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May-Hegglin Anomaly

  • Author: Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP; Chief Editor: Hassan M Yaish, MD  more...
 
Updated: May 03, 2016
 

Practice Essentials

May-Hegglin anomaly (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, well-defined, basophilic, cytoplasmic inclusion bodies in granulocytes that resemble Döhle bodies (see the image below).[1]

Blood smear (original magnification ×2000) in pati Blood smear (original magnification ×2000) in patient with May-Hegglin anomaly (MHA) demonstrates characteristic giant platelet with poorly defined granulation. Normal-sized platelet is also present. Trilobed neutrophil contains large, well-defined, basophilic, peripherally placed cytoplasmic inclusion body (resembling Döhle body). Image used with permission from Little, Brown.

Signs and symptoms

Patients are often asymptomatic. The bleeding tendency associated with MHA is generally mild and is thought to mainly depend 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
  • Postpartum hemorrhage

Physical findings are often normal. Findings of abnormal bleeding may be subtle and may include the following:

  • Bruising
  • Petechiae
  • Active bleeding from mucosal surfaces
  • Prolonged and excessive bleeding and oozing associated with lacerations and sutures

It is important to look for associated clinical features of other MYH9 -related disorders (ie, Sebastian syndrome, Epstein syndrome, and Fechtner syndrome in addition to MHA). The following findings may be noted in initially suspected MHA or Sebastian syndrome:

  • High frequency hearing loss
  • Cataracts
  • Hematuria
  • Proteinuria

See Presentation for more detail.

Diagnosis

Laboratory studies that may be helpful include the following:

  • Complete blood count (CBC)
  • Assessment of platelet size, volume, and morphology
  • Peripheral blood smear
  • Immunocytochemistry of leukocytes (demonstrating NMMHCIIA complexes, for confirmation)
  • Bleeding time

See Workup for more detail.

Management

Most patients with MHA do not appear to have clinically significant bleeding problems, and specific treatment is not required. The following points may be considered:

  • Corticosteroids and splenectomy are ineffective
  • In rare patients with severe bleeding, platelet transfusion may be required
  • Bleeding risk is not significantly increased by normal vaginal delivery
  • For patients scheduled to undergo surgery, intravenous desmopressin acetate (DDAVP) may be valuable; routine prophylactic platelet transfusions are not usually indicated, but platelets should be kept available
  • Depending on circumstances, refraining from participation in contact or collision sports may be prudent

See Treatment and Medication for more detail.

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Background

In 1909, May described the presence of leukocyte inclusions and large platelets in an asymptomatic young woman. In 1945, Hegglin described a man and his 2 sons who were healthy but had a triad consisting of thrombocytopenia, giant platelets, and leukocyte inclusions. This diagnostic triad was later given the eponym May-Hegglin anomaly (MHA).[2]

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 µm), well-defined, basophilic, cytoplasmic inclusion bodies in granulocytes that resemble Döhle bodies.[1]

MHA is one of a family of macrothrombocytopenias characterized by mutations in the MYH9 gene.[3] The other members of this family include Sebastian syndrome,[4] Epstein syndrome,[5] and Fechtner syndrome.[6]

Most patients with MHA do not have clinically significant problems with bleeding and therefore do not require treatment.

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Pathophysiology

Patients with MHA have a mutation of the MYH9 gene present in chromosomal region 22q12-13.[7, 3] The mutation results in disordered production of nonmuscle myosin heavy-chain type IIA, which leads to invariable macrothrombocytopenia secondary to defective megakaryocyte maturation.[8] Platelet function in patients with MHA has been reported as normal.[9, 10] ; however, in one study, epinephrine response was described as abnormal in 8 of 15 patients.[11]

Leukocyte Döhlelike inclusion bodies are visualized on standard Wright stain and appear bright blue and spindle-shaped. Ultrastructural studies reveal that these bodies consist of clusters of ribosomes oriented along parallel myosin heavy-chain filaments 7–10 nm in diameter.[12] Neutrophil function is considered to be normal, and patients have no increased susceptibility to infections.

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Etiology

May-Hegglin anomaly is one of a family of macrothrombocytopenias characterized by mutations in the MYH9 gene, which is present at chromosomal region 22q12-13 and codes for nonmuscle myosin heavy-chain IIA.[3] The Döhlelike leukocyte inclusions in MHA are due to precipitation of myosin heavy chains in leukocytes.

Analysis of more than 70 families confirms that mutations in MYH9 can lead to May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, or Epstein syndrome.[13] In one fifth of individuals, the mutation may sporadically arise.[14] Macrothrombocytopenia is invariably present (see the Table below).[15]

Table. Clinical Features of MYH9 -Related Thrombocytopenias (Open Table in a new window)

Condition Macrothrombocytopenia Granulocyte inclusions Nephritis and Deafness Cataracts
MHA Yes Linear Döhlelike No No
Epstein syndrome Yes Absent or faint Yes No
Fechtner syndrome Yes Spherical granules Yes Yes
Sebastian syndrome Yes Spherical granules No No

 

The clinical description of these syndromes predated the discovery of the MYH9 gene mutations. Although the theory was that genotype-phenotype correlations would be found, this has not been the case overall.[16] The MYH9 R702 mutation is reportedly associated with the smaller neutrophil inclusions seen in Sebastian syndrome, Fechtner syndrome, and Epstein syndrome.[17]

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Epidemiology

MHA is a rare autosomal dominant disorder. In one review, 180 cases had been reported in the literature.[11] Kindreds have been reported from Italy, France, Germany, and North America.[3] MHA was reported in 15 families in Japan in 1993.[18] The exact incidence of the syndrome is unknown.

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Prognosis

The rarity of MHA has led to conflicting literature regarding the risk for bleeding. Asymptomatic patients have been described[9, 10] ; however, abnormal bleeding has also been documented.[11] The bleeding risk is increased by taking drugs that decrease platelet function. The risk for excess bleeding with surgical procedures is unclear.[19] Rare reports have described arterial thrombotic events associated with May-Hegglin anomaly, though the risk remains unclear.[20]

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Patient Education

Individuals with MHA should be informed regarding their personal risk of bleeding. They should be made aware that their bleeding risks are associated with the degree of thrombocytopenia.

In patients who are scheduled to undergo surgical procedures or have sustained 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.

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Contributor Information and Disclosures
Author

Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP Professor of Pediatrics, Albany Medical College; Chief, Division of Pediatric Hematology-Oncology, John and Anna Landis Endowed Chair for Pediatric Hematology-Oncology, Medical Director, Melodies Center for Childhood Cancer and Blood Disorders, Albany Medical Center

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, Children's Oncology Group, International Society of Pediatric Oncology

Disclosure: Nothing to disclose.

Chief Editor

Hassan M Yaish, MD Medical Director, Intermountain Hemophilia and Thrombophilia Treatment Center; Professor of Pediatrics, University of Utah School of Medicine; Director of Hematology, Pediatric Hematologist/Oncologist, Department of Pediatrics, Primary Children's Medical Center

Hassan M Yaish, MD is a member of the following medical societies: American Academy of Pediatrics, New York Academy of Sciences, American Medical Association, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Michigan State Medical Society

Disclosure: Nothing to disclose.

Acknowledgements

Gary D Crouch, MD Associate Professor, Program Director of Pediatric Hematology-Oncology Fellowship, Department of Pediatrics, Uniformed Services University of the Health Sciences

Gary D Crouch, MD is a member of the following medical societies: American Academy of Pediatrics and American Society of Hematology

Disclosure: Nothing to disclose.

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

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

References
  1. Fatima S. May hegglin anomaly: rare entity with review of literature. Indian J Hematol Blood Transfus. 2012 Mar. 28 (1):58-60. [Medline]. [Full Text].

  2. Saito H, Kunishima S. Historical hematology: May-Hegglin anomaly. Am J Hematol. 2008 Apr. 83(4):304-6. [Medline].

  3. 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].

  4. 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].

  5. Epstein CJ, Sahud MA, Piel CF, Goodman JR, Bernfield MR, Kushner JH. Hereditary macrothrombocytopathia, nephritis and deafness. Am J Med. 1972 Mar. 52(3):299-310. [Medline].

  6. Peterson LC, Rao KV, Crosson JT, White JG. Fechtner syndrome--a variant of Alport's syndrome with leukocyte inclusions and macrothrombocytopenia. Blood. 1985 Feb. 65(2):397-406. [Medline].

  7. 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].

  8. Chen Z, Shivdasani RA. Regulation of platelet biogenesis: insights from the May-Hegglin anomaly and other MYH9-related disorders. J Thromb Haemost. 2009 Jul. 7 Suppl 1:272-6. [Medline].

  9. 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].

  10. Mayer K, Schildknecht O, von Felten A. [May-Hegglin anomaly: further studies on thrombocyte dysfunction]. Schweiz Med Wochenschr. 1997 Jun 28. 127(26):1134-40. [Medline].

  11. 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].

  12. Pujol-Moix N, Kelley MJ, Hernandez A, Muniz-Diaz E, Espanol I. Ultrastructural analysis of granulocyte inclusions in genetically confirmed MYH9-related disorders. Haematologica. 2004 Mar. 89(3):330-7. [Medline].

  13. Heath KE, Campos-Barros A, Toren A, Rozenfeld-Granot G, Carlsson LE, Savige J. Nonmuscle myosin heavy chain IIA mutations define a spectrum of autosomal dominant macrothrombocytopenias: May-Hegglin anomaly and Fechtner, Sebastian, Epstein, and Alport-like syndromes. Am J Hum Genet. 2001 Nov. 69(5):1033-45. [Medline].

  14. Otsubo K, Kanegane H, Nomura K, Ogawa J, Miyawaki T, Kunishima S. Identification of a novel MYH9 mutation in a patient with May-Hegglin anomaly. Pediatr Blood Cancer. 2006 Dec. 47(7):968-9. [Medline].

  15. 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].

  16. 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].

  17. Kunishima S, Yoshinari M, Nishio H, Ida K, Miura T, Matsushita T. Haematological characteristics of MYH9 disorders due to MYH9 R702 mutations. Eur J Haematol. 2007 Mar. 78(3):220-6. [Medline].

  18. Ishii A, Honnma T, Ishida M, Sano F, Hamada H, Takayanagi M. Pregnancy complicated by the May-Hegglin anomaly. J Perinat Med. 1993. 21(3):247-52. [Medline].

  19. Sehbai AS, Abraham J, Brown VK. Perioperative management of a patient with May-Hegglin anomaly requiring craniotomy. Am J Hematol. 2005 Aug. 79(4):303-8. [Medline].

  20. Antonio G, Silvia V, Emanuela B, Fabrizio F. Thrombotic events in MYH9 gene-related autosomal macrothrombocytopenias (old May-Hegglin, Sebastian, Fechtner and Epstein syndromes). J Thromb Thrombolysis. 2011 Nov. 32(4):474-7. [Medline].

  21. Hussein BA, Gomez K, Kadir RA. May-Hegglin anomaly and pregnancy: a systematic review. Blood Coagul Fibrinolysis. 2013 Jul. 24 (5):554-61. [Medline].

  22. Kunishima S, Matsushita T, Kojima T, Sako M, Kimura F, Jo EK. Immunofluorescence analysis of neutrophil nonmuscle myosin heavy chain-A in MYH9 disorders: association of subcellular localization with MYH9 mutations. Lab Invest. 2003 Jan. 83(1):115-22. [Medline].

  23. Bizzaro N. May-Hegglin anomaly and uncomplicated vaginal delivery: a report of 41 cases. Am J Obstet Gynecol. 1999 Jul. 181(1):226-7. [Medline].

  24. Chabane H, Gallais Y, Pathier D, Tchernia G, Gaussem P. Delivery management in a woman with thrombocytopenia of the May-Hegglin anomaly type. Eur J Obstet Gynecol Reprod Biol. 2001 Nov. 99(1):124-5. [Medline].

  25. DiMichele DM, Hathaway WE. Use of DDAVP in inherited and acquired platelet dysfunction. Am J Hematol. 1990 Jan. 33(1):39-45. [Medline].

 
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Blood smear (original magnification ×2000) in patient with May-Hegglin anomaly (MHA) demonstrates characteristic giant platelet with poorly defined granulation. Normal-sized platelet is also present. Trilobed neutrophil contains large, well-defined, basophilic, peripherally placed cytoplasmic inclusion body (resembling Döhle body). Image used with permission from Little, Brown.
Table. Clinical Features of MYH9 -Related Thrombocytopenias
Condition Macrothrombocytopenia Granulocyte inclusions Nephritis and Deafness Cataracts
MHA Yes Linear Döhlelike No No
Epstein syndrome Yes Absent or faint Yes No
Fechtner syndrome Yes Spherical granules Yes Yes
Sebastian syndrome Yes Spherical granules No No
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