Marble bone disease and sclerosteosis
Marble bone disease is an umbrella term for genetic conditions characterised by very hard, dense bone formation. Sclerosteosis is the variant seen in South Africa, and patients present with recurrent facial nerve palsies in childhood, hearing loss and abnormalities of the toes and fingers. Hearing aids are usually indicated for hearing loss. Surgery may correct the abnormal bone growth of the ear and the hearing loss. Early surgical decompression of the inner ear canal can prevent future facial nerve weakness and hearing loss.
A child who presents with Bell’s palsy in South Africa may be suffering from sclerosteosis. If there are also any abnormalities of the fingers or toes, it heightens the suspicion
The contribution of Prof Herman Hamersma
Professor Herman Hamersma (1929-2020), the former Professor and Head of the ENT Department at the University of Pretoria, has devoted his entire career to managing patients with sclerosteosis. His unwavering dedication and commitment to the field have made him a respected figure in the medical community. The tireless efforts of Professor Hamersma have undoubtedly contributed significantly to advancing our understanding and treatment of this rare genetic disorder. His legacy is of diligence, compassion, and excellence in patient care. The medical community owes an outstanding debt of gratitude to Professor Hamersma for his selfless service in medicine.
In 1958, the late Prof Herman Hamersma diagnosed the first case of sclerosteosis in South Africa. Since then, nearly 100 cases have been diagnosed. Over the recent years, Dr Hofmeyr has closely collaborated with Dr Hamersma and currently oversees the surgical care of these patients.
Credit also has to go to Prof Peter Beighton, a distinguished geneticist from Cape Town who collaborated and worked closely with Prof Hamersma through the years. Their extensive research and work within Sclerosteosis have led to numerous noteworthy publications, contributing significantly to the scientific community (1,2).
Sclerostin and the SOST gene
Sclerosteosis is inherited in an autosomal recessive fashion. This means that both parents must be carriers of the abnormal gene to transmit the condition. Sclerostin is a protein encoded by the SOST gene, primarily expressed in the bone. It works as an extracellular antagonist of the Wnt signalling pathway, essential for regulating bone tissue formation and maintenance. The SOST gene is located on chromosome 17, and mutations in this gene have been associated with sclerosteosis(3). Sclerostin is absent in patients with sclerosteosis.
Sclerosteosis and Van Buchems disease
Van Buchem disease is also a rare genetic conditions that affect bone growth. It is closely related to sclerosteosis. Van Buchem disease is characterised by bone overgrowth, particularly in the limbs’ skull, jaw, and long bones (4). Sclerosteosis, on the other hand, is a more severe form of bone overgrowth that can cause compression of the nervous system and restrict the movement of joints.
Van Buchem disease is uncommon in South Africa. It originated in the fishing village Urk in the Netherlands. It is believed that mutation of the defective gene in South African descendants of the Dutch is to blame for sclerosteosis
The difference between sclerosteosis and osteopetrosis
Sclerosteosis and osteopetrosis are distinct diseases that differ in several aspects. While abnormalities in osteoclastic function cause osteopetrosis, sclerosteosis is mainly a disorder of osteoblastic hyperactivity. Therefore, bone overgrowth and generalised skeletal sclerosis in sclerosteosis are not observed in osteopetrosis. It is essential to reserve the term “osteopetrosis” for the specific condition where generalised bony sclerosis predominates without bone overgrowth. The differences between these two diseases highlight their unique pathology, which may require different treatment approaches (5).
The link between sclerosteosis and osteoporosis
Osteocytes in the bone primarily secrete sclerostin, which regulates bone formation and turnover. It works by inhibiting osteoblasts’ activity, the cells responsible for bone formation. While sclerostin is crucial in maintaining bone mass and strength, excessive protein production can lead to osteoporosis, a condition characterised by low bone density and an increased risk of fractures.
The pathology of sclerosteosis
Bones in the human body are constantly undergoing modification. This process consists of two stages: bone formation by the osteoblasts, balanced with bone resorption by the osteoclasts. Abnormal bone growth can be explained by either an increase in the function of osteoblasts (formation) or a decrease in the function of osteoclasts (resorption). Sclerosteosis is explicitly associated with an increase in bone formation (hyperostosis). In sclerosteosis, the lack of sclerostin leads to the loss of regulation of osteoblasts, which leads to hyperostosis.
Sclerostin inhibits bone formation by suppressing osteoblasts. The Wnt pathway is initiated when LRP5/6, Wnt, and Frizzled interact. This interaction leads to the release of b-catenin, which moves into the nucleus and activates transcription from Wnt target genes. However, it blocks the Wnt canonical pathway when Sclerostin binds to LRP5/6 and Frizzled coreceptors on osteoblasts. This binding causes b-catenin to be phosphorylated and degraded. Consequently, Sclerostin inhibits bone formation by suppressing osteoblasts and increases bone resorption by promoting RANKL production by osteoblasts (4).
The clinical findings of sclerosteosis
Sclerosteosis is a medical condition that manifests various clinical findings, such as overgrowth of the skull, denser bones, more prominent jaws, and thickened limb bones. All the bones in the body are affected. Patients suffering from this condition may also experience hearing loss, facial palsy, dental problems, and vision impairment. Those afflicted may have finger and toe abnormalities, including absent or deformed digits and nails (6,7,8).
In some cases, the initial sign of sclerosteosis is facial nerve paralysis, similar to Bell’s palsy. Therefore, those children with Bell’s palsy should be tested for sclerosteosis. Patients can also present with bilateral facial nerve paralysis (9).
Patients affected by the condition tend to be above average in height. Still, their intelligence and life expectancy are normal if their raised intracranial pressure is prevented through timely childhood cranial decompression surgery (10).
Special tests in sclerosteosis
Plain X-rays of the skull base and spine can help show dense bone and X-rays of the hands and feet define finger and toe abnormalities.
Cone beam CT scanning is the preferred method for assessing bony skull base abnormalities and foramina narrowing before surgery and during follow-up examinations. MRI is useful for evaluating any effect of encroaching bone on soft tissue and identifying raised intracranial pressure. It is vital to perform this imaging until the disease settles in adult life.
Regular hearing and eye tests are necessary to manage and monitor patients (11).
Genetic testing
Genetic testing can help identify individuals at risk of developing the disease or carriers of the condition. It can also provide vital information for families with a history of sclerosteosis, enabling them to make informed decisions about their health and future reproductive plans.
Genetic testing involves the collection of a small sample of DNA, typically taken from a blood or saliva sample. The DNA is then analysed in a laboratory to identify mutations in the gene responsible for developing sclerosteosis.
Hearing and hearing loss in sclerosteosis
Sclerosteosis results in both conductive and mixed hearing loss (11). The former is caused primarily by the abnormal bone interfering with the ear’s ossicles or hearing bones (12). Drilling excess bone away may provide transient relief, but bone regrowth occurs. Consequently, decompressing the ossicles through surgery could pose a risk of further hearing loss resulting from cochlear noise damage. Therefore, it is recommended that affected individuals resort to hearing aids initially, with surgery being a last resort, administered only when the condition has stabilised and the patient is older.
While sclerosteosis narrows the external ear canal, the resultant hearing loss is rare except when total occlusion or excessive wax buildup is a contributing factor.
Internal auditory canal narrowing may result in sensorineural hearing loss. Decompressing this canal could prevent facial nerve paralysis and sensorineural hearing loss.
Patients could consider using implantable hearing devices such as Bonebridge or cochlear implants. It is essential to seek medical help upon detecting signs of hearing loss and adhere strictly to professional guidance.
Modifying sclerosteosis at the molecular level
The treatment options for sclerosteosis are limited and often surgical, with little to no impact on the underlying disease process. The reduction of the space inside the skull and the narrowing of the foramina, where blood vessels and nerves traverse, causes the problem.
Recent preclinical studies and the work of Dr Timothy Dreyer have demonstrated the potential of recombinant sclerostin as a treatment for sclerosteosis. Administered intravenously or subcutaneously, recombinant sclerostin has been shown to inhibit bone formation and reduce bone mineral density in animal models of the disease, offering a promising avenue for further research and development of therapeutic interventions. If successful, it may prevent or reduce the narrowing effect. (14).
Further preclinical and clinical studies are necessary to fully realise this approach’s therapeutic potential, but the current evidence suggests an exciting future for this field of research. We wish Timothy all the best in his research.
Sclerostin and osteoporosis treament
Researchers have developed osteoporosis treatments targeting excess sclerostin production. These treatments are typically administered through injections and work by neutralising the inhibitory effects of sclerostin on bone formation. This promotes the activity of osteoblasts, resulting in increased bone formation and higher bone mineral density (3).
One such treatment is the monoclonal antibody Romosozumab, which has been shown to reduce fracture risk in postmenopausal women with osteoporosis significantly. Other treatments that target sclerostin include the monoclonal antibodies blosozumab and LSK-85. While these treatments have shown promising results in clinical trials, more research is needed to fully understand their safety and efficacy.
After meticulously examining findings stemming from the ARCH inquiry, the FDA has ultimately sanctioned Romosozumab for addressing osteoporosis in postmenopausal women with a heightened likelihood of fracturing. Nonetheless, the European Medicines Agency (EMA) still scrutinises the drug for conclusive approval. Nevertheless, given that the drug has been validated, it holds promise for individuals who suffer from this ailment
Surgery for sclerosteosis
Recurrent episodes of facial nerve paralysis can result in the gradual weakening of the facial muscles over time. Despite partial recovery after each episode, the muscles may never fully regain their strength, leading to a mask-like appearance of the face.
Timely surgical decompression, which involves relieving pressure on the facial nerve, can prevent future attacks and halt further deterioration of facial movement (13).
Dr Hofmeyr is the only surgeon in South Africa who can perform this procedure.
Partial success has also been noted with middle-ear surgery for conductive deafness at a younger age. Bone re-growth is aggressive, and the effect of surgery is often temporary.
Those with conductive hearing loss should ideally postpone middle ear surgery until they are older and the condition has stabilised.
Elevated intracranial pressure (ICP) poses a significant threat to the quality of life and survival, as it can cause intellectual impairment, vision deterioration, and even sudden death in young individuals due to medullary compression in the foramen magnum during episodes of coughing or straining. It is worth mentioning that these patients are born with normal intelligence, and cranial decompressive procedures can improve their quality of life and extend their survival. Although prevalent in these patients, osteoblastic hyperactivity tends to decrease after the third decade of life, which may allow for relatively everyday life if normal ICP is maintained (10).
Orbital and spinal nerve decompression may be necessary. Orbital nerve decompression involves the enlargement of the bony orbit to reduce pressure on the optic nerve and improve vision. On the other hand, spinal nerve decompression aims to relieve pressure on the spinal cord and nerves to reduce pain and improve mobility.
In addition to decompression surgeries, cosmetic procedures such as a reduction in the size of the jaw may be required to address the cosmetic manifestations of the disease. These corrective surgeries can improve the physical appearance of individuals with sclerosteosis and help alleviate related symptoms, leading to a better quality of life.
A cure for sclerosteosis
There is currently no cure for this condition. Continued ongoing research into the SOST gene and sclerostin may prove beneficial in the management of osteoporosis.
Recombinant sclerostin is a protease-resistant version of the glycoprotein sclerostin produced by osteocytes and functions as a negative regulator of bone formation. It has been shown to suppress bone formation effectively and, therefore, holds potential as a therapeutic target for conditions characterised by excessive bone growth, such as sclerosteosis (14).
The Rare Bone Disease Foundation
The Rare Bone Disease Foundation is a non-profit organisation dedicated to improving the lives of individuals affected by rare bone diseases. This foundation promotes education, research, and support to patients and their families affected by uncommon skeletal conditions. The foundation provides a network of resources and programs for patients and doctors alike to help advance knowledge of the causes and treatments for these diseases. The Rare Bone Disease Foundation strives to find a cure for these debilitating conditions by raising awareness and funds for research.
The contribution of Dr Timothy Dreyer, PhD
Dr Timothy Dreyer is widely recognised as a distinguished case of sclerosteosis – having been featured in various medical television programs such as the BBC and Japanese television. He is in his 30s and holds a Doctorate in molecular biology from the University of Pretoria. He has published an animal study on recombinant sclerostin (14). His latest contribution looks into the effect of sclerostin on bone and other organs (15). He is presently engaged in research work in the UK, concentrating on finding a cure for the condition. He collaborates with the prominent pharmaceutical corporation UCB and the Royal Veterinarian College RVC, London.
