autosomal recessive osteopetrosis 3

Autosomal recessive osteopetrosis 3 is a very rare condition that affects the skeleton, kidneys, and nervous system. It results from pathogenic variants in the CA2 gene, which encodes the carbonic anhydrase II enzyme that helps regulate acid–base balance in many tissues. Children are usually diagnosed in infancy or early childhood when dense, brittle bones and problems with maintaining normal blood acidity become apparent. Because the disorder affects fewer than one in a million people, many clinicians are unfamiliar with its full spectrum of features. Early recognition and coordinated care are important for maximizing growth, development, and quality of life.

The condition is characterized by markedly dense bones that can paradoxically be brittle, leading to recurrent fractures and short stature. Impaired kidney function causes renal tubular acidosis, so affected children may struggle with episodes of vomiting, dehydration, or poor weight gain when blood acidity rises. Neurological involvement stems largely from calcium deposits in the brain and from cranial nerve compression within the thickened skull; this can lead to developmental delay, intellectual disability, vision or hearing problems, and movement difficulties. Many individuals also develop distinctive facial features such as a high palate or narrow mouth, and some have enlarged livers or low blood counts because bone crowding limits bone-marrow space. Not all individuals experience all features, and severity varies considerably.

Autosomal recessive osteopetrosis 3 is caused by biallelic pathogenic variants in the CA2 gene. Carbonic anhydrase II normally helps bone-resorbing cells (osteoclasts) dissolve bone mineral and allows the kidneys to reclaim bicarbonate, keeping blood pH in a healthy range. When the enzyme does not work, bones become overly dense and kidneys cannot correct acid buildup, leading to the combination of osteopetrosis and renal tubular acidosis. The condition is inherited in an autosomal recessive pattern, meaning a child must receive one altered CA2 copy from each parent to be affected. Parents who each carry one altered copy (carriers) are typically healthy but have a 25 percent chance with every pregnancy of having an affected child. This condition is more common when parents share a common ancestor because they are more likely to carry the same rare genetic change. Genetic counseling is recommended for families to discuss carrier testing and family-planning options.

Currently, management focuses on supportive care and symptom management. Alkali therapy such as bicarbonate or citrate preparations may be used to correct blood acidity, and calcium levels are monitored closely to avoid hypocalcemia. Orthopedic care addresses fractures and helps maintain mobility, while neurosurgical or ophthalmologic input may be needed if cranial nerve compression affects vision or hearing. Because the disorder involves multiple organ systems, care is best coordinated through a multidisciplinary team that can include nephrology, endocrinology, neurology, orthopedics, rehabilitation specialists, and nutrition services. Regular surveillance is an essential part of long-term care, helping to identify potential complications before they become serious. Suggested monitoring often includes periodic renal function and electrolyte testing, growth assessment, vision and hearing checks, and imaging to follow skeletal changes. Families should work with their healthcare team to tailor surveillance to the individual’s needs and adjust strategies as new issues emerge. Genetic counseling provides ongoing support and helps relatives understand carrier risks.

Outcomes for autosomal recessive osteopetrosis 3 depend on the severity of bone disease, the effectiveness of acid–base management, and the extent of neurological involvement. Some children grow into adulthood with manageable symptoms, while others experience significant physical disability or learning challenges. Early fracture control, attentive metabolic management, and access to supportive therapies can improve mobility, growth, and cognitive development. Severity and symptoms vary widely between individuals. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with specialist centers familiar with complex bone and metabolic disorders, and to participate in disease registries that collect long-term data. Genetic counseling can help families understand recurrence risks and support informed family planning.