What are the other Names for this Condition? (Also known as/Symptoms)

• Autosomal Dominant MYH9 Spectrum Disorders
• MYH9RD (MYH9-Related Disorder)
• Myosin Heavy Chain 9 (MYH9)-Related Platelet Disorder

What is MYH9-Related Disorder? (Definition/Background Information)

• MYH9-Related Disorder (MYH9RD) is a rare genetic disorder that is caused by mutation(s) in the MYH9 gene, which codes for myosin-9 protein
• When the myosin protein is dysfunctional due to the mutations, immature platelets (giant platelets) are released in blood. It also causes the formation of aggregates in leukocytes, a type of white blood cells resulting in abnormal bleeding disorders
• Due to these defects, the affected individuals exhibit symptoms, such as easy bruising, profuse bleeding even with small cuts, menorrhagia in women, excessive bleeding during surgery or childbirth, and including kidney malfunction, hearing loss, and cataracts
• Over 65% of the individuals affected by this disorder inherit MYH9-Related Disorder in an autosomal dominant pattern, from an affected parent. The presence of one defective gene copy is sufficient to cause the disorder
• A diagnosis of MYH9-Related Disorder typically involves checking for inclusion bodies in leukocytes, which are present in all individuals with the condition. Additional tests for genetic confirmation may be required. Tests to diagnose and evaluate other associated symptoms may also be necessary
• Treatment for MYH9-Related Disorder is usually geared toward addressing any bleeding conditions. Other treatment measures are targeted towards treating the kidney disorders, surgery for cataracts, and hearing aids or cochlear implants for hearing abnormalities associated with MYH9RD
• Several methods are reported to reduce or mitigate symptoms of MYH9-Related Disorder, particularly with respect to bleeding. Avoiding aspirin, taking medications to improve platelet count, platelets transfusion before surgery or childbirth, and periodic testing to avoid anemia, are a few preventive methods to arrest any excessive bleeding
• The prognosis of MYH9-Related Disorder depends upon the severity of the signs and symptoms. The condition does not reduce the life-expectancy of those affected. However, progressive kidney disease and hearing loss can severely affect the quality of life in individuals with MYH9-Related Disorder

Who gets MYH9-Related Disorder? (Age and Sex Distribution)

• MYH9-Related Disorder is a rare condition that is manifested in a newborn child
• The exact prevalence of the disease is not known. Over 200 families affected by the disorder are described in scientific literature; however, many scientists believe that the reported numbers may be misleading since many cases are either not diagnosed or are misdiagnosed
• Both male and female genders may be affected by MYH9-Related Disorder
• It is reported to occur worldwide without racial or ethnic predilection

What are the Risk Factors for MYH9-Related Disorder? (Predisposing Factors)

• Having a parent or a family member with MYH9-Related Disorder is the single most important risk factor for the condition, since it has been reported that approximately two-thirds of the affected individuals have a parent with the disorder
• About 33% of affected individuals have no family history of the disorder, and the risk factor(s) for spontaneous mutations in the relevant genes are not known

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of MYH9-Related Disorder? (Etiology)

• MYH9-Related Disorder is reported to be caused by mutations in the MYH9 gene, which codes for a protein ‘myosin-9‘. The disorder is known as Myosin Heavy Chain 9 (MYH9)-Related Platelet Disorder
  • Myosin-9 is a subunit of myosin IIA protein, which belongs to a family of proteins that plays a role in cellular movement, the maintenance of structural integrity of a cell, and cell division
  • All members of the myosin II family (myosin IIA, myosin IIB and myosin IIC) are present throughout the body. Cells may use more than one type of myosin protein for its proper functioning. However, certain cells in blood, such as white blood cells (leukocytes) and platelets, exclusively use myosin IIA
• When a mutation occurs in myosin-9 protein, it is rendered non-functional. This leads to compromised interaction with other subunits, making myosin IIA non-functional as well
• When there is scarcity of functional myosin IIA, the number of normal platelets in blood is reduced, with the release of abnormal, giant, immature platelets into blood. These giant platelets are hindered in their movement through the small aperture of blood capillaries, leading to an overall drop in levels of circulating platelets
• In the leukocytes, the abnormal myosin-9 protein aggregate. These aggregates are known as “inclusion bodies,” and are a characteristic feature in blood of all the affected individuals

In a majority of individuals, MYH9-Related Disorder is inherited in an autosomal dominant pattern, in which a single copy of the mutated gene is sufficient to cause the disorder.

Autosomal dominant: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

What are the Signs and Symptoms of MYH9-Related Disorder?

The signs and symptoms of MYH9-Related Disorder include:

• Thrombocytopenia or issues with blood clotting as a result of reduced platelets in blood. This can lead to:
  • Easy bruising
  • Bleeding into the skin (superficial) that can have a rash-like appearance
  • Bleeding for a prolonged time from small cuts
  • Nosebleeds
  • Bleeding from the gums
  • Hemorrhage following biopsy and/or surgery
  • In women, heavy bleeding during mestruation (menorrhagia)
  • Hemorrhage after delivery
• Progressive hearing loss owing to abnormalities in the inner ear. Hearing problems may be present at birth or can develop later in life
• Kidney disease begins in young adulthood; it affects about 30-70% of individuals with the condition. It can result in abnormal filtering of the kidneys leading to the following signs:
  • Protein in urine
  • Blood in urine
• Elevated liver enzymes
• The development of cataract; this is an atypical symptom of the disorder

Note:

Previously, the different symptoms were classified into 4 different syndromes, namely:

• May-Hegglin anomaly (large platelets, inclusion bodies in leukocytes)
• Epstein syndrome (kidney disorder owing to myosin-9 mutations)
• Fechtner syndrome (inclusion bodies and large platelets)
• Sebastian platelet syndrome (impaired platelets, inclusion bodies in leukocytes, without renal or auditory symptoms)

However, the symptoms have now been recognized to be clinical manifestations of MYH9 mutations, and hence, the 4 syndromes have been clubbed under MYH9-Related Disorders.

How is MYH9-Related Disorder Diagnosed?

The following tools may be used by a healthcare professional for the diagnosis of MYH9-Related Disorders:

• A thorough physical examination
• An evaluation of family history of the disorder
• An assessment of symptoms
• Blood tests to check for the following:
  • MYH9 leukocyte inclusion bodies by immunostaining techniques; a positive test is generally indicative of the disorder
  • Platelets and granulocytes morphology
  • Anemia (for exclusionary purposes, particularly in women of child-bearing age)
• Urine analysis:
  • Checking for protein or blood in urine
  • Creatinine clearance test
• An audiogram to check for loss of hearing
• Eye examination to check for development of cataracts
• Genetic testing to confirm mutation(s) in myosin-9
• Prenatal diagnosis is a possibility, by performing genetic testing of fetal cells

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of MYH9-Related Disorder?

Some complications arising from MYH9-Related Disorders include:

• Renal disease: Damage to kidneys may result in kidney failure or end-stage renal disease
• Progressive cataracts
• Progressive hearing loss

How is MYH9-Related Disorder Treated?

The following are treatment options for MYH9-Related Disorders:

• Bleeding disorders are treated through the following:
  • Oral thrombopoietin receptor agonist to improve platelet production
  • Oral vasopressin analogs to curb bleeding
  • Antifibrinolytic agents for arresting bleeding
  • Hormone supplement to help reduce bleeding during menstruation in women
  • Platelet transfusion, preferably with human leukocyte antigen (HLA) matched donors. This may be performed ahead of a surgery, or before a pregnant woman with the condition delivers a baby
• Kidney malfunction is treated by:
  • Renin-angiotensin system blockers to reduce proteinuria
  • Angiotensin II receptor blockers to slow progression of the disorder
  • Dialysis
  • Kidney transplantation in case of severe kidney damage 
• Hearing impairment can be improved by:
  • Hearing aids
  • Cochlear implants
• Cataracts: If necessary, surgical removal of the cataract may be performed
• Vaccinations for whooping cough (to avoid bleeding) and viral diseases, such as measles: Vaccination against measles will potentially help prevent damage to bone marrow megakaryocytes. Platelets are produced by megakaryocytes in the bone marrow, and hence, any damage to the megakaryocytes may result in abnormal platelet function

MYH9-Related Disorder can have a variety of signs and symptoms. Some signs and symptoms require surgery, whereas others require non-surgical treatments.

The wide varieties of surgical interventions that may be required include:

• Dental extraction
• Tonsillectomy
• Adenectomy (removal of a gland)
• Cataract lens replacement
• Orthopedic joint replacement
• Cardiopulmonary bypass surgery
• Neurosurgical intervention

How can MYH9-Related Disorder be Prevented?

MYH9-Related Disorder is a genetic disorder, and so there are no specific methods or guidelines to prevent the occurrence of this disorder.

• Genetic counseling in those with a family history of the condition may help those planning for a baby understand the risks better
• Prenatal genetic testing with fetal cells and genetic counseling for expecting parents are suggested
• Bleeding disorders can be prevented by the following measures:
  • Antifibrolytic agents and vasopressin analogs
  • Avoiding aspirin
  • Routine dental care to keep from gum disease development
  • Avoiding nosebleeds by keeping nose moist with oily nasal ointments
  • Oral contraceptives in women as a means of reducing bleeding during menstruation
  • Platelet transfusion before surgery to minimize bleeding
  • Routine blood count monitoring to avoid anemia, which can worsen the platelets-driven clotting process
  • Vaccinations against whooping cough can help prevent incessant coughing and resultant bleeding
  • Getting vaccinated for viral diseases, such as measles, to help avoid loss of bone marrow cells, known as megakaryocytes, from which platelets arise
• Routine physical examinations, blood and urine tests, hearing tests and eye exams can help identify if the condition is progressing, in order to take early effective treatment measures

Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders such as MYH9-Related Disorder.

What is the Prognosis of MYH9-Related Disorder? (Outcomes/Resolutions)

• The prognosis of MYH9-Related Disorder is dependent upon the severity of the signs and symptoms. An individual’s life expectancy is not reported to be compromised by this disorder
• However, owing to progressive kidney disease, as well as hearing impairment and spontaneous bleeding episodes (even though rare), an individual’s quality of life may be moderately-to-even-severely affected

Additional and Relevant Useful Information for MYH9-Related Disorder:

MYH9-Related Disorder was previously thought to be a group of 4 separate disorders including:

• May-Hegglin anomaly
• Epstein syndrome
• Fechtner syndrome
• 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 4 conditions all had the same genetic cause, they were combined and renamed MYH9-Related Disorder.