Clinical Diagnosis

Sclerosteosis and van Buchem disease are clinically and radiographically similar disorders that are caused by mutations in SOST [Balemans et al 2001, Brunkow et al 2001, Balemans et al 2002b, Staehling-Hampton et al 2002].

Sclerosteosis. The diagnosis of sclerosteosis is based on characteristic clinical and radiographic features and a family history consistent with autosomal recessive inheritance.

Clinical features include the following:

• Generalized progressive skeletal overgrowth, most pronounced in the skull and mandible, leading to:
  • Potentially lethal elevation of intracranial pressure in childhood or early adulthood as a result of calvarial overgrowth
  • Entrapment of the seventh cranial nerve leading to recurrent facial palsy that is initially intermittent and eventually constant, resulting in impaired facial movements in adulthood
  • Conductive hearing loss in childhood followed by additional entrapment of the eighth cranial nerve and closure of the oval and round windows, leading to sensorineural hearing loss in adulthood
  • Distortion of the face with asymmetric mandibular hypertrophy, frontal bossing, midface hypoplasia, and proptosis
  • Tall stature with accelerated bone growth beginning in childhood
• Variable cutaneous or bony syndactyly of fingers two (index) and three (middle), and occasionally fingers three and other fingers. The syndactyly is usually bilateral but not necessarily symmetric
• Radial deviation of the terminal phalanges
• Dysplastic or absent nails

The majority of persons affected with sclerosteosis are members of the Afrikaner (Dutch ancestry) population of South Africa. The diagnosis should be suspected in any neonate in this population with syndactyly of the second and third fingers particularly in the presence of fluctuating facial palsy, which later may become permanent.

Radiographic findings include the following:

• Widening (hyperostosis) and increased density (sclerosis) of the calvarium, the base of the skull, and the shafts of the tubular bones
• Undermodeling of the shafts of the tubular bones of the metacarpals and phalanges
• Broad and dense clavicles and ribs
• Sclerosis of the scapulae and pelvis without an increase in size
• Relative sparing of the spine [Beighton et al 1976, Hamersma et al 2003]

Van Buchem disease. This disorder is milder than sclerosteosis. Neurologic complications are less common and syndactyly does not occur.

Testing

Serum concentration of calcium and phosphorus are normal in individuals with sclerosteosis and van Buchem disease.

Serum concentration of alkaline phosphatase may be elevated.

Urinary cross-linked N-telopeptide was significantly elevated in one study of six individuals with van Buchem disease [Wergedal et al 2003]. Serum procollagen peptide and osteocalcin concentrations were also significantly elevated in these individuals.

Histologic examination of the bone reveals increased bone density with thicker than normal trabeculae and cortices.

Molecular Genetic Testing

Gene. SOST is the only gene in which mutations are known to cause sclerosteosis and van Buchem disease.

• Sclerosteosis. SOST mutations reported thus far in individuals with sclerosteosis: three distinct stop mutations in families of Afrikaner, Brazilian, and mixed descent (northern European/Native American/African American), a splicing mutation in an individual of African heritage from Senegal [Balemans et al 2001, Brunkow et al 2001], and a missense mutation in siblings of Turkish stock [Piters et al 2010]
• Van Buchem disease. Balemans et al [2002b] and Staehling-Hampton et al [2002] identified a 52-kb homozygous deletion downstream of SOST in all Dutch individuals with van Buchem disease studied to date. The deletion does not appear to overlap the coding region of SOST or any other gene and potentially results in reduced SOST transcription by cis regulatory action or a position effect. None of the Dutch individuals affected with van Buchem disease in these studies were found to have mutations within SOST. A putative disease-causing splicing mutation in SOST was found in a brother and sister of German origin who were diagnosed with van Buchem disease [Balemans et al 2005].

Clinical testing

• Targeted mutation analysis. Targeted mutation analysis for the 52-kb deletion downstream of SOST is available on a clinical basis. It is not clear what percentage of individuals with van Buchem disease (or potentially sclerosteosis) have this mutation.

Table 1. Summary of Molecular Genetic Testing Used in SOST-Related Sclerosing Bone Dysplasias

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
SOST	Sequence analysis	Sequence variants 2	Unknown	Clinical
	Targeted mutation analysis	52-kb deletion downstream of SOST 3	Unknown

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

3. Balemans et al [2002b] and Staehling-Hampton et al [2002]

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To establish the diagnosis in a proband. Diagnosis is based on recognition of the characteristic clinical and radiologic manifestations, along with any relevant family data.

To confirm the diagnosis in a proband. Molecular genetic testing can be used, when available.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

Apart from sclerosteosis, van Buchem disease, and craniodiaphyseal dysplasia, no other simple genetic disorders are known to be associated with mutations in SOST. However, common non-coding polymorphisms in the gene were found to moderately affect bone mineral density in the elderly, suggesting a role for the product encoded by SOST in the complex disorder, osteoporosis [Uitterlinden et al 2004].

Natural History

Hypothesized to be allelic disorders [Beighton et al 1984], sclerosteosis and van Buchem disease were confirmed to be caused by mutations in the same gene in 2002 [Balemans et al 2002b, Staehling-Hampton et al 2002]. The manifestations of van Buchem disease are generally milder than those in sclerosteosis and syndactyly is absent (Table 2) [Beighton et al 1984].

Sclerosteosis. The major clinical features of sclerosteosis are progressive skeletal overgrowth and variable syndactyly, usually of the second (index) and third (middle) fingers. Affected individuals appear normal at birth except for syndactyly (seen in 76%). The distinctive facial features are usually apparent by age five years. The risk for fractures, osteomyelitis, or bone marrow failure is not increased.

Hyperostosis of the skull results in narrowing of the foramina, causing entrapment of the seventh cranial nerve often leading to facial palsy [Hamersma & Hofmeyr 2007]. Entrapment of the eighth cranial nerve resulting in deafness in mid-childhood occurs in 82% of affected individuals [Hamersma et al 2003]. Anosmia may develop in adulthood.

Asymmetric overgrowth of the mandible and malalignment of the teeth are common [Stephen et al 2001], occurring in 73% in one study [Hamersma et al 2003]. Proptosis is common (25%).

Hyperostosis of the calvarium reduces intracranial volume, leading to potentially lethal elevation of intracranial pressure. Affected individuals typically experience headache from brain compression. Sudden death can result from compression of the medulla at the level of the foramen magnum. Thus, even though the occipital frontal circumference (OFC) may be at the 95th centile, the intracranial volume is typically smaller than normal. The calvarial bone itself can be up to 3-4 cm thick.

Dual x-ray absorptiometry in seven affected persons revealed markedly increased bone mineral density (BMD). In 18 phenotypically normal heterozygotes, the BMD was above the mean values of age-matched controls [Gardner et al 2005].

Survival into old age is unusual but not unprecedented [Barnard et al 1980]. Mean age of death is 33 years [Hamersma et al 2003], but with increasing use of early craniectomy, longer term survival is likely. The natural history of sclerosteosis has been reviewed in Beighton [1988], Beighton [1995], and Hamersma et al [2003].

Van Buchem disease. Individuals with van Buchem disease have normal stature and no syndactyly. The course of the disorder is similar to that of sclerosteosis but generally milder. Facial distortion is less severe and the frequency of neurologic complications is lower.

Craniodiaphyseal dysplasia (CDD). In the autosomal dominant form of CDD [OMIM 122860] heterozygous SOST mutations have been documented in two affected children in Korea and Poland [Kim et al 2011]. Details of the phenotype in the latter child had been published previously [Bieganski et al 2007]. The main phenotypic features are progressive overgrowth of the craniofacial bones with deafness, facial palsy, and visual disturbance as a result of nerve entrapment. Choanal stenosis is a clinically significant complication. Radiologically the cranial and facial bones are hyperostotic while the diaphyses of the limb bones are expanded with thin cortices. The authors suggested that this form of CDD was part of the spectrum that includes sclerosteosis and van Buchem disease.

Genotype-Phenotype Correlations

If sclerosteosis, van Buchem disease, and CDD are regarded as a spectrum of disorders caused by mutations in SOST [Kim et al 2011], the concept of genotype-phenotype correlation in this group of disorders is tenable.

In CDD, SOST mutations are located in the secretion signal of the gene and prevented sclerostin secretion possibly by a dominant negative mechanism [Kim et al 2011].

Nomenclature

In the past, sclerosteosis and van Buchem disease have been grouped with other dense bone disorders under nonspecific general terms including marble bones, osteopetrosis, and Albers-Schönberg disease. Diagnostic precision and syndromic delineation followed and the term "sclerosteosis" became established. Similarly, van Buchem and his colleagues employed the designation "hyperostosis corticalis generalisata familiaris" for the condition that is now known as "van Buchem disease."

In the nosology of the dense bone disorders, sclerosteosis and van Buchem disease have been categorized as "craniotubular hyperostoses." With the elucidation of the molecular basis of these conditions, they are now classified together as SOST-related sclerosing bone dysplasias.

Prevalence

Sclerosteosis. During the last 40 years, sclerosteosis has been recognized in more than 70 persons in the Afrikaner (Dutch ancestry) community of South Africa [Beighton & Hamersma 1979, Hamersma et al 2003]. In the Afrikaner population of South Africa, the carrier rate for the single founder-derived mutation is approximately one in 100 [Gardner 1999].

Simplex cases (i.e., a single affected individual in a family) or occurrences of familial sclerosteosis have been recorded in the following populations:

• United States [Higinbotham & Alexander 1941, Kelley & Lawlah 1946, Stein et al 1983]
• Germany [Pietruschka 1958]
• Japan [Sugiura & Yasuhara 1975]
• Brazil [Freire de Paes Alves et al 1982, Kim et al 2008]
• Spain [Bueno et al 1994]
• Senegal [Tacconi et al 1998]
• Greek Cypriot [Itin et al 2001]
• Turkey [Piters et al 2010]

Van Buchem disease. Van Buchem disease has been recognized predominantly in the Dutch population (±20 cases). Several of the affected families have ancestral origins on the former island of Urk in the Zuider Zee. In addition, a brother and sister of German origin with a possible diagnosis of van Buchem disease were described [Balemans et al 2005].

Craniodiaphyseal dysplasia (CDD). The two children reported to date with SOST-related CDD were from Korea and Poland [Kim et al 2011].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with SOST-related sclerosing bone dysplasias, the following evaluations are recommended:

• Formal audiologic evaluation
• Neurologic evaluation for consequences of cranial nerve entrapment
• Ophthalmologic evaluation for evidence of increased intracranial pressure and/or proptosis
• Assessment of the necessity for surgical correction of syndactyly in individuals with sclerosteosis
• Radiographic and imaging studies
• Dental assessment

Treatment of Manifestations

The bones in sclerosteosis are thick and dense; surgical intervention may be difficult and prolonged. Standard neurosurgical instruments may not be sufficient (i.e., drill bits may be too short and power tools may be damaged by the dense bone) [du Plessis 1993]. In addition, bone regrowth occurs and may cause recurrence of symptoms.

Management is based on surgical decompression of the entrapped cranial nerves that can cause recurrent facial paralysis similar to Bell's palsy (from age two years onwards). Trigeminal nerve decompression can help if facial pain is severe.

Craniectomy is required if intracranial pressure becomes elevated (from age five years onwards but usually in young adulthood). In South Africa this procedure is undertaken at an increasingly younger age.

Middle ear surgery to correct conductive hearing loss and the provision of hearing aids may be helpful. Brain stem implantation of electrodes is indicated if there is obliteration of the internal auricular canal and damage to the auditory nerve.

Spinal cord decompression may occasionally be needed in adulthood to alleviate backache.

Surgical correction of syndactyly may be necessary in early childhood in order to improve function and cosmetic appearance in those with sclerosteosis.

Mandible reduction may be performed for cosmetic reasons or if mouth closure is impaired as a result of overgrowth of the mandible. Tooth extraction may be difficult. Management by an orthodontic or craniofacial team is recommended.

Surveillance

Annually from infancy onwards for the following:

• Audiologic assessment
• Assessment for increased intracranial pressure and medullary compression
• Neurologic and otologic examination for consequences of cranial nerve entrapment
• Dental and orthodontic evaluation of tooth malalignment and malocclusion on an individual basis.

Evaluation of Relatives at Risk

The following are appropriate:

• Clinical appraisal and lateral skull radiograph as indicated
• Molecular genetic testing of the parents if the SOST mutations have been identified in the proband

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Surgery for proptosis has not been successful [De Villiers & du Plessis 1995].

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

Sclerosteosis and van Buchem disease are SOST-related sclerosing bone dysplasias which are inherited in an autosomal recessive manner.

SOST-related craniodiaphyseal dysplasia is inherited in an autosomal dominant manner. Since molecular investigations in only two cases have been reported to date, this mode of inheritance is yet to be confirmed.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are heterozygotes (carriers).
• In sclerosteosis, some heterozygotes have calvarial widening.

Sibs of a proband

• At conception, each sib of a proband has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.

Offspring of a proband

• The offspring of an individual with sclerosteosis or van Buchem disease are obligate heterozygotes (carriers) for a disease-causing mutation in SOST.
• If the reproductive partner of the proband is heterozygous for an SOST mutation, each offspring has a 50% chance of inheriting two copies of an SOST mutation and being affected. Reproductive partners are more likely to be carriers of an SOST mutation if they are related to the proband or are members of populations with a high carrier frequency.
• Sclerosteosis. In the Afrikaner population of South Africa, the carrier rate is approximately 1:100.
• Van Buchem disease. The Dutch population is the only population known to have an elevated carrier rate for mutations in SOST.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations in the family have been identified.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutations in the family must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Ultrasound examination. Ultrasound examination may be able to detect syndactyly in fetuses at risk for sclerosteosis. This finding is variable in sclerosteosis and therefore its presence in an at-risk fetus is indicative of SCL, but its absence is not indicative of an unaffected fetus.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

Sclerosteosis is a disorder of bone modeling and remodeling, especially of the skull and diaphyseal region of the long bones. Current evidence supports a deficiency of sclerostin, a novel regulatory protein that is normally secreted from terminally differentiated cells embedded within a mineralized matrix, such as osteocytes, mineralized hypertrophic chondrocytes, and cementocytes [Winkler et al 2003, van Bezooijen et al 2004, Poole et al 2005, van Bezooijen et al 2009] resulting in the increased bone density observed in sclerosteosis and van Buchem disease. Carriers (heterozygotes) of pathologic SOST gene variants, while free of any clinical symptoms or complications of sclerosteosis, undergo the process of bone turnover and exhibit bone mineral densities at levels that are intermediate between normal and affected individuals, pointing to the body’s exquisite sensitivity to absolute levels of sclerostin [Gardner et al 2005, van Lierop et al 2011].

Normal allelic variants. Normal allelic variants within the sclerostin signal sequence as well as in the non-coding sequence flanking the two-exon SOST gene have been reported [Balemans et al 2002a, Uitterlinden et al 2004].

Pathologic allelic variants. Consistent with the autosomal recessive inheritance pattern of the disorder, all SOST mutations reported thus far result in loss of function of the gene product, by introduction of a termination codon, splice site mutations, or missense mutation [Balemans et al 2001, Brunkow et al 2001, Balemans et al 2005, Piters et al 2010]. A 52-kb downstream deletion potentially resulting in altered regulation of SOST was shown to be associated with van Buchem disease in Dutch individuals studied by Balemans et al [2002b] and Staehling-Hampton et al [2002]. The inhibitory effect of this deletion on SOST expression was demonstrated in a transgenic mouse model [Loots et al 2005]. See Table A.

Normal gene product. SOST encodes a 213-amino acid propeptide (sclerostin) with a cystine-knot motif that participates in dimerization and receptor binding and a signal sequence for secretion. It was first described as a secreted bone morphogenetic protein (BMP) antagonist, thought to be derived from either osteoblasts/osteocytes after onset of mineralization [Winkler et al 2003, Van Bezooijen et al 2004, Poole et al 2005] or from osteoclasts [Kusu et al 2003]. For reviews, see van Bezooijen et al [2005a], van Bezooijen et al [2005b], and Moester et al [2010].

Sclerostin has been shown to dimerize with the BMP antagonist noggin, suggesting an efficient mechanism for the fine-tuning of BMP activity and bone formation [Winkler et al 2004].

One study found that expression of sclerostin effected apoptosis of osteoblasts in a differentiating culture [Sutherland et al 2004a]. More recent evidence points to a major role for sclerostin in regulating bone growth via down-modulation of Wnt signaling through its association with the Wnt co-receptors LRP5 and LRP6 [Li et al 2005, Semënov et al 2005]. The expression of SOST is positively influenced by the presence of specific BMPs [Ohyama et al 2004, Sutherland et al 2004b] and may be a direct target of the osteoblast-specific transcription factor Cbfa1/RUNX2 (see Cleidocranial Dysplasia) [Sevetson et al 2004].

Osteocytes are thought to be involved in mechanosensing and initiation of the bone anabolic response to mechanical loading; interestingly, expression of SOST in these cells decreases with loading and increases with unloading, suggesting a role for Wnt signaling in response to mechanical loading [Robling et al 2008, Lin et al 2009, Moustafa et al 2009].

Abnormal gene product. The type of mutations in SOST suggests loss of function of the gene product.

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Acknowledgments

Peter Beighton is the grateful recipient of support from the Medical Research Council and the National Research Foundation of South Africa.

Revision History

• 10 January 2013 (cd) Revision: prenatal testing for SOST mutations available clinically
• 12 January 2012 (me) Comprehensive update posted live
• 5 October 2007 (cd) Revision: sequence analysis available on a clinical basis
• 2 February 2007 (me) Comprehensive update posted to live Web site
• 23 September 2004 (me) Comprehensive update posted to live Web site
• 4 June 2002 (tk/me) Review posted to live Web site
• 5 February 2002 (phb) Original submission