May Heggling anomaly (MHA) is a rare autosomal dominant disease that results from MYH9 gene mutation and features abnormal cytoplasmic inclusions in neutrophils, large platelets, and variable thrombocytopenia. It is one of the five myosin heavy chain (MHC) single defect group that also contains Epstein syndrome, Sebastian syndrome, Fechtner syndrome, and Alport-like syndrome (1citation HsiaCC). MHA and other NYH9-related syndromes are hereditary forms of macrocthrombocytopenia linked to leukocyte inclusions (Dohle-like bodies), and different symptoms of presenile (early) cataracts, sensorineural hearing loss, and renal failure (2 Nord). Synonyms of MHA include Hegglin’s disease, Macrothrombocytopenia with Leukocyte Inclusions, Dohle Leucocyte Inclusions with Giant Platelets, Leukocytic Inclusions with platelet Abnormality, and Dohle’s Bodies-Myelopathy (2NORD). This paper provides an overview of May Heglin Anomaly.
Incidence/Genetics/Epidemiology
MHA is inherited as an autosomal dominant genetic trait (NORD). MHA is a rare disease, as only a few cases reported have been reported. A German doctor, Richard May, reported the first case in 1909, a young female patient with leukocytic inclusions, and was asymptomatic. Then doctor Hegglin from Switzerland reported another case in 1945; a father and his two sons with thrombocytopenia, leukocytic inclusions, and giant platelets (3citation Essa3). Although the exact global incident is unknown, the total number of cases reported was about 170 cases as of 1993 in North America, Europe, and Asia (ramona, NORD). In 1993, Japan reported MHA in 15 families (3citation essa). A low incidence of MHA may be attributed to misdiagnosis of the condition as thrombocytopenia purpura (4citation Vandana). Misdiagnosis also leads to erroneous treatment interventions such as the administration of immunosuppressive agents, corticosteroids, or splenectomy.
Etiology
Chromosome 22q12-13 contains the mutated MYH9, which encodes the nonmuscle myosin heavy chain class IIA (NMMHC-IIA) (5citation rare). Researchers have identified over 33 mutations in the MYH9 gene. NMHCA is a cytoplasmic protein found in a majority of tissues, including platelets. MYH9 mutation causes abnormal production of NMMHC-IIA leading to macrothrombocytopenia secondary to defective megakaryocytic maturation and fragmentation [1] It is in the motor region of NMMHC-IIA that most common mutations occur and which have a higher risk of developing into systemic complications in comparison with mutations of the tail region (4citation Vandana). As a result, genetic studies not only confirm MHA but also identify those patients at risk of developing severe manifestations. The crescent-shaped Dohle-like inclusion bodies are precipitates of myosin heavy chain within the cytoplasm of monocytes, neutrophils, and eosinophils. Platelet and neutrophil function appears to be normal (1citation ramona). Analysis of over 70 families reveals that there is a 20% of mutation sporadically arising. Table 1 below summarizes the clinical features of MYH9-related thrombocytopenia
Pathophysiology
There is no clear definition of the pathophysiology and clinical spectrum of MHA. Initially, researchers considered thrombocytopenia as the cause of bleeding. However, observations in recent research findings suggest that dysfunctional platelets are the cause of bleeding in MHA patients with near-normal platelet counts (6citation Vandana). A defect in the platelet tubulin is thought to be the cause of dysfunctional platelets with uneven distribution of tubulins instead of the normal circumferential pattern resulting in abnormal structure and defective function. Reduced clot stability likely results from the large-sized platelets and defective tubulin and that the severity of bleeding is the summative effect of the qualitative defect and low platelet count.
Usual Clinical Findings
Some MHA patients may have no symptoms, and their physical findings are normal, while others may have various bleeding abnormalities (3NORD). Of the reported cases, about half the patients have platelet count <50K/uL and abnormal bleeding while the other half are asymptomatic. Clinical features of MHA include easy bruising, epistaxis, gingival bleeding, excessive postoperative bleeding, menorrhagia, red or colored spots on the skin (purpura), headaches, and/or muscle weakness on one side of the body as a result of intracranial bleeding (1ramona, 3NORD). While some people with MHA may have symptoms at birth, others may not have any symptoms throughout their lifetime (NORD). The extent of thrombocytopenia determines the bleeding symptoms, which varies from mild with no need for specific treatment to rare, severe bleeding episodes following surgical procedures that require blood transfusions. Occasionally, there have been some reports of fatal bleeding. Some people with MHA may experience excessive bleeding following the cessation of steroid drugs used to treat another disorder (NORD).
Quantitative and qualitative disorders are the two broad classifications of platelet disorders. The frequency of qualitative disorders is less than that of qualitative disorders (6citation Vandana). The implication of this imbalance in clinical practice is often misdiagnoses of patients presenting with bleeding diathesis and low platelet count as having idiopathic thrombocytopenia purpura.
Usual Laboratory Findings
Diagnostic tests of MHA include a review of complete blood count (CBC) and careful examination of peripheral blood smear together with a comprehensive family history of bleeding diathesis [1] The tests reveal giant, oddly shaped platelets and characteristics cellular inclusions in certain leukocytes. In some cases, mild thrombocytopenia is present (NORD).
Peripheral Smear
The range of platelet count is 40-80 K/uL to normal values. Peripheral blood smear presents characteristic morphological findings of platelets and white blood cells. Dohle-like cytoplasmic inclusions are observed in basophils, eosinophils, monocytes, and neutrophils. The inclusions are large, spindle-shaped, and appear pale blue on Wright-Giemsa stain [1] However, platelets do not contain the inclusion bodies, but they appear larger in size with large and giant forms present. In some patients, automated analyzers often underestimate the platelet count due to the presence of macrothrombocytes [1] Standard automatic particle counters often count large platelets as red blood cells or leukocytes (5citation essa). In such cases, careful morphologic evaluation of the periphery blood smear can lead to a better estimate of platelet count [1]. The presence of an increased amount of abnormally organized microtubules (the inclusion’s parallel ordered filaments) makes platelets have an abnormal lentiform shape on the electron microscope.
Bone Marrow Exam
Bone marrow examination shows both the morphology and number of megakaryocytes to be normal without any evidence of dysplasia [1] Researchers believe that the abnormal megakaryocytes fragmentation to be the cause of decreased platelet count.
Platelet Aggregation Studies
Most MHA patients show a normal pattern of platelet aggregation and ATP secretion.
Additional Findings
Prolonged bleeding time is proportional to the degree of thrombocytopenia [1] Usually, the life span of platelets is normal. For diagnosis of MHA in patients without leukocyte inclusion bodies, immunofluorescence study of neutrophil NMMHC-IIA may be helpful. The presence of leucocyte inclusion bodies helps in distinguishing MHA from immune-mediated thrombocytopenia. In some instances, genetic studies of MYH9 can confirm the diagnosis of MHA [1] Screening of 40 exons forms part of a comprehensive molecular evaluation. There a debatable hypothesis that genetic assessment can evaluate the risk of developing kidney disease, deafness, and cataracts.
Differential Diagnosis
MHA patients exhibit some symptoms also seen in Epstein, Alport, Sebastian, and Fechtner syndromes, the other MYH9-related disorders, or MYHR9RDs (citation Vandana). Leukocyte inclusions are absent in Epstein syndrome. An audiogram, renal function testing (proteinuria, blood urea nitrogen, and creatinine) and ophthalmologic examination are necessary for suspected Alport-syndrome like features (nephritis, cataracts, and deafness) [1] Both MHA and Sebastian syndrome have thrombocytopenia, large platelets, and leukocyte inclusions as common features. Ultrastructural features of leukocyte inclusion bodies distinguish Sebastian syndrome from MHA. While Sebastian syndrome has ribosomes but without parallel filaments depolymerized ribosomes, MHA shows ribosomes clusters oriented along the axis of thin parallel films in addition to the absence of limiting membrane on electron microscopy.
Epstein syndrome is linked to interstitial nephritis and nerve deafness and Fechtner syndrome to nephritis, nerve deafness, and congenital cataracts (citation rare). Despite macrothrombocytopenia being a common finding in all MYH9 syndromes, MHA has a unique pathognomonic feature: the presence of a large, solitary, spindle-shaped inclusion (citation Vandana).
Treatment
In most cases, MHA patients do not have clinically significant bleeding problems, and the discovery of the condition is incidental. The patients do not require specific treatment. Only in rare cases of severe bleeding that platelet transfusion may be necessary. There is a need to consult a hematologist before surgery, and prophylactic preoperative platelet transfusion may be warranted [1] Administration of preoperative desmopressin may be necessary for patients requiring craniotomy to any platelet transfusion or bleeding complications (citation 3sehbai). There is an indication on the administration of immunosuppressive agents, corticosteroids, or splenectomy.
MHA in Pregnancy
Pregnancy is a special circumstance that requires the consideration of MHA (citation essa). In rare cases, MHA can cause thrombocytopenia in pregnancy. There is no clarity on the effect of MHA on pregnancy due to a limited number of research studies, and the available information is based on case reports and reviews of few case reports (citation essa). As a result of the rarity of MHA, there is conflicting literature about the risk of bleeding and management in pregnant women. Some women have a diagnosis of MHA before pregnancy, but others may only realize they have the condition during pregnancy when a routine CBC count picks up thrombocytopenia. Initially, MHA in most pregnant women is misdiagnosed as immune-mediated thrombocytopenia (ITP) that is not responding to treatment [1] In a systematic review of literature for MHA that included 26 articles, out of 11 women who presented incidental thrombocytopenia during a routine antenatal blood test, 5 were misdiagnosed as idiopathic thrombocytopenic purpura (ITP) (citation essa10). If the platelet count does not improve after treating ITP, then a diagnosis of MHA should be considered. Although detecting MHA early in pregnancy is a challenging task, it enhances the most favorable outcome for the neonate and the mother [1] However, there is research data available on the clinical course and outcome of MHA in pregnant women (citation essa). The chances of the fetus inheriting MHA are 50%. The recommended approach for managing MHA in pregnant women is multidisciplinary, including an anesthetist, hematologist, and obstetrician [1]. The approach aims at minimizing maternal and neonatal bleeding risks as well as securing the best treatment options.
Enhancing Patient Outcomes
Enhancing MHA patients’ outcomes requires an interprofessional team to manage the condition. Although MHA does not require treatment in most cases, it is often misdiagnosed as idiopathic thrombocytopenia purpura (ITP) in instances when health professionals fail to take a thorough blood smear evaluation and a comprehensive bleeding history which includes family history (citation sung). An accurate diagnosis may require genetic studies. Misdiagnosis of MHA often leads to unnecessary diagnostic tests such as biopsy, and bone marrow aspiration, and misdirected therapeutic interventions with immunosuppressive agents, corticosteroids, and splenectomy.
Prognosis
Due to the rarity of MHA, the available literature is conflicting on the risk of bleeding (citation). While in most cases, patients were reported to be asymptomatic and in no need of specific treatment, in some cases, severe bleeding has been reported requiring blood, and platelet transfusions [1] The risk of bleeding rises with an intake of drugs that decrease platelet functions such as steroids (citation). In rare cases, arterial thrombotic events link to MHA have been reported though the risk remains unclear (citation).
Need for Further Research
Since there is no clear definition of the pathophysiology and clinical spectrum of MHA, there is a need to further research into the incidences and reviews of existing literature of both MHA and other MYH9-related disorders. A better understanding of one of these syndromes may help in advancing the understanding of the others (2NORD).
New/Future Directions
MYH9RDs form a continuous clinical spectrum of a single disease with clinical manifestations ranging from mild macrothrombocytopenia with leukocyte inclusions to an advanced systematic illness with renal failure, visual loss, and hearing complications (4citation Vandana, 6citation Marco). Researchers propose the term MYH9RD as a new term to redefine this group of disorders to facilitate the identification of all patients at risk of developing systemic complications. Additionally, clinical features can evolve with time, and the appearance of new symptoms can result in reclassification of the MYH9 related disorders.
May Hegglin anomaly should be a consideration in the differential diagnosis of severe thrombocytopenia, particularly if it large platelet and if patients do not respond to steroid treatment (citation essa). For the laboratory diagnosis of MHA, there is a need for a careful evaluation of the morphology of platelets and granulocytes. All modern cell counters determine mean platelet value (MVP), and a majority of machines also generate a histogram displaying the size distribution of platelets. Patients showing the symptoms including a high MVP, large platelets, a broad platelet histogram, and a peak preceding the leukocyte histogram should be considered as suspected cases of MHA (citation essa). In the case of pregnancy, a comprehensive past medical history and family history will provide a clue. Misdiagnoses will result in inappropriate therapeutic intervention including splenectomy and steroid therapy as well as exposing patients to the risk of complications such as recurrent severe abruption, recurrent premature rapture of membrane, intrauterine fetal death, and postpartum hemorrhage (citation essa).
Patient education is essential for patients with MHA on their personal risk of bleeding, which depends on the degree of thrombocytopenia. For patients about to undergo surgery, there should be a discussion on MHA diagnosis as special precautions and procedures are necessary to prevent bleeding complications (citation). Persons with MHA need education to avoid certain drugs such as aspirin, which can negatively affect platelet function.
In conclusion, May Heggling anomaly (MHA) is a rare autosomal dominant disease that results from MYH9 gene mutation. It is one of the five MYH9-related disorders. Although the exact global incident is unknown, the total number of cases reported is less than 200 in ranging from North America, Europe, to Asia. Pregnancy is a special circumstance that requires the consideration of MHA. There is no clear definition of the pathophysiology and clinical spectrum of MHA. Some MHA patients may have no symptoms, and their physical findings are normal, while others may have various bleeding abnormalities. In clinical practice, MHA is often misdiagnosed as having idiopathic thrombocytopenia purpura. Misdiagnosis also leads to erroneous treatment interventions. Differential diagnosis usually involves ruling out other MYH9-related orders. In most cases, MHA patients do not have clinically significant bleeding problems and not require specific treatment. Only in rare cases of severe bleeding that platelet transfusion may be necessary. Patient education is essential for patients with MHA on their personal risk of bleeding.