Marble bone disease

Marble bone disease

Marble bone disease is a genetic condition 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. Dr Hofmeyr successfully manages numerous of these patients.

Marble bone disease is a genetic condition characterised by very hard, dense bone formation. Sclerosteosis is the variant seen in South Africa and is related to Van Buchem’s disease, inherited in a recessive way from our Dutch ancestors. Affected patients have a dysfunctional SOST gene on chromosome 17 and cannot produce enough functional sclerostin. Sclerostin is a glycoprotein necessary for bone remodulation. Without sclerostin, bone growth increases and bone become very hard, compressing nerves and other structures.

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.

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. The partnership between the two experts has been instrumental in advancing the understanding and treatment of this rare genetic disorder.

In 1958, the initial occurrence of sclerosteosis was diagnosed by Prof Herman Hamersma. Since then, 78 cases have been established in South Africa up till now. Over the recent years, Dr Hofmeyr has closely collaborated with Dr Hamersma and currently oversees the surgical care of these patients. The diction of this passage is formal. No writing technique was utilised.

Prof Herman Hamersma diagnosed the first patient with sclerosteosis in 1958; since then, 78 patients have been diagnosed in South Africa. Dr Hofmeyr has worked closely with Dr Hamersma in the last couple of years and has taken over the surgical management of these patients. Patients present with recurrent facial nerve palsies in childhood, hearing loss and abnormalities of the toes and fingers. All the bones in the body are affected. Diagnosis can be made by X-ray. Computed tomography(CT) is the examination of choice for a detailed evaluation of the skull.

There is currently no cure for this condition. 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. Continued ongoing research into the SOST gene and sclerostin may prove beneficial in the management of osteoporosis.

Sclerostin and the SOST gene

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, a rare genetic disorder characterised by excessive bone growth.

 Studies have shown that sclerostin inhibition has therapeutic potential for bone loss diseases such as osteoporosis, and drugs targeting this protein have been developed and tested in clinical trials. The SOST gene and its protein product have played a key role in advancing our understanding of bone biology and the development of new strategies for treating bone-related diseases.

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. These two diseases’ differences highlight their unique pathology, which may require different treatment approaches.

Sclerosteosis and Van Buchems disease

Van Buchem disease and sclerosteosis are rare genetic conditions that affect bone growth. Van Buchem disease is characterised by bone overgrowth, particularly in the limbs’ skull, jaw, and long bones. 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.

Both conditions are caused by mutations in the SOST gene, which produces a protein that inhibits bone growth. When this protein is absent or present in reduced amounts, bone growth is stimulated, leading to the characteristic bone overgrowth seen in these conditions.

Symptoms of van Buchem disease and sclerosteosis include visual and hearing impairment, facial deformities, and joint stiffness. Treatment options are limited, with conservative management including physical therapy and pain management as crucial components.

The pathology of sclerosteosis

Bone in the human body is 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 osteoblastsThe 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.

The clinical findings of sclerosteosis

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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. 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. These symptoms can significantly impact the patient’s overall quality of life, and their severity can vary. 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 affected by the condition tend to have above-average height. Still, their intelligence and life expectancy are normal if their raised intracranial pressure is prevented through timely childhood cranial decompression surgery.

The diagnosis of sclerosteosis

The diagnosis of sclerosteosis is typically made through clinical examination, with the first sign often being abnormalities in the fingers or toes at birth. However, this initial symptom is frequently overlooked. The appearance of facial nerve paralysis, similar to Bell’s palsy in childhood, is another significant indicator that raises suspicion. Subsequent hearing loss also indicates the condition that may occur later in life.

In older patients, the effect of sclerosteosis becomes more apparent. 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 foraminae 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.

Hearing tests and eye tests are necessary for a proper diagnosis. Although genetic testing is not mandatory, it can be done to help confirm the diagnosis. In conclusion, a formal tone is used when discussing the diagnosis of sclerosteosis.

CT scan of the skull of a patient with sclerosteosis
Computed tomography (CT) scan of the skull of a patient with sclerosteosis

Genetic testing for sclerosteosis

Genetic testing for sclerosteosis is a medical procedure that involves the analysis of a patient’s DNA to identify mutations in the gene responsible for the development of the condition.

Genetic testing can help identify individuals at risk of developing the disease or carriers of the condition. It can also provide important information for families with a history of sclerosteosis, enabling them to make informed decisions about their health and future reproductive plans.

This type of 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.

Surgical management of sclerosteosis

Although patient usually recover after facial nerve paralysis, the recovery is always incomplete, with more functional problems after each episode. Ultimately, patients may end up with a permanent mask-like appearance due to damage to the facial nerves. Surgical decompression of the facial nerves can prevent recurrent facial nerve paralysis.

Partial success has also been noted with middle-ear surgery for conductive deafness. Bone re-growth is aggressive, and the effect is usually 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 a relatively normal life if normal ICP is maintained.

Orbital and spinal nerve decompression may be necessary to alleviate symptoms associated with sclerosteosis. 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 mandibula may be required to address the physical manifestations of sclerosteosis. These corrective surgeries can improve the physical appearance of individuals with sclerosteosis and help to alleviate related symptoms, leading to a better quality of life. Overall, a comprehensive approach to managing sclerosteosis involves a combination of medical and surgical interventions tailored to the specific needs of each individual.

Hearing and hearing loss in sclerosteosis

Sclerosteosis is known to result in both conductive and mixed hearing loss. The former is caused primarily by the abnormal bone interfering with the ear’s ossicles or hearing bones. While drilling the bone out may provide transient relief, it is expected to regrow. 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 where total occlusion or excessive wax buildup contributes.

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.

A cure for sclerosteosis

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.

Treatment options for sclerosteosis are limited and often surgical, with little to no impact on the underlying disease process.

Recent preclinical studies and the work of 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.

Further preclinical and clinical studies are necessary to realise this approach’s therapeutic potential fully, but the current evidence suggests an exciting future for this field of research. We wish Timothy all the best in his research.

The link between sclerosteosis and osteoporosis

Osteocytes in the bone primarily secrete Sclerostin, which primarily 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.

To address this issue, 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.

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 understand their safety and efficacy fully.

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.

Further research in sclerosteosis

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 33 years old and holds a Doctorate in molecular biology from the University of Pretoria. He has published an animal study on recombinant sclerostin. Presently, he is engaged in research work in the UK, concentrating on finding a cure for the condition. He is collaborating with the prominent pharmaceutical corporation UCB, and the Royal Veterinarian College RVC, London.

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. By raising awareness and funds for research, the Rare Bone Disease Foundation strives to find a cure for these debilitating conditions.

sclerosteosis
Marble bone disease is characterized by the formation of very hard dense bone

Links to Bloomberg interviews with Timothy Dreyer one of Dr Hofmeyr’s patients.[/fusion_title][fusion_text]

Research in sclerosteosis.