eMedicine Specialties > Pediatrics: General Medicine > Hematology
May-Hegglin Anomaly
Updated: Aug 1, 2008
Introduction
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 leukocyte 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 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.2 The other members of this family include Sebastian syndrome,3 Epstein syndrome,4 and Fechtner syndrome.5
Pathophysiology
Patients have a mutation of the MYH9 gene present in chromosomal region 22q12-13.6,2 The mutation results in disordered production of nonmuscle myosin heavy-chain type IIA, which leads to invariable macrothrombocytopenia secondary to defective megakaryocyte maturation. Platelet function in patients with MHA has been reported as normal.7,8 However, in one study, epinephrine response was described as abnormal in 8 of 15 patients.9
Leukocyte Döhlelike inclusion bodies are visualized on standard Wright stain. Ultrastructural studies reveal that these bodies consist of clusters of ribosomes oriented along parallel myosin heavy-chain filaments 7–10 nm in diameter.10 Neutrophil function is considered to be normal, and patients have no increased susceptibility to infections.
Frequency
United States
MHA is a rare autosomal dominant disorder. In one review, 180 cases had been reported in the literature.9 The exact incidence of the syndrome is unknown.
International
MHA is a rare autosomal dominant disorder, and the exact incidence is unknown. Kindreds have been reported from Italy, France, Germany, and North America.2 MHA was reported in 15 families in Japan in 1993.11
Mortality/Morbidity
The rarity of MHA has led to conflicting literature regarding the risk for bleeding. Asymptomatic patients have been described.7,8 However, abnormal bleeding has also been documented.9 The risk for excess bleeding with surgical procedures is unclear.12
Clinical
History
Individuals with May-Hegglin anomaly (MHA) are often asymptomatic. The bleeding tendency associated with MHA is generally mild and is thought to mainly depend on the degree of thrombocytopenia.7
Symptoms of bleeding can include the following:
- Recurrent epistaxis
- Gingival bleeding
- Easy bruising
- Menorrhagia
- Excessive bleeding associated with surgical procedures
Physical
Physical findings are often 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 also be observed.
Looking for the associated clinical features of MYH9 -related disorders is important in enabling an accurate diagnosis. In patients initially thought to have MHA or Sebastian syndrome, the following findings were noted.13
- High frequency hearing loss (82%)
- Cataracts (25%)
- Hematuria (25%)
- Proteinuria (40%)
Causes
MHA 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.2 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 MHA, Sebastian syndrome, Fechtner syndrome, or Epstein syndrome.14 In one fifth of individuals, the mutation may sporadically arise.15 Macrothrombocytopenia is invariable, and the clinical features of these 4 entities are described below. 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, overall this has not been the case.16 The MYH9 R702 mutation is reportedly associated with the smaller neutrophil inclusions seen in Sebastian syndrome, Fechtner syndrome, and Epstein syndrome.17
Clinical Features of MYH9 -Related Thrombocytopenias13Open table in new window
Table
| 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 |
| 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 |
More on May-Hegglin Anomaly |
 Overview: May-Hegglin Anomaly |
| Differential Diagnoses & Workup: May-Hegglin Anomaly |
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| Follow-up: May-Hegglin Anomaly |
| Multimedia: May-Hegglin Anomaly |
| References |
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References
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. Dec 1962;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. Sep 2000;26(1):103-5. [Medline].
Greinacher A, Nieuwenhuis HK, White JG. Sebastian platelet syndrome: a new variant of hereditary macrothrombocytopenia with leukocyte inclusions. Blut. Nov 1990;61(5):282-8. [Medline].
Epstein CJ, Sahud MA, Piel CF, Goodman JR, Bernfield MR, Kushner JH. Hereditary macrothrombocytopathia, nephritis and deafness. Am J Med. Mar 1972;52(3):299-310. [Medline].
Peterson LC, Rao KV, Crosson JT, White JG. Fechtner syndrome--a variant of Alport's syndrome with leukocyte inclusions and macrothrombocytopenia. Blood. Feb 1985;65(2):397-406. [Medline].
Kunishima S, Kojima T, Tanaka T, et al. Mapping of a gene for May-Hegglin anomaly to chromosome 22q. Hum Genet. Nov 1999;105(5):379-83. [Medline].
Burns ER. Platelet studies in the pathogenesis of thrombocytopenia in May-Hegglin anomaly. Am J Pediatr Hematol Oncol. Winter 1991;13(4):431-6. [Medline].
Mayer K, Schildknecht O, von Felten A. [May-Hegglin anomaly: further studies on thrombocyte dysfunction]. Schweiz Med Wochenschr. Jun 28 1997;127(26):1134-40. [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. Apr 1998;104(4):355-60. [Medline].
Pujol-Moix N, Kelley MJ, Hernandez A, Muniz-Diaz E, Espanol I. Ultrastructural analysis of granulocyte inclusions in genetically confirmed MYH9-related disorders. Haematologica. Mar 2004;89(3):330-7. [Medline].
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].
Sehbai AS, Abraham J, Brown VK. Perioperative management of a patient with May-Hegglin anomaly requiring craniotomy. Am J Hematol. Aug 2005;79(4):303-8. [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). May 2003;82(3):203-15. [Medline].
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. Nov 2001;69(5):1033-45. [Medline].
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. Dec 2006;47(7):968-9. [Medline].
Dong F, Li S, Pujol-Moix N, et al. Genotype-phenotype correlation in MYH9-related thrombocytopenia. Br J Haematol. Aug 2005;130(4):620-7. [Medline].
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. Mar 2007;78(3):220-6. [Medline].
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. Jan 2003;83(1):115-22. [Medline].
Bizzaro N. May-Hegglin anomaly and uncomplicated vaginal delivery: a report of 41 cases. Am J Obstet Gynecol. Jul 1999;181(1):226-7. [Medline].
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. Nov 2001;99(1):124-5. [Medline].
DiMichele DM, Hathaway WE. Use of DDAVP in inherited and acquired platelet dysfunction. Am J Hematol. Jan 1990;33(1):39-45. [Medline].
Further Reading
Keywords
May-Hegglin anomaly, MHA, thrombocytopenia, MYH9 gene, leukocytic inclusions, leukocyte inclusions, macrothrombocytopenia, Döhle bodies, Sebastian syndrome, Epstein syndrome, Fechtner syndrome, recurrent epistaxis, gingival bleeding, easy bruising, menorrhagia, hearing loss, cataracts, hematuria, proteinuria
