May-Hegglin Anomaly 

Updated: Feb 28, 2019
Author: Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP; Chief Editor: Hassan M Yaish, MD 

Overview

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, 2, 3]  MHA is one of a family of macrothrombocytopenias characterized by mutations in the MYH9 gene.[4, 5] The other members of this family include Sebastian syndrome,[6] Epstein syndrome,[7] and Fechtner syndrome,[8]  although it is likely, as MYH9-related disorders are better characterized, that these time-honored eponyms will fade away.

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, Fechtner syndrome). The following findings may be noted in these syndromes, which may overlap depending on the underlying mutation.

  • 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.

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).[9]

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.[4] The other members of this family include Sebastian syndrome,[6] Epstein syndrome,[7] and Fechtner syndrome.[8]

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

Pathophysiology

Patients with MHA have a mutation of the MYH9 gene present in chromosomal region 22q12-13.[10, 4] The mutation results in disordered production of nonmuscle myosin heavy-chain type IIA, which leads to invariable macrothrombocytopenia secondary to defective megakaryocyte maturation.[11] Platelet function in patients with MHA has been reported as normal.[12, 13] ; however, in one study, epinephrine response was described as abnormal in 8 of 15 patients.[14]

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.[15] Neutrophil function is considered to be normal, and patients have no increased susceptibility to infections.

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.[4] 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.[16] In one fifth of individuals, the mutation may sporadically arise.[17] Macrothrombocytopenia is invariably present (see the Table below).[18] 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.[19] The MYH9 R702 mutation is reportedly associated with the smaller neutrophil inclusions seen in Sebastian syndrome, Fechtner syndrome, and Epstein syndrome.[20] In addition MYH9 exon 24 indel mutations may be associated with nephritis, deafness, and congenital cataracts.[21]

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

Epidemiology

MHA is a rare autosomal dominant disorder. In one review, 180 cases had been reported in the literature.[14] Kindreds have been reported from Italy, France, Germany, and North America.[4] MHA was reported in 15 families in Japan in 1993.[22] The exact incidence of the syndrome is unknown.

Prognosis

The rarity of MHA has led to conflicting literature regarding the risk for bleeding. Asymptomatic patients have been described[12, 13] ; however, abnormal bleeding has also been documented.[14] The bleeding risk is increased by taking drugs that decrease platelet function. The risk for excess bleeding with surgical procedures is unclear.[23] Rare reports have described arterial thrombotic events associated with May-Hegglin anomaly, though the risk remains unclear.[24]

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.

 

Presentation

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.[12]

Symptoms of bleeding can include the following:

  • Recurrent epistaxis

  • Gingival bleeding

  • Easy bruising

  • Menorrhagia

  • Excessive bleeding associated with surgical procedures

  • Postpartum hemorrhage 

Physical Examination

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, on the neck, overlying the clavicles, on the waist, or in 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[18] :

  • High frequency hearing loss (82%)

  • Cataracts (25%)

  • Hematuria (25%)

  • Proteinuria (40%)

Complications

Despite mild bleeding symptoms, pregnancy in women with MHA can pose risk. A literature review by Hussein et al revealed that in 40 patients with MHA with 75 pregnancies, postpartum hemorrhage (PPH) occurred in four pregnancies, with three cases of primary and one of secondary PPH. There were two intrauterine fetal deaths, but no documented morbidity in the 34 newborns who were found to have thrombocytopenia after delivery.[25]

 

DDx

Diagnostic Considerations

In addition to acute immune thrombocytic purpura, the differential diagnosis for thrombocytopenia associated with large platelets (elevated mean platelet volume) includes Bernard-Soulier syndrome, Montreal platelet syndrome, gray-platelet syndrome, and Alport syndrome.

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.

Differential Diagnoses

 

Workup

Approach Considerations

Because of the increased risks of bleeding (particularly intracranial hemorrhage) in young children who have thrombocytopenia, special attention must be paid to pediatric patients with May-Hegglin anomaly (MHA) who have sustained severe head trauma. Imaging studies of the head (computed tomography [CT] or magnetic resonance imaging [MRI]) should be considered in these patients. Because MHA is an autosomal dominant inherited condition, genetic counseling is important.

Laboratory Studies

The complete blood count (CBC) is essential in assessing MHA. The platelet count is decreased (usually in the range of 40-80 ´ 109/L), but the degree of thrombocytopenia varies. The disorder is also characterized by giant platelets. Platelets are enlarged (>15 µm in diameter), and the mean volume of MHA platelets can be as high as 30 fL.[26] Platelet morphology is otherwise normal.

On electron microscopy, platelets are seen to contain normal organelles (alpha granules, dense granules, lysosomes, and mitochondria). The most conspicuous ultrastructural feature of the platelets is an increased amount of disorganized microtubules.

The Wright-stained peripheral blood smear shows cytoplasmic inclusion bodies (see the image below), particularly in the neutrophils but also in monocytes, eosinophils, and basophils. The inclusions are large (>5 µm), 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 resemble Döhle bodies.[27]

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.

Immunocytochemistry can detect NMMHCIIA complexes within the leukocytes and is a useful confirmatory test.[28]

The bleeding time is prolonged in concordance with the degree of thrombocytopenia. Platelets usually aggregate normally in response to various agonists. The glycoprotein composition of the platelet surface is normal.[13]

A study by Rabbolini et al suggested that there would be less likelihood of missing cases of MYH9-related disorders if immunofluorescence and next-generation sequencing were prioritized in diagnostic algorithms during the workup of patients with thrombocytopenia associated with giant platelets. The investigators suggested that such prioritization is necessary even if peripheral blood film does not appear to reveal Döhle-like bodies.[29]

 

Treatment

Approach Considerations

The literature is conflicting, but most patients with May-Hegglin anomaly (MHA) do not appear to have clinically significant bleeding problems, and specific treatment is not required. Corticosteroids and splenectomy are ineffective. In rare patients with severe bleeding, platelet transfusion may be required.

Patients with MHA who undergo normal vaginal or cesarean delivery do not appear to have a significantly increased risk of bleeding.[30, 31]

For patients with MHA scheduled for surgery, a careful personal and family history of bleeding tendency should be obtained and a manual platelet count performed to determine the actual risk for bleeding. Intravenous desmopressin acetate (DDAVP) may be valuable.[23, 32] A patient with MHA who successfully underwent craniotomy after DDAVP infusion alone has been described.[23] Routine prophylactic platelet transfusions are not usually indicated, though it is prudent to ensure that platelets are available in case unexpected bleeding occurs.

Depending on the degree of thrombocytopenia and family history, individuals may be at an increased risk for bleeding, and refraining from participation in contact or collision sports may be prudent.

A hematologist should be consulted to assist in the management of patients who are undergoing surgery or vaginal delivery and patients who have experienced severe trauma.

 

Medication

Medication Summary

Most patients with May-Hegglin anomaly (MHA) do not have clinically significant problems with bleeding and do not require treatment. Corticosteroids and splenectomy are ineffective. On rare occasions when patients have severe bleeding, platelet transfusions may be required. Prophylactic platelet transfusions are not routinely used before surgery and delivery. Intravenous desmopressin has been used preoperatively as a nonspecific agent to improve hemostasis. Stimate (nasal desmopressin) should be as effective in such cases.

Pituitary Hormone

Class Summary

Desmopressin acetate, a synthetic analogue of vasopressin, may be used before surgery.

Desmopressin acetate (DDAVP, Stimate)

Desmopressin acetate releases von Willebrand protein from endothelial cells. It improves bleeding time and hemostasis in patients with some von Willebrand factor (ie, with mild and moderate von Willebrand disease without abnormal molecular forms of von Willebrand protein). It is effective in uremic bleeding. Tachyphylaxis usually develops after 48 hours, but desmopressin acetate can be effective again after several days. A nasal solution is available in strengths of 0.1 mg/mL (10 µg/0.1 mL) and 0.6 mg/mL (1.5 mg/2.5 mL).

 

Questions & Answers

Overview

What is May-Hegglin anomaly (MHA)?

What are the signs and symptoms of May-Hegglin anomaly (MHA)?

What are the signs of abnormal bleeding in May-Hegglin anomaly (MHA)?

Which physical findings are characteristic of associated MYH9-related disorders in May-Hegglin anomaly (MHA)?

Which lab tests are performed in the workup of May-Hegglin anomaly (MHA)?

How is May-Hegglin anomaly (MHA) treated?

How was the May-Hegglin anomaly (MHA) first identified?

How is May-Hegglin anomaly (MHA) characterized?

What are the other MYH9-related syndromes associated with May-Hegglin anomaly (MHA)?

How frequently does May-Hegglin anomaly (MHA) require treatment?

What is the pathophysiology of May-Hegglin anomaly (MHA)?

What causes May-Hegglin anomaly (MHA)?

What is the prevalence of May-Hegglin anomaly (MHA)?

What is the prognosis of May-Hegglin anomaly (MHA)?

What is included in patient education about May-Hegglin anomaly (MHA)?

Presentation

Which clinical history findings are characteristic of May-Hegglin anomaly (MHA)?

Which physical findings are characteristic of May-Hegglin anomaly (MHA)?

What are the possible complications of May-Hegglin anomaly (MHA)?

DDX

Which conditions are included in the differential diagnoses of May-Hegglin anomaly (MHA)?

What are the differential diagnoses for May-Hegglin Anomaly?

Workup

What are specific concerns in young children with May-Hegglin anomaly (MHA) who sustain severe head trauma?

What is the role of lab tests in the workup of May-Hegglin anomaly (MHA)?

Treatment

What are effective treatments for May-Hegglin anomaly (MHA)?

What is the risk increased bleeding during delivery in women with May-Hegglin anomaly (MHA)?

How is May-Hegglin anomaly (MHA) managed in patients undergoing surgical procedures?

Which activity modifications are recommended in patients with May-Hegglin anomaly (MHA)?

Which specialist consultations are beneficial to patients with May-Hegglin anomaly (MHA)?

Medications

What is the role of medications in the treatment of May-Hegglin anomaly (MHA)?

Which medications in the drug class Pituitary Hormone are used in the treatment of May-Hegglin Anomaly?