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MYH9-Related Disorders

, PhD and , MD, PhD.

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Initial Posting: ; Last Update: July 16, 2015.

Estimated reading time: 28 minutes


Clinical characteristics.

MYH9-related disorders (MYH9RD) are characterized by large platelets (i.e., >40% of platelets >3.9 μm in diameter) and thrombocytopenia (platelet count <150 x 109/L), both of which are present from birth. MYH9RD is variably associated with young-adult onset of progressive sensorineural hearing loss, presenile cataract, elevation of liver enzymes, and renal disease manifesting initially as glomerular nephropathy. Before identification of the gene in which mutation is causative, MYH9, individuals with MYH9RD were diagnosed as having Epstein syndrome, Fechtner syndrome, May-Hegglin anomaly, or Sebastian syndrome based on the combination of different clinical findings at the time of diagnosis. However, the realization that they all are due to heterozygous pathogenic variants in MYH9 and that the clinical findings often worsen throughout life as a result of late onset of non-hematologic manifestations has led the four conditions to be regarded as one disorder, now known as MYH9RD.


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 of manifestations: For active hemorrhage, application of local measures, desmopressin (DDAVP), and antifibrinolytic agents are used; platelet transfusion is necessary for: hemorrhages not controlled by the above treatments, life-threatening bleeding, or hemorrhages at critical sites. Hearing loss, renal complications, and cataract are managed in a standard fashion; individuals with severe/profound deafness benefit from cochlear implantation.

Prevention of primary manifestations: Platelet transfusion, desmopressin, antifibrinolytic drugs, or eltrombopag can be used to reduce the risk of bleeding prior to surgery or invasive procedures; oral contraceptives may be effective in preventing or treating menorrhagia; regular dental care to prevent gingival bleeding.

Surveillance: In those with bleeding episodes, blood count at least every six months to identify anemia. In all affected individuals, annual urinalysis (including 24-hour protein or protein [albumin]/creatinine ratio on a spot urine sample) and measurement of serum concentration of creatinine prior to onset of renal disease; serum liver enzyme measurements and audiometric and ophthalmologic evaluations every three years.

Agents/circumstances to avoid: Drugs that inhibit platelet function or blood coagulation; ototoxic, nephrotoxic, and hepatotoxic drugs should be used only after careful assessment of risk versus benefit; hazardous noise and activities with high risk of injury should be avoided.

Evaluation of relatives at risk: Screen at-risk newborns with molecular genetic testing if the family-specific pathogenic variant is identified; otherwise assess platelet count and size.

Pregnancy management: Deliveries should be managed as they are in women with other forms of thrombocytopenia; a platelet count of ≥50 x 109/L is generally recommended for safe delivery.

Genetic counseling.

MYH9RD is inherited in an autosomal dominant manner. Approximately 35% of affected individuals represent simplex cases, half of whom have a documented de novo pathogenic variant. Each offspring of an individual with MYH9RD has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in the family is known.

GeneReview Scope

MYH9-Related Disorders: Included Phenotypes 1
  • Epstein syndrome
  • Fechtner syndrome
  • May-Hegglin anomaly
  • Sebastian syndrome

For synonyms and outdated names see Nomenclature.


For other genetic causes of these phenotypes see Differential Diagnosis.


The MYH9-related disorders (MYH9RD) were thought to be separate conditions involving congenital macrothrombocytopenia prior to the understanding of their shared molecular genetic basis.

Suggestive Findings

MYH9-related disorders (MYH9RD) should be suspected in individuals with the following clinical and laboratory findings.

Clinical findings

  • Manifestations of thrombocytopenia
    • Easy bruising
    • Spontaneous mucocutaneous bleedings
    • Excessive bleeding after hemostatic challenges (major or minor surgery, deliveries, treatment with antiplatelet drugs).
  • Sensorineural hearing loss. See Hereditary Hearing Loss and Deafness Overview for discussion of audiologic methods to detect hearing loss.
  • Glomerular nephropathy with possible renal failure (see Laboratory Findings below).
  • Presenile cataract (occurring in early or middle life detected on slit lamp evaluation).
  • Family history consistent with autosomal dominant inheritance.
    Note: Lack of a family history of MYH9RD does not preclude the diagnosis.

Laboratory findings

  • Routine blood cell counts demonstrate thrombocytopenia (platelet count <150 x 109/L [normal: 150 to 400 x 109/L])
  • Microscopic assessment of a peripheral blood smear after conventional staining (such as May-Grünwald-Giemsa) demonstrates:
    • Large platelets (mean platelet diameter >3.7 μm and/or >40% of platelets with diameter >3.9 µm [about half a red blood cell])
      Note: Electronic cell counters do not recognize the largest platelets of individuals with MYH9RD and therefore underestimate both platelet count and size in these subjects.
    • Döhle-like bodies (faint, light blue basophilic inclusion bodies similar to the Döhle bodies that may be found in persons with an infection) in the cytoplasm of neutrophils
      Note: Döhle-like bodies are present in 42%-84% of individuals with MYH9RD. They may escape detection because they are very faint and/or small [Kunishima et al 2003, Seri et al 2003].
  • Immunofluorescence of a peripheral blood smear demonstrates typical MYH9 protein aggregates in the cytoplasm of neutrophils. These aggregates are:
  • Elevated liver enzymes (serum alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST] and occasionally serum gamma-glutamyltransferase [GGT])
  • Urinalysis demonstrating proteinuria and microhematuria
    Note: Proteinuria is the earlier sign of kidney involvement
  • Elevated serum creatinine concentration (indicating progression to renal failure and risk for end-stage renal disease [ESRD])

Establishing the Diagnosis

The diagnosis of MYH9RD is established in a proband with 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 (see Table 1).

Molecular testing approaches can include single-gene testing and use of a multigene panel.

Single-gene testing. Sequence analysis of MYH9 is performed first followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.

Tiered approaches to sequence analysis and exon numbering may vary among laboratories (see Molecular Genetics for exon numbering information).

  • Tier 1. Of the 40 coding exons of MYH9, sequence first the five exons in which pathogenic variants are found in 84% of cases. Pathogenic missense variants at amino acid residues 96 (exon 1), 702 (exon 17), 1165 (exon 27), 1424 (exon 31), and 1841 (exon 39), or nonsense and frameshift pathogenic variants in exon 41 have been found in 79% of affected individuals (see Table 2).
  • Tier 2. When pathogenic variants are not detected in Tier 1 testing, the analysis is extended to exons 2, 11, 25, 26, 32, 33, 35, and 38, in which the remaining 16% of pathogenic variants have been identified [Balduini et al 2011].
  • Tier 3. In individuals without an identifiable pathogenic variant in Tier 1 or Tier 2 testing, sequence analysis of all coding exons is performed.

A multigene panel that includes MYH9 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in MYH9-Related Disorders

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
MYH9Sequence analysis 3, 498% 5, 6
Gene-targeted deletion/duplication analysis 7Unknown 8

See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Sequence analysis may be performed with a tiered approach that focuses initially on exons in which pathogenic variants are most commonly found, then on exons in which pathogenic variants have previously been identified, and finally on the remainder of the gene.


Affected individuals: those with an aggregate distribution of MYH9 protein in neutrophils [Savoia et al 2010]


No MYH9 pathogenic variants have been detected in individuals of two case series (36 and 39 subjects, respectively) with clinical findings suggestive of MYH9RD but without MYH9 protein aggregates detected through immunofluorescence [Savoia et al 2010, Kitamura et al 2013].


Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used can include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.


Because a large deletion of 1220 nucleotides leading to an in-frame removal of exon 25 has been identified in MYH9 [Kunishima et al 2008b], gene-targeted deletion/duplication analysis may be appropriate in families with a strong clinical history and no identifiable MYH9 pathogenic variant on sequence analysis.

Clinical Characteristics

Clinical Description

In all individuals with an MYH9-related disorder (MYH9RD), macrothrombocytopenia is present at birth. Mean platelet diameter was 4.5 μm (95% confidence interval, 4.2-4.8) in 125 persons with MYH9RD and 2.6 μm (95% confidence interval, 2.4-2.7) in 55 healthy controls [Noris et al 2014a]. Thrombocytopenia ranges from mild to severe and remains stable in an individual throughout life. Platelet counts at the lower limit of normal range have been reported in a few individuals with MYH9RD. Thus, large platelets are the only finding shared among all affected individuals.

Presence and severity of spontaneous bleeding tendency correlate with the degree of thrombocytopenia. Most affected individuals have no spontaneous bleeding or only easy bruising. About 28% of persons with MYH9RD have spontaneous mucocutaneous bleeding, including epistaxis, gum bleeding, or menorrhagia [Pecci et al 2014a]. Life-threatening bleeding is rare.

The noncongenital manifestations of MYH9RD can develop anytime between infancy and adulthood. The overall annual rates per 100 affected persons are 1.71 for sensorineural hearing loss, 0.77 for nephropathy, and 0.57 for cataract [Pecci et al 2014a] (i.e., for example, 0.57% of individuals with MYH9RD develop cataract every year). Alteration of liver enzymes has been found in about 50% of individuals with MYH9RD who have been evaluated [Pecci et al 2012a].

Sensorineural hearing loss. Onset of hearing loss is distributed evenly from the first to sixth decade. Of those who develop hearing loss, 36% do so before age 20 years, 33% between ages 20 and 40 years, and 31% after age 40 years. Once diagnosed, hearing loss frequently progresses over time, although it remains stable in a minority of affected individuals [Verver et al 2016]. Hearing loss interfering with activities of daily living is present in 90% of those individuals who have an abnormal audiometric examination [Pecci et al 2014a].

Glomerular nephropathy presents with proteinuria and microhematuria. However, in MYH9RD, hematuria may result from thrombocytopenia rather than glomerular disease; therefore, proteinuria is the more reliable indicator of glomerular involvement. The mean age at onset is 27 years. Of those who develop renal disease, 72% are diagnosed before age 35 years. In most affected individuals with nephropathy, kidney damage is progressive and evolves to end-stage renal disease (ESRD). Among those with nephropathy, the overall annual rate for 100 affected persons for progression to ESRD is 6.79. After a median follow-up of 36 months, 64% of 61 affected individuals with nephropathy developed renal failure and 43% developed ESRD [Pecci et al 2014a].

Cataract. The mean age of onset of cataract is 37 years, although congenital forms have been reported. In most cases, cataract is bilateral and progresses over time.

Elevated liver enzyme levels. Elevated AST and/or ALT (possibly associated with increased GGT) usually remains stable over time. In some affected individuals, normalization of enzyme levels has been observed. Progression to impairment of liver function has not been reported in any affected individual [Pecci et al 2012a, Favier et al 2013a].

Genotype-Phenotype Correlations

Identification of the family-specific MYH9 pathogenic variant can help assess the risk of developing the noncongenital features of the disease.

Affected 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 [Pecci et al 2014a]. See Molecular Genetics, Normal gene product for domain structure, Molecular Genetics, Pathogenic variants, and Table 2.

  • Pathogenic variants in the codon for arginine residue 702, which is located in the short functional SH1 helix of the head domain, are associated with the most severe phenotype. Individuals with Arg702 substitutions (Table 2) present with severe thrombocytopenia (platelet count usually <50 x 109/L) and all are expected to develop nephropathy and hearing loss before age 40 years. Moreover, nephropathy usually progresses rapidly to ESRD in these individuals.
  • The p.Asp1424His substitution is associated with an intermediate to high risk of developing the noncongenital manifestations of the disease. Most affected individuals with the p.Asp1424His variant develop kidney damage before age 60 years; all are expected to develop hearing loss within 60 years; the risk for cataracts is higher than in those with other genotypes.
  • Pathogenic variants involving the residues at the interface between the SH3-like motif and the motor domain or those resulting in substitutions of the arginine residue 1165 (see Table 2) are associated with a high risk for hearing loss (all are expected to develop hearing loss before age 60 years) and a low risk for nephropathy and cataract.
  • The p.Asp1424Asn and p.Glu1841Lys substitutions, as well as the nonsense or frameshift pathogenic variants resulting in alterations of the non-helical tailpiece (see Table 2), are associated with low risk of developing the noncongenital manifestations of the disease. In individuals with these pathogenic variants, thrombocytopenia usually remains the only manifestation of the disease throughout life [Pecci et al 2014a].

To date, no significant genotype-phenotype correlations have been identified for the occurrence of liver enzyme alteration [Pecci et al 2012a].


Penetrance is complete for the following congenital findings:

  • Large platelets
  • MYH9 aggregates in neutrophils

Except for a 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.


In the past, the conditions included in MYH9RD were known as

  • Epstein syndrome
  • Fechtner syndrome
  • May-Hegglin anomaly
  • Sebastian syndrome (Sebastian platelet syndrome)

These four disorders, characterized by thrombocytopenia with giant platelets, were classified on the basis of morphologic aspects of Döhle-like bodies and different combinations of the other manifestations of MYH9RD: hearing loss, glomerular nephropathy, and cataract. However, because the phenotype of a person with an MYH9 pathogenic variant often evolves over time, the diagnosis of an individual can change over time based on the appearance of a new finding or findings. Moreover, the four syndromes do not define all the possible manifestations deriving from heterozygous MYH9 pathogenic variants. Finally, members of the same family may have different phenotypes and receive different diagnoses within the spectrum of MYH9RD. For these reasons, MYH9RD has been proposed as a new nosologic entity that includes all individuals with heterozygous MYH9 pathogenic variants independent of their neutrophil phenotype (i.e., presence of morphologic aspects of Döhle-like bodies) and clinical phenotype (late-onset non-hematologic manifestations) [Seri et al 2003].


MYH9RD is considered a very rare disease. The Italian Registry for MYH9RD includes 180 Italian affected individuals, indicating that the prevalence of the disorder in Italy is at least 3:1,000,000. Because mild forms are discovered incidentally and severe forms are often misdiagnosed as other disorders, the actual prevalence is expected to be higher.

MYH9RD has been diagnosed worldwide and there is no evidence of variation in prevalence across ethnic populations.

Differential Diagnosis

MYH9-related disorder (MYH9RD) should be suspected in all individuals with congenital thrombocytopenia and giant platelets. It should also be considered when macrothrombocytopenia is discovered incidentally in infancy or adulthood and no previous blood counts are available to determine if the macrothrombocytopenia is congenital or acquired.

Absence of thrombocytopenia in other family members does not exclude MYH9RD because the frequency of de novo pathogenic variants is high (~35% of probands) [Balduini et al 2011].

The differential diagnosis of MYH9RD should take into consideration acquired and congenital forms of thrombocytopenia as well as collagen IV-related nephropathies.

Acquired thrombocytopenia. Differentiating MYH9RD from acquired forms of thrombocytopenia may be difficult and several individuals with MYH9RD have been misdiagnosed with idiopathic (autoimmune) thrombocytopenic purpura (ITP). This led to administration of treatments (immunosuppressive drugs and splenectomy) that are ineffective in individuals with MYH9RD. Whenever a family history of thrombocytopenia is absent or unclear, evaluation of peripheral blood slides is a simple and effective tool to distinguish individuals with MYH9RD from those with ITP, as platelets are significantly larger in persons with MYH9RD than in those with ITP. In particular, a mean platelet diameter >3.7 µm distinguishes MYH9RD from ITP with 86% sensitivity and 87% specificity. Otherwise, a proportion of platelets with diameter >3.9 µm (about half a red blood cell) higher than 40% differentiates MYH9RD from ITP with 85% sensitivity and 87% specificity [Noris et al 2014a].

Congenital thrombocytopenia. The following inherited thrombocytopenias presenting with large platelets should be considered in the differential diagnosis of MYH9RD:

  • Bernard-Soulier syndrome (BSS) (OMIM 231200), an autosomal recessive nonsyndromic thrombocytopenia resulting from pathogenic variants in the genes coding for platelet glycoproteins (GP) GPIbα, GPIbβ, and GPIX, which together with subunit GPV constitute the von Willebrand factor receptor, GPIb/IX/V. Platelets in BSS can be as large as in MYH9RD. Bernard-Soulier syndrome is recognized by (1) failure of platelets to agglutinate in vitro after stimulation with ristocetin, and (2) absence or severe reduction of the GPIb/IX/V complex on the platelet surface detected by flow cytometry. More than 200 cases with a molecular diagnosis have been reported in the literature.
  • Gray platelet syndrome (OMIM 139090), a very rare autosomal recessive nonsyndromic thrombocytopenia resulting from pathogenic variants in NBEAL2. The hallmark of Gray platelet syndrome is the finding of "pale" platelets on peripheral blood films as a result of lack of alpha granules. Electron microscopy of platelets or the finding of biallelic pathogenic variants in NBEAL2 confirms the diagnosis. Approximately 30 families have been reported in the literature.
  • GATA1-related X-linked cytopenia, another rare condition characterized by a mild to moderate hemolytic anemia sometimes associated with hemoglobin changes similar to heterozygous beta-thalassemia. An estimated fourteen families have been reported in the literature.

Collagen IV-related nephropathies, including X-linked and autosomal (dominant and recessive) forms of Alport syndrome and thin basement membrane nephropathy. Whereas the latter is characterized mainly by persistent microscopic hematuria, which rarely progresses to renal failure, Alport syndrome is associated with renal disease that evolves from microscopic hematuria to proteinuria, progressive renal insufficiency, and ESRD. It is also characterized by extrarenal abnormalities including progressive sensorineural hearing loss (usually present by late childhood or early adolescence), anterior lenticonus, maculopathy, corneal endothelial vesicles, and recurrent corneal erosion. Platelet defects have not been described in either Alport syndrome or thin basement membrane nephropathy. Therefore, whenever nephropathies are associated with macrothrombocytopenia, MYH9RD should be strongly considered.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with an MYH9-related disorder (MYH9RD), the following evaluations are recommended:

  • Microscopic assessment of platelet count (phase contrast microscopy by a counting chamber) to determine the degree of thrombocytopenia
  • In individuals with bleeding episodes, complete blood count to evaluate for anemia
  • In individuals with anemia, serum concentration of iron and ferritin level to evaluate for iron deficiency
  • Audiometric evaluation
    In those with severe to profound deafness, speech recognition tests
  • Measurement of serum concentration of AST, ALT, and GGT
  • Urinalysis, including measurement of 24-hour protein or protein (or albumin)/creatinine ratio on a spot urine sample, and measurement of serum concentration of creatinine
  • In individuals with established renal involvement, testing appropriate to the severity of renal disease
  • Ophthalmologic examination
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Bleeding tendency

  • Local measures are the first-line treatment for mucocutaneous bleeding and often are sufficient to control mild or moderate bleeding. Local measures include packing or endoscopic cauterization of the bleeding site for treatment of epistaxis; suturing for treatment of accidental or surgical wounds; and compression and application of gauzes soaked in tranexamic acid for bleeding from superficial wounds. Mouthwash with tranexamic acid may control gingival bleeding.
  • Transfusions of platelet concentrates are currently used to transiently increase platelet count. Platelet transfusions have associated risks of possible alloimmunization and subsequent refractoriness to platelet infusions, infectious diseases, and acute reactions. Thus, platelet transfusions should be limited to treatment for active hemorrhages that cannot be otherwise managed, life-threatening bleedings, and/or hemorrhages at critical sites; platelet concentrates may also be used as prophylaxis prior to surgery or other major hemostatic stresses. When available, platelets from HLA-matched donors should be used to prevent or overcome alloimmunization.
  • Eltrombopag. A Phase II study in 12 persons with MYH9RD and severe thrombocytopenia demonstrated that eltrombopag, an oral drug mimicking the natural hormone that stimulates platelet production, increased platelet counts and abolished bleeding tendency in most instances [Pecci et al 2010]. Thereafter, short-term eltrombopag courses have been successfully used in one affected adult prior to major surgery and in one child with MYH9RD and severe thrombocytopenia [Pecci et al 2012b, Favier et al 2013b]. At the present time, this drug is approved in the US and Europe only for individuals with some forms of acquired thrombocytopenia.
  • Antifibrinolytic agents. Some authors recommend the systemic administration of antifibrinolytic agents, such as tranexamic or epsilon-aminocaproic acid, to treat mild or moderate mucocutaneous bleeding [Bolton-Maggs et al 2006, Althaus & Greinacher 2009].
  • Desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) shortened bleeding time in some individuals with MYH9RD [Balduini et al 1999]. Successful surgery after prophylaxis with DDAVP has been reported [Pecci et al 2014b]. As not all affected individuals respond to the treatment, a test dose is recommended to identify those who will benefit from this treatment either in future bleeding episodes or in prevention of bleeding at the time of invasive procedures.

Deafness. A total of 11 individuals with an established diagnosis of MYH9RD and severe to profound deafness have received cochlear implantations [Pecci et al 2014b, Nabekura et al 2015]. Ten of them benefited from cochlear implants; nine of them obtained restoration of practically normal hearing and verbal communication abilities.

Glomerular nephropathy

  • Four affected individuals with renal involvement had their proteinuria greatly reduced by treatment with angiotensin receptor blockers and/or angiotensin-converting enzyme inhibitors [Pecci et al 2008]. It is premature to conclude whether this therapeutic approach prevents or delays the development of ESRD.
  • Dialysis or kidney transplantation is required in individuals with ESRD.

Cataracts. Cataract surgery remedies clouding of the lens.

Elevation of liver enzymes does not require any specific treatment.

Prevention of Primary Manifestations

Thrombocytopenia cannot be prevented; however, the risk of bleeding can be significantly reduced through education regarding drugs that affect platelet function (see Agents/Circumstances to Avoid).

Affected individuals should be prepared for surgery or other invasive procedures with platelet transfusions, desmopressin, antifibrinolytic drugs, or eltrombopag according to the individual's platelet count and history of bleeding.

Oral contraceptives are often effective in preventing or controlling menorrhagia; however, oral contraceptives increase the risk of thrombosis, which has also been described in individuals with MYH9RD. Thus, the balance between risks and benefits associated with use of oral contraceptives should be considered [Heller et al 2006, Nishiyama et al 2008, Girolami et al 2011].

Regular dental care and good oral hygiene are essential to prevent gingival bleeding.


The following evaluations should be considered at the suggested maximum intervals:

Every six months. blood count in individuals with bleeding episodes to identify anemia; more frequent counts are appropriate in cases of recurrent profuse bleeding.

Every year

  • Urinalysis (including measurement of 24-hour protein or protein (or albumin)/creatinine ratio on spot urine sample)
  • Measurement of serum concentration of creatinine
  • For individuals with an established renal defect, referral to a nephrologist

Every three years

  • Audiometric evaluation. Once hearing loss is identified, the frequency of follow-up evaluations is determined by the treating hearing specialists.
  • Ophthalmologic evaluation. Once cataract is identified, the frequency of evaluations is determined by the treating ophthalmologist.
  • Measurement of serum AST, ALT and GGT
    • In individuals with alterations of liver enzymes, alternative causes of liver damage should be investigated.
    • If alternative causes are excluded, the frequency of the liver enzyme measurements depends on the severity of the alteration.

Agents/Circumstances to Avoid

Bleeding tendency

  • Agents. Drugs that inhibit platelet function or blood coagulation:
    • Nonsteroidal anti-inflammatory drugs (NSAIDs), especially aspirin, which are strong inhibitors of platelet aggregation
    • Other substances that interfere with platelet function including some antibiotics; cardiovascular, psychotropic, and oncologic drugs; drugs that affect platelet cAMP; some anesthetics; antihistamines; and radiographic contrast agents
      Note: (1) Drugs that impair platelet function should be prescribed only after a careful assessment of the risks versus the benefits. (2) Physicians should try to avoid prescribing any other drugs that increase the risk of bleeding in individuals with MYH9RD. (3) Individuals with MYH9RD can develop thromboembolic events [Girolami et al 2011]. The use of antithrombotic agents (such as heparin) must be carefully balanced against the risks according to the overall clinical picture of each affected individual.
  • Circumstances. In individuals with moderate to severe thrombocytopenia, avoidance of activities at high risk of trauma (e.g., contact sports)

Hearing loss

  • Agents. Ototoxic drugs (e.g., aminoglycoside antibiotics, salicylates in large quantities, loop diuretics, some drugs used in chemotherapy regimens). These should be used only after a careful assessment of the risks versus the benefits.
  • Circumstances. Exposure to hazardous noise. If noise exposure cannot be avoided, use ear devices (e.g., earplugs, headphones) to attenuate intense sound.


  • Agents that can damage renal function, including radiocontrast, antibiotics, NSAIDs, diuretics, and oncologic drugs. The balance between benefit and risk of such agents should be carefully considered, especially in individuals with established kidney involvement or with MYH9 pathogenic variants associated with high risk for kidney damage.


  • Agents. Glucocorticoids and radiation therapy, which predispose to development of cataracts

Elevation of liver enzymes

  • Agents. In affected individuals with liver enzyme elevation, assessment of risks versus benefits before use of potentially hepatotoxic drugs

Evaluation of Relatives at Risk

It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures.

  • Assessing platelet count and size in a newborn at risk for MYH9RD identifies those at risk for bleeding.
  • If the family-specific pathogenic variant is known, molecular genetic testing can be used to evaluate at-risk family members so that early diagnosis can inform treatment.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Deliveries should be managed as they are in women with other forms of thrombocytopenia (MYH9RD is not usually associated with defects of platelet function). As expected, pregnant women whose thrombocytopenia and bleeding history before pregnancy are more severe have a higher incidence of delivery-related bleeding. In general, a platelet count of ≥50 x 109/L is recommended for safe delivery. Vaginal deliveries in women with severe thrombocytopenia should be considered at increased risk for neonatal intracranial bleeding [Noris et al 2014b].

Therapies Under Investigation

Search in the US and 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

MYH9-related disorders (MYH9RD) are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

Note: Absence of a family history of macrothrombocytopenia does not exclude the diagnosis of MYH9RD, as about 35% of probands have sporadic forms resulting from de novo pathogenic variants [Balduini et al 2011].

  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, two possible explanations are a de novo pathogenic variant in the proband or somatic/germline mosaicism in a parent. Both germline mosaicism and somatic mosaicism including the germline have been reported [Kunishima et al 2005, Kunishima et al 2009, Kunishima et al 2014] (see Note).
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include molecular genetic testing if the family-specific pathogenic variant is known. Alternatively, when the family-specific pathogenic variant is not known or a mild phenotype resulting from potential somatic mosaicism is suspected in one parent, hematologic testing (e.g., evaluation of platelet number and size, distribution of the MYH9 protein in neutrophils) should be considered.
  • Apparently healthy parents must be carefully evaluated for accurate genetic counseling in the family. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. Therefore, a negative family history cannot be confirmed until molecular genetic testing and/or appropriate hematologic testing has been performed.

Note: If the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected. In two families, apparently healthy parents of probands with typical MYH9RD had de novo somatic pathogenic variants with 14% or 24% of neutrophils with MYH9 aggregates but not thrombocytopenia [Kunishima et al 2005, Kunishima et al 2014]. In another family, the father of a proband with a severe syndromic phenotype had only mild macrothrombocytopenia associated with somatic mosaicism [Gresele at al 2013].

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband’s parents:

  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each offspring of an individual with MYH9RD has a 50% chance of inheriting the MYH9 pathogenic variant and being affected.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents: if a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the pathogenic variant is de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the MYH9 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for MYH9RD are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Society for Deaf Children (ASDC)
    800 Florida Avenue Northeast
    Suite 2047
    Washington DC 20002-3695
    Phone: 800-942-2732 (Toll-free Parent Hotline); 866-895-4206 (toll free voice/TTY)
    Fax: 410-795-0965
  • Medline Plus
  • National Association of the Deaf (NAD)
    8630 Fenton Street
    Suite 820
    Silver Spring MD 20910
    Phone: 301-587-1788; 301-587-1789 (TTY)
    Fax: 301-587-1791
  • National Eye Institute
    31 Center Drive
    MSC 2510
    Bethesda MD 20892-2510
  • National Kidney Foundation (NKF)
    30 East 33rd Street
    New York NY 10016
    Phone: 800-622-9010 (toll-free); 212-889-2210
  • Platelet Disorder Support Association (PDSA)
    8751 Brecksville Road
    Suite 150
    Cleveland OH 44141
    Phone: 877-528-3538 (toll-free); 440-746-9003
    Fax: 844-270-1277
  • Italian Registry of MYH9-Related Disease
    Clinica Medica III IRCCS Policlinico
    San Matteo Foundation
    Piazzale Golgi, 2
    Pavia 27100
    Phone: +39 0382.526284; +39 0382 501358
    Fax: +39 0382 526223

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

MYH9-Related Disorders: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
MYH922q12​.3Myosin-9Hereditary Hearing Loss Homepage (MYH9)
MYH9 database

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for MYH9-Related Disorders (View All in OMIM)


Gene structure. MYH9 consists of 41 exons. The first exon does not code for amino acids; the first methionine of the open reading frame is in exon 2. Exon numbering may vary among different testing laboratories. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. See Table 2.

Pathogenic variants. See Table 2. Pathogenic variants occur in regions that encode the head or the tail domain of the MYH9 protein (see Normal gene product). Almost all the pathogenic variants involving the head domain are single-residue substitutions hitting one of two specific regions: (1) a group of residues clustered together to form a distinct hydrophobic interface between the SH3-like motif and the motor domain [Dominguez et al 1998, Kahr et al 2009], including Trp33, Val34, Asn93, Ala95 or Ser96; or (2) the residue Arg702 located in the short SH1 helix of the motor domain [Eddinger & Meer 2007, Balduini et al 2011, Pecci et al 2014a, Saposnik et al 2014] (see Normal gene product). Most of the pathogenic variants involving the tail domain are either single-residue substitutions in the coiled-coil region, or nonsense/frameshift variants resulting in the deletion and/or alteration of the C-terminal non-helical tailpiece [Balduini et al 2011, Pecci et al 2014a, Saposnik et al 2014]. In a few families, short in-frame deletions or duplications, usually involving the region encoding the N-terminal portion of the coiled-coil, have been identified [Balduini et al 2011, Pecci et al 2014a]. Almost 80% of affected individuals have pathogenic variants involving only six residues: Ser96 or Arg702 of the head domain; Arg1165, Asp1424, Glu1841, or Arg1933 of the tail domain [Balduini et al 2011].

Table 2.

Selected MYH9 Variants

Variant ClassificationDNA Nucleotide ChangeMYH9 Protein DomainMYH9 Protein RegionPredicted Protein ChangeReference Sequences
Pathogenicc.279C>GHeadSH3/MD ip.Asn93Lys
c.287C>THeadSH3/MD ip.Ser96Leu
c.2104C>THeadSH1 helixp.Arg702Cys
c.2105G>AHeadSH1 helixp.Arg702His

SH3/MD i = interface between the SH3-like motif and the motor domain

NHT = non-helical tailpiece

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.

Normal gene product. The 1960-amino acid product of MYH9 is the heavy chain of the non-muscle myosin IIA (MYH9 protein or myosin 9) [Sellers 2000]. Non-muscle myosin IIA is a cytoplasmic myosin expressed in most cell types and tissues that participates in several key processes requiring generation of chemomechanical forces by the cytoskeleton, such as cell motility, cytokinesis, cell polarization and maintenance of cell shape [Sellers 2000, Vicente-Manzanares et al 2009]. Like all conventional myosins, non-muscle myosin IIA is a hexameric enzyme composed of a dimer of heavy chains (MYH9 protein or myosin-9) and two pairs of light chains.

The MYH9 protein comprised two anatomically distinct domains: the N-terminal globular head domain (residues 1-835), and the C-terminal tail domain (residues 836-1960) [Sellers 2000, Eddinger & Meer 2007]. The three-dimensional structure of the globular head domain consists of four subdomains connected by flexible linkers: the N-terminal SH3-like motif, the upper and the lower 50-kd subdomains, and the converter subdomain [Sellers 2000]. The two 50-kd subdomains form the so-called ‘motor domain,’ as it includes the highly conserved functional regions essential for production of chemomechanical force, such as the actin-binding and the ATP-binding regions, the ‘relay’ loop, and the short functional SH1 helix [Dominguez et al 1998, Sweeney & Houdusse 2010, Baumketner 2012]. The tail domain comprises two regions: a long alpha-helical coiled-coil (residues 836-1927) that connects two MYH9 proteins to form one dimer and represents the binding site of different dimers to form functional myosin filaments, and a 34-residue (amino acids 1928-1960) C-terminal non-helical tailpiece, which is a phosphorylation site with regulatory functions [Eddinger & Meer 2007, Sanborn et al 2011].

Abnormal gene product. Recent reports suggest that MYH9 pathogenic variants act through different mechanisms in different cell types and that cell-specific regulation mechanisms function in MYH9RD [Pecci et al 2005, Kunishima et al 2008a]. In neutrophils the defective gene product aggregates and forms inclusion bodies that also contain the wild-type protein [Kunishima et al 2008a]. In platelets and megakaryocytes the mutated polypeptide is also expressed but at lower levels, and it does not form inclusions [Deutsch et al 2003, Kunishima et al 2008a]. Little is known about the expression of the defective protein in kidney, lens, and inner ear. Because MYH9RD is an autosomal dominant disorder and myosin consists of dimerization of two MYH9 protein molecules, the pathogenic mechanisms are likely to be associated with a dominant-negative effect of the pathogenic variants. This hypothesis was supported by in vitro experiments showing that mutated MYH9 proteins, expressed from any of four known pathogenic alleles, interfered with the proper assembly of wild-type myosin filaments [Franke et al 2005]. However, the mechanisms leading to MYH9RD are poorly defined at both the molecular and cellular level.

In mouse megakaryocytes, phosphorylation of the myosin light chain has an important role in regulating proplatelet formation and platelet release [Chen et al 2007]. Murine myosin-9 (myh9 protein) is a negative regulator of thrombopoiesis mediated by the Rho-ROCK pathway. It has been hypothesized that when the myh9 protein is defective, platelet release occurs prematurely in the marrow interstitium instead of the sinusoidal vasculature, thus leading to thrombocytopenia.


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Chapter Notes

Author History

Carlo L Balduini, MD; University of Pavia (2008-2015)
Alessandro Pecci, MD, PhD (2015-present)
Anna Savoia, PhD (2008-present)

Revision History

  • 16 July 2015 (me) Comprehensive update posted live
  • 5 April 2011 (me) Comprehensive update posted live
  • 25 June 2009 (cd) Revision: deletion/duplication analysis available clinically
  • 20 November 2008 (me) Review posted live
  • 9 July 2008 (as) Original submission
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