May Hegglin Anomaly

Article Author:
Ramona Untanu
Article Editor:
Neerja Vajpayee
Updated:
10/27/2018 12:31:42 PM
PubMed Link:
May Hegglin Anomaly

Introduction

The May-Hegglin anomaly (MHA) is a rare autosomal dominant disease due to MYH9 gene mutation characterized by neutrophils with abnormal cytoplasmic inclusions, large platelets, and variable thrombocytopenia. It is part of myosin heavy chain (MHC) single gene defect group that also includes Fechtner syndrome, Sebastian syndrome, and Epstein syndrome. All of these entities represent hereditary forms of macrothrombocytopenia associated with leukocyte inclusions (Dohle-like bodies), and variable clinical features of sensorineural hearing loss, presenile (early) cataracts, and renal failure.

Etiology

The mutated MYH9 gene is present on chromosome 22q12–13 and encodes the nonmuscle myosin heavy chain class IIA (NMMHC-IIA). At least 33 mutations in the MYH9 gene have been identified. NMMHC-IIA is a cytoplasmic protein that is present in many tissues including platelets. The mutation causes abnormal production of NMMHC-IIA. This leads to macrothrombocytopenia secondary to defective megakaryocytic maturation and fragmentation. The crescent shaped Dohle-like inclusion bodies are precipitates of MHC within the cytoplasm of eosinophils, neutrophils, and monocytes. Neutrophil and platelet function is considered to be normal.

Epidemiology

May Hegglin anomaly is a rare disease with a few reported cases. It was first described by german doctor May in 1909 and then in 1945 by doctor Hegglin from Switzerland. The exact worldwide incidence of this anomaly is unknown, but there are fewer than a hundred cases reported in the literature.

History and Physical

Physical findings may be normal. About half of the reported patients are asymptomatic, and the other half have platelet counts < 50 K/uL and abnormal bleeding. Characteristic features of MHA include epistaxis, easy bruising, gingival bleeding, menorrhagia and excessive postoperative bleeding. The bleeding symptoms depend on the degree of thrombocytopenia. They vary from generally mild not requiring specific treatment to rare, severe bleeding episodes after surgical procedures that need blood transfusions. Fatal bleeding has not been reported. 

Evaluation

Review of complete blood count (CBC) and careful evaluation of peripheral blood smear along with a detailed family history of bleeding diathesis are key for establishing the diagnosis of MHA.

Peripheral Smear

The platelet count ranges from 40–80 K/uL to normal values. Characteristic morphological findings of white blood cells and platelets are present on peripheral blood smear. Cytoplasmic inclusions resembling Dohle bodies are seen in neutrophils, but also in monocytes, eosinophils, and basophils. The inclusions appear pale blue on Wright–Giemsa stain, are large and spindle shaped. The inclusion bodies are not seen in platelets. Platelets appear larger in size with the presence of large and giant forms. The presence of macrothrombocytes in some patients can often lead to underestimation of platelet count by automated analyzers. In such cases, platelet count can be better estimated based on a careful morphologic evaluation of the peripheral blood smear. On electron microscopy, the platelets have abnormal lentiform shape due to the presence of increased amount of abnormally organized microtubules (parallel order of filaments in the inclusions).

Bone Marrow Exam

Both the number and morphology of megakaryocytes are normal on bone marrow examination. There is no evidence of dysplasia. The abnormal megakaryocytic fragmentation is believed to be the cause of the decreased platelet count.

Platelet Aggregation Studies

The normal pattern of platelet aggregation and ATP secretion are seen in most cases of MHA.

Additional Findings

Bleeding time is prolonged in proportion to the degree of thrombocytopenia. The life span of platelets is usually normal. Immunofluorescence study of neutrophil NMMHC-IIA can be helpful for diagnosis of MHA in patients without leukocyte inclusion bodies. The presence of inclusion bodies in leukocytes helps to distinguish MHA from immune-mediated thrombocytopenia. Genetic studies for MYH9 gene mutation can confirm the diagnosis of MHA in uncertain cases. A comprehensive molecular evaluation includes a screening of 40 exons. It is hypothesized that genetic assessment can evaluate the risk of development of cataracts, deafness and kidney disease but this is debatable.

Differential Diagnosis

Epstein syndrome lacks leukocyte inclusions. If Alport syndrome-like features (deafness, cataracts, and nephritis) are suspected, an audiogram, renal function testing (creatinine, blood urea nitrogen, proteinuria) and ophthalmologic examination should be performed. Both Epstein and Fechtner syndromes have clinical characteristics similar to Alport syndrome. Ultrastructural features of leukocyte inclusion bodies differentiate Sebastian syndrome from MHA. MHA does not have limiting membrane on electron microscopy and shows ribosomes clusters oriented along the axis of thin parallel filaments. In contrast, Sebastian syndrome has ribosomes but without parallel filaments depolymerized ribosomes.

Treatment / Management

Most patients do not have clinically significant bleeding problems and are discovered incidentally. These patients require no specific treatment. In rare cases of severe bleeding, platelet transfusions may be necessary. Prophylactic preoperative platelet transfusion may be warranted, and a hematologist should be consulted before surgery. Preoperative Desmopressin can be administered in patients requiring craniotomy in order to avoid any bleeding complications or platelet transfusion. Administration of corticosteroids, immunosuppressive agents or splenectomy is not indicated.

MHA can often be misdiagnosed as idiopathic thrombocytopenic purpura (ITP) if a thorough evaluation of blood smear and a detailed bleeding history including family history is not taken. Genetic studies may be required to make an accurate diagnosis. It is essential not to misdiagnose MHA as this can lead to unnecessary diagnostic studies, such as bone marrow aspiration and biopsy and even misdirected therapeutic intervention with corticosteroids, immunosuppressive agents, and splenectomy.

Pearls and Other Issues

A special circumstance when MHA should be considered is pregnancy. MHA is a rare cause of thrombocytopenia in pregnancy. While some women are diagnosed with MHA before pregnancy, in other patients the disease is first recognized during pregnancy when thrombocytopenia is picked up on a routine CBC count. Often a majority of these pregnant women are initially believed to have immune-mediated thrombocytopenia (ITP) not responding to treatment. The diagnosis of MHA should, however, be considered when platelet count does not improve despite treatment for ITP. Early recognition of MHA during pregnancy can be challenging, but it ensures the most favorable outcome for the mother and the neonate. There is very limited data in the literature on the clinical course and outcome of MHA in pregnant women. Both the mother and the newborn are at risk of bleeding complications. The fetus has 50% chance of inheriting the disease. A multidisciplinary approach is recommended for the management of pregnant women with MHA, including obstetrician, hematologist, and anesthetist. This will minimize maternal and neonatal bleeding risks and secure the best treatment options.