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. In some cases, this is also accompanied by 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 transplant.
There are three types of osteopetrosis, 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 present 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. Finally, 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 exact gene change (mutation). Affected individuals may have an abnormally large head (macrocephaly). They may also have hydrocephalus, 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 affect the eyes may include wasting away (atrophy) of the retina, eyes that appear widely spaced (hypertelorism), eyes that protrude from their orbits (exophthalmos), cross-eyes (strabismus), involuntary rhythmic movements of the eyes (nystagmus), and blindness.
Other symptoms associated with malignant infantile type of osteopetrosis include hearing loss, abnormally small jaw (micrognathia), chronic inflammation of the mucous membranes in the nose (rhinitis), eating difficulties and/or growth retardation. 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 or severe dental caries. 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) leading to nerve compression; and/or increased pressure inside the skull may also occur. Patients can also present with seizures due to low levels of calcium in the blood. Symptoms of severe neurodegeneration can manifest in rare variants of malignant infantile osteopetrosis.
Some affected individuals with the malignant infantile type of osteopetrosis may also experience consequences of reduced bone marrow space: marked deficiency of all types of blood cells (pancytopenia), the formation and development of blood cells outside the bone marrow, as in the spleen and liver (extramedullary hematopoiesis), and the occurrence of myeloid tissue in extramedullary sites (myeloid metaplasia). This may lead to frequent infections such as pneumonia and urinary tract infections. Affected individuals may also experience low levels of iron in red blood cells (anemia), due to both reduced bone marrow space and increased destruction of red blood cells due to an enlarged spleen. Of note, hematological defects usually present before neurological ones.
Osteopetrosis, Autosomal Dominant; Adult Type
A milder form of osteopetrosis, the adult type, is usually diagnosed in late childhood or adulthood. There is predominance of bone symptoms, including osteosclerosis, fractures after minimal trauma (usually of the ribs and long bones), osteomyelitis (especially of the jaw) and cranial hyperostosis. 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 may also experience rhinitis, hepatosplenomegaly, anemia and extramedullary hematopoiesis.
Osteopetrosis, Intermediate Autosomal Recessive
The intermediate type is usually found in children and can be inherited as a autosomal recessive or autosomal dominant trait. The severity of the disease is variable. Symptoms may include abnormal hardening of some bones; fractures; osteomyelitis especially of the mandible, knees that are abnormally close together and ankles that are abnormally wide apart (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 experience abnormal protrusion of the lower jaw (mandibular prognathism), dental anomalies, baby teeth that do not fall out (deciduous retention), tooth crown malformation, 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 a 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 the bone turnover (replacement of old bone by new bone), bone remodeling, as well as micro-fracture repair.
Human traits including the classic genetic diseases are the product of the interaction of two alleles for that condition, one received from the father and one from the mother.
The adult type of osteopetrosis is inherited as an autosomal dominant genetic trait. Dominant genetic disorders occur when only a single mutated copy of a gene is sufficient to cause a particular disease. The mutated copy of the gene can be inherited from either parent or can be the result of a mutational event occurred directly in the affected individual. The risk of passing the abnormal copy of the gene from an affected parent to an offspring is 50% at each pregnancy. The risk is the same for males and females.
The malignant infantile type of osteopetrosis is inherited as an autosomal recessive genetic trait. Recessive genetic disorders occur when an individual inherits two abnormal copies of a gene, one from each parent. If an individual receives one normal and one abnormal copy of a 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 abnormal copy of the same gene and, therefore, have an affected child is 25% at each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% at each pregnancy. The chance for a child to receive the normal copy of the gene 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 recessive disorders are caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have an abnormal copy of a gene present on one of their X chromosomes are carriers for that disorder: they usually do not display symptoms because females have two X chromosomes. Males have a single X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains an abnormal gene, he will develop the disease. Female carriers of an X-linked recessive 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.
The intermediate type of osteopetrosis can be inherited as an autosomal recessive or autosomal dominant genetic trait.
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 affects predominantly males due to the mode of inheritance of the mutation. Due to the rarity of cases, there are no population-wide studies.
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 pinpoint the mutation in over 90% of cases: this can identify forms of osteopetrosis with unique clinical associations 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 non-negligible 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 of the brain should be arranged to evaluate cranial nerve involvement, hydrocephalus and vascular abnormalities. Affected individuals should be evaluated regularly by an ophthalmologist for optic nerve involvement, and benefit from a multidisciplinary approach including endocrinology, ophthalmology, genetics, and dentistry, with input from orthopedics, otorhinolaryngology, neurology, neurosurgery, nephrology, infectious disease and hematology specialists as needed.
Prenatal diagnosis is theoretically possible in families in whom the genetic mutation has been identified.
At present, the only established cure for autosomal recessive malignant infantile osteopetrosis is hematopoietic stem cell transplantation (HSCT) for specific cases. This allows the restoration of bone resorption by donor-derived osteoclasts. Genetic studies are important to determine whether HSCT is appropriate, as certain specific mutations will not benefit from the transplant (those in the RANKL gene); moreover, some patients (all those with mutations in the OSTM1 gene and some of those with two mutations in the CLCN7 gene) develop progressive neurodegeneration, which is not cured by HSCT. In mild forms of osteopetrosis it is important to weight the risks and benefits as they may not warrant the dangerous risks associated with HSCT like rejection, severe infections and very high levels of calcium in the blood leading to a significant mortality rate in the first year. For patients in whom HSCT has been deemed not appropriate, corticosteroids may be considered, but there is not enough evidence to support their routine use.
Gamma-1b (Actimmune) was approved by the U.S. Food and Drug Administration to delay disease progression in individuals with severe malignant infantile osteopetrosis. Actimmune is manufactured by Horizon Pharma. Inc.
Good nutrition is very important for patients with osteopetrosis, including the use of 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 families in which this disorder occurs.
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. Moreover, groups are investigating the use of interferon Gamma-1b for non-infantile osteopetrosis: although experimental, it has been reported to improve immune function and increase bone resorption.
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