May-Hegglin Anomaly - Causes, Symptoms, Diagnosis, and Treatment

Introduction

May–Hegglin anomaly is an inherited autosomal dominant platelet disease characterized by giant platelets, decreased number of platelets (thrombocytopenia), and the presence of abnormal granules inside the white blood cells (defective leukocyte inclusions). It is a rare disease with a minimal number of reported cases. This disorder is named after two eminent scientists who worked independently on this unknown entity and contributed to its recognition. In 1909, a famous German physician Richard May discovered giant platelets and leukocyte inclusions. In 1945 Robert Hegglin, an eminent physician from Switzerland identified abnormalities in platelets, leukocytes associated with thrombocytopenia, and familial inheritance of the disorder. Thus, it was named the May-Hegglin anomaly and categorized as a hereditary form of macrothrombocytopenia.

What Is May-Hegglin Anomaly?

May-Hegglin anomaly is a rare, autosomal dominant syndrome caused due to the mutation in the MYH9 (myosin heavy chain 9) gene present on chromosome 22q12-13. This mutation results in the defective synthesis of myosin heavy chain type IIA (a nonmuscular protein). These abnormal myosin-heavy chains precipitate and accumulate in the cytoplasm of basophils (leukocytes) as basophilic inclusions (Dohle-like bodies). Also, these defective heavy chains affect the maturation of megakaryocytes. This leads to the fragmentation of platelets when they are shed from megakaryocytes (bone marrow cells from which platelets develop). May-Hegglin anomaly is characterized by,

• Thrombocytopenia (mild to severe).

• Abnormally large platelets.

• Large cytoplasmic inclusions (Dohle-like bodies) in neutrophils, basophils, eosinophils, and monocytes.

• Absence of renal dysfunction.

• Absence of hearing defects.

What Is Meant By Hereditary Forms of Macrothrombocytopenia?

• These disorders are usually passed on genetically in an autosomal dominant pattern.

• MYH9 gene encodes for a huge cytoplasmic protein, nonmuscular myosin heavy chain (NMMHC-IIA).

• This protein is present in different tissues such as platelets, leukocytes, kidneys, and the cochlea (a part of the inner ear) and contributes to various cellular activities (cell mobility, cell polarity, cytokinesis) and the maintenance of cell structure.

• In MYH9 mutation, this protein is not produced which causes abnormalities in platelets, kidneys, leukocytes, and cochlea.

• May-Hegglin anomaly is a syndrome that belongs to this group of hereditary forms of macrothrombocytopenia.

Other Syndromes in Hereditary Forms of Macrothrombocytopenia

• Sebastian syndrome.

• Fechtner syndrome.

• Epstein syndrome.

Common Characteristics of Hereditary Forms of Macrothrombocytopenia

• Autosomal Dominant Pattern of Inheritance - the anomaly is caused by only one copy of the mutated gene either from the father or mother. Both father and mother have an equal chance of transferring the defective gene to the child, and the child has a 50 % risk of acquiring the disease.

• Giant platelets with lower platelet count (macrothrombocytopenia).

• Aggregation of abnormal myosin protein as inclusions in white blood cells (leukocytes).

• Renal dysfunction (nephritis, nephropathy, renal failure).

• Presenile (early onset) cataract formation.

• Hearing loss (sensorineural deficit).

What Are the Signs and Symptoms of May-Hegglin Anomaly?

Majority of individuals with May-Hegglin anomaly remain asymptomatic throughout their lifetime. Few of them show mild to severe bleeding tendencies depending on the severity of thrombocytopenia. Both males and females are equally affected. But severity would increase in women of reproductive age (menstrual cycles and postpartum bleeding).

• Reddish purple-colored spots under the skin (purpura).

• Epistaxis (bleeding from the nose).

• Easy bruising.

• Gingival bleeding (bleeding from the gums).

• increased bleeding from the oral cavity during dental procedures.

• Menorrhagia (abnormally heavy menstrual flow in women).

• Excessive postoperative bleeding.

• severe bleeding episodes following surgery have been reported.

• Postpartum bleeding complications.

• Headaches.

• Intracranial bleeding (bleeding within the brain).

• Bleeding events when steroid drugs are given.

• Profuse bleeding from minor cuts and injuries.

• Blood in vomit (bleeding from the gastrointestinal tract).

• Purple spots (petechiae) around the feet and ankles.

• No signs or symptoms of renal failure, defective hearing, or visual abnormalities.

How Is May-Hegglin Anomaly Diagnosed?

Complete blood count (CBC), preliminary blood screening tests, and detailed examination of peripheral blood smear help in identifying abnormalities in platelets and leukocytes. A comprehensive family history of past or recurrent bleeding events of the affected individuals or the family members plays a key role in the diagnosis of the May-Hegglin anomaly.

• Decreased platelet count (40–80 K/uL).

• Peripheral Smear - shows abnormally large (giant) platelets and cytoplasmic inclusions of Dohle bodies in neutrophils, eosinophils, basophils, and also monocytes.

• Wright–Giemsa Stain - Dohle bodies are stained in pale blue color and appear as large, spindle-shaped inclusions. They are not detected in platelets.

• Megakaryocytes appear normal in bone marrow examination.

• Normal platelet aggregation was observed in platelet aggregation tests.

• The duration of bleeding time is prolonged according to the severity of existing thrombocytopenia.

• Immunofluorescence study of neutrophils helps to differentiate the May-Hegglin anomaly from immune-mediated thrombocytopenia.

• Genetic studies and DNA (deoxyribonucleic acid) sequencing helps to detect MYH9 gene mutation and identify the defective gene responsible for the May-Hegglin anomaly.

• A comprehensive genetic assessment and molecular evaluation help in the early detection of the risk progression of cataracts, kidney disease, and deafness thereby preventing such complications.

• Genetic testing predicts abnormal genes and helps in genetic counseling.

• Renal function tests, audiometric analysis, and ophthalmic examinations are done to exclude other syndromes of hereditary forms of macrothrombocytopenia.

How Is May-Hegglin Anomaly Treated?

Asymptomatic individuals who do not show specific clinical symptoms or bleeding episodes do not require any therapeutic intervention. Some of the symptomatic and supportive treatment procedures include,

• Platelet transfusions are administered in severe bleeding.

• Prophylactic platelet transfusions are given preoperatively before elective surgeries.

• Antidiuretics (Desmopressin) are administered preoperatively before elaborate surgical procedures like craniotomy to avoid bleeding complications.

• Pregnant women with a known case of May-Hegglin anomaly should be regularly monitored to prevent abnormal bleeding or hemorrhagic events.

• Genetic counseling proves beneficial for affected individuals and their family members.

How Is Genetic Counseling Beneficial in May-Hegglin Anomaly?

• Genetic counseling is a scientific measure to prevent or reduce the inheritance of defective genes in the affected families.

• Inform consent and willingness of the individuals and family members are documented prior to the commencement of the therapy.

• In counseling sessions, individuals and family members diagnosed with May-Hegglin anomaly are informed about relevant details of genetics and inheritance.

• The counselor educates them and makes them aware of the various genetic risks and inheritance patterns of the May-Hegglin anomaly.

• They clarify doubts pertaining to pregnancy planning and prenatal analysis.

• Genetic counseling also gives information about the various facilities and screening tests available to predict and assess genetic risks.

• The most common genetic testing procedures are carrier screening programs, prenatal anomaly detection, screening for anomalies in newborns, and prediction of late-onset anomalies.

• These diagnostic methods help in the early prediction and reduction of inherited syndromes like the May-Hegglin anomaly.

Conclusion

May-Hegglin anomaly is asymptomatic in most individuals. Generally, it does not require therapeutic interventions. However, a thorough evaluation of blood screening tests and detailed bleeding and family history is essential to prevent bleeding complications. Genetic studies help to make an accurate diagnosis and thus prevent unnecessary diagnostic investigations like bone marrow biopsy and miscalculated therapeutic interventions. This greatly reduces anxiety and the economic burden on the affected individuals. Genetic counseling helps in better understanding the anomaly.