AUTHOR INFORMATION

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Authored by Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP, Assistant Professor of Pediatric Hematology-Oncology, Department of Pediatrics, Children's Hospital at Albany Medical Center

Coauthored by Frank E Shafer, MD, Associate Professor, Department of Pediatrics, Section of Hematology-Oncology, St. Christopher's Hospital for Children, MCP Hahnemann University School

Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP, is a member of the following medical societies: American Academy of Pediatrics, American Society of Hematology, American Society of Pediatric Hematology/Oncology, and Royal College of Physicians

Edited by Gary R Jones, MD, Associate Medical Director, Clinical Development, Berlex Laboratories; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Gary D Crouch, MD, Program Director of Pediatric Hematology-Oncology Fellowship, Associate Professor, Department of Pediatrics, Uniformed Services University of the Health Sciences; Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida, Clinical Professor, Department of Pediatrics, UNC, Adjunct Professor, Department of Pediatrics, Duke University; and Robert J Arceci, MD, PhD, King Fahd Professor, Division of Pediatric Oncology, Johns Hopkins University School of Medicine

Author's Email:	Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP
Editor's Email:	Gary R Jones, MD

eMedicine Journal, November 30 2006, VOLUME 7, Number 11

INTRODUCTION

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Background: In 1909, May described the presence of leukocytic inclusions in a young female patient who was asymptomatic. In 1945, Hegglin described a man and his 2 sons who were healthy but who had a triad consisting of thrombocytopenia, giant platelets, and leukocytic inclusions. This condition gave rise to the eponym May-Hegglin anomaly (MHA). MHA is an autosomal dominant disorder characterized by various degrees of thrombocytopenia that may be associated with purpura and bleeding, giant platelets containing few granules, and large (2-5 mm), well-defined, basophilic, cytoplasmic inclusion bodies (resembling Döhle bodies) in the granulocytes (neutrophils, eosinophils, basophils, monocytes).

Pathophysiology: The pathogenesis of MHA is becoming clear. Patients have a mutation of the MYH9 gene present in chromosomal region 22q12-13. The mutation results in disordered production of nonmuscle myosin heavy-chain type IIA. This leads to macrothrombocytopenia, secondary to defective megakaryocyte maturation and fragmentation. In addition, leukocytic inclusions are present, which consist of precipitates of myosin heavy chains.

Both neutrophil and platelet function is otherwise considered to be normal. No evidence suggests increased susceptibility to infections.

Thrombocytopenia occurs in almost all patients, but severe bleeding is unusual. Individuals may bruise easily, and they may have recurrent epistaxis, gingival bleeding, menorrhagia, or excessive bleeding associated with surgical procedures.

Frequency:

• In the US: MHA is a rare autosomal dominant disorder. In 2000-2005, 85 families with MHA were described. The exact incidence of the syndrome is unknown.

• Internationally: MHA is a rare autosomal dominant disorder. The exact incidence of the syndrome is unknown.

Mortality/Morbidity: Approximately one half of the reported patients with MHA were asymptomatic, but the other half had platelet counts <50 X 10⁹/L and abnormal bleeding in the form of recurrent epistaxis, gingival bleeding, easy bruising, menorrhagia, and excessive bleeding associated with surgical procedures. Fatal bleeding has not been reported in this syndrome.

CLINICAL

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History: Individuals with MHA may be asymptomatic. The bleeding tendency associated with MHA is generally mild and depends on the degree of thrombocytopenia.

Symptoms of bleeding can include the following:

• Recurrent epistaxis



• Gingival bleeding



• Easy bruising



• Menorrhagia



• Excessive bleeding associated with surgical procedures

Physical: Physical findings may be normal. Findings of abnormal bleeding may be subtle.

• Bruising, which may or may not be associated with a history of clinically significant trauma, may be noted.



• Petechiae may be present on the skin and are most common in pressure-point areas (eg, neck, overlying the clavicles, on the waist, areas where clothes are tight). Petechiae are associated with restricting conditions, such as the application of a tourniquet for venipuncture. Petechiae may also be observed on the oral and nasal mucosal surfaces.



• Active bleeding from the mucosal surfaces may be observed. The most common sites of bleeding include the mouth and nose.



• Prolonged and excessive bleeding and oozing associated with lacerations and sutures may be observed.

Causes: MHA is one of a family of macrothrombocytopenias characterized by mutations in the MYH9 gene present at chromosomal region 22q12-13, which codes for nonmuscle myosin heavy-chain IIA. The Döhle-like leukocyte inclusions in MHA are due to precipitation of myosin heavy chains in leukocytes.

Analysis of more than 30 families who European and American researchers described confirms that mutations in MYH9 can lead to MHA and Sebastian, Fechtner, or Epstein syndromes. The features of these 4 entities are described in the Table below. Recognizing that these diseases represent variable expression of a single genetic defect is important.

Hereditary Forms of Thrombocytopenia

Condition	Degree of Thrombocytopenia	Platelet Size	Platelet Function	Megakaryocyte and Bone Marrow Features	Inheritance	Other features
MHA	Mild	Large	Normal	Defective fragmentation of megakaryocytes	Autosomal dominant	Döhle body inclusions in granulocytes
Epstein syndrome	Moderate to severe	Large	Variable to abnormal aggregation to adenosine diphosphate and collagen, may be associated with uremia	Normal	Autosomal dominant	Interstitial nephritis and nerve deafness
Fechtner syndrome	Moderate	Large	Normal	Normal	Autosomal dominant	Leukocyte inclusions similar to Döhle body inclusions of MHA; clinical features include nephritis, deafness, and congenital cataracts
Sebastian syndrome	Moderate	Large	Normal	Normal	Autosomal dominant	Similar to Fechtner syndrome without clinical features

DIFFERENTIALS

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Alport Syndrome
Bernard-Soulier Syndrome
Wiskott-Aldrich Syndrome

Other Problems to be Considered:

The differential diagnosis for thrombocytopenia associated with large platelets (elevated mean platelet volume [MPV]) includes Bernard-Soulier syndrome, Montreal platelet syndrome, gray-platelet syndrome, Alport syndrome, and immune thrombocytopenic purpura (ITP).

The differential diagnosis for thrombocytopenia due to ineffective thrombopoiesis includes Bernard-Soulier syndrome, Wiskott-Aldrich syndrome, Greaves syndrome, thrombopoietin deficiency, and megaloblastic anemia.

The differential diagnosis for leukocytic inclusions, sometimes called Döhle bodies, includes septicemia, myeloproliferative disorders, and pregnancy.

Isolated thrombocytopenia in childhood is most commonly due to acquired autoimmune causes, with ITP being the most common disease. In ITP, reticuloendothelial macrophages, predominantly those in the spleen, remove antibody- and/or complement-coated platelets. Viral infections are thought to account for most cases of ITP. The degree of thrombocytopenia in most children with acute ITP is usually severe (platelet count <50 X 10⁹/L). Large, young platelets are often present and reflect an increase in platelet production by the megakaryocytes in the bone marrow. Reactive lymphocytes and toxic changes in the neutrophils may be present depending on the nature of the viral infection. However, unlike MHA, Döhle bodies are not present in the granulocytes. For most patients, the prognosis is promising. Although initial treatment may be necessary in cases of severe thrombocytopenia, the platelet count usually recovers in several weeks to months.

WORKUP

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Lab Studies:

• The CBC is essential.


• • The platelet count is decreased, but the degree of thrombocytopenia varies. The platelet count is usually 40-80 X 10⁹/L.
  
  
  
  • The disorder is also characterized by giant platelets. Platelets are enlarged (up to 15 mm in diameter), but platelet morphology is otherwise normal.
  
  
  
  • The MPV of MHA platelets can be as high as 30 fL (normal, <10 fL).
  
  
  
  • On electron microscopy, platelets contain normal organelles (alpha granules, dense granules, lysosomes, mitochondria). The most conspicuous ultrastructural feature of the platelets is an increased amount of disorganized microtubuli.
  
  
  
• The Wright-stained peripheral blood smear shows cytoplasmic inclusion bodies, particularly in the neutrophils, but also in the monocytes, eosinophils, and basophils. The inclusions are large (up to 5 mm), spindle shaped, pale, blue-staining bodies that consist of ribosomes, segments of endoplasmic reticulum, and microfilaments. They are located in the periphery of the cytoplasm and are similar to Döhle bodies in gross appearance.



• The bleeding time is prolonged in concordance with the degree of thrombocytopenia. Platelets aggregate normally in response to various agonists. The glycoprotein composition of the platelet surface is normal in this syndrome.

TREATMENT

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Medical Care: Most patients with MHA do not have clinically significant bleeding problems. Therefore, treatment may not be required. Corticosteroids and splenectomy are ineffective. In rare patients with severe bleeding, platelet transfusion may be required. Prophylactic preoperative transfusions of platelets may also be warranted.

Surgical Care: Prophylactic preoperative transfusions of platelets may be warranted. Consult a hematologist before undertaking surgical procedures.

Consultations: Consult a hematologist before patients undergo surgical procedures and in patients with severe trauma.

Activity: Depending on the degree of thrombocytopenia, individuals may be at an increased risk for severe bleeding problems. For these patients, refraining from participation in contact or collision sports may be prudent.

MEDICATION

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Most patients with MHA do not have clinically significant problems with bleeding. Therefore, they do not require treatment. Corticosteroids and splenectomy are ineffective. On the rare occasions when patients have severe bleeding, platelet transfusions may be required. Prophylactic platelet transfusions before surgery and delivery may be warranted to prevent severe bleeding.

FOLLOW-UP

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Complications:

• Most individuals with MHA do not have bleeding problems; however, severe bleeding may occur.



• The bleeding risk is increased if patients are taking drugs that decrease platelet function.

Prognosis:

• Most patients with MHA do not have clinically significant problems with bleeding. Therefore, they do not require treatment.

Patient Education:

• Individuals with MHA should understand their personal risk of bleeding. They should understand that their bleeding risks are associated with the degree of thrombocytopenia.



• Before patients undergo surgical procedures or in patients with trauma, the diagnosis of MHA must be discussed because special precautions and procedures may be required to prevent bleeding complications.



• Individuals with MHA should be educated to avoid drugs (eg, aspirin) that can adversely affect platelet function.

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Because of the increased risk of bleeding in individuals with chronic thrombocytopenia (especially intracranial hemorrhage), pay special attention to individuals with MHA who have an injury. Consider ordering imaging studies in these patients. Failure to recognize internal bleeding associated with thrombocytopenia could delay treatment.



• Failure to appropriately diagnose MHA could result in inappropriate treatment. In clinical states of chronic thrombocytopenia associated with large and giant platelets, including chronic ITP, consider MHA in the differential diagnosis. A familial history of thrombocytopenia can be an important feature. Rule out MHA before undertaking procedures (eg, splenectomy) or medical therapy with potentially toxic adverse effects.



• MHA is occasionally associated with deafness and nephritis. In a patient with this diagnosis, renal function and hearing should be evaluated.

Special Concerns:

• Because of the increased risks (particularly intracranial hemorrhage) of bleeding in young children who have thrombocytopenia, pay special attention to children with MHA who have severe head trauma. Imaging studies of the head (CT or MRI) should be considered in these patients.



• Because MHA is an autosomal dominant inherited condition, genetic counseling is important.

TEST QUESTIONS

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CME Question 1: Which feature is not a characteristic of May-Hegglin anomaly (MHA)?

A: Microcytic anemia
B: Thrombocytopenia
C: Giant platelets containing few granules
D: All of the above
E: None of the above

The correct answer is A: Microcytic anemia is not usually characteristic of MHA. MHA is characterized by various degrees of thrombocytopenia that may be associated with purpura and bleeding, giant platelets containing few granules, and large (2-5 mm), well-defined, basophilic, and cytoplasmic inclusion bodies.

CME Question 2: What is the inheritance pattern of May-Hegglin anomaly (MHA)?

A: X-linked recessive
B: Autosomal dominant
C: Autosomal recessive
D: X-linked dominant
E: Multifactorial pattern

The correct answer is B: MHA is a rare autosomal dominant disorder. Patients have a mutation of the MYH9 gene present in chromosomal region 22q12-13.

Pearl Question 1 (T/F): May-Hegglin anomaly (MHA) is characterized by small platelets.

The correct answer is False: MHA is characterized by giant platelets containing few granules.

Pearl Question 2 (T/F): May-Hegglin anomaly (MHA) should be included in the differential diagnosis of immune thrombocytopenic purpura (ITP).

The correct answer is True: The differential diagnosis for thrombocytopenia associated with large platelets (elevated mean platelet volume [MPV]) includes Bernard-Soulier syndrome, MHA, gray-platelet syndrome, Alport syndrome, Montreal platelet syndrome, and ITP.

Pearl Question 3 (T/F): May-Hegglin anomaly (MHA) is characterized by cytoplasmic inclusion bodies in only the granulocytes.

The correct answer is False: A hallmark of MHA is the presence of large (2-5 mm), well-defined, basophilic, cytoplasmic inclusion bodies (resembling Döhle bodies) in the granulocytes (neutrophils, eosinophils, basophils, monocytes).

Pearl Question 4 (T/F): Severe and recurrent episodes of hemarthrosis are a common feature of May-Hegglin anomaly (MHA).

The correct answer is False: Approximately one half of the reported patients with MHA were asymptomatic. However, the other half had abnormal bleeding in the form of mucosal bleeding, such as recurrent epistaxis, gingival bleeding, easy bruising, menorrhagia, or excessive bleeding in association with surgical procedures.

PICTURES

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Caption: Picture 1. Blood smear (original magnification X2000) in a patient with May-Hegglin anomaly (MHA) demonstrates a characteristic giant platelet with poorly defined granulation. A normal-sized platelet is also present. The trilobed neutrophil contains a large, well-defined, basophilic, peripherally placed cytoplasmic inclusion body (resembling a Döhle body). Used with permission from Little, Brown.
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BIBLIOGRAPHY

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• Burns ER: Platelet studies in the pathogenesis of thrombocytopenia in May-Hegglin anomaly. Am J Pediatr Hematol Oncol 1991 Winter; 13(4): 431-6[Medline].
• Dong F, Li S, Pujol-Moix N, et al: Genotype-phenotype correlation in MYH9-related thrombocytopenia. Br J Haematol 2005 Aug; 130(4): 620-7[Medline].
• Greinacher A, Nieuwenhuis HK, White JG: Sebastian platelet syndrome: a new variant of hereditary macrothrombocytopenia with leukocyte inclusions. Blut 1990 Nov; 61(5): 282-8[Medline].
• Kunishima S, Kojima T, Tanaka T, et al: Mapping of a gene for May-Hegglin anomaly to chromosome 22q. Hum Genet 1999 Nov; 105(5): 379-83[Medline].
• Noris P, Spedini P, Belletti S, et al: Thrombocytopenia, giant platelets, and leukocyte inclusion bodies (May- Hegglin anomaly): clinical and laboratory findings. Am J Med 1998 Apr; 104(4): 355-60[Medline].
• Oski FA, Naiman JL, Allen DM, Diamond LK: Leukocytic inclusions--Dohle bodies--associated with platelet abnormality (the May-Hegglin anomaly). Report of a family and review of the literature. Blood 1962 Dec; 20: 657-67[Medline].
• Seri M, Cusano R, Gangarossa S, et al: Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes. The May-Heggllin/Fechtner Syndrome Consortium. Nat Genet 2000 Sep; 26(1): 103-5[Medline].
• Seri M, Pecci A, Di Bari F, et al: MYH9-related disease: May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but represent a variable expression of a single illness. Medicine (Baltimore) 2003 May; 82(3): 203-15[Medline].

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