Adult-onset osteopetrosis (Albers-Schönberg Disease)
X-ray of thepelvis of a patient with osteopetrosis, adult onset form (Albers-Schönberg disease). Note the dense appearance.
Specialty	Medical genetics

Osteopetrosis, literally'stone bone', also known asmarble bone disease orAlbers-Schönberg disease, is an extremely rareinheriteddisorder whereby thebones harden, becomingdenser, in contrast to more prevalent conditions likeosteoporosis, in which the bones become less dense and more brittle, orosteomalacia, in which the bones soften. Osteopetrosis can cause bones to dissolve and break.^[1]

It is one of the hereditary causes ofosteosclerosis.^[2] It is considered to be the prototype of osteosclerosing dysplasias. The cause of the disease is understood to be malfunctioningosteoclasts and their inability to resorb bone. Although human osteopetrosis is a heterogeneous disorder encompassing differentmolecular lesions and a range of clinical features, all forms share a single pathogenic nexus in the osteoclast. The exact molecular defects or location of the mutations taking place are unknown.^[3] Osteopetrosis was first described in 1903 by German radiologistAlbers-Schönberg.^[4]

Despite this excess bone formation, people with osteopetrosis tend to have bones that are more brittle than normal. Mild osteopetrosis may cause no symptoms, and present no problems.^[5]

However, serious forms can result in the following:^[5]

• Stunted growth, deformity, and increased likelihood of fractures
• Patients experience anemia, recurrent infections, andhepatosplenomegaly due to bone expansion leading to bone marrow narrowing andextramedullary hematopoiesis
• It can also result inblindness,facial paralysis, anddeafness, due to the increased pressure put on the nerves by the extra bone
• Abnormal cortical bonemorphology
• Abnormal form of thevertebral bodies
• Abnormality oftemperature regulation
• Abnormality of the ribs
• Abnormality of vertebralepiphysis morphology
• Bone pain
• Cranial nerveparalysis
• Craniosynostosis
• Hearing impairment
• Hypocalcemia

Autosomal recessive osteopetrosis (ARO), also known as malignant infantile osteopetrosis or infantile malignant osteopetrosis (IMO), is a rare type of skeletal dysplasia characterized by a distinct radiographic pattern of overall increased density of the bones with fundamental involvement of the medullary portion. Infantile osteopetrosis typically manifests in infancy. Diagnosis is principally based on clinical and radiographic evaluation, confirmed by gene analysis where applicable.^[7] As a result of medullary canal obliteration and bony expansion, gravepancytopenia, cranial nerve compression, and pathologic fractures may ensue. Theprognosis is poor if untreated. The classicradiographic features include endobone or "bone-within-bone" appearance in the spine, pelvis and proximal femora, upper limbs, and short tubular bones of the hand. Additionally, there is theErlenmeyer flask deformity type 2 which is characterized by the absence of normal diaphyseal metaphysical modeling of the distal femora with abnormal radiographic appearance of trabecular bone and alternating radiolucent metaphyseal bands.^[7]

The precise and early diagnosis of infantile osteopetrosis is important for management of complications, genetic counselling, and timely institution of appropriate treatment, namelyhematopoietic stem cell transplantation (HSCT), which offers a satisfactory treatment modality for a considerable percentage of infantile osteopetrosis.^[8] Amelioration of radiographic bone lesions after HSCT in infantile osteopetrosis has been proposed as an important indicator of success of the therapy. A few publications with limited study participants have demonstrated the resolution of skeletal radiographic pathology following HSCT.^[9][10]

Autosomal dominant osteopetrosis (ADO) is also known as Albers-Schönberg disease. Most do not know they have this disorder because most individuals do not show any symptoms. However, those who do show symptoms will typically have a curvature of the spine (scoliosis) and multiple bone fractures. There are two types of adult osteopetrosis based on the basis of radiographic, biochemical, and clinical features.^[11]

Many patients will havebone pains. The defects are very common and includeneuropathies due to cranialnerve entrapment,osteoarthritis, andcarpal tunnel syndrome. About 40% of patients will experience recurrent fractures of their bones. 10% of patients will haveosteomyelitis of themandible.^[11]

The various types of osteopetrosis are caused by genetic changes (mutations) in one of at least ten genes. There is nothing a parent can do before, during or after a pregnancy to cause osteopetrosis in a child.^[5]

Normally, bone growth is a balance between osteoblasts (cells that create bone tissue) and osteoclasts (cells that destroy bone tissue). This process is necessary to keep bones strong and healthy. Those with osteopetrosis have a deficiency of osteoclasts, meaning too little bone is being resorbed, resulting in too much bone being created. The genes associated with osteopetrosis are involved in the development and/or function of osteoclasts, cells that break down bone tissue when old bone is being replaced by new bone (bone remodeling). Mutations in these genes can lead to abnormalosteoclasts(termed osteoclast-rich osteopetrosis), or having too few osteoclasts(osteoclast-poor osteopetrosis).^[13] If this happens, old bone cannot be broken down as new bone is formed, so bones become too dense and prone to breaking.^[5]

Three different types of inheritance-autosomal dominant, autosomal recessive and X-linked recessive have been observed.^[11]

• Mutations in theCLCN7 gene cause most cases of autosomal dominant(in a dominant negative manner) osteopetrosis, 10-15% of cases ofautosomal recessive osteopetrosis (the most severe form), and all known cases of intermediate autosomal osteopetrosis.
• Mutations in theTCIRG1 gene cause about 50% of cases of AR(autosomal recessive) osteopetrosis.
• Mutations in theIKBKG gene causeX-linked osteopetrosis.
• Mutations in theCA-II gene can be an extremely rare cause of AR osteopetrosis in the setting of renal defects.
• Mutations in theRANKL gene cause AR osteoclast-poor osteopetrosis.
• Mutations in other genes are less common causes of osteopetrosis.^[13]
• In about 30% of affected people, the cause is unknown.^[14]

Normal bone growth is achieved by a balance between bone formation byosteoblasts and bone resorption (breakdown of bone matrix) by osteoclasts.^[15] In osteopetrosis, the number of osteoclasts may be reduced, normal, or increased. Most importantly, osteoclast dysfunction mediates the pathogenesis of this disease.^[16]

Osteopetrosis can be caused by underlying mutations that interfere with the acidification of the osteoclast resorption pit, for example due to a deficiency of thecarbonic anhydrase enzyme encoded by theCA2 gene.^[17] Carbonic anhydrase is required by osteoclasts for proton production. Without this enzyme hydrogen ion pumping is inhibited and bone resorption by osteoclasts is defective, as an acidic environment is needed to dissociatecalcium hydroxyapatite from the bone matrix. As bone resorption fails while bone formation continues, excessive bone is formed.^[18]

Mutations in any of the genes associated with osteopetrosis lead to abnormal or missing osteoclasts. Without functional osteoclasts, old bone is not broken down as new bone is formed. As a result, bones throughout the skeleton become unusually dense. The bones are also structurally abnormal, making them prone to fracture. These problems with bone remodeling underlie all of the major features of osteopetrosis.^[19]

The differential diagnosis of osteopetrosis includes other disorders that produceosteosclerosis. They constitute a wide array of disorders with clinically and radiologically diverse manifestations. Among thedifferential diagnosis are hereditary ostoesclerosing dysplasias such as; neuropathic infantile osteopetrosis, infantile osteopetrosis with renal tubular acidosis, infantile osteopetrosis with immunodeficiency, infantile osteopetrosis with leukocyte adhesion deficiency syndrome (LAD-III),pyknodysostosis (osteopetrosis acro-osteolytica),osteopoikilosis (Buschke–Ollendorff syndrome),osteopathia striata with cranial sclerosis, mixed sclerosingskeletal dysplasias, progressive diaphyseal dysplasia (Camurati–Engelmann disease), SOST-related sclerosingskeletal dysplasias.^[7] Besides, the differential diagnosis includes acquired conditions that induce osteosclerosis such as osteosclerotic metastasis notablycarcinomas of the prostate gland and breast,Paget's disease of bone,myelofibrosis (primary disorder or secondary to intoxication or malignancy),Erdheim–Chester disease, osteosclerosing types ofosteomyelitis,sickle cell disease, hypervitaminosis D, andhypoparathyroidism.^[20]

It was the first genetic disease treated withhematopoietic stem cell transplantation (osteoclasts are derived from hematopoietic precursors).^[21][22] There is no cure, although curative therapy withbone marrow transplantation is being investigated in clinical trials. It is believed the healthy marrow will provide cells from which osteoclasts will develop.^[5] If complications occur in children, patients can be treated withvitamin D. Gamma interferon has also been shown to be effective, and it can be associated to vitamin D.Erythropoetin has been used to treat any associatedanemia.Corticosteroids may alleviate both the anemia and stimulate bone resorption. Fractures andosteomyelitis can be treated as usual.^[5] 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. Acalcium-deficient diet has been beneficial for some affected people.^[5]

Treatment is necessary for the infantile form:^[5]

• Vitamin D (calcitriol) appears to stimulate dormant osteoclasts, which stimulates bone resorption
• Gamma interferon can have long-term benefits. It improveswhite blood cell function (leading to fewer infections), decreases bone volume, and increases bone marrow volume.
• Erythropoietin can be used for anemia, andcorticosteroids can be used for anemia and to stimulate bone resorption.

Bone marrow transplantation (BMT) 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.^[5]

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 foraesthetic or functional reasons (such as multiple fractures, deformity, and loss of function), or for severe degenerative joint disease.^[5]

The long-term outlook for people with osteopetrosis depends on the subtype and the severity of the condition in each person. The severe infantile forms of osteopetrosis are associated with shortened life expectancy, with most untreated children not surviving past their first decade.Bone marrow transplantation seems to have cured some infants with early-onset disease. However, the long-term prognosis after transplantation is unknown. For those with onset in childhood or adolescence, the effect of the condition depends on the specific symptoms (including how fragile the bones are and how much pain is present). Life expectancy in the adult-onset forms is normal.^[23]

Approximately eight to 40 children are born in theUnited 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 inDenmark andCosta Rica. Males and females are affected in equal numbers.^[24]

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 inBrazil. Males and females are affected in equal numbers.^[24]

Osteopetrosis affects one newborn out of every 20,000 to 250,000^[25] worldwide, but the odds are much higher in the Russian region ofChuvashia (1 of every 3,500–4,000 newborns) due to genetic traits of theChuvash people.^[26][27]

Recent research demonstrated that the systematic administration of RANKL for one month to Rankl(-/-) mice, which closely resemble the human disease, significantly improved the bone phenotype and has beneficial effects on bone marrow, spleen and thymus; major adverse effects arise only when mice are clearly overtreated. Overall, it provided evidence that the pharmacological administration of RANKL represents the appropriate treatment option for RANKL-deficient ARO patients, to be validated in a pilot clinical trial.^[28]

Interferon gamma-1b is FDA-approved to delay the time to disease progression in patients with severe, malignant osteopetrosis.^[29]

• Laurel Burch^[30]
• Henri de Toulouse-Lautrec (osteopetrosis was at one time thought to be what he suffered from, but it was later discovered to bepycnodysostosis)^[31]

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