Osteopetrosis (infantile, malignant)

Overview

Infantile malignant osteopetrosis (IMO) is a rare inherited disorder that primarily affects bone development. In individuals with IMO, bones become abnormally dense and thick, but despite their density, they are also very fragile and prone to breaking [PMID:33678071]. This increased bone density occurs because the body's cells responsible for breaking down old bone tissue, called osteoclasts, do not function correctly. As a result, old bone is not reabsorbed and new bone continues to be formed, leading to a build-up of bone mass.

This excessive bone growth can cause several severe health problems from early infancy. The condition can narrow the spaces within bones, including those that house the bone marrow, leading to a reduction in blood cell production. It can also put pressure on nerves, particularly those in the skull, affecting sight and hearing. IMO is considered a malignant form because of its severe symptoms and early onset, often presenting in the first few months of life.

Symptoms & clinical features

The symptoms of infantile malignant osteopetrosis typically appear during infancy. A key feature is frequent bone fractures, often occurring with minimal trauma due to the bones' paradoxical fragility. The increased bone density can also lead to narrowing of the bone marrow cavity, which is crucial for producing blood cells. This can result in anaemia (low red blood cells), thrombocytopenia (low platelets, leading to bleeding problems), and leukopenia (low white blood cells, increasing infection risk) [PMID:33678071].

Another common symptom is macrocephaly, where the head circumference is larger than expected, sometimes accompanied by a prominent forehead. The abnormal bone growth in the skull can compress nerves, leading to vision impairment (due to optic nerve compression) and hearing loss (due to auditory nerve compression). Other potential symptoms include facial abnormalities, delayed tooth eruption, and susceptibility to infections due to impaired immune function.

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Affected organs

Infantile malignant osteopetrosis primarily affects the skeletal system, leading to widespread bone abnormalities throughout the body. The skull, spine, and long bones of the limbs are particularly impacted. The excessive bone growth can also indirectly affect other organ systems. For instance, the bone marrow, located within bones, is severely affected, leading to problems with blood cell production. The eyes and ears can be affected due to compression of the optic and auditory nerves as they pass through narrowed channels in the skull. In some cases, the spleen and liver may become enlarged as they try to compensate for the bone marrow's inability to produce enough blood cells.

Multiple body systems

Systemic involvement

Cellular impact

Mechanism at cellular level

Risks & severity

Infantile malignant osteopetrosis is a severe condition with significant health risks. Without treatment, the prognosis is often poor, with many affected children not surviving beyond early childhood due to complications such as bone marrow failure, severe infections, or neurological problems [PMID:33678071]. The severity of symptoms can vary, but generally, the infantile malignant form is the most severe type of osteopetrosis.

The condition typically manifests within the first few months of life. Bone marrow failure, neurological issues like blindness and deafness, and recurrent infections are common complications. The risk of fractures is lifelong. Early diagnosis and intervention are crucial for managing the condition and improving outcomes.

Genetic causes

Infantile malignant osteopetrosis is a genetic condition caused by pathogenic variants in specific genes. The most common genetic causes are variants in the *TCIRG1* gene, accounting for about 50-60% of cases, and the *CLCN7* gene, responsible for around 10-15% of cases. Both genes play critical roles in the function of osteoclasts, the cells responsible for breaking down old bone tissue.

The *TCIRG1* gene provides instructions for making a component of a 'proton pump' in osteoclasts. This pump is essential for creating the acidic environment needed to dissolve bone mineral. Pathogenic variants in *TCIRG1* impair the pump's function, preventing osteoclasts from effectively resorbing bone. Similarly, the *CLCN7* gene provides instructions for a protein that helps transport chloride ions, which is also critical for the osteoclast's ability to create an acidic environment for bone breakdown. When either of these genes has a pathogenic variant, osteoclast function is severely compromised, leading to the accumulation of dense, fragile bone characteristic of osteopetrosis.

• CLCN7
  Cl-/H+ antiporter 7
• TCIRG1
  T cell immune regulator 1, ATPase H+ transporting V0 subunit a3

Inheritance pattern

Infantile malignant osteopetrosis is inherited in an autosomal recessive pattern. This means that an individual must inherit two copies of the altered gene - one from each parent - to develop the condition. People who have only one copy of the altered gene are called carriers. Carriers typically do not show any symptoms of the condition themselves because their other unaffected copy of the gene can compensate.

When both parents are carriers of the same altered gene, there is a 25% (1 in 4) chance with each pregnancy that their child will inherit two altered copies and develop infantile malignant osteopetrosis. There is a 50% (2 in 4) chance that their child will be a carrier like them, and a 25% (1 in 4) chance that their child will inherit two unaffected copies and not be affected or a carrier.

Diagnosis & testing

Diagnosis of infantile malignant osteopetrosis often begins with clinical suspicion based on characteristic symptoms such as recurrent fractures, anaemia, neurological signs (e.g., vision/hearing problems), and characteristic X-ray findings showing increased bone density. Blood tests may reveal anaemia, low platelet counts, and other abnormalities related to bone marrow dysfunction.

Confirmation of the diagnosis typically involves genetic testing. This can identify pathogenic variants in genes known to be associated with osteopetrosis, such as *TCIRG1* and *CLCN7*. Genetic testing can be arranged through the NHS Genomic Medicine Service (GMS) via a referral to a clinical genetics service. Specific R-codes for genomic testing related to osteopetrosis may be applicable for eligible patients within the NHS. A genetic counsellor can provide more information about the testing process and implications.

Management & lifestyle

Management of infantile malignant osteopetrosis is complex and requires a multidisciplinary team of specialists. The primary treatment option that can significantly improve outcomes for many children is haematopoietic stem cell transplantation (HSCT), also known as bone marrow transplant [PMID:24075191]. This procedure aims to replace the faulty osteoclasts with healthy ones, restoring proper bone resorption.

Other management strategies focus on supportive care to address specific symptoms. This may include regular blood transfusions for anaemia, medications to manage infections, and surgical interventions to relieve nerve compression or correct bone deformities. Nutritional support, including vitamin D and calcium supplementation, may also be considered, although this does not address the underlying bone remodelling defect. Regular monitoring by specialists, including neurologists, ophthalmologists, and audiologists, is essential to manage complications as they arise.

UK care pathway

In the UK, individuals with suspected infantile malignant osteopetrosis will typically be referred to a clinical genetics service through their GP or paediatrician. Genetic counsellors within these services provide information, support, and facilitate genomic testing, which aligns with the NHS Genomic Medicine Service (GMS) pathways. Relevant R-codes from the National Genomic Test Directory guide which genomic tests are available and when. A confirmed genetic diagnosis helps in understanding the condition, its inheritance pattern, and informing management strategies.

Related conditions

Other forms of osteopetrosis exist, which can sometimes be confused with the infantile malignant type. These include intermediate osteopetrosis and adult-onset osteopetrosis (also known as Albers-Schönberg disease), which tend to be less severe and have a later onset. While they share the characteristic of increased bone density, their genetic causes, clinical presentation, and prognosis differ. It is important to distinguish between these types for accurate diagnosis and appropriate management.

• Osteopetrosis (AD, benign)
  Skeletal
  Shares 1 gene

Frequently asked questions