ORPHA: 1513; DO: 0080807;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q21.31 | Craniodiaphyseal dysplasia, autosomal dominant | 122860 | Autosomal dominant | 3 | SOST | 605740 |
A number sign (#) is used with this entry because of evidence that autosomal dominant craniodiaphyseal dysplasia (CDD) is caused by heterozygous mutation in the SOST gene (605740) on chromosome 17q21.
Sclerosteosis (SOST1; 269500) and van Buchem disease (VBCH; 239100) are allelic disorders that are less severe and show autosomal recessive inheritance.
Craniodiaphyseal dysplasia (CDD) is a severe bone dysplasia characterized by massive generalized hyperostosis and sclerosis, especially involving the skull and facial bones. Progressive bony encroachment upon cranial foramina leads to severe neurologic impairment in childhood (summary by Brueton and Winter, 1990). The sclerosis is so severe that the resulting facial distortion is referred to as 'leontiasis ossea' (leonine facies), and the bone deposition results in progressive stenosis of craniofacial foramina (summary by Kim et al., 2011).
Schaefer et al. (1986) described a mother and her male infant affected with a craniotubular dysplasia characterized by severe craniofacial hyperostosis and sclerosis with obliteration of paranasal sinuses and foramina of the skull base. A severe bilateral hearing loss and facial diplegia with relative sparing of the optic nerves resulted. The long bones showed an extreme asymmetric hyperostosis and sclerosis of the diaphyses and evidence of a modeling defect in the metaphyses. The spine, ribs, clavicles, and pelvis all showed some degree of sclerosis and defective modeling but were less severely involved. Features distinguishing the disorder in these patients from the previously defined craniodiaphyseal dysplasia (218300) were a greater degree of hyperostosis and sclerosis, apparent dominant transmission, and metaphyseal involvement.
Bieganski et al. (2007) reported a boy with severe craniodiaphyseal dysplasia and his apparently unaffected mother. The boy had extensive osteosclerosis present at birth and the diagnosis of CDD was made at 4 weeks of age. His facial changes progressed with age with marked facial bone hyperplasia. He developed facial diplegia, bilateral conductive hearing loss, and optic nerve atrophy. At age 7, he developed progressive genu valgum and small cyst-like radiotranslucencies of the distal femoral epiphyses as seen in hyperparathyroidism. Metabolic studies revealed elevated PTH to 306.1 pg/ml (normal, 15-65 pg/ml) and serum alkaline phosphatase was 1491 IU/ L (normal, less than 455 IU/L). Total calcium was normal and serum phosphate was slightly decreased. A scan of the neck and chest showed a focus of increased tracer uptake corresponding to a parathyroid adenoma. Bieganski et al. (2007) noted some similarity in facial appearance between the mother and son. Radiographs in the mother revealed thickened, sclerotic bones of the calvarium and skull base. Leg and hand bones were normal. Biochemical studies revealed increased alkaline phosphatase and normal serum calcium, phosphorus, and parathyroid hormone. Bieganski et al. (2007) suggested that the mother had somatic and gonadal mosaicism, explaining her subclinical course and her severely affected son. Hyperparathyroidism had not previously been reported in CDD. Parathyroid hormone was normal in the patient reported by Schaefer et al. (1986) and elevated in a 5-year-old boy reported by Brueton and Winter (1990).
Hennekam et al. (2010) suggested that the patient described by Lelek (1961) as an example of Camurati-Engelmann disease may have had craniodiaphyseal dysplasia.
Kim et al. (2011) reported a Korean girl with severe CDD. At age 3 months, she had difficulty breathing through her nostrils, requiring surgical correction of suspected choanal atresia. Physical examination at age 3 years showed macrocephaly, hypertelorism, a broad flat nasal bridge with saddle nose, and prominent mandibles. Ophthalmologic examination showed papilledema secondary to increased intracranial pressure. CT scan of the head showed profound osteosclerosis and hyperostosis of the facial bones, resulting in obliteration of the paranasal sinuses, middle ear cavities, internal acoustic canals, and the optic nerve canals. Histologic studies of the palatine bones showed cortical sclerosis with cement lines. There was mild undermodeling of the metadiaphyses of the long bones and thickening of the ribs. Laboratory studies showed increased parathyroid hormone and alkaline phosphatase. The disorder was progressive, resulting in deterioration of hearing and vision, and chronic headaches. The patient died at age 8.5 years following surgery to reduce intracranial pressure.
The transmission pattern of CDD in the families reported by Kim et al. (2011) was consistent with autosomal dominant inheritance.
In a Korean girl with autosomal dominant CDD, Kim et al. (2011) identified a de novo heterozygous mutation in the SOST gene (V21M; 605740.0005). Genetic analysis of the patient reported by Bieganski et al. (2007) identified a second heterozygous SOST mutation affecting the same residue (V21L; 605740.0006). DNA from the possibly affected mother of the second patient was not available. Both mutations affected the secretion signal peptide of the protein, and in vitro functional expression studies showed that the mutations resulted in significantly decreased SOST secretion, although the proteins were produced in the cells. Kim et al. (2011) noted the phenotypic differences from other disorders due to SOST mutations, which are less severe and transmitted in an autosomal recessive pattern, and postulated a dominant-negative mechanism in CDD.
Bieganski, T., Baranska, D., Miastkowska, I., Kobielski, A., Gorska-Chrzastek, M., Kozlowski, K. A boy with severe craniodiaphyseal dysplasia and apparently normal mother. Am. J. Med. Genet. 143A: 2435-2443, 2007. [PubMed: 17853455] [Full Text: https://doi.org/10.1002/ajmg.a.31938]
Brueton, L. A., Winter, R. M. Craniodiaphyseal dysplasia. J. Med. Genet. 27: 701-706, 1990. [PubMed: 2277386] [Full Text: https://doi.org/10.1136/jmg.27.11.701]
Hennekam, R. C. M., Krantz, I. D., Allanson, J. E. Gorlin's Syndromes of the Head and Neck. (5th ed.) New York: Oxford (pub.) 2010. P. 264.
Kim, S. J., Bieganski, T., Sohn, Y. B., Kozlowski, K., Semenov, M., Okamoto, N., Kim, C. H., Ko, A.-R., Ahn, G. H., Choi, Y.-L., Park, S. W., Ki, C.-S., Kim, O.-H., Nishimura, G., Unger, S., Superti-Furga, A., Jin, D.-K. Identification of signal peptide domain SOST mutations in autosomal dominant craniodiaphyseal dysplasia. Hum. Genet. 129: 497-502, 2011. [PubMed: 21221996] [Full Text: https://doi.org/10.1007/s00439-011-0947-3]
Lelek, I. Camurati-Engelmann disease. Fortschr. Roentgenstr. 94: 702-712, 1961. [PubMed: 13760661]
Schaefer, B., Stein, S., Oshman, D., Rennert, O., Thurnau, G., Wall, J., Bodensteiner, J., Brown, O. Dominantly inherited craniodiaphyseal dysplasia: a new craniotubular dysplasia. Clin. Genet. 30: 381-391, 1986. [PubMed: 3802557] [Full Text: https://doi.org/10.1111/j.1399-0004.1986.tb01895.x]