MYH9 related thrombocytopenia

Other Names: MYH9 related disorders; Sebastian syndrome (subtype); May-Hegglin anomaly (subtype); Fechtner syndrome (subtype); Epstein syndrome (subtype); MYH9-RD; MYH9-related disease; MYH9-related disorder; MYH9-related syndrome; MYH9-related syndromic thrombocytopenia; Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss

MYH9-related disorder is a condition that can have many signs and symptoms, including bleeding problems, hearing loss, kidney (renal) disease, and clouding of the lens of the eyes (cataracts).

MYH9-related disorder was previously thought to be four separate disorders: May-Hegglin anomaly, Epstein syndrome, Fechtner syndrome, and Sebastian syndrome. All of these disorders involved thrombocytopenia and enlarged platelets and were distinguished by some combination of hearing loss, renal disease, and cataracts. When it was discovered that these four conditions all had the same genetic cause, they were combined and renamed MYH9-related disorder.

Epidemiology

The incidence of MYH9-related disorder is unknown. More than 200 affected families have been reported in the scientific literature.

Cause

MYH9-related disorder is caused by mutations in the MYH9 gene. The MYH9 gene provides instructions for making a protein called myosin-9. This protein is one part (subunit) of the myosin IIA protein.

There are three forms of myosin II, called myosin IIA, myosin IIB and myosin IIC. The three forms are found throughout the body and perform similar functions. They play roles in cell movement (cell motility); maintenance of cell shape; and cytokinesis, which is the step in cell division when the fluid surrounding the nucleus (the cytoplasm) divides to form two separate cells. While some cells use more than one type of myosin II, certain blood cells such as platelets and white blood cells (leukocytes) use only myosin IIA.

MYH9 gene mutations that cause MYH9-related disorder typically result in a nonfunctional version of the myosin-9 protein. The nonfunctional protein cannot properly interact with other subunits to form myosin IIA. Platelets and leukocytes, which only use myosin IIA, are most affected by a lack of functional myosin-9. It is thought that a lack of functional myosin IIA leads to the release of large, immature platelets in the bloodstream, resulting in a reduced amount of normal platelets. In leukocytes, the nonfunctional myosin-9 clumps together. These clumps of protein, called inclusion bodies, are a hallmark of MYH9-related disorder and are present in the leukocytes of everyone with this condition.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In most cases, an affected person inherits the mutation from one affected parent. Approximately 30 percent of cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

Signs and symptoms

The bleeding problems in people with MYH9-related disorder are due to thrombocytopenia. Thrombocytopenia is a reduced level of circulating platelets, which are small cells that normally assist with blood clotting. People with MYH9-related disorder typically experience easy bruising, and affected women have excessive bleeding during menstruation (menorrhagia). The platelets in people with MYH9-related disorder are larger than normal. These enlarged platelets have difficulty moving into tiny blood vessels like capillaries. As a result, the platelet level is even lower in these small vessels, further impairing clotting.

Some people with MYH9-related disorder develop hearing loss caused by abnormalities of the inner ear (sensorineural hearing loss). Hearing loss may be present from birth or can develop anytime into late adulthood.

An estimated 30 to 70 percent of people with MYH9-related disorder develop renal disease, usually beginning in early adulthood. The first sign of renal disease in MYH9-related disorder is typically protein or blood in the urine. Renal disease in these individuals particularly affects structures called glomeruli, which are clusters of tiny blood vessels that help filter waste products from the blood. The resulting damage to the kidneys can lead to kidney failure and end-stage renal disease (ESRD).

Some affected individuals develop cataracts in early adulthood that worsen over time.

Not everyone with MYH9-related disorder has all of the major features. All individuals with MYH9-related disorder have thrombocytopenia and enlarged platelets. Most commonly, affected individuals will also have hearing loss and renal disease. Cataracts are the least common sign of this disorder.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

80%-99% of people have these symptoms

• Congenital thrombocytopenia

30%-79% of people have these symptoms

• Bruising susceptibility(Bruise easily)
• Elevated hepatic transaminase(High liver enzymes)
• Giant platelets
• Menorrhagia(Abnormally heavy bleeding during menstruation)
• Nephritis(Kidney inflammation)
• Nephropathy
• Neutrophil inclusion bodies
• Presenile cataracts
• Prolonged bleeding time
• Proteinuria(High urine protein levels)
• Renal insufficiency(Renal failure)
• Sensorineural hearing impairment
• Spontaneous, recurrent epistaxis(Recurring nosebleed)

1%-4% of people have these symptoms

• Myocardial infarction(Heart attack)

Diagnosis

The diagnosis is established by the finding of typical MYH9 protein aggregates in neutrophils detected through immunofluorescence analysis of a peripheral blood smear and/or by the identification of a heterozygous pathogenic variant in MYH9. Absence of MYH9 protein aggregates in neutrophils excludes the diagnosis of MYH9RD.

Treatment

There is currently no cure for MYH9-related thrombocytopenia. Measures that can be taken to prevent bleeding episodes may include platelet transfusion, desmopressin, or antifibrinolytic drug administration prior to surgery or invasive procedures, and regular dental care to prevent bleeding of the gums. People with MYH9RD should avoid drugs that inhibit platelet function or blood coagulation, activities with high risk for injury, ototoxic drugs, hazardous noise, nephrotoxic agents (agents that are toxic to the kidneys), glucocorticoids (steroids) and radiation therapy. Bleeding episodes are treated with platelet transfusion and sometimes with desmopressin (this helps to shorten bleeding time in some people). People with bleeding episodes should be monitored for anemia. Once a year urine analysis (including 2-hour protein) and a measurement of serum concentration of creatinine should be done to monitor for kidney disease. Hearing and vision evaluations are needed every three years prior to onset of hearing loss and cataracts. Kidney complications, hearing loss, and cataracts are all managed in a standard fashion.

NIH genetic and rare disease info

• NIH info on MYH9 related thrombocytopenia

MYH9 related thrombocytopenia is a rare disease.

MYH9 related thrombocytopenia Resources
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