Osteopetrosis – ‘marble bone’ disease

Osteopetrosis – ‘marble bone’ disease – Radiographic Highlights

Eron G. Manusov

In 1904, Albers-Schonberg first described the uniformly dense appearance of bone in patients with “marble bone” disease. In 1926, Karshner described the pathologic alteration of osteoclast resorption of bone that results in abnormal density and thickening of cortical and lamellar bone and renamed the disorder ‘stony bone” disease, or osteopetrosis.[1,2] This condition has also been referred to as osteosclerosis fragilis generalisata.

The term osteopetrosis now refers to a group of bone disorders that is divided into two types: the infantile (severe) autosomal recessive form and the adult (benign) autosomal dominant form. Infantile osteopetrosis is usually diagnosed before the child reaches one year of age, and survival beyond the first decade is rare. The adult form is often diagnosed incidentally on routine radiographs and follows a benign course.

The overall incidence of osteopetrosis is estimated to be 1 in 100,000 to 1 in 500,000.[3] The actual incidence is unknown, because epidemiologic studies have never been performed.

Although the etiology of osteopetrosis is unknown, transmission is known to occur in a hereditary pattern.[3,4] Recent research has uncovered evidence suggesting that a retrovirus may be associated with both the autosomal recessive and autosomal dominant forms of the disease.[5,6]

To ensure early diagnosis and optimal management, the family physician must maintain a high index of suspicion for osteopetrosis. The following illustrative case describes the clinical presentation of the infantile form.

Illustrative Case

An eight-week-old female infant was found lying face down in her crib; she was cold and unresponsive. Resuscitation efforts were unsuccessful. She and her twin had been delivered by cesarean section, and their neonatal courses were uneventful. Initial autopsy findings were unremarkable, and the infant’s death was attributed to sudden infant death syndrome.

Two days later, the mother brought the surviving twin to the emergency department after she noticed that the infant’s left arm was swollen and immobile. A radiograph revealed a comminuted fracture of the left humerus (Figure 1). The diagnosis of battered child syndrome was considered, and the infant was admitted to the hospital for further evaluation.

Physical examination revealed a swollen upper left arm, splenomegaly, and weight (3.4 kg [7 lb, 8 oz]) and height (47 cm [18.5 in]) below the fifth percentile.

The classic signs of osteopetrosis were noted on a skeletal radiograph series (Figure 2). The fracture of the humerus was determined to be of pathologic origin, related to osteopetrosis.

Laboratory studies indicated mild anemia (hemoglobin, 10.8 g per dL [108 g per L]; hematocrit, 32.4 percent [0.32]) and thrombocytopenia (platelet count, 56,000 per [mm.sup.3] [56.0 x [10.sup.9] per L]). The white blood cell count, electrolytes, alkaline phosphatase level, urinalysis and carbonic anhydrase II level were normal.

Neurologic and ophthalmologic evaluation revealed no evidence of compression neuropathy, retinal degeneration or optic nerve pathology.

The infant was thought to have the severe autosomal recessive form of osteopetrosis. She is currently awaiting bone marrow transplantation.

Review of the radiographs of the deceased twin revealed osteosclerosis. A postmortem bone biopsy and findings of extramedullary hematopoiesis supported the diagnosis of osteopetrosis (Figure 3).


Recent DNA-probe studies have identified a retrovirus that may be propagated both as an infectious agent and as cellular genetic material. (A retrovirus enters the cell genome as a provirus and is transmitted as a gene.) The severity of the disease may vary, depending on the site of integration of the provirus. Other rare diseases that may be retroviral in etiology are sporadically inherited with osteopetrosis.[5]

Infantile osteopetrosis is characterized by normal bone production without physiologic resorption. Bone biopsy reveals increased cortical width due to decreased endosteal resorption, and large osteoclasts with multinucleated nuclei. Primitive bone and cartilage remain, interfering with the normal development of medullary canals and hematopoietic marrow.[7-10]

The adult, or benign, form varies in the degree of intensity and is intermittently active, which can result in normal bone density alternating with abnormal bone density.[11] Histologic findings are similar to those seen in the infantile form, but depend on the activity of the disease.

Clinical Presentation

Infantile osteopetrosis is characterized by signs and symptoms related to abnormal bone formation that invades the marrow space. Diagnosis is made early in life secondary to failure to thrive, fractures and/or multiple infections. Hepatosplenomegaly and lymphadenopathy commonly occur as a result of extramedullary hematopoiesis.

Progressive thickening of the base of the skull causes foraminal narrowing, resulting in nerve entrapment syndromes. Ocular sequelae, including optic atrophy, papilledema, nystagmus, limitation of extraocular muscle use and proptosis, are caused by abnormal bone growth and the resultant nerve entrapment. However, the severe visual loss experienced by up to 80 percent of patients is considered to be due to primary retinal degeneration.

Dentition is delayed and the teeth are small. Osteomyelitis of the mandible due to the abnormal intraosseous blood supply is a common presentation.[1,11]

Often discovered incidentally on routine radiographs in late adolescence, adult osteopetrosis is the more common and benign form. Bone pain is common, but symptoms and severity may vary among family members. Recurrent fractures are estimated to occur in up to 40 percent of patients. Osteomyelitis of the jaw is seen in 10 percent of adults with osteopetrosis. Entrapment syndromes may also be present.


Radiographic abnormalities in infantile osteopetrosis are the result of secondary invasion of the bone marrow space by abnormal bone formation. The autosomal recessive form of osteopetrosis is characterized by generalized osteosclerosis. Defects in modeling of long bones can produce a club-like appearance.[12] Blood vessels and their surrounding connective tissue may appear as longitudinal striations. Transverse striations are common and result from alternating areas of mature bone and intensely sclerotic or disorganized osseous tissue. The appearance of “bone within bone,” most characteristic of adult osteopetrosis, is an unusual finding in the infantile form.

The entire skull is usually involved in infantile osteopetrosis, with the base of the cranium being the most severely affected. Vertebral bodies are usually uniform and extremely radiodense. Maturation of the vertebral bodies results in the excessively sclerotic end plates that give the “rugger jersey” appearance to the spine. Bone marrow scintigraphy, magnetic resonance imaging and bone densitometry are useful for diagnosis.

Levels of carbonic anhydrase isoenzyme II (CA II) and creatine kinase BB enzyme (CK BB) have been used as laboratory markers for osteopetrosis?[13-15] Other biochemical variables of bone metabolism currently under investigation include fasting renal excretion of hydroxyproline, bone fractions of alkaline phosphatase and osteocalcin (bone GLA protein), and acid phosphatase and 1,25-dihydroxyvitamin [D.sub.3] levels.


The differential diagnosis of osteopetrosis includes skeletal disorders capable of stimulating new bone growth (Table 1). The categories are divided into reactive, tumor, congenital and developmental abnormalities. [TABULAR DATA 1 OMITTED]

In the absence of a family history of bone disease to support the diagnosis of osteopetrosis, the infantile form can be confused with rare congenital abnormalities such as hyperostosis corticalis generalisata (van Buchem’s syndrome) and progressive diaphyseal dysplasia (Camurati-Engelmann disease). Sclerosing skeletal dysplasias and osteitis deformans (Paget’s disease) can also have a radiographic appearance similar to that of osteopetrosis, but can be distinguished by the characteristic bone findings and unique clinical presentation of severe osteopetrosis.

Heavy metals, such as lead and bismuth, can cause radiodense lines (Harris or Park lines) at the end of the long bones, and blood levels of the heavy metals will be elevated. Mastocytosis can result in osseous lesions of the pelvis, ribs, vertebrae, skull and proximal long bones. Many tumors metastasize to bone, but metastasis does not occur in a regular or symmetric pattern. Osteosclerosis or myelofibrosis can also lead to bone growth and diffuse osteosclerosis. All of these conditions can be confused with variations of the adult form of osteopetrosis. The various pathologic processes can usually be distinguished on bone marrow biopsy.


No specific treatment exists for the benign adult form of osteopetrosis. In the infantile form, blood replacement, splenectomy and systemic corticosteroids are temporizing measures.[16] Bone marrow transplantation is considered to be an effective, sometimes curative, treatment for severe infantile osteopetrosis.[17,18]

Complete resolution of hematologic and biochemical abnormalities was described in 1990 by Coccia and colleagues[17] in a five-month-old infant who received bone marrow from her five-year-old HLA-MCL-identical brother. Kaplan and co-workers[18] also reported success using transplantation in a patient with severe infantile osteopetrosis. The two children described by Coccia and Kaplan are doing well 12 and four years, respectively, after transplantation. The patient described by Coccia experienced a slow loss of the graft. Although she developed the characteristic osteosclerosis, she has none of the other manifestations of infantile osteopetrosis.

Another treatment for infantile osteopetrosis is high doses of calcitriol (a metabolite of vitamin D) to stimulate bone resorption. Although calcitriol is successful in increasing bone turnover, it produces only a modest clinical improvement, which is not sustained after treatment is discontinued.[19]

The opinions contained herein are those of the authors and should not be construed as official or as reflecting the views of the Department of the Air Force or the Department of Defense.


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