Sclerosteosis 1

A number sign (#) is used with this entry because of evidence that sclerosteosis-1 (SOST1) is caused by homozygous mutation in the gene encoding sclerostin (SOST; 605740) on chromosome 17q21.

Description

Sclerosteosis is a severe sclerosing bone dysplasia characterized by progressive skeletal overgrowth. Syndactyly is a variable manifestation. The disorder is rare and the majority of affected individuals have been reported in the Afrikaner population of South Africa (summary by Brunkow et al., 2001).

Genetic Heterogeneity of Sclerosteosis

Sclerosteosis-2 (SOST2; 614305) is caused by mutation in the LRP4 gene (604270) on chromosome 11p11.

Clinical Features

Sclerosteosis is a term that was applied by Hansen (1967) to a disorder similar to van Buchem hyperostosis corticalis generalisata (239100) but differing in radiologic appearance of the bone changes and in the presence of asymmetric cutaneous syndactyly of the index and middle fingers in many cases. The jaw has an unusually square appearance in this condition.

The cases of Kelley and Lawlah (1946) and of Witkop (1965) were from an inbred triracial group in southern Maryland known as the 'We-Sorts.' Stein et al. (1983) provided a full report on the triracial Maryland kindred. They concluded that sclerosteosis is primarily a disorder of osteoblast hyperactivity. Syndactyly was present in 43 of 54 patients from 4 series; in the series of Stein et al. (1983), syndactyly was present in 4 of 5 patients in whom the relevant observations were recorded.

Epstein et al. (1979) could demonstrate no abnormality of pituitary function or of calcium homeostasis.

Beighton et al. (1984) examined 50 persons with sclerosteosis in the Afrikaner community of South Africa and 15 persons with van Buchem disease in Holland. The clinical and radiographic manifestations were very similar; the only notable difference was greater severity and syndactyly in most patients with sclerosteosis. Beighton et al. (1984) suggested that since the Afrikaners have Dutch antecedents, these 2 disorders may in fact be the same; modifying genes in the Afrikaner population may, they suggested, be responsible for the special features of sclerosteosis. Beighton (1988) reviewed sclerosteosis on the basis of the frequent cases observed in the Afrikaner population of South Africa.

Nager et al. (1983) reviewed clinical and radiologic aspects in detail and gave useful information on the changes in the temporal bones affecting hearing. Excessive height and weight are frequent in this condition. The terminal phalanges show radial deviation, and the fingernails tend to be dystrophic. Facial nerve paralysis may be present as early as birth or develop soon afterwards. It may be unilateral for many years. In some instances, anosmia, facial esthesia, optic nerve atrophy, convergent strabismus, and exophthalmos are present. Increased intracranial pressure may result from a combination of circumstances and may have led in several instances to sudden death from impaction of the brainstem in the foramen magnum. The patient studied by Nager et al. (1983) was related to the Maryland cases studied by Witkop (1965).

Tacconi et al. (1998) described sclerosteosis in a black man born in Senegal. He presented with full features of the disorder: tall stature, syndactyly, nail dysplasia, massive sclerosis of the long tubular bones, ribs, pelvis, and skull, and multiple cranial nerve involvement resulting in optic atrophy, facial palsy, and trigeminal neuralgia.

Hamersma et al. (2003) analyzed the course and complications of 63 individuals with sclerosteosis in South Africa who were seen over a 38-year period. Of these, 34 had died during the course of the survey, 24 from complications related to elevation of intracranial pressure as a result of calvarial overgrowth. The mean age of death was 33 years, with an even gender distribution. Facial palsy and deafness, as a result of cranial nerve entrapment, developed in childhood in 52 (82%) of affected individuals. Mandibular overgrowth was present in 46 (73%) adults and syndactyly in 48 (76%). In South Africa in 2002, 29 affected persons were alive, 10 being 20 years of age or younger.

Stephen et al. (2001) reviewed the dental and oral manifestations of sclerosteosis on the basis of 8 patients.

Inheritance

Sclerosteosis-1 is an autosomal recessive disorder (Brunkow et al., 2001). Affected sibs were observed by Hirsch (1929), Falconer and Ryrie (1937), Higinbotham and Alexander (1941), Kelley and Lawlah (1946), Truswell (1958) and Klintworth (1963). Parental consanguinity was observed by Falconer and Ryrie (1937) and by Truswell (1958).

Population Genetics

Sclerosteosis is unusually frequent in the Afrikaner population of South Africa, where Beighton et al. (1976) estimated that 1 in 140 persons is a heterozygous carrier. The patient reported by Truswell (1958) was of that origin, and Beighton et al. (1976) studied 25 such patients.

In a highly consanguineous family, Freire de Paes Alves et al. (1982) observed affected aunt and niece. The authors pointed out that the disorder is rare in populations other than the Afrikaners of Dutch extraction, that their patients came from a small city in the state of Bahia, Brazil, and that Bahia and the bordering state of Pernambuco were invaded and occupied by the Dutch in the 17th century at the same time as the settlement of South Africa.

Mapping

Through a genomewide search with highly polymorphic microsatellite markers, Van Hul et al. (1998) mapped the gene responsible for van Buchem disease to 17q12-q21.

Balemans et al. (1999) tested the hypothesis of Beighton et al. (1984) that sclerosteosis and van Buchem disease may be caused by mutations in the same gene. By 2-point linkage analysis in 2 consanguineous families with sclerosteosis, Balemans et al. (1999) assigned the locus for this disease to 17q12-q21, the same region where the van Buchem disease locus maps, providing genetic support for the hypothesis of allelism.

Molecular Genetics

Through homozygosity mapping followed by positional cloning in Afrikaner families, Brunkow et al. (2001) found 2 independent mutations in a novel gene, termed SOST (605740). Affected Afrikaners were found to carry a nonsense mutation in the N terminus of the encoded protein (605740.0001), whereas an unrelated affected person of Senegalese origin described by Tacconi et al. (1998) carried a splice mutation within the single intron of the gene (605740.0002). Brunkow et al. (2001) analyzed the SOST gene in 7 Dutch patients with van Buchem disease and detected no mutations in the coding region.