years of age which progresses steadily thereafter (5). Sudden death can be caused by increased intracranial pressure (1).

Notes:

• Van Buchem disease (3)
  • less severe disorder than sclerostiosis
  • individuals have a separate noncoding deletion of a gene required for normal transcription of the SOST gene
  • heterozygous cases have moderately high bone mass without other phenotypic or clinical features

Reference:

• (1) Gardner JC et al. Bone mineral density in sclerosteosis; affected individuals and gene carriers. J Clin Endocrinol Metab. 2005;90(12):6392-5.
• (2) Moester MJ et al. Sclerostin: current knowledge and future perspectives. Calcif Tissue Int. 2010;87(2):99-107.
• (3) Hamersma H, Gardner J, Beighton P. The natural history of sclerosteosis. Clin Genet. 2003;63(3):192-7.
• (4) Balemans W et al. Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet. 2001;10(5):537-43.
• (5) Balemans W et al. Localization of the gene for sclerosteosis to the van Buchem disease-gene region on chromosome 17q12-q21. Am J Hum Genet. 1999;64(6):1661-9.
• (6) McClung MR. Romosozumab for the treatment of osteoporosis. Osteoporos Sarcopenia. 2018;4(1):11-15. doi:10.1016/j.afos.2018.03.002