Osteopetroses are characterized by increased bone density and skeletal modeling abnormalities.

Osteopetroses can be categorized based on whether sclerosis or defective skeletal modeling predominates. Some types are comparatively benign; others are progressive and fatal. Bony overgrowth sometimes severely distorts the face. Malocclusion of the teeth may require specialized orthodontic measures. Surgical decompression may be required to relieve elevated intracranial pressure or to release a trapped facial or auditory nerve.

Craniotubular Dysplasias

Craniotubular dysplasias involve minor osteosclerosis with normal skeletal modeling.

Metaphyseal dysplasia (Pyle's disease)

This rare, autosomal recessive disorder is often confused semantically with craniometaphyseal dysplasia. Affected people are clinically normal, apart from genu valgum, although scoliosis and bone fragility occasionally occur. The diagnosis is usually made when x-ray studies are done for an unrelated reason. X-ray changes are striking. Long bones are undermodeled, and bony cortices are generally thin. Tubular leg bones have gross Erlenmeyer flask flaring, particularly in the distal femur. Pelvic bones and thoracic cage are expanded. However, the skull is virtually spared.

Craniometaphyseal dysplasia

In this autosomal dominant disorder, paranasal bossing develops during infancy, and progressive expansion and thickening of the skull and mandible distort the jaw and face. The encroaching bone entraps cranial nerves, causing dysfunction. Malocclusion of the teeth may be troublesome; partial sinus obliteration predisposes to recurrent nasorespiratory infection. Height and general health are normal, but progressive elevation of intracranial pressure is a rare, serious complication.

X-ray study changes are age-related and usually evident by age 5 yr. Sclerosis is the main feature in the skull. Long bones have widened metaphyses, appearing club- shaped, particularly at the distal femur. However, these changes are much less severe than those in Pyle's disease. The spine and pelvis are unaffected.

Frontometaphyseal dysplasia

This disorder has distinct autosomal dominant and X-linked forms; it becomes evident during early childhood. The supraorbital ridge is prominent, resembling a knight's visor. The mandible is hypoplastic with anterior constriction; dental anomalies are common. Deafness develops during adulthood because sclerosis narrows the internal acoustic foramina and middle ear. Long leg bones are moderately bowed. Progressive contractures in the digits may simulate RA. Height and general health are normal.

On x-ray examination, bony overgrowth of the frontal region is obvious; patchy sclerosis occurs in the cranial vault. Vertebral bodies are dysplastic but not sclerotic. Iliac crests are abruptly flared, and pelvic inlet is distorted. Femoral capital epiphyses are flattened, with expansion of the femoral heads and coxa valga (hip deformity). Finger bones are undermodeled, with erosion and loss of joint space. Corrective surgery is indicated for severely disfiguring deformities or those causing orthopedic problems.

Craniotubular Hyperostoses

Craniotubular hyperostoses are bony overgrowths that alter contour and increase skeletal density.

Endosteal hyperostosis (van Buchem's syndrome)

Endosteal hyperostosis is usually an autosomal recessive disorder. Overgrowth and distortion of the mandible and brow become evident during mid-childhood. Subsequently, cranial nerves become entrapped, leading to facial palsy and deafness. Life span is not compromised, stature is normal, and bones are not fragile. X-ray studies show widening and sclerosis of the calvaria, cranial base, and mandible. Diaphyseal endosteum in the tubular bones is thickened. Surgical decompression of entrapped nerves may be helpful.

Sclerosteosis

Sclerosteosis, an autosomal recessive disorder, is most common among Afrikaners of South Africa. Overgrowth and sclerosis of the skeleton, particularly of the skull, develop during early childhood. Height and weight are often excessive. Initial symptoms and signs may include deafness and facial palsy due to cranial nerve entrapment. Distortion of facies, apparent by age 10 yr, eventually becomes severe. Cutaneous or bony syndactyly of the 2nd and 3rd fingers distinguishes sclerosteosis from other forms of craniotubular hyperostoses. Predominant x-ray study features are gross widening and sclerosis of the calvaria and mandible. Vertebral bodies are spared, although their pedicles are dense. Pelvic bones are sclerotic but have normal contours. Long bones have sclerosed, hyperostotic cortices and undermodeled shafts. Surgery to relieve intracranial pressure may help.

Diaphyseal dysplasia (Camurati-Engelmann disease)

Diaphyseal dysplasia, an autosomal dominant disorder, manifests during mid-childhood with muscular pain, weakness, and wasting, typically in the legs. These symptoms usually resolve by age 30. Cranial nerve compression and elevated intracranial pressure occur occasionally. Some patients are severely handicapped; others are virtually asymptomatic. The predominant x-ray study feature is marked thickening of the periosteal and medullary surfaces of the diaphyseal cortices of the long bones, but findings vary. Medullary canals and external bone contours are irregular. The extremities and axial skeleton usually are spared. Rarely, the skull is involved, with calvarial widening and basal sclerosis. Corticosteroids may help relieve bone pain and improve muscle strength.

Osteosclerosis

Osteosclerosis is abnormal hardening of bone that involves increased skeletal density with little disturbance of modeling.

Osteopetrosis with delayed manifestations (Albers-Schönberg disease)

This type is autosomal dominant, benign, and delayed (tarda), manifesting during childhood, adolescence, or young adulthood. The defective CLCN7 gene encodes a chloride channel apparently important in osteoclast function. It is relatively common and has a wide geographic and ethnic distribution. Affected people may be asymptomatic; general health is usually unimpaired. However, facial palsy, deafness, and anemia (from bone marrow compromise or hypersplenism) may occur.

The skeleton usually is radiologically normal at birth. However, bone sclerosis becomes increasingly apparent as children age, and diagnosis is typically based on x- ray studies done for unrelated reasons. Bony involvement is widespread but patchy. The calvaria is dense, and sinuses may be obliterated. Sclerosis of the vertebral end plate causes the characteristic rugby-shirt appearance (horizontal banding). Bone marrow can be compromised by bony overgrowth leading to pancytopenia. Extramedullary hematopoiesis may occur resulting in hepatosplenomegaly. Some patients require transfusion or splenectomy to treat anemia.

Osteopetrosis with precocious manifestations

This type of osteopetrosis is autosomal recessive, malignant, and congenital, manifesting during infancy. It is uncommon, frequently lethal, and often due to a mutation in the osteoclast-associated gene TCIRG1. Bony overgrowth causes marrow dysfunction. Initial symptoms include failure to thrive, spontaneous bruising, abnormal bleeding, and anemia. Palsies of the 2nd, 3rd, and 7th cranial nerves and hepatosplenomegaly occur later. Death due to bone marrow failure (anemia, overwhelming infection, or hemorrhage) usually occurs in the 1st year of life.

General increased bone density is the predominant feature on x-ray studies. Penetrated x-ray studies of long bones show transverse bands in the metaphyseal regions and longitudinal striations in the shafts. As the disorder progresses, the ends of the long bones, particularly the proximal humerus and distal femur, become flask-shaped. Characteristic endobones (bone within a bone) form in the vertebrae, pelvis, and tubular bones. The skull becomes thickened, and the spine has a rugby-shirt appearance.

Bone marrow transplantation with HLA-identical sibling grafts has had excellent results. However, prognosis is poor with HLA-mismatched grafts. Prednisone, calcitriol, and interferon-γ are effective in some cases.

Osteopetrosis with renal tubular acidosis

This type is autosomal recessive. It causes weakness, stunted stature, and failure to thrive. Bones appear dense on x-ray studies, and cerebral calcifications are seen; renal tubular acidosis (RTA) is present, and RBC carbonic anhydrase activity is decreased. The genetic defect involves mutations of the gene encoding carbonic anhydrase II. Bone marrow transplant cures the osteopetrosis but has no effect on the RTA. Maintenance therapy consists of bicarbonate and electrolyte supplementation to correct renal losses.

Pyknodysostosis

This autosomal recessive disorder is caused by loss of function mutations in the gene encoding cathepsin K, an osteoclast-derived protease important in degradation of extracellular matrix. Short stature becomes evident in early childhood; adult height is ≤ 150 cm (5 ft). Other manifestations include an enlarged skull, short and broad hands, and feet, dystrophic nails. Blue sclerae (due to a deficiency in connective tissue allowing the underlying vessels to show through) are usually recognized during infancy. Affected people resemble each other closely; they have a small face, a receding chin, and carious, misplaced teeth. The cranium bulges, and the anterior fontanelle remains patent. Terminal phalanges are short, and fingernails are dysplastic. Pathologic fractures are a complication.

Bone sclerosis appears on x-ray studies during childhood, but neither bone striations nor endobones are seen. Facial bones and paranasal sinuses are hypoplastic, and the mandibular angle is obtuse. Clavicles may be gracile, and their lateral portions underdeveloped; distal phalanges are rudimentary. Plastic surgery has been used to correct severe deformities of the face and jaw.

Last full review/revision February 2008 by Frank Pessler, MD, PhD; David D. Sherry, MD