Autosomal recessive malignant osteopetrosis (ORPHA:667)
A rare congenital disorder of bone resorption characterized by generalized skeletal densification.
Epidemiology
Osteopetrosis is very rare. The incidence is estimated at 1/250 000 live births. The disease is more frequent in specific geographic regions and ethnic groups where consanguinity is common.
Clinical description
Bone marrow failure, fractures and visual impairment are the classical features of the disease, which begins in early infancy or in fetal life. It results from the failure of osteoclasts to resorb immature bone. This leads to abnormal bone marrow cavity formation and to the clinical signs and symptoms of bone marrow failure. It is accompanied by hepatosplenomegaly due to compensatory extramedullary hematopoiesis. Impaired bone remodeling causes bony narrowing of the cranial nerve foramina, which results in cranial nerve (especially optic nerve) compression. Pathologically, there is a persistence of the primary spongiosa characterized by cores of calcified cartilage within bone. Abnormal remodeling of primary, woven bone to lamellar bone results in 'brittle' bone that is prone to fracture. A rare form of the disease is associated with severe central nervous system dysfunction.
Etiology
The disease is genetically heterogeneous and caused by biallelic mutations. Over 50% of cases are due to mutations in the TCIRG1 gene and another 15% are due to mutations in the CLCN7 gene. A small number of patients with 'pure' recessive osteopetrosis have been described with mutations in OSTM1, and SNX10 gene, whereas mutations in TNFSF11 (RANKL) or TNFRSF11A (RANK) were found in some of the 'osteoclast-poor' forms.
Diagnostic methods
The clinical and radiological features establish the diagnosis. The genetic tests can be performed to confirm the diagnosis and to distinguish the exact form of the disease. Among imaging studies conventional radiography alone can show all the main radiological patterns of osteopetrosis, above all the abnormal increased bone density. Computed Tomography (CT) offers a higher level of detail and a higher spatial resolution than conventional radiography (helpful in a better detection of small associated fractures). MRI of the brain should be performed to assess the presence of cranial nerves involvement, hydrocephalus, and vascular abnormalities. Dual-Energy-X-rays-absorptiometry (DXA) can be used to quantify the increase in bone mass density, even if this tool is unable to predict the fracture risk in patients with osteopetrosis.
Differential diagnosis
Infantile onset osteopetrosis should be distinguished from the much milder autosomal dominant adult disease, the intermediated recessive form of osteopetrosis, and the carbonic anhydrase II deficiency syndrome, which is associated with renal tubular acidosis and less severe osteopetrosis. In doubtful cases a bone biopsy may help in excluding other differential diagnoses.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variants have previously been identified in both parents.
Genetic counseling
Genetic analysis is important to recognize classical and atypical forms, being also essential for treatment strategy. Transmission is autosomal recessive. Genetic counseling should be offered to affected individuals, as well as to at-risk couples (both subjects are carriers of a disease-causing mutation) which have a 25% risk of having an affected child at each pregnancy.
Management and treatment
Patients may require blood transfusions, treatment for infections and management of their developmental and visual problems. Bone marrow transplant can alleviate many features of the disease but needs to be performed early to minimize optic nerve encroachment. Hematopoietic stem cell transplantation is contraindicated in presence of mutations in OSTM1 or TNFSF11 (RANKL) gene.
Prognosis
The prognosis is variable but improves if bone marrow transplant is performed early.

                            Last update: 
                            July 2023


                            - Expert reviewer(s): 
                            Dr Elena PEDRINI | ERN BOND* - Dr Paolo SPINNATO 


                                * European Reference Network