May-Hegglin anomaly

Etiology and clinical presentation

The development of the pathology is caused by a mutation in the MYH9 gene. Normally, this genomic region encodes the structure of the non-muscle myosin IIA heavy chain (abbreviated as NMMHC-IIA). Damage to this protein is inherited in an autosomal dominant manner. This genetic defect forms an entire group of related nosologies, which, in addition to the classic May-Hegglin anomaly, include Epstein, Fechtner, and Sebastian syndromes.

Often, the disease has a latent course and does not bother the patient at all. When fully clinically manifested, the main hematological sign is a tendency to bleeding due to a decreased platelet count—thrombocytopenia.

In addition to hemostatic disorders, the syndrome is characterized by systemic (extrahematological) lesions:

• Nephropathy — involvement of the renal tissue in the pathological process.
• Sensorineural hearing loss — decrease in hearing acuity.
• Cataract — clouding of the lens.
• Alopecia — hair loss (not always present).

It is extremely important to keep in mind that the listed extrahematological symptoms may appear asynchronously, which often complicates timely diagnosis.

Diagnostic Algorithms

The combination of thrombocytopenia and renal impairment necessitates mandatory differential diagnosis with systemic lupus erythematosus (SLE). To rule out the autoimmune nature of the symptoms, the physician should be guided by two criteria: the complete absence of laboratory markers of immune inflammation and zero efficacy of glucocorticosteroid treatment.

The laboratory investigation is structured in two stages:

1. Screening: Examination of the peripheral blood smear (May-Grünwald-Giemsa staining) reveals specific basophilic structures—large Döhle bodies—in the cytoplasm of granulocytes and monocytes.
2. Confirmatory test: Using immunofluorescence assay, clusters of the defective NMMHC-IIA protein are detected inside neutrophils, which clinches the diagnosis.

Place in the Classification of Hereditary Thrombocytopathies

May-Hegglin anomaly is one of the syndromic forms of platelet formation disorders. To understand the pathogenesis of such conditions, all genetic defects of platelet hemostasis are grouped according to the stages of cellular function.

1. Primary attachment (adhesion) disorders In this group, the interaction of blood platelets with damaged subendothelium is impaired due to a defect in receptors or bridging proteins:

• Bernard-Soulier syndrome: qualitative anomaly or quantitative deficiency of the von Willebrand factor receptor (glycoprotein complex [GPIb-IX-V]).
• von Willebrand disease: deficiency or defect of the von Willebrand factor [vWF] itself, which acts as an adhesive "bridge".

2. Clumping (aggregation) disorders Characterized by the inability of platelets to bind to each other:

• Glanzmann thrombasthenia: mutation deprives the cell of the main fibrinogen receptor—the [GPIIb-IIIa] complex.
• Congenital afibrinogenemia: absence of fibrin bridges due to a lack of fibrinogen or impairment of the [$\alpha$IIb$\beta$3] integrin.

Degranulation and Storage Pool Defects

For proper platelet function, it must release active substances from its granules. Pathologies occur when they are absent or exocytosis is impossible:

• $\alpha$-granule deficiency: underlies gray platelet syndrome, Quebec platelet disorder, as well as Paris-Trousseau and Jacobsen syndromes.
• Dense $\delta$-granule deficiency: detected in Chediak-Higashi syndrome, Hermansky-Pudlak syndrome, and TAR syndrome.
• Combined deficiency: characterized by a lack of both types of storage pools.

Intracellular Signaling and Structural Impairments

The most extensive group of thrombocytopathies, which includes impairments in signal transduction from the receptor to the nucleus, as well as structural abnormalities of the membrane and cytoskeleton:

• Receptor defects: absence of response to collagen, adrenaline, ADP, or thromboxane A2.
• G-protein abnormalities: activating mutations (G$\alpha$s) or direct protein deficiency (G$\alpha$q, G$\alpha$i1).
• Enzymatic blocks: impairment of phosphatidylinositol metabolism (due to phospholipase C-2 deficiency), impaired calcium efflux into the cytoplasm, or pleckstrin phosphorylation defect against the background of protein kinase C deficiency.
• Arachidonic acid cascade impairment: inability to synthesize thromboxane due to cyclooxygenase or thromboxane synthase deficiency.
• Structural-membrane breakdowns: cytoskeletal defects (characteristic of Wiskott-Aldrich syndrome) or loss of procoagulant activity due to a membrane phospholipid abnormality, when the cell cannot bind to clotting factors (Scott syndrome).
• Syndromic pathologies: specifically the May-Hegglin anomaly, TAR syndrome, as well as hematological manifestations in mesenchymal dysplasia and Down syndrome.

Class and exam questions

What else to study on this topic

• Pathophysiology of the arachidonic acid cascade and thromboxane synthesis mechanisms
• The role of secondary messengers (calcium, phospholipase C-2) in cellular activation
• Morphology and functions of platelet storage pools (alpha and delta granules)
• Clinical course and diagnosis of Wiskott-Aldrich syndrome
• Mechanisms of platelet interaction with plasma clotting factors

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.