Clinical Guidance

Observed genotype-phenotype correlations are discussed in this section. (See Molecular Genetics, for more details.) Individuals with pathogenic variants involving the head domain of the MYH9 protein have more severe thrombocytopenia compared to those with pathogenic variants affecting the tail domain. The risk of developing kidney damage, hearing loss, and cataract also depends on the specific MYH9 pathogenic variant .

Source: GeneReviews — "MYH9-Related Disease"

Penetrance

Penetrance is complete for the following congenital findings:

• Platelet macrocytosis with giant platelets

• Aggregates of the MYH9 proteins in neutrophils

Except for a very few individuals in whom platelet count was just above the conventional cut-off value for thrombocytopenia (150 x 109/L), thrombocytopenia is a congenital manifestation of the disease. Expressivity varies for onset and severity of sensorineural deafness, glomerular nephropathy, presenile cataract, and alterations of liver enzymes.

Source: GeneReviews — "MYH9-Related Disease"

Diagnostic Criteria

No consensus clinical diagnostic criteria for MYH9-related disease (MYH9-RD) have been published.

Suggestive Findings

MYH9-RD should be suspected in individuals with the following clinical and laboratory findings and family history.

Clinical findings

• Manifestations of thrombocytopenia

• Easy bruising

• Spontaneous mucocutaneous bleeding

• Excessive bleeding after hemostatic challenges (major or minor surgery, deliveries, treatment with antiplatelet drugs)

• Sensorineural hearing loss ranging from a slight defect occurring in the elderly to profound deafness that may manifest at a young age

• Glomerular nephropathy manifest as proteinuria, with possible evidence of chronic kidney disease

• Presenile cataract (occurring in early or middle life)

Laboratory findings

• Platelet abnormalities

Source: GeneReviews — "MYH9-Related Disease"

Differential Diagnosis

The differential diagnosis of MYH9-related disease (MYH9-RD) should take into consideration acquired and inherited forms of thrombocytopenia as well as collagen IV-related nephropathies. Acquired Thrombocytopenia Idiopathic (autoimmune) thrombocytopenic purpura (ITP). Differentiating between MYH9-RD and ITP (the most frequent form of acquired thrombocytopenia) is challenging and individuals with MYH9-RD are frequently misdiagnosed with ITP. Misdiagnosis with ITP often leads to treatments (immunosuppressive drugs and splenectomy) that are not only ineffective in individuals with MYH9-RD but also potentially harmful. For instance, among individuals enrolled in the Italian Registry for MYH9-RD, about 60% of index cases had received a previous diagnosis of ITP and 30% received inappropriate treatments, including splenectomy . If the genetic origin of thrombocytopenia is not obvious because a family history is absent or unclear, the following findings on microscopic evaluation of peripheral blood slides are a simple and effective way to distinguish individuals with MYH9-RD from those with ITP : • Platelets are significantly larger in persons with MYH9-RD than in those with ITP: a mean platelet diameter 3.7 m distinguishes MYH9-RD from ITP with 86% sensitivity and 87% specificity. • More than 40% of platelets 3.9 m (i.e., about half the diameter of a red blood cell) distinguishes MYH9-RD from ITP with 85% sensitivity and 87% specificity. Assay of immunofluorescence staining of MYH9 protein distribution in neutrophils can also be used to differentiate MYH9-RD from ITP (see Diagnosis, ). Molecular genetic testing provides confirmation of the diagnosis of MYH9-RD. Inherited Thrombocytopenia summarizes the main forms of inherited thrombocytopenia with platelet macrocytosis (inherited macrothrombocytopenias) that should, therefore, be considered in the differential diagnosis of MYH9-RD. Note: All congenital macrothrombocytopenias are very rare disorders. Table 4. Inherited Macrothrombocytopenias in the Differential Diagnosis of MYH9-Related Disease

Management Guidelines

No clinical practice guidelines for MYH9-related disease (MYH9-RD) have been published. Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with MYH9-RD, the evaluations summarized in are recommended at the time of diagnosis. Table 5. Recommended Evaluations Following Initial Diagnosis in Individuals with MYH9-Related Disease

Source: GeneReviews — "MYH9-Related Disease"

Clinical Guidance

Bleeding Tendency

Agents. Drugs that can inhibit platelet function or reduce platelet count should be administered only after a careful assessment of the risks versus the benefits. Patients and treating physicians should be informed about such drugs.

• Drugs that inhibit platelet function include:

• Nonsteroidal anti-inflammatory drugs, especially aspirin, which are strong inhibitors of platelet aggregation;

• Other drugs that interfere with platelet function, including some antidepressants, antibiotics, and anesthetics.

• Drugs that may reduce platelet count include oncologic treatments and some antibiotics.

Antithrombotic drugs (such as heparin or oral anticoagulants) should be prescribed with caution and after a careful assessment of the risk-to-benefit ratio, as in patients affected with other forms of thrombocytopenia. MYH9 pathogenic variants are usually not associated with defects of platelet function, and therefore platelet function is usually normal in patients with MYH9-RD. Circumstances. In individuals with severe thrombocytopenia and significant bleeding tendency, activities at high risk of trauma (e.g., contact sports) should be avoided.

Hearing Loss

Agents.

Source: GeneReviews — "MYH9-Related Disease"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "MYH9-Related Disease"

Surveillance Guidelines

Table 7. Recommended Surveillance for Individuals with MYH9-Related Disease

Source: GeneReviews — "MYH9-Related Disease"