Information on the following diseases can be found in the Related Disorders section of this report:

• Melorheostosis
• Osteopoikilosis
• Osteogenesis Imperfecta
• Osteopetrosis with renal tubular acidosis; carbonic anhydrase II deficiency
• .

Osteopetrosis is a rare inherited disorder that is present at birth (congenital). Osteopetrosis is characterized by overly dense bones throughout the body. Symptoms include fractures, low blood cell production, and loss of cranial nerve function causing blindness, deafness, and/or facial nerve paralysis. Affected individuals may experience frequent infections of teeth and the bone in the jaw.

OSTEOPETROSIS, AUTOSOMAL RECESSIVE; MALIGNANT INFANTILE TYPE
The most severe type of osteopetrosis, malignant infantile type, is apparent from birth. Affected individuals may have an abnormally large head (macrocephaly). Some affected individuals may have a condition called hydrocephalus that is characterized by inhibition of the normal flow of cerebrospinal fluid (CSF) within and abnormal widening (dilatation) of the cerebral spaces of the brain (ventricles), causing accumulation of CSF in the skull and potentially increased pressure on brain tissue. Symptoms that may affect the eyes may include wasting away (atrophy) of the retina, eyes that appear widely spaced (hypertelorism), eyes that are crossed (strabismus), involuntary rhythmic movements of the eyes (nystagmus), and blindness.

Other symptoms associated with malignant infantile type of osteopetrosis include hearing loss, chronic inflammation of the mucous membranes in the nose (rhinitis), frequent infections (such as pneumonia, sepsis, and urinary tract infections), and/or failure to thrive. Some affected individuals experience delays in acquiring skills that require the coordination of muscles and voluntary movements(delayed psychomotor development). Some affected individuals may experience delayed tooth development (delayed dentition), severe tooth decay (dental caries), and/or no or inadequate tooth eruption. In addition, abnormal enlargement of the liver and spleen (hepatosplenomegaly); abnormal hardening of some bones (osteosclerosis); fractures, usually of the ribs and long bones; inflammation of the lumbar vertebrae (osteomyelitis); increased density of the cranial bones (cranial hyperostosis); hardening of the shaft of a long bone (diaphyseal sclerosis); nerve compression; and/or increased intracranial pressure may also occur.

Some affected individuals with the malignant infantile type of osteopetrosis may also experience low levels of iron in red blood cells (anemia), a marked deficiency of all types of blood cells (pancytopenia), the formation and development of blood cells outside the bone marrow, as in the spleen, liver, and lymphnodes (extramedullary hematopoiesis), and the occurrence of myeloid tissue in extramedullary sites (myeloid metaplasia).

OSTEOPETROSIS, AUTOSOMAL DOMINANT; ADULT TYPE
A milder form of osteopetrosis, the adult type, is apparent from birth but is usually not diagnosed until adulthood. Symptoms of the adult type of osteopetrosis include abnormal hardening of some bones (osteosclerosis), fractures usually of the ribs and long bones, inflammation of bone (osteomyelitis) especially the lower jaw bone (mandible), increased density of the cranial bones (cranial hyperostosis), and/or hardening of the shaft of a long bone (diaphyseal sclerosis). In some cases, affected individuals may have pus-filled sacs in the tissue around the teeth (dental abscess). In many cases, individuals may exhibit no symptoms (asymptomatic).

Affected individuals with the adult type of osteopetrosis may also experience chronic inflammation of the mucous membranes in the nose (rhinitis), abnormal enlargement of the liver and spleen (hepatosplenomegaly), low level of iron in the red blood cells (anemia), the formation and development of blood cells outside the bone marrow, as in the spleen, liver, and lymphnodes (extramedullary hematopoiesis).

OSTEOPETROSIS, MILD AUTOSOMAL RECESSIVE; INTERMEDIATE TYPE
A less severe type of osteopetrosis, the intermediate type, is usually found in children under the age of 10. Symptoms of the intermediate type of osteopetrosis may include abnormal hardening of some bones (osteosclerosis); fractures; inflammation of bone (osteomyelitis) especially of the lower jaw bone (mandible); knees that are abnormally close together and ankles that are abnormally wide apart (genu valgum); increased density of the cranial bones (cranial hyperostosis); and hardening of the shaft of a long bone (diaphyseal sclerosis).

Symptoms of the intermediate type of osteopetrosis may also include gradual deterioration of the nerves of the eyes (optic atrophy), loss of vision, and chronic inflammation of the mucous membranes in the nose (rhinitis). Some affected individuals may experience abnormal protrusion of the lower jaw (mandibular prognathism), dental anomalies, baby teeth that do not fall out (deciduous retention), tooth crown malformation, severe tooth decay (dental caries), and facial paralysis. Other symptoms include abnormal enlargement of the liver and spleen (hepatosplenomegaly), low levels of iron in red blood cells (anemia), decreased levels of circulating blood platelets (thrombocytopenia), a marked deficiency of all types of blood cells (pancytopenia), and the formation and development of blood cells outside the bone marrow, as in the spleen, liver, and lymphnodes (extramedullary hematopoiesis).

Osteopetrosis can be inherited as either a dominant or recessive trait. The basic defect in bone growth involves an insufficient production of intercellular bone tissue by cells called osteoblasts. These osteoblasts aid in the production of bone by maintaining a balance between formation and loss of calcium (resorption) in the bone.

Human traits including the classic genetic diseases, are the product of the interaction of two genes for that condition, one received from the father and one from the mother.

In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed "dominating" the normal gene and resulting in appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.

In recessive disorders, the condition does not appear unless a person inherits the same defective gene from each parent. If one receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will show no symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is twenty-five percent. Fifty percent of their children will be carriers, but healthy as described above. Twenty-five percent of their children will receive both normal genes, one from each parent and will be genetically normal (for that particular trait).

The malignant infantile type of osteopetrosis is inherited as an autosomal recessive genetic trait. The defective gene that causes this type of osteopetrosis has been located on the long arm of chromosome 11 (11q12-q13).

The adult type of osteopetrosis is inherited as an autosomal dominant genetic trait. The defective gene that causes the adult type of osteopetrosis has been located on the short arm of chromosome 1 (1p21).

The intermediate type of osteopetrosis is inherited as an autosomal recessive genetic trait. However, some cases of autosomal dominant inheritance have been documented. Most cases of the intermediate type of osteopetrosis occur randomly with no known inheritance pattern (sporadic).
.

Approximately eight to 40 children are born in the United States each year with the malignant infantile type of osteopetrosis. One in every 100,000 to 500,000 individuals is born with this form of osteopetrosis. Higher rates have been found in Denmark and Costa Rica. Males and females are affected in equal numbers.

The adult type of osteopetrosis affects about 1,250 individuals in the United States. One in every 200,000 individuals is affected by the adult type of osteopetrosis. Higher rates have been found in Brazil. Males and females are affected in equal numbers.

The intermediate type of osteopetrosis is believed to affect males more often than females.
.

Symptoms of the following disorders may be similar to those of osteopetrosis. Comparisons may be useful for a differential diagnosis:

Melorheostosis is a rare disorder characterized by shortening or deformity of one or more limbs due to a problem with calcium density in bones. It is inherited as a dominant trait. Pain and limitation of movement of the affected arm(s) or leg(s) is usually present. The prognosis for this disorder is guardedly favorable.

Osteopoikilosis, also known as "spotted bones," is a rare disorder which may occur in conjunction with melorheostosis. Usually without apparent symptoms, osteopoikilosis may be discovered during x-ray examination for other bone growth disorders. Symptoms usually occur most often between the ages of 15 and 60. Spotty shadows appear on x-rays of wrist and ankle bones, finger or toe bones, long bones, pelvis, skull, and/or ribs (spinal bones exempted). These spots are less than one centimeter in diameter and usually of uniform density. Bone growth nodules can grow larger or diminish and disappear. Osteopoikilosis is inherited as an autosomal dominant genetic trait.

Osteogenesis imperfecta, or "brittle bone disease," is a group of hereditary connective tissue disorders characterized by unusual bone fragility and tendency to fracture. Traditionally, the disease has been recognized in two forms: osteogenesis imperfecta congenita, which is apparent at birth, and osteogenesis imperfecta tarda, which manifests itself later, usually at three or four years of age. Osteogenesis imperfecta tarda tends to be a milder form of the disease. Both forms of osteogenesis imperfecta affect one in 20,000 to 50,000 births in the United States. (For more information on this disorder, choose "osteogenesis imperfecta" as your search term in the Rare Disease Database.)

Osteopetrosis with renal tubular acidosis, also known as carbonic anhydrase II deficiency and Guibaud-Vainsel syndrome, is a rare inherited disorder characterized by multiple fractures within the first two years of life. Affected infants have a deficiency of the enzyme carbonic anhydrase II within certain red blood cells (erythrocytes). Affected infants demonstrate abnormal accumulation of acid in the body (metabolic acidosis), including within the tubes of the kidneys (renal tubular acidosis). Physical findings associated with the disorder include short stature, hardening of bones (osteoclerosis), abnormally large liver and spleen (hepatosplenomegaly), upper and lower teeth that do not meet properly (malocclusion), increased density of the cranial bones (cranial hyperostosis), and/or low levels of iron in the blood (anemia). In most cases, affected children have normal intelligence. However, some affected children may have mental retardation. Osteopetrosis with renal tubular acidosis is inherited as an autosomal recessive genetic trait.

Diagnosis
A diagnosis of osteopetrosis is made based upon a thorough clinical evaluation, detailed patient history, and a variety of specialized tests such as x-ray tests. The diagnosis can be confirmed by testing the bone and by the presence of other distinct symptoms such as vision impairment.

Treatment
In 2000, the drug Interferon Gamma-1b (Actimmune) was approved by the U.S. Food and Drug Administration to halt the progression of osteopetrosis. The drug delays disease progression in affected individuals with severe malignant osteopetrosis. For more information, contact:

InterMune Pharmaceuticals, Inc.
3280 Bayshore Blvd.
Brisbane, CA 94005

Phone: (415) 466-2200
Website: www.Intermune.com

Good nutrition is very important for patients with osteopetrosis. Physical therapy may be of benefit in some cases. Other treatment is symptomatic and supportive. Genetic counseling can be of assistance for families in which this disorder occurs.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact
www.centerwatch.com

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:166600; Last Update:5/3/99. Entry No:259700; Last Update:9/21/98. Entry No:258710; Last Update:4/22/94. Entry No:259730; Last Update:9/28/98.

TEXTBOOKS
Buyce ML, ed. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications; For: The Center for Birth Defects Information Services Inc; 1990:1331-34, 1466.

Behrman RE, ed. Nelson Textbook of Pediatrics, 15th ed. Philadelphia, PA: W.B. Saunders Company; 1996:1980-1.

Kelley WN, et al., eds. Textbook of Rheumatology. 4th ed. Philadelphia, PA: W.B. Saunders Company; 1993:1621-2.

Fauci AS, et al., eds. Harrison's Principles of Internal Medicine, 14th Ed. New York, NY: McGraw-Hill, Inc; 1998:2270-71.

Beers MH, Berkow R, eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:2409-13.

Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 3rd. ed. Lippincott-Raven; 1996:363-6.

JOURNAL ARTICLES
Tolar J, et al. Mechanisms of disease: osteopetrosis. N Engl J Med. 2004;351;2839-47.

White KE, et al., Locus heterogeneity of autosomal dominant osteopetrosis (ADO). J Clin Endocrinol Metab. 1999;84:1047-51.

Armstrong DG, et al., Orthopedic management of osteopetrosis: results of a survey and review of the literature. J Pediatr Orthop. 1999;19:122-32.

Charles JM, et al., Developmental spectrum of children with congenital osteopetrosis. J Pediatr. 1998;132:371-4.

Carolino J, et al., Osteopetrosis. Am Fam Physician. 1998;57:1293-6.

Kovanlikaya A, et al., Pathogenesis of osteosclerosis in autosomal dominant osteopetrosis. AJR Am J Roentgenol. 1997;168:929-32.

Van Hul W, et al., Localization of a gene for autosomal dominant osteopetrosis (Albers-Schonberg disease) to chromosome 1p21. Am J Hum Genet. 1997;61:363-9.

Nagai R, et al., Renal tubular acidosis and osteopetrosis with carbonic anhydrase ii deficiency: pathogenesis of impaired acidification. Pediatr Nephrol. 1997;11:633-6.

Key LL, et al. Long-term treatment of osteopetrosis with recombinant human interferon gamma. N Engl J Med. 1995;332:1594-9.

Dorantes LM, et al., Juvenile osteopetrosis: effects on blood and bone of prednisone and a low calcium, high phosphate diet. Arch Dis Child. 1986;61:666-70.

QUESTIONS AND ANSWERS ABOUT OSTEOPETROSIS. The Paget Foundation for Paget's Disease of Bone and Related Disorders and the Osteopetrosis and Related Bone Diseases-National Resource Center.