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.
Clinical Features of Sclerosteosis
Syndactyly, ranging from soft-tissue webbing to bony union of the phalanges, is found at birth in 66% of individuals. It most often affects the second and third fingers, although other fingers or toes can be affected as well.
More subtle deformity of the digits can also be seen, such as radial deviation of the phalanges or nail aplasia [Itin et al 2001].
Facial distortion due to bossing of the forehead and mandibular overgrowth is seen in 90% of individuals, with proptosis, hypertelorism, or midfacial hypoplasia found in some. These facial findings become apparent in early childhood and progress into adulthood [Hamersma et al 2003, van Lierop et al 2017].
Tall stature appears at school age. Longitudinal growth arrests at puberty, by which time individuals can reach heights exceeding two meters (6.5 feet).
Recurrent facial palsies are hallmark complications in sclerosteosis, affecting 93% of individuals. The first episodes develop in early childhood and in some cases within the first months of life. The palsies are caused by narrowing of the neural foramina due to bone overgrowth of the skull.
Other, less common nerve entrapment syndromes in sclerosteosis are visual loss (2nd cranial nerve), neuralgia or anosmia (5th cranial nerve), and sensory hearing loss (8th cranial nerve) [van Lierop et al 2017].
Hearing loss is also highly prevalent, affecting 94% of individuals. It starts as conductive hearing loss in childhood, but often progresses into mixed conductive, sensorineural hearing loss later in life [Hamersma et al 2003, van Lierop et al 2017].
Increased intracranial pressure can develop due to narrowing of the intracranial cavity by the thickening of calvaria. It often starts in late adolescence. In a recent study, it was reported in 71% of individuals with sclerosteosis, and was considered the cause of death in 12 out of 33 deceased individuals of Afrikaner background, while six additional individuals died due to perioperative complications [van Lierop et al 2017].
Clinical course of the disease. While syndactyly is the only symptom of sclerosteosis present at birth, other symptoms develop early in childhood. The disease progresses into adulthood but appears to stabilize in the third decade in the majority of those with sclerosteosis [van Lierop et al 2011, van Lierop et al 2013].
Clinical Features of van Buchem Disease
All of the above features can be found, except for syndactyly.
Overall there is a milder phenotype than observed in sclerosteosis. For example, increased intracranial pressure is rare in individuals with van Buchem disease [van Lierop et al 2010, van Lierop et al 2013].
Van Buchem disease also tends to stabilize in adulthood [van Lierop et al 2013].
Table 2.
Distinguishing Features of Sclerosteosis and van Buchem Disease
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| Sclerosteosis | van Buchem Disease |
---|
Reported cases
| 96 | 31 |
Prognosis
| Potentially lethal | Comparatively benign |
Habitus
| Gigantism | Normal stature |
Facies
| Gross distortion | Prominent mandible |
Teeth
| Malaligned, w/malocclusion | Normal |
Cranial nerve palsy
| Very common | Common |
Intracranial pressure
| Raised | Inconsistent elevation |
Syndactyly
| Frequent | Absent |
Nail hypoplasia
| Frequent | Absent |
Cranial hyperostosis
| Gross | Moderate |
Distortion of tubular bones of hands & feet
| Marked | Mild |
Laboratory Tests
Sclerostin. Serum levels of sclerostin are undetectable in sclerosteosis [van Lierop et al 2011], but low levels can be detected in patients with van Buchem disease [van Lierop et al 2013].
Bone formation markers. Levels of bone formation markers, such as procollagen type 1 aminoterminal propeptide (P1NP), alkaline phosphatase, or osteocalcin, are elevated in both sclerosteosis and van Buchem disease. Levels decline with age but remain elevated above the upper limit of normal in the majority of individuals [Wergedal et al 2003, van Lierop et al 2011, van Lierop et al 2013].
Bone resorption markers. Levels of the bone resorption marker serum collagen type 1 cross-linked C-telopeptide (sCTX) are increased in childhood, but levels decrease with age toward the lower end of the reference range in adulthood [van Lierop et al 2011, van Lierop et al 2013]. Urinary cross-linker N-telopeptide (uNTX) was elevated in six individuals with van Buchem disease [Wergedal et al 2003].
Normal findings. Serum concentrations of calcium and phosphorus and levels of parathyroid hormone are normal [Epstein et al 1979, van Lierop et al 2011].
Bone Findings
Bone mineral density measured by DXA is greatly increased with Z-scores ranging from +7.7 to +14.4 at the spine and +7.8 to +11.5 at the hip in individuals with sclerosteosis [Balemans et al 2005, Piters et al 2010, Power et al 2010, van Lierop et al 2011], and from +5.4 to +12.3 at the spine and +5.2 to +12.1 at the hip, in individuals with van Buchem disease [van Lierop et al 2013].
Histologic examination of bone reveals increased bone volume and thickness of cortex and trabeculae, increased osteoblastic bone formation with normal or decreased osteoclastic bone resorption, and no abnormal mineralization of bone tissue [Stein et al 1983, van Lierop et al 2017, Hassler et al 2014].
The high bone density in sclerosteosis is not associated with increased mineralization [Hassler et al 2014], as is seen in osteopetrosis, but there is an increased biomechanical competence of the bone and resistance to fractures [van Lierop et al 2017].
The risk for fractures, osteomyelitis, or bone marrow failure is not increased.
Life Expectancy
Survival into old age is unusual in sclerosteosis but not unprecedented [Barnard et al 1980, van Lierop et al 2011, van Lierop et al 2013]. Life expectancy is reduced because of sudden deaths due to herniation of the brain stem, or perioperative complications from surgery to correct increased intracranial pressure. 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], Hamersma et al [2003], and van Lierop et al [2017].
Life expectancy in van Buchem disease appears to be normal and individuals have had no significant comorbidities. Sudden death due to herniation of the brain stem has never been reported in patients with van Buchem disease. The oldest individual to be studied was 81 years old with type 2 diabetes mellitus, mild heart failure, and non-metastasized prostate cancer, comorbidities frequent in elderly populations [van Lierop et al 2017].
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].