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Disease Profile

Osteopetrosis

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

All ages

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ICD-10

Q78.2

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Osteopetroses; Marble bones; Marble bone disease;

Categories

Congenital and Genetic Diseases

Summary

Osteopetrosis refers to a group of rare, inherited skeletal disorders characterized by increased bone density and abnormal bone growth.[1][2] Symptoms and severity can vary greatly, ranging from neonatal onset with life-threatening complications (such as bone marrow failure) to the incidental finding of osteopetrosis on X-ray. Depending on severity and age of onset, features may include fractures, short stature, compressive neuropathies (pressure on the nerves), hypocalcemia with attendant tetanic seizures, and life-threatening pancytopenia. In rare cases, there may be neurological impairment or involvement of other body systems.[1] Osteopetrosis may be caused by mutations in at least 10 genes. Inheritance can be autosomal recessiveautosomal dominant, or X-linked recessive with the most severe forms being autosomal recessive. Management depends on the specific symptoms and severity and may include vitamin D supplements, various medications, and/or surgery. Adult osteopetrosis requires no treatment by itself, but complications may require intervention.[3]

Symptoms

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Abnormal cortical bone morphology
0003103
Abnormal cranial nerve morphology
0001291
Abnormal pelvis bone ossification
0009106
Abnormality of the ribs
Rib abnormalities
0000772
Abnormality of vertebral epiphysis morphology
Abnormal shape of the end part of the vertebra bone
0100734
Abnormality of vision
Abnormality of sight
Vision issue

[ more ]

0000504
Bone pain
0002653
Cranial nerve paralysis
0006824
Craniosynostosis
0001363
Fever
0001945
Growth delay
Delayed growth
Growth deficiency
Growth failure
Growth retardation
Poor growth
Retarded growth

[ more ]

0001510
Hearing impairment
Deafness
Hearing defect

[ more ]

0000365
Hypocalcemia
Low blood calcium levels
0002901
Hypophosphatemia
Low blood phosphate level
0002148
Lymphadenopathy
Swollen lymph nodes
0002716
Macrocephaly
Increased size of skull
Large head
Large head circumference

[ more ]

0000256
Osteomyelitis
Bone infection
0002754
Osteopetrosis
Harder, denser, fracture-prone bones
0011002
Peripheral neuropathy
0009830
Petechiae
0000967
Recurrent fractures
Increased fracture rate
Increased fractures
Multiple fractures
Multiple spontaneous fractures
Varying degree of multiple fractures

[ more ]

0002757
Reduced bone mineral density
Low solidness and mass of the bones
0004349
Sandwich appearance of vertebral bodies
0004618
Sclerotic vertebral endplates
0004576
30%-79% of people have these symptoms
Bruising susceptibility
Bruise easily
Easy bruisability
Easy bruising

[ more ]

0000978
Immunodeficiency
Decreased immune function
0002721
Leukocytosis
Elevated white blood count
High white blood count
Increased blood leukocyte number

[ more ]

0001974
Persistence of primary teeth
Delayed loss of baby teeth
Failure to lose baby teeth
Retained baby teeth

[ more ]

0006335
5%-29% of people have these symptoms
Abnormal chorioretinal morphology
0000532
Abnormal pulmonary valve morphology
0001641
Bone marrow hypocellularity
Bone marrow failure
0005528
Carious teeth
Dental cavities
Tooth cavities
Tooth decay

[ more ]

0000670
Genu valgum
Knock knees
0002857
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation

[ more ]

0001249
Mandibular prognathia
Big lower jaw
Increased projection of lower jaw
Increased size of lower jaw
Large lower jaw
Prominent chin
Prominent lower jaw

[ more ]

0000303
Nystagmus
Involuntary, rapid, rhythmic eye movements
0000639
Osteoarthritis
Degenerative joint disease
0002758
Renal tubular acidosis
Accumulation of acid in body due to kidney problem
0001947
Sleep apnea
Pauses in breathing while sleeping
0010535
Splenomegaly
Increased spleen size
0001744
Thrombocytopenia
Low platelet count
0001873

Cause

The various types of osteopetrosis are caused by genetic changes (mutations) in one of at least ten genes.[1] There is nothing a parent can do before, during or after a pregnancy to cause osteopetrosis in a child.

The genes associated with osteopetrosis are involved in the development and/or function of osteoclasts,[4] cells that break down bone tissue when old bone is being replaced by new bone (bone remodeling). This process is necessary to keep bones strong and healthy. Mutations in these genes can lead to abnormal osteoclasts, or having too few osteoclasts. If this happens, old bone cannot be broken down as new bone is formed, so bones become too dense and prone to breaking.[5]

  • Mutations in the CLCN7 gene cause most cases of autosomal dominant osteopetrosis, 10-15% of cases of autosomal recessive osteopetrosis (the most severe form), and all known cases of intermediate autosomal osteopetrosis.
  • Mutations in the TCIRG1 gene cause about 50% of cases of autosomal recessive osteopetrosis.
  • Mutations in the IKBKG  gene cause X-linked osteopetrosis.
  • Mutations in other genes are less common causes of osteopetrosis.
  • In about 30% percent of affected people, the cause is unknown.[5]

People with questions about the specific cause of osteopetrosis in themselves or a family member are encouraged to speak with a genetics professional.

Diagnosis

Yes. Genetic testing for the various subtypes of osteopetrosis is available. Genetic testing can be used to confirm the diagnosis and to differentiate between different subtypes of osteopetrosis. This may provide additional information regarding the long-term outlook (prognosis), likely response to treatment, and recurrence risks.[4]

The Genetic Testing Registry (GTR) is a central online resource for information about genetic tests. The intended audience for the GTR is health care professionals and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional. Click on the link above to view the information that the GTR provides about genetic testing for osteopetrosis.

Treatment

Treatment for osteopetrosis depends on the specific symptoms present and the severity in each person. Therefore, treatment options must be evaluated on an individual basis.

Nutritional support is important to improve growth and it also enhances responsiveness to other treatment options. A calcium-deficient diet has been beneficial for some affected people.

Treatment is necessary for the infantile form:

  • Vitamin D (calcitriol) appears to stimulate dormant osteoclasts, which stimulates bone resorption. Large doses of calcitriol with restricted calcium intake sometimes improves osteopetrosis dramatically, but the improvement seen with calcitrol is not sustained when therapy is stopped.
  • Gamma interferon can have long-term benefits. It improves white blood cell function (leading to fewer infections), decreases bone volume, and increases bone marrow volume.
  • Erythropoietin can be used for anemia, and corticosteroids can be used for anemia and to stimulate bone resorption.[3]

Bone marrow transplantation (BMT) markedly improves some cases of severe, infantile osteopetrosis associated with bone marrow failure, and offers the best chance of longer-term survival for individuals with this type.[3][1]

In pediatric (childhood) osteopetrosis, surgery is sometimes needed because of fractures.

Adult osteopetrosis typically does not require treatment, but complications of the condition may require intervention. Surgery may be needed for aesthetic or functional reasons (such as multiple fractures, deformity, and loss of function), or for severe degenerative joint disease.[3]

FDA-Approved Treatments

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition. Learn more orphan products.

Organizations

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Social Networking Websites

    Learn more

    These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

    Where to Start

      In-Depth Information

      • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
      • Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
      • The Merck Manual for health care professionals provides information on Osteopetrosis.
      • MeSH® (Medical Subject Headings) is a terminology tool used by the National Library of Medicine. Click on the link to view information on this topic.
      • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
      • Online Mendelian Inheritance in Man (OMIM) lists the subtypes and associated genes for Osteopetrosis in a table called Phenotypic Series. Each entry in OMIM includes a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine.
      • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
      • PubMed is a searchable database of medical literature and lists journal articles that discuss Osteopetrosis. Click on the link to view a sample search on this topic.

        References

        1. Zornitza Stark and Ravi Savarirayan. Osteopetrosis. Orphanet. October, 2012; https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=2781.
        2. David D. Sherry Frank Pessler. Osteopetroses. Merck Manual. 2016; https://www.merckmanuals.com/home/children-s-health-issues/bone-disorders-in-children/osteopetroses.
        3. Robert Blank. Osteopetrosis. Medscape Reference. December 17, 2014; https://emedicine.medscape.com/article/123968-overview.
        4. Zornitza Stark and Ravi Savarirayan. Osteopetrosis. Orphanet J Rare Dis. 2009; 4:5:https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-4-5.
        5. Osteopetrosis. Genetics Home Reference. September 2010; https://ghr.nlm.nih.gov/condition/osteopetrosis.

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