Osteopetrosis

Osteopetrosis is a group of inherited disorders of reduced osteoclast function or formation, with dense but brittle bone, marrow failure and cranial nerve compression.

Autosomal recessive osteopetrosis (infantile or malignant, about 1 in 250,000 births) presents in infancy with anaemia, thrombocytopenia, hepatosplenomegaly, blindness, deafness and early death without stem cell transplantation. Autosomal dominant osteopetrosis type II (Albers-Schonberg disease, about 1 in 20,000) is milder and presents in adolescence or adulthood.

Other forms include intermediate autosomal recessive disease, X-linked disease (with ectodermal dysplasia and immunodeficiency) and osteopetrosis with renal tubular acidosis (carbonic anhydrase II deficiency).

Pathophysiology.

Variants in TCIRG1, CLCN7, OSTM1, SNX10, TNFSF11 and other genes impair osteoclast acidification of the resorption lacuna or osteoclast formation. Bone resorption fails and primary bone is retained, so bone is dense but weak.

Marrow cavities are narrowed, giving anaemia and extramedullary haematopoiesis. Cranial foramina narrow, causing nerve compression.

• Infants: failure to thrive, pallor, bruising, recurrent infection, hepatosplenomegaly, macrocephaly, nasal obstruction, visual impairment (optic nerve compression), deafness, hypocalcaemic seizures.
• Dominant disease: fractures after low trauma, back pain, osteomyelitis (especially of the mandible after dental work), osteoarthritis, cranial nerve palsies, and mild anaemia, though many are asymptomatic.

Red flags.

• Infant with pallor, bleeding, hepatosplenomegaly or visual impairment.
• Hypocalcaemic seizure, osteomyelitis or progressive cranial nerve deficit.

• Radiographs: generalised sclerosis, "bone within bone" appearance, sandwich vertebrae (rugger jersey spine), Erlenmeyer flask deformity of the distal femur and thick skull base.
• Full blood count and film (leucoerythroblastic anaemia), calcium (often low in infants), phosphate, alkaline phosphatase, parathyroid hormone, and creatine kinase BB and tartrate resistant acid phosphatase (raised in dominant disease).
• Genetic testing (TCIRG1, CLCN7, OSTM1, SNX10, TNFSF11, TNFRSF11A, CA2). Brain MRI for hydrocephalus and Chiari malformation, ophthalmology (optic atrophy), audiology and optic canal imaging.
• Infants should be assessed urgently for the neuropathic form (OSTM1, which carries a poor outcome even with transplantation).

Differential diagnosis.

• Pycnodysostosis, craniometaphyseal dysplasia and van Buchem disease.
• Sclerosing bone disease from fluorosis, heavy metal poisoning or hypervitaminosis A.
• Osteosclerotic metastases, myelofibrosis, Paget disease and renal osteodystrophy.

• Infantile recessive disease: haematopoietic stem cell transplantation as early as possible (ideally before 3 months of age, and before neurological and visual damage), after genetic confirmation, in a specialist centre. Not suitable for neuropathic OSTM1 or severe neurological disease.
• Supportive: transfusions, calcium and vitamin D for hypocalcaemia, antibiotics for infection, feeding support and ophthalmic and hearing care. Interferon gamma-1b 50 micrograms/m2 subcutaneously three times weekly reduces infections and may improve bone resorption in some patients.
• Dominant disease: no curative treatment. Treat fractures with experienced orthopaedic surgeons (hard bone, delayed healing, infection risk), prevent and treat osteomyelitis with early prolonged antibiotics and surgical debridement, give good dental care, and treat pain.
• Carbonic anhydrase II deficiency: treat the renal tubular acidosis with bicarbonate.
• Optic canal or other nerve decompression for progressive loss of function.

Special groups. Genetic counselling: 25% recurrence risk in siblings (recessive), and 50% risk for children of an affected parent (dominant, with incomplete penetrance). Pregnancy in dominant disease: bone and obstetric review, since fractures and spinal anaesthesia can be difficult.

Monitoring. Children: growth, blood counts, calcium, vision and hearing every 3 to 6 months. Adults: symptoms, fractures and dental review yearly.

Referral and escalation. Paediatric haematology and transplant service for infants; endocrinology or metabolic bone service; orthopaedics and ENT for complications.