Osteopetrosis (marble disease): what is it, symptoms, treatment, prognosis

What is osteopetrosis?

Osteopetrosis(also known as "marble disease», Albers-Schoenberg disease) Is a descriptive term for a group of rare hereditary skeletal diseases characterized by increased bone density due to a defect in bone reabsorption by cells called osteoclasts. This leads to the accumulation of bones with defective architecture, making them fragile and prone to fracture. Although symptoms may initially not appear in people with mild marble disease, trivial injuries can cause bone fractures due to fragility. Early diagnosis is important in the most severe forms of these disorders because they cause irreversible complications and can be treated with hematopoietic stem cell transplantation.

There are three types of osteopetrosis classified by inheritance: autosomal dominant, autosomal recessive, and X-linked recessive. The autosomal dominant form is the most common: patients usually have mild symptoms that appear in late childhood and adulthood. The autosomal recessive form, also called malignant infantile, appears soon after birth and often shortens life expectancy. Finally, X-linked osteopetrosis is extremely rare, with only a few cases reported. There is also an intermediate type of osteopetrosis, including both mild autosomal recessive forms and dominant ones with early and severe manifestation.

Osteopetrosis was first discovered by the radiologist Albers-Schoenberg in 1904.

Signs and symptoms

Osteopetrosis is characterized by excessive bone density throughout the body. Symptoms include fractures, low blood cell production, and loss of cranial nerve function, causing blindness, deafness, and / or facial nerve palsy. Patients may have frequent infections of the teeth and jaw bones.

- Osteopetrosis, autosomal recessive; malignant child type.

The most severe type of osteopetrosis, the childhood malignant type, manifests itself from birth and, if left untreated, can lead to death within the first decade of life. Symptoms vary depending on the exact change in the gene (mutation). Patients may have an abnormally large head (macrocephaly). They may also have hydrocephaluscharacterized by suppression of the normal flow of cerebrospinal fluid (CSF) within and abnormal expansion (dilatation) cerebral spaces of the brain (ventricles), causing accumulation of CSF in the skull and potentially increasing pressure on tissues brain. Symptoms affecting the eyes may include:

• wasting (atrophy) of the retina;
• wide-set eyes (hypertelorism);
• displacement of the eyeball forward (exophthalmos);
• strabismus;
• involuntary rhythmic eye movements (nystagmus);
• blindness.

Other symptoms associated with malignant childhood marble disease include hearing loss, abnormally small jaw (micrognathia), chronic inflammation of the nasal mucous membranes (rhinitis), difficulty eating and / or delay growth. In some affected individuals, there is a delay in the acquisition of skills that require muscle coordination and voluntary movement (psychomotor retardation). Some patients may have delayed tooth development or severe caries. In addition, the following are observed:

• abnormal increase 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 bones of the skull (hyperostosis of the skull), leading to compression of the nerves;
• increased pressure inside the skull.

Patients may also experience seizures due to low blood calcium levels. In rare cases of malignant osteopetrosis, infants may present with symptoms of severe neurodegeneration (loss of neuronal structure or function).

Some patients with malignant infantile type of osteopetrosis may also experience the effects of space contraction. bone marrow: severe deficiency of all types of blood cells (pancytopenia), formation and development of blood cells outside the bone marrow, for example, in the spleen and liver (extramedullary hematopoiesis) and the occurrence of myeloid tissue in extramedullary sites (myeloid metaplasia). This can lead to frequent infections such as pneumonia and urinary tract infections. Patients may also have low levels of iron in red blood cells (anemia) due to a decrease in the space of the bone marrow and an increase in the destruction of red blood cells due to enlargement of the spleen. It should be noted that hematologic defects usually precede neurologic defects.

- Osteopetrosis, autosomal dominant; adult type.

The milder form of osteopetrosis, the adult type, is usually diagnosed in late childhood or adulthood. Bone symptoms predominate, 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 people may have pus-filled sacs in the tissues around the teeth (dental abscess). In many cases, symptoms may not be present.

Patients may also develop rhinitis, hepatosplenomegaly, anemia, and extramedullary hematopoiesis.

- Osteopetrosis, intermediate autosomal recessive.

The intermediate type usually occurs in children and can be inherited as an autosomal recessive or autosomal dominant trait. The severity of the disease varies. Symptoms may include:

• abnormal hardening of some bones;
• fractures;
• osteomyelitis, especially of the lower jaw;
• abnormally close knees;
• abnormally wide ankles;
• hyperostosis of the skull.

Symptoms of intermediate osteopetrosis may also include gradual deterioration of the optic nerves (optic atrophy), loss of vision, muscle weakness, and rhinitis. Some affected individuals may have abnormal protrusion of the mandible (mandibular prognathism), dental pathology, milk retention, deformation of the crown of the tooth, dental caries and facial paralysis nerve. Other symptoms include hepatosplenomegaly, anemia, decreased platelet count in the circulating blood (thrombocytopenia), pancytopenia and extramedullary hematopoiesis.

- X-linked recessive osteopetrosis.

X-linked osteopetrosis is extremely rare but severe, with only a few cases reported worldwide. In addition to the classic symptoms associated with osteopetrosis, it is associated with immunodeficiency, localized retention fluid and tissue edema (lymphedema), as well as pathologies of the hair, skin, nails and sweat glands (ectodermal dysplasia).

Causes

Osteopetrosis can be inherited in an autosomal dominant or recessive pattern, and very rarely in an X-linked recessive pattern. The main defect in bone reabsorption is insufficient production or dysfunction of cells called osteoclasts. These cells are responsible for bone resorption and help maintain bone health, which depends on the balance between bone resorption (osteoclasts) and bone formation (other specialized cells called osteoblasts). The human skeleton is completely regenerated every 10 years. In this context, osteoclasts are required for bone renewal (replacing old bone with new one), bone remodeling, and repair of microcracks.

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

The adult type of osteopetrosis is inherited as an autosomal dominant genetic trait. Dominant genetic disorders occur when only one mutated copy of a gene is enough to cause a specific disease. A mutated copy of a gene can be inherited from either parent, or it can be the result of a mutational event that occurs directly in the affected person. The risk of passing an abnormal copy of a gene from an affected parent to an offspring is 50% with every pregnancy. The risk is the same for men and women.

Malignant childhood osteopetrosis is inherited as an autosomal recessive genetic trait. Recessive genetic disorders occur when a person inherits two abnormal copies of a gene, one from each parent. If a person receives one normal and one abnormal copy of a disease gene, they will be a carrier of the disease, but usually asymptomatic. The risk for two carrier parents to pass on an abnormal copy of the same gene and, therefore, to have a sick child, is 25% in every pregnancy. The risk of having a carrier child, like that of a parent, is 50% with every pregnancy. The probability that a child will receive a normal copy of a gene from both parents is 25%. The risk is the same for men and women.

The X-linked form of osteopetrosis is recessive and extremely rare. X-linked recessive diseases are caused by an abnormal gene on the X chromosome and occur primarily in males. Women who have an abnormal copy of a gene present on one of their X chromosomes are carriers of the disease: they usually do not show symptoms because women have two X chromosomes. Men have one X chromosome inherited from their mother, and if a man inherits an X chromosome containing an abnormal (abnormal) gene, he will develop the disease. Women who are carriers of X-linked recessive disorder have a 25% risk of having a carrier daughter like themselves in every pregnancy, 25% chance of having a daughter who is not a carrier of the disease, 25% chance of having a son affected by the disease and 25% chance of having a healthy one son.

The intermediate type of osteopetrosis can be inherited as an autosomal recessive or autosomal dominant genetic trait.

Affected populations

In the general population, 1 in 250,000 people are born with malignant childhood osteopetrosis. Higher rates were found in selected regions of Costa Rica, the Middle East, Sweden and Russia. Men and women suffer equally.

The adult type of osteopetrosis affects about 1 in 20,000 people. Men and women suffer equally.

The X-linked form of osteopetrosis affects mainly men due to the way the mutation is inherited. Due to the rarity of cases, there are no population studies.

Symptomatic disorders

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

• Meloreostosis - a rare disease that occurs as a result of abnormal development of the outer layer of the bone (cortex), which becomes hyperdense and expanded. Also affects the surrounding soft tissue. Melorheostosis is characterized by deformity of one or more limbs with pain and limitation of movement of the affected limb. Usually occurs sporadically.
• OsteopoikilosisAlso known as congenital macular multiple osteopathy, it is a rare condition that can occur in association with melorheostosis. Usually, X-ray examination can detect osteopoikilosis without visible symptoms. The diagnosis is usually made between the ages of 15 and 60. Spotted shadows appear on x-rays of the wrist and ankle bones, finger or toe bones, long bones, pelvis, skull, and / or ribs. These spots are less than one centimeter in diameter and usually have the same density. Bone growth nodules can grow or shrink and disappear. Osteopoikilosis can be transmitted in an autosomal dominant genetic pattern; sporadic forms also exist.
• Osteogenesis imperfecta or "crystal man" disease is a group of inherited connective tissue diseases characterized by unusual fragility of bones and a tendency to fracture. Traditionally, the disease is distinguished in two forms: osteogenesis imperfecta, which manifests itself at birth, and late osteogenesis, which usually manifests itself in early childhood with milder symptoms. However, it is important to note that at present there are 17 forms of osteogenesis imperfecta, differing in terms of various genetic and clinical data.
• Osteopetrosis with renal tubular acidosis, also known as type II carbonic anhydrase deficiency and Guibault-Wansel syndrome, is a rare hereditary disorder characterized by multiple fractures during the first years life. Affected infants have abnormal acid buildup in the body (metabolic acidosis), including in the kidney tubes (renal tubular acidosis). Physical signs associated with the disease include short stature, osteosclerosis, hepatosplenomegaly, improper connection of the upper and lower teeth (malocclusion), hyperostosis skull and / or anemia. Some affected children may have mental retardation and cerebral calcifications. Osteopetrosis with renal tubular acidosis is inherited as an autosomal recessive trait.

Diagnostics

The diagnosis of osteopetrosis is based on a careful clinical assessment, a detailed history of the patient, and various specialized tests, such as x-rays and measurements of bone density, which increases. Skeletal X-ray is very specific and is considered sufficient for a diagnosis. Biochemical findings, such as elevated concentrations of the isoenzyme creatine kinase BB and tartrate-resistant acid phosphatase (TRAP), can also aid in the diagnosis.

- Clinical testing and examination.

Genetic testing can detect a mutation in more than 90% of cases: it can identify forms of osteopetrosis with unique clinical associations or complications and determine a treatment plan. A bone biopsy is sometimes done to confirm the diagnosis, but is usually not done because it is an invasive procedure with considerable risks.

After the diagnosis is made, the following blood tests must be done: serum calcium, parathyroid hormone, phosphorus, creatinine, 25-hydroxyvitamin D, complete blood count with differential, creatine kinase isoenzymes (specifically BB isoenzyme creatine kinase), and lactate dehydrogenase. Analysis of these substances will determine the need for supplements and referral to specialists. Basic magnetic resonance imaging of the brain should be done to assess cranial nerve damage, hydrocephalus, and vascular abnormalities.

Affected people should have regular check-ups by an ophthalmologist for optic nerve involvement and take an interdisciplinary approach that includes endocrinology, ophthalmology, genetics and dentistry, with the participation of specialists in the field of orthopedics, otorhinolaryngology, neurology, neurosurgery, nephrology, infectious diseases and hematology, as necessity.

Theoretically, prenatal diagnosis is possible in families in which a genetic mutation has been identified.

Standard treatments

Currently, the only cure for autosomal recessive malignant childhood osteopetrosis is case-specific hematopoietic stem cell transplantation (HSCT). This allows you to restore bone resorption by osteoclasts of donor origin. However, genetic studies are important to determine the feasibility of HSCT, since certain specific mutations will not benefit the transplant (those in the gene RANKL); in addition, in some patients (all with mutations in the gene OSTM1 and some of the patients with two mutations in the gene CLCN7) progressive neurodegeneration develops, which cannot be cured with HSCT therapy. In milder forms of osteopetrosis, it is important to weigh the risks and benefits, as they may not match the dangerous risks associated with HSCT, such as rejection (graft versus host disease), severe infections, and very high blood calcium levels leading to significant mortality in the first year. For patients in whom HSCT was considered inappropriate, the possibility of using corticosteroidsbut there is insufficient evidence to support their routine use.

Interferon gamma-1b (Actimmun) has been approved by the FDA and US medication to slow the progression of the disease in people with severe malignant childhood osteopetrosis. Actimmune is manufactured by Horizon Pharma. Inc.

For patients with osteopetrosis, proper nutrition is very important, including the use of calcium supplements and vitamin D with a low level of calcium in the blood. Other treatments are symptomatic and supportive. Genetic counseling is recommended for families with this condition.

Forecast

Severe childhood forms of osteopetrosis are associated with decreased life expectancy, with most untreated children dying within the first decade due to bone marrow suppression. Life expectancy in adult initial forms is normal.