Osteopetrosis, autosomal dominant

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Diagnosis and reasoning

This young woman has presented with a fracture of the left femur, following only minor trauma. Subsequently, x-rays of the affected limb showed a puzzling finding: increased bone density (i.e. osteosclerosis). The key causes of osteosclerosis can be recalled via the '3 M's PROOF' mnemonic: M: malignancy (metastases, lymphoma, and leukemia) M: myelofibrosis M: mastocytosis S: sickle cell disease P: Paget’s disease and pycnodysostosis R: renal osteodystrophy O: osteopetrosis O: other (sclerotic dysplasias, hyperthyroidism, and hypoparathyroidism) F: skeletal fluorosis An analysis of her history provides some clues. First of all, her mother has a history of fractures. This may imply a genetic etiology, i.e. osteopetrosis, pycnodysostosis, or sclerotic dysplasias. However, the latter two conditions can be excluded, as they are associated with characteristic dysmorphisms. Paget’s disease is almost unheard of at her age, while metastatic malignancies are also clinically less likely. Fluorosis is also unlikely, as most cases occur in the developing world, following occupational exposure to fluoride fumes or dust or consumption of groundwater contaminated with fluoride. A series of investigations should follow, including a complete blood count with peripheral smears; ESR; liver and renal profiles; serum thyroid stimulating hormone (TSH) and parathyroid hormone (PTH) levels; and, a skeletal survey. Hematological studies show normochromic normocytic anemia, with normal reticulocyte levels. The latter suggests at impaired medullary erythropoiesis, but in isolation, these findings are nonspecific. Her biochemical studies show normal renal functions, and normal TSH and PTH levels. This effectively excludes renal osteodystrophy, hyperthyroidism, and hypoparathyroidism respectively. However, the skeletal survey shows generalized osteosclerosis, with "sandwiched vertebrae" and "bone within a bone" appearances. These radiological findings are strongly suggestive of osteopetrosis. Note that this tallies with the earlier suspicion of a genetically inherited disorder. Estimation of serum tartrate-resistant acid phosphatase (TRAP) levels should follow. The elevated values seen here, when considered with the clinical and radiographic evidence, are sufficient to clinch the diagnosis. Note that impaired medullary erythropoiesis is a known accompaniment of this condition. Osteopetrosis can be classified as either autosomal recessive (ARO) and autosomal dominant (ADO), depending on the pattern of inheritance. In this case, the older age of onset, relatively mild symptoms and radiographic appearance favor the latter, with ADO type 2 (ADO2) being a strong possibility. Note that transiliac bone biopsy is used to distinguish between the various subtypes of ARO, but has no role in the management of patients with suspected ADO. Osteopetrosis is incurable. Treatment is supportive, with symptomatic management, and prevention and treatment of complications being key goals. In this patient's case, the anemia can be treated by administration of erythropoietin. Note that high dose vitamin D and gamma-1b interferon are used in the management of ARO, not ADO. There is no justification for parathyroidectomy here.


Osteopetrosis encompasses a heterogeneous group of disorders with the shared hallmark of increased bone density. Based on genetic determination, they can be classified into two main forms: - Autosomal recessive (also known as osteopetrosis congenital, malignant osteopetrosis or ARO) - Autosomal dominant (also termed osteopetrosis tarda, benign osteopetrosis or ADO) ADO is further divided into ADO type 1 and ADO type 2, depending on radiological findings. Note that the remainder of this monograph is focused on ADO type 2 (also known as Albers-Schönberg Disease or ADO2). ADO2 is the most common form of osteopetrosis, although it is rare in an absolute sense, occurring in an estimated ~1 in 20,000 births. It shows incomplete penetrance, with a maximum estimated penetrance rate of 75%. Similar to the other forms of osteopetrosis, the primary underlying pathogenesis is failure of normal bone resorption, due to irregularities in osteoclast differentiation or function. The ultimate outcome is bony overgrowth resulting in abnormally dense and brittle bones. Over half of affected individuals are asymptomatic and discovered incidentally, typically following a fracture. These may occur spontaneously or with minimal trauma. Long bones such as the femur are affected more frequently. The posterior vertebral arches are another common site of involvement. Patients may also present with back and bone pain, without any obvious fractures. Accompanying degenerative joint diseases are common, with hip arthritis seen in 50% of cases. The oral cavity may be involved, resulting in frequent dental abscesses, carious cavities, or even mandibular osteomyelitis. Cranial nerve compression is a rare but important complication. This results in hearing and visual loss in ~5% of patients. Bone marrow compression may result in hematological manifestations, although frank bone marrow failure is uncommon, unlike ARO. The diagnosis is based on clinical and radiological evidence. Note that the classic radiological features of osteopetrosis comprise: 1. Diffuse sclerosis affecting the skull, spine, pelvis and appendicular bones. 2. Bone modeling defects of the metaphysis of long bones, i.e. a funnel-like appearance (Erlenmeyer flask deformity) and characteristic lucent bands. 3. "Bone within a bone" appearance, particularly in the vertebrae and phalanges. 4. "Sandwich vertebrae" (dense bands of sclerosis parallel to the vertebral endplate), and "rugger-jersey" spine (alternative sclerotic-lucent-sclerotic appearance due to sclerotic endplate bands at contiguous vertebral levels). Symptomatic individuals with ADO2 also have elevated serum levels of tartrate-resistant acid phosphatase (TRAP) and the BB isoenzyme of creatine kinase (CK-BB). Note also that other differentials which can cause secondary bone sclerosis should be considered and excluded. These include myelofibrosis, malignancies such as osteoblastic metastases, the sclerosing form of Paget’s disease, and fluorosis. Genetic testing is not required for diagnosis but is helpful in distinguishing between the various forms of the disease, and thus helping determine the management, and evaluate the prognosis. At present, there is no effective medical treatment for ADO2. Supportive treatment is the mainstay of management, along with early identification and treatment of complications, and personal and genetic counseling. Given the brittle nature of the bones, and high potential for secondary complications such as delayed union, non-union, or osteomyelitis, all fractures should be treated by an experienced orthopedic surgeon. Due to the high risk of infection and susceptibility for jaw fractures, regular dental surveillance and maintenance of good oral hygiene are also important. Note that persons with ADO2 can generally expect a normal lifespan, although their quality of life may be severely affected if they are left unattended, or not managed properly.

Take home messages

  1. Osteopetrosis is a group of rare, heritable disorders of the skeleton that share the hallmark of increased bone density on radiographs.
  2. Autosomal dominant osteopetrosis type 2 (ADO2) is the most common form. This presents in late childhood or adolescence, although over half of the affected individuals are completely asymptomatic.
  3. Patients with ADO2 have a normal life expectancy. Proper management will ensure a good quality of life as well.

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