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NORD gratefully acknowledges Yi Tong, MD Candidate, McGill University School of Medicine, and Dr. Cristina Sobacchi, Humanitas Clinical and Research Institute, Rozzano, Italy; National Research Council-Institute of Genetics and Biomedical Research (CNR-IRGB), Milan Unit, Milan, Italy, for assistance in the preparation of this report.
Osteopetrosis is marked by increased bone density due to a defect in bone reabsorption by cells called osteoclasts. This leads to accumulation of bone with defective architecture, making them brittle and susceptible to fracture and to skeletal abnormalities. Although symptoms may not initially be apparent in people with mild forms of this disorder, trivial injuries may cause bone fractures due to bone fragility. Early diagnosis is important in the most severe forms of these disorders, as they cause irreversible complications and may be treated with hematopoietic stem cell transplantation.
There are three types of osteopetrosis, and they are classified by their mode of inheritance: autosomal dominant, autosomal recessive and X-linked recessive. The autosomal dominant form is the most common: usually, patients have mild symptoms that begin in late childhood to adulthood. The autosomal recessive form, also called the malignant infantile type, is apparent soon after birth and frequently shortens life expectancy. The X-linked form of osteopetrosis is extremely rare, with only a few cases reported. There is also an intermediate type of osteopetrosis, comprising both milder autosomal recessive forms and dominant ones with early and severe presentation.
Osteopetrosis was first identified by radiologist Albers-Schonberg in 1904.
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, and if left untreated, can lead to death in the first decade of life. Symptoms vary depending on the gene variant (mutation). Affected individuals have abnormal hardening of bone (osteosclerosis); fragility fractures, usually of the ribs and long bones; large head (macrocephaly) and small jaw (micrognathia); growth delay and increased density of the cranial bones (cranial hyperostosis) leading to nerve compression. They may also have hydrocephalus, which is the accumulation of cerebrospinal fluid (CSF) in the skull owing to inhibition of CSF normal flow and abnormal widening (dilatation) of the cerebral spaces of the brain (ventricles), causing increased pressure on brain tissue. Symptoms that affect vision may include wasting away (atrophy) of the retina, widely spaced eyes (hypertelorism), eyes protruding from the orbits (exophthalmos), crossed eyes (strabismus), involuntary rhythmic movements of the eyes (nystagmus) and blindness.
Other symptoms associated with malignant infantile type of osteopetrosis include effects of reduced bone marrow space, such as marked deficiency of all types of blood cells (pancytopenia), formation and development of blood cells outside the bone marrow, as in the spleen and liver (extramedullary hematopoiesis) leading to abnormal enlargement of these organs (hepatosplenomegaly) and the occurrence of myeloid tissue in extramedullary sites (myeloid metaplasia). This may lead to frequent infections such as pneumonia and urinary tract infections and chronic inflammation of the mucous membranes in the nose (rhinitis). Affected individuals may also have low levels of iron in red blood cells (anemia) due to both reduced bone marrow space and red blood cell production and to increased destruction of red blood cells due to an enlarged spleen. Of note, hematological problems usually present before neurological ones.
Some affected individuals experience hearing loss, eating difficulties, delays in acquiring skills that require the coordination of muscles and voluntary movements (delayed psychomotor development), delayed tooth development and severe dental caries, and inflammation of the lumbar vertebrae (osteomyelitis). Patients can also have seizures due to low levels of calcium in the blood. Symptoms of severe neurodegeneration can develop in some people with rare variants of malignant infantile osteopetrosis.
Osteopetrosis, autosomal dominant; adult type
A milder form of osteopetrosis, the adult type, is usually diagnosed in late childhood or adulthood. There are mostly bone symptoms, including osteosclerosis, fractures after minimal trauma (usually of the ribs and long bones), dental abscess, osteomyelitis (especially of the jaw) and cranial hyperostosis. Some individuals with this type may not have any symptoms (asymptomatic).
Affected individuals sometimes also experience rhinitis, hepatosplenomegaly, anemia and extramedullary hematopoiesis.
Osteopetrosis, intermediate autosomal
The intermediate type is usually found in children and can be inherited as an autosomal recessive or autosomal dominant pattern. The severity of the disease is variable, but in general distinguished from “classical” recessive and dominant forms. Symptoms include abnormal hardening of bones; fractures; osteomyelitis especially of the mandible, abnormally close knees in the presence of markedly diverging ankles (genu valgum) and cranial hyperostosis.
Symptoms of the intermediate type of osteopetrosis may also include gradual deterioration of the nerves of the eyes (optic atrophy), loss of vision, muscular weakness and rhinitis. Some affected individuals may have abnormal protrusion of the lower jaw (mandibular prognathism); dental anomalies such as deciduous teeth retention (a condition where baby teeth do not fall out), tooth crown malformation and dental caries and facial paralysis. Other symptoms include hepatosplenomegaly, anemia, decreased levels of circulating blood platelets (thrombocytopenia), pancytopenia and extramedullary hematopoiesis.
Osteopetrosis: X-linked recessive
X-linked osteopetrosis is extremely rare but severe, with only a few cases reported worldwide. In addition to classical symptoms linked with osteopetrosis, it is associated with immunodeficiency, localized fluid retention and tissue swelling (lymphedema) as well as abnormalities of the hair, skin, nails and sweat glands (ectodermal dysplasia).
Osteopetrosis can be inherited in either an autosomal dominant or recessive pattern, and extremely rarely, in an X-linked recessive pattern. The basic defect in bone reabsorption is an insufficient production or defective function of cells called osteoclasts. These cells are responsible for bone resorption and aid in the maintenance of healthy bone, which relies on a balance between bone resorption (by osteoclasts) and bone formation (by other specialized cells called osteoblasts). The human skeleton is completely regenerated every 10 years. In this context, osteoclasts are essential for bone turnover (replacement of old bone by new bone), bone remodeling as well as micro-fracture repair.
The adult type of osteopetrosis is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
The malignant infantile type of osteopetrosis is inherited as an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
The X-linked form of osteopetrosis is recessive and extremely rare. X-linked genetic disorders are conditions caused by a mutated gene on the X chromosome and mostly affect males. Females who have a mutated gene on one of their X chromosomes are carriers for that disorder. Carrier females usually do not have symptoms because females have two X chromosomes and only one carries the mutated gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a mutated gene, he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder can reproduce, he will pass the mutated gene to all his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male children.
The intermediate type of osteopetrosis can be inherited in an autosomal recessive or autosomal dominant pattern.
Approximately eight to 40 children are born in the United States each year with the malignant infantile type of osteopetrosis. In the general population, one in every 250,000 individuals is born with this form of osteopetrosis. Higher rates have been found in specific regions of Costa Rica, the Middle East, Sweden and Russia. Males and females are affected in equal numbers.
The adult type of osteopetrosis affects about 1,250 individuals in the United States. The incidence is about one in every 20,000 individuals. Males and females are affected in equal numbers.
The X-linked form of osteopetrosis mostly affects males. The prevalence is unknown, but it is extremely rare.
A diagnosis of osteopetrosis is based on a thorough clinical evaluation, detailed patient history and a variety of specialized tests such as X-ray imaging and measurement of bone mass density (BMD) which is increased. Skeletal X-ray findings are very specific and are considered sufficient to make a diagnosis. Biochemical findings like increased concentration of creatinine kinase BB isoenzyme and tartrate-resistant acid phosphatase (TRAP) can also help making the diagnosis.
Clinical Testing and Work-Up
Genetic testing can identify the gene variant in over 90% of patients. This can help diagnose the type of osteopetrosis, the unique features or complications and direct the management plan. A bone biopsy is sometimes performed to confirm the diagnosis, but not routinely done as it is an invasive procedure with some risks.
Once the diagnosis is made, the following blood tests should be done: serum calcium, parathyroid hormone, phosphorus, creatinine, 25-hydroxyvitamin D, complete blood count with differential, creatine kinase isoenzymes (specifically the BB isozyme of creatine kinase) and lactate dehydrogenase. These measurements will determine the need for supplementation and for referral to specialists. Baseline magnetic resonance imaging (MRI) of the brain should be done to evaluate cranial nerve involvement, hydrocephalus and vascular abnormalities.
Affected individuals should be evaluated regularly by an ophthalmologist for optic nerve involvement and be evaluated by other specialists as needed including endocrinology, genetics and dentistry, with input from orthopedics, otorhinolaryngology, neurology, neurosurgery, nephrology, infectious disease and hematology.
Currently, the only established cure for autosomal recessive malignant infantile osteopetrosis is hematopoietic stem cell transplantation (HSCT) for some patients. This allows the restoration of bone resorption by donor-derived osteoclasts. Genetic studies are important to determine whether HSCT is appropriate because patients with some gene variants will not benefit from the transplant (those in the RANKL gene). Some patients (all those with variants in the OSTM1 gene and some of those with two variants in the CLCN7 gene) develop progressive neurodegeneration, which is not cured by HSCT. In mild forms of osteopetrosis it is important to weigh the risks and benefits as they may not warrant the risks associated with HSCT like rejection, severe infections and very high levels of calcium in the blood leading to a high risk for death in the first year. For patients in whom HSCT is not appropriate, corticosteroids may be considered, but there is not enough evidence to support their routine use.
Interferon gamma-1b (Actimmune) was approved by the U.S. Food and Drug Administration (FDA) to delay disease progression in individuals with severe malignant infantile osteopetrosis.
Good nutrition is very important for patients with osteopetrosis, including calcium and vitamin D supplements if there are low levels of calcium in the blood. Other treatments are symptomatic and supportive.
Genetic counseling is recommended for affected individuals and their families.
There are ongoing studies on the use of gene therapy, especially in patients who would not benefit from hematopoietic stem cell transplant or who have no matched donor, but they remain experimental. Researchers are investigating the use of interferon gamma-1b for non-infantile osteopetrosis and it has been reported to improve immune function and increase bone resorption.
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Teti A, Whyte MP. Osteopetrosis: Gene-based nosology and significance. Bone. 2023;175:116854. doi:10.1016/j.bone.2023.116854
Palagano E, Menale C, Sobacchi C, Villa A. Genetics of Osteopetrosis. Curr Osteoporos Rep. 2018;16:13-25. doi:10.1007/s11914-018-0415-2.
Arruda M, Coelho MCA, Moraes AB, et al. Bone mineral density and microarchitecture in patients with autosomal dominant osteopetrosis: A report of two cases. J Bone Miner Res. 2016;31(3):657-662. doi:10.1002/jbmr.2715.
Wu CC, Econs MJ, DiMeglio LA, et al. Diagnosis and Management of Osteopetrosis: Consensus Guidelines From the Osteopetrosis Working Group. J Clin Endocrinol Metab. 2017;102(9):3111-3123. doi:10.1210/jc.2017-01127.
Coudert AE, De Vernejoul MC, Muraca M, Del Fattore A. Osteopetrosis and its relevance for the discovery of new functions associated with the skeleton. Int J Endocrinol. 2015;2015. doi:10.1155/2015/372156.
Orchard PJ, Fasth AL, Le Rademacher JL, et al. Hematopoietic stem cell transplantation for infantile osteopetrosis. Blood. 2015;126(2):270-277. doi:10.1182/blood-2015-01-625541.
Sobacchi C, Schulz A, Coxon FP, Villa A, Helfrich MH. Osteopetrosis: Genetics, treatment and new insights into osteoclast function. Nat Rev Endocrinol. 2013;9(9):522-536. doi:10.1038/nrendo.2013.137.
Pangrazio A, Pusch M, Caldana E et al. Molecular and clinical heterogeneity in CLCN7-dependent osteopetrosis: report of 20 novel mutations. Molecular and clinical heterogeneity in CLCN7-dependent osteopetrosis: report of 20 novel mutations. Hum Mutat. 2010;31(1):E1071-80. doi: 10.1002/humu.21167.
Del Fattore A, Cappariello A, Teti A. Genetics, pathogenesis and complications of osteopetrosis. Bone. 2008;42(1):19-29. doi:10.1016/j.bone.2007.08.029.
Tolar J, et al. Mechanisms of disease: osteopetrosis. N Engl J Med. 2004;351;2839-47.
Dupuis-Girod S, Corradini N, Hadj-Rabia S, et al. Osteopetrosis, Lymphedema, Anhidrotic Ectodermal Dysplasia and Immunodeficiency in a Boy and Incontinentia Pigmenti in His Mother. Pediatrics. 2002;109(6); 1-6.
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Entry No:166600. Last Update:9/04/2018 https://www.omim.org/entry/166600?search=166600&highlight=166600 Accessed Nov 16, 2023.
Entry No:259700. 05/03/2023. https://www.omim.org/entry/259700?search=259700&highlight=259700 Accessed Nov 16, 2023.
Entry No:259730. Last Update: 04/08/2021 https://www.omim.org/entry/259730?search=259730&highlight=259730 Accessed Nov 16, 2023.
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