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May-Hegglin Anomaly
Introduction
May-Hegglin anomaly represents a rare autosomal-dominant disorder resulting from mutations in the MYH9 gene. Hallmark features include macrothrombocytes, neutrophils containing cytoplasmic inclusions known as Döhle-like bodies, and variable degrees of thrombocytopenia. This condition belongs to a broader spectrum of MYH9-related disorders that also includes Fechtner, Sebastian, and Epstein syndromes. Once classified as distinct entities, these disorders now reflect variable phenotypic expressions of a single underlying genetic defect.[1][2] Beyond hematologic abnormalities, affected individuals may exhibit nonhematologic manifestations, eg, sensorineural hearing loss, cataracts, hematuria, and proteinuria.
Etiology
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Etiology
The MYH9 gene, located on chromosome 22q12.3, encodes non-muscle myosin heavy chain IIA (NM2A). NM2A is critical for cytoskeletal integrity, cell migration, and intracellular protein transport. Mutations lead to abnormal NM2A production or function, predominantly affecting megakaryocyte maturation and platelet formation.[3][4][5][6] Platelet counts may appear low due to abnormal clumping on automated analyzers, and platelet function is variably affected. Cytoplasmic inclusion bodies in leukocytes result from aggregated, dysfunctional myosin and serve as a pathognomonic feature.[7]
Renal involvement arises from defective NM2A in podocytes and mesangial cells, leading to proteinuria and progressive kidney disease. Cochlear hair cell dysfunction likely accounts for sensorineural hearing loss.[8][9]
Epidemiology
May-Hegglin anomaly and MYH9-related disease, although classified as rare, remain likely underreported due to frequent misdiagnosis as idiopathic thrombocytopenic purpura. Many patients initially receive this incorrect diagnosis and only undergo further evaluation after demonstrating resistance to standard therapies, prompting additional testing that ultimately establishes the correct diagnosis. De novo mutations further complicate efforts to define the true prevalence, with up to 35% of cases arising sporadically rather than being inherited.[10]
Prevalence varies widely depending on the specific phenotypic expression of the disorder. Data from the Italian Registry suggest an incidence as low as 3.75 per 1,000,000,000 persons.[4]] However, consideration of de novo mutations, underreporting, and misdiagnosis, along with extrapolation from genomic databases, supports an estimated prevalence of approximately 1:20,000 to 1:25,000.[11]
History and Physical
Clinical manifestations are heterogeneous and may occur at any point in the lifespan. Symptoms and presentation often reflect the severity of the patient's thrombocytopenia. Hematologic: Epistaxis, easy bruising, purpura, petechiae, gingival bleeding, menorrhagia, and postoperative hemorrhage. Bleeding typically occurs with platelet counts below 50 × 10³/µL. Nonhematologic features include sensorineural hearing loss, early-onset cataracts, proteinuria, and occasionally elevated liver enzymes. Approximately 50% of patients are asymptomatic. Severe bleeding episodes are rare, and fatal hemorrhage has not been reported.[12]
Evaluation
Diagnostic Studies
Peripheral blood smear and complete blood count findings demonstrate platelet counts ranging from mildly reduced to less than 10 × 10³/µL, with relative stability throughout the patient’s lifetime.[13] Characteristic features include large platelets and Döhle-like cytoplasmic inclusions within leukocytes. Automated analyzers may underestimate platelet counts due to the presence of macrothrombocytes. Electron microscopy identifies abnormal platelet ultrastructure, including lentiform shapes and disorganized microtubules.[14]
Epstein syndrome lacks leukocyte inclusions, whereas Sebastian syndrome demonstrates distinct ultrastructural differences in ribosome organization compared with May-Hegglin anomaly.[2] Viscoelastic testing using TEG (thromboelastography), ROTEM (rotational thromboelastometry), and VCM (viscoelastic coagulation monitor) may show reduced maximum amplitude based on platelet count and function. TEG offers a comprehensive evaluation of hemostasis and supports transfusion decision-making.[15] Bone marrow evaluation typically shows normal megakaryocyte number and morphology, with abnormal platelet formation occurring after marrow release. Genetic testing using targeted next-generation sequencing, whole-exome sequencing, or whole-genome sequencing confirms the diagnosis.[16]
Treatment / Management
No curative therapy exists, and management is supportive and guided by thrombocytopenia severity and bleeding risk. Most patients do not require routine therapy. Acutely, platelet transfusions are reserved for active bleeding or before invasive procedures. In pregnant patients, platelet counts are preferred to be kept below 50,000/µL before delivery to reduce the risk of hemorrhage.
Adjunctive therapies include desmopressin, antifibrinolytic agents (eg, tranexamic acid), and, in select cases, thrombopoietin receptor agonists such as eltrombopag or romiplostim, which increase platelet counts and reduce bleeding risk.[17][18][11] Less-established options include immunomodulatory agents for refractory cases.
Long-term management addresses hematologic monitoring as well as extra-hematologic manifestations, including renal disease, hearing loss, and vision loss. Surveillance of renal morbidity is defined by disease progression and may include annual or semi-annual laboratory studies, eg, urinalysis for proteinuria, serum creatinine, and, when indicated, renal biopsy for staging and management, given that nephropathy is progressive and can lead to end-stage renal disease.[11] Furthermore, audiologic and vision screenings are recommended due to the progressive nature of sensory loss, which typically appears before the mid-third decade of life. First-degree relatives should be offered genetic testing to determine whether the presentation is hereditary or de novo.[19][20]
Differential Diagnosis
Differential diagnoses that should be considered when evaluating patients with clinical features of May-Hegglin anomaly include:
- Sebastian syndrome
- Fechtner syndrome
- Epstein syndrome
- Bernard-Soulier syndrome
- Gray platelet syndrome
- Wiskott-Aldrich syndrome
- X-linked thrombocytopenia
- Septicemia
- Leukemoid reaction
- Burns
- Drug-induced cytoplasmic inclusions
- Pregnancy
Prognosis
The prognosis for May-Hegglin anomaly and MYH9-related disease is generally good to fair. Outcomes depend on the severity of gene expression and the degree of end-organ involvement. The disorder itself is not life-threatening but can cause significant morbidity.
Nearly all patients have platelet macrocytosis and thrombocytopenia. Approximately 30% experience spontaneous bleeding during their lifetime. Sensorineural hearing loss affects up to 85% of patients. About half of these cases present by the early 30s. Mild liver enzyme elevations may occur but rarely progress to end-stage liver disease.[11]
Cataracts and nephropathy develop in roughly 25% of patients. These complications are progressive and can lead to clinically significant impairment. Long-term outcomes are primarily determined by extra-hematologic complications rather than hematologic findings alone.[21]
Complications
Complications of MYH9-related disease arise from both hematologic and extra-hematologic manifestations, including:
- Hematologic: Bleeding risk due to thrombocytopenia. Severe spontaneous hemorrhage occurs in a minority of patients.
- Renal: Progressive nephropathy develops in roughly 25% of patients, potentially leading to chronic kidney disease and end-stage renal disease.[11]
- Auditory: Sensorineural hearing loss affects up to 85% of patients and may present before the mid-30s.[21]
- Ophthalmologic: Cataracts occur in approximately 25% and may require surgical intervention.
- Hepatic: Mild elevations in liver enzymes are common but rarely progress to clinically significant liver disease.
- Preventive considerations: Patients should avoid medications that impair platelet function or induce thrombocytopenia when possible. Renal-dosing adjustments are recommended for those with kidney disease. Exposure to hepatotoxic or ototoxic agents should be minimized.[11][21]
Consultations
Patients with MYH9-related disease benefit from an interprofessional approach, particularly at the time of initial diagnosis, including:
- Hematology: For confirmation of diagnosis, ongoing management of thrombocytopenia, guidance on bleeding risk, and peri-procedural planning.
- Nephrology: For assessment and long-term monitoring of renal function, especially in patients with proteinuria or progressive nephropathy.
- Otolaryngology/Audiology: For baseline and follow-up evaluation of hearing, with early intervention for sensorineural hearing loss.
- Ophthalmology: For cataract screening and management of progressive vision loss.
- Obstetrics/Gynecology: For women of childbearing age, particularly if pregnant or planning pregnancy, to optimize maternal and fetal outcomes and coordinate platelet management.
- Surgery/Anesthesiology: For patients undergoing elective or urgent procedures, to plan perioperative management and minimize bleeding risk.
Deterrence and Patient Education
Patients with MYH9-related disease should be educated about the nature of their condition, potential complications, and strategies to reduce risk, regarding the following:
- Hematologic awareness: Understand that thrombocytopenia is usually mild to moderate. Most patients do not experience significant bleeding, but precautions are necessary with surgery, dental procedures, or trauma. Avoid medications that impair platelet function (eg, NSAIDs, certain antiplatelet agents) unless prescribed by a physician and an appropriate risk-benefit analysis has been considered.
- Pregnancy considerations: Women with the condition should consult their hematologist or obstetrician before conception and throughout pregnancy. Platelet counts may need close monitoring to reduce the risk of bleeding during delivery.
- Renal health: Regular follow-up with urinalysis and kidney function testing is important, as some patients may develop progressive nephropathy. Early detection allows timely intervention and may slow disease progression.
- Hearing and vision monitoring: Annual audiologic and ophthalmologic screenings are recommended. Early detection of hearing loss or cataracts allows for timely treatment and improves quality of life.
- Lifestyle considerations: Minimize exposure to activities, medications, or substances that are hepatotoxic, nephrotoxic, or ototoxic. Discuss all new medications with a clinician.
- Genetic counseling: Family members may benefit from genetic testing to understand inheritance patterns and identify carriers. This is particularly relevant for family planning and defining likely disease severity and progression.
- General guidance: Maintain routine follow-up with hematology and relevant specialties. Patients should be aware of warning signs for bleeding, kidney dysfunction, or changes in vision or hearing, and seek prompt medical evaluation if these occur.
Pearls and Other Issues
A special circumstance when the May-Hegglin anomaly should be considered is pregnancy.[22] While May-Hegglin anomaly/MYH9-RD is a rare cause of thrombocytopenia in pregnancy, some women are diagnosed in pregnancy when the disease is first recognized due to thrombocytopenia on a routine complete blood count. Often, a majority of these pregnant women are initially believed to have immune-mediated thrombocytopenia (ITP), not responding to treatment. The diagnosis of May-Hegglin anomaly/MYH9-RD should, however, be considered when platelet count does not improve despite treatment for ITP.
Early recognition of May-Hegglin anomaly during pregnancy can be challenging, but it ensures the most favorable outcome for the mother and the neonate. Very limited data exist in the literature on the clinical course and outcomes of May-Hegglin anomaly in pregnant women. Both the mother and the newborn are at risk of bleeding complications. The fetus has a 50% chance of inheriting the disease. An interprofessional approach is recommended for the management of pregnant women with May-Hegglin anomaly, including an obstetrician, hematologist, and anesthetist. This will minimize maternal and neonatal bleeding risks and secure the best treatment options.
Early-onset sensorineural hearing loss, progressive nephropathy, and cataracts are the strongest predictors of long-term morbidity in MYH9-related disease. Complications are primarily determined by progressive nephropathy, hearing loss, and cataracts rather than the severity of thrombocytopenia alone. Early engagement of an interprofessional team improves monitoring, timely intervention for extra-hematologic complications, and peri-procedural safety, particularly during pregnancy or surgical procedures. Patient education empowers individuals to participate in monitoring and risk minimization actively, improving long-term outcomes and quality of life in MYH9-related disease.
Enhancing Healthcare Team Outcomes
May-Hegglin anomaly is a rare autosomal-dominant MYH9-related disorder caused by mutations affecting non-muscle myosin heavy chain IIA, leading to impaired megakaryocyte maturation and abnormal platelet formation. Hallmark findings include macrothrombocytes, thrombocytopenia, and Döhle-like inclusions in leukocytes, with platelet counts ranging from mildly reduced to <10 ×10³/µL. Clinical presentation varies widely, from asymptomatic individuals to patients with mucocutaneous bleeding such as epistaxis, purpura, and menorrhagia, typically when platelet counts fall below 50 ×10³/µL. Nonhematologic manifestations include progressive nephropathy, sensorineural hearing loss, cataracts, and mild hepatic enzyme elevation. Diagnosis relies on peripheral smear evaluation and confirmatory genetic testing, while viscoelastic assays may guide hemostatic assessment. Management remains supportive, with platelet transfusions reserved for active bleeding or invasive procedures and adjunctive therapies used selectively.
Interprofessional collaboration plays a critical role in optimizing outcomes and reducing complications. Physicians and advanced practitioners lead diagnostic evaluation and risk stratification, while primary care clinicians coordinate longitudinal monitoring and preventive care. Nurses support patient education, bleeding risk assessment, and adherence to follow-up, and pharmacists guide safe medication use, avoiding agents that impair platelet function. Nephrologists, audiologists, and ophthalmologists contribute to early detection and management of organ-specific complications through timely referral. Coordinated communication and shared decision-making enable individualized care plans, proactive surveillance, and risk reduction, ultimately improving safety, preserving organ function, and enhancing quality of life.
References
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Level 1 (high-level) evidence