Sost-Related Sclerosing Bone Dysplasias

Clinical characteristics.

SOST-related sclerosing bone dysplasias include sclerosteosis and van Buchem disease, both disorders of progressive bone overgrowth due to increased bone formation.

The major clinical features of sclerosteosis are progressive skeletal overgrowth, most pronounced in the skull and mandible, and variable syndactyly, usually of the second (index) and third (middle) fingers. Affected individuals appear normal at birth except for syndactyly. Facial distortion due to bossing of the forehead and mandibular overgrowth is seen in nearly all individuals and becomes apparent in early childhood with progression into adulthood. Hyperostosis of the skull results in narrowing of the foramina, causing entrapment of the seventh cranial nerve (leading to facial palsy) with other, less common nerve entrapment syndromes including visual loss (2nd cranial nerve), neuralgia or anosmia (5th cranial nerve), and sensory hearing loss (8th cranial nerve). In sclerosteosis, hyperostosis of the calvarium reduces intracranial volume, increasing the risk for potentially lethal elevation of intracranial pressure. Survival of individuals with sclerosteosis into old age is unusual, but not unprecedented.

The manifestations of van Buchem disease are generally milder than sclerosteosis and syndactyly is absent; life span appears to be normal.

Diagnosis/testing.

The diagnosis of SOST-related sclerosing bone dysplasia is established in a proband with typical clinical and radiographic findings and identification of biallelic pathogenic variants in SOST (for sclerosteosis) or the presence of a biallelic 52-kb deletion downstream of SOST (for van Buchem disease) on molecular genetic testing.

Management.

No specific treatment is currently available, and management aims at relieving symptoms and preventing complications.

Treatment of manifestations: Surgical correction of syndactyly; surgical decompression of entrapped cranial nerves, notably the facial nerve; craniectomy and ventriculo-peritoneal drain for increased intracranial pressure; surgical reduction of mandibular overgrowth; hearing aids with middle ear surgery or cochlear implant depending on nature of hearing loss; spinal cord decompression for radiculopathy; orbital decompression for proptosis or glaucoma.

Surveillance: At least annual assessments from infancy for bone mass, evidence of cranial nerve entrapment and of increased intracranial pressure, vision issues, hearing loss, and tooth malalignment/malocclusion.

Agents to avoid: Agents known to suppress bone resorption (e.g., bisphosphonates, denosumab, selective estrogen receptor modulators) and agents known to stimulate bone formation (e.g., teriparatide, abaloparatide, romozosumab).

Genetic counseling.

SOST-related sclerosing bone dysplasia is inherited in an autosomal recessive manner. Each sib of an affected individual 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. Prenatal diagnosis for pregnancies at increased risk and preimplantation diagnosis for SOST-related sclerosing bone dysplasias are possible if the pathogenic variants in the family have been identified. Ultrasound examination may detect syndactyly in fetuses at risk for sclerosteosis, but its absence on ultrasound examination does not rule out an affected fetus.

Suggestive Findings

SOST-related sclerosing bone dysplasias should be suspected in individuals with the following findings.

Clinical findings

• 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, or 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. (Note: Syndactyly is not found in van Buchem disease.)
• Radial deviation of the terminal phalanges
• Dysplastic or absent nails

Radiographic findings

• 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
• High bone mineral density (Z-score >5) measured by dual energy x-ray absorptiometry (DXA) [van Lierop et al 2017]

Ethnicity and neonatal findings. The majority of persons affected with sclerosteosis are members of the Afrikaner (Dutch ancestry) population of South Africa. Within this population the diagnosis should be suspected in any neonate with syndactyly, or in the presence of fluctuating facial palsy.

Van Buchem disease is almost exclusively found within the Netherlands. There are no specific neonatal findings in patients with van Buchem disease, although facial palsy can already be present at birth [van Egmond et al 2012].

Establishing the Diagnosis

The diagnosis of SOST-related sclerosing bone dysplasia is established in a proband with typical clinical and radiographic findings and biallelic pathogenic variants involving SOST identified on molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of SOST-related sclerosing bone dysplasia is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with atypical findings in whom the diagnosis of SOST-related sclerosing bone dysplasia has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Hypothesized to be allelic disorders [Beighton et al 1984], sclerosteosis and van Buchem disease were confirmed to be caused by pathogenic variants in the same gene in 2002 [Balemans et al 2002, Staehling-Hampton et al 2002]. The two disorders have very similar phenotypes caused by genetic deficiency of sclerostin; however, the manifestations of van Buchem disease are generally milder than those in sclerosteosis and syndactyly is absent (Table 2) [Beighton 1995]. Taken together, these two disorders are known as SOST-related sclerosing bone dysplasias.

Genotype-Phenotype Correlations

There is no apparent difference in phenotype associated with any of the known SOST pathogenic variants. The phenotype of van Buchem disease, which is not caused by pathogenic variants in SOST itself but by a 52-kb deletion downstream of SOST, is milder than that of sclerosteosis.

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 is primarily found among the Afrikaner (Dutch ancestry) community of South Africa, where the carrier rate is estimated at 1:100 and prevalence at 1: 60.000 [Beighton & Hamersma 1979]. However, cases outside the Afrikaner population have been reported [van Lierop et al 2017]. With 96 cases reported worldwide up to 2017, of which 66 were from South Africa, sclerosteosis is an extremely rare disease outside South Africa.

There have been only 31 reported cases of van Buchem disease, of which 29 were from the Netherlands and two were from Germany [van Lierop et al 2017].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with a SOST-related sclerosing bone dysplasia, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended:

Treatment of Manifestations

No specific treatment for sclerosteosis or van Buchem disease is currently available, and management aims at relieving symptoms and preventing complications. Treatment of these disorders therefore mainly consists of surgical intervention to ameliorate complications.

In one adult case of severe van Buchem disease, treatment with glucocorticoids was successful in suppressing bone formation and disease progression [van Lierop et al 2010], although the individual still needed repeated surgery [Datema et al 2015]. In two children with van Buchem disease short courses of prednisolone were given during exacerbations of facial palsies. While biochemical bone turnover markers decreased during therapy, there was no clinical improvement of steroid treatment in these cases [van Egmond et al 2012] The long-term benefits of this treatment in sclerosteosis or van Buchem disease have not been studied.

Important note: 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.

Surveillance