MYH9 Related Platelet Disorders – Often Unknown and Misdiagnosed

Abstract

MYH9 related platelet disorders are a relatively rare cause of thrombocytopenia. Located on chromosome 22, the MYH9 gene encodes the motorprotein non-muscular myosin heavy chain IIA (NMMHCIIA). Heterozygous defects in this gene lead to 4 different autosomal dominant syndromes namely May-Hegglin anomaly, Epstein syndrome, Fechtner syndrome and Sebastian platelet syndrome. All 4 syndromes are characterized by macrothrombocytopenia and a mild bleeding tendency. Depending on the position of the causative mutation within the gene, the risk increases for syndromic manifestations such as renal failure, hearing loss and pre-senile cataract. Mutations in the neck region of the NMMHCIIA protein are more likely associated with these comorbidities than mutations in the N- or C-terminal part of the gene. MYH9 related platelet disorders should be excluded in patients with chronic thrombocytopenia and large platelets. Most sensitive for diagnosis/exclusion are immunofluorescence studies using a blood smear. The biggest risk for these patients is ineffective but potentially harmful treatment based on the misdiagnosis of immune thrombocytopenia. This review provides a workflow for diagnosis and treatment of MYH9 related thrombocytopenia.

Zusammenfassung

MYH9-assoziierte Erkrankungen gehören zu den angeborenen Makrothrombozytopenien. Sie sind verursacht durch Veränderungen im MYH9-Gen auf dem langen Arm von Chromosom 22. Heterozygote Mutationen in diesem Gen führen zu den 4 unterschiedlichen Syndromen: May-Hegglin-Anomalie, Epstein-Syndrom, Fechtner-Syndrom und Sebastian-Platelet-Syndrom. Klinisch gemeinsam ist den 4 Syndromen eine Makrothrombozytopenie mit einer leichter Blutungsneigung. Abhängig von Lage und Art der Mutation können sich bei den Patienten zusätzlich Nierenversagen, Hörverlust im Hochtonbereich und Katarakt manifestieren. Die Erkrankung scheint deutlich häufiger zu sein, als bislang angenommen. Eine MYH9-assoziierte Erkrankung sollte bei allen Patienten mit chronischer Thrombozytopenie und vergrößerten Thrombozyten ausgeschlossen werden. Das größte Risiko ist derzeit eine nebenwirkungsreiche und dabei ineffektive Behandlung auf Grundlage der Fehldiagnose „Autoimmunthrombozytopenie”. Die Arbeit zeigt einen Weg zur rationellen Diagnostik dieser Erkrankung, diskutiert verschiedene Behandlungsmöglichkeitenund beschreibt klinische Manifestation und molekulare Pathogenese der MYH9-assoziierten Thrombozytopenie.

Key words

MYH9 - platelet - ITP - macrothrombocytopenia - May Hegglin anomaly - Epstein syndrome - Fechtner syndrome - Sebastian platelet syndrome

Schlüsselwörter

MYH9 - Thrombozyten - ITP - Makrothrombozytopenie - Epstein-Syndrom

References

• 1 Althaus K, Najm J, Blumentritt C. et al . MYH9 disorders revisited – morphology of leukocyte inclusion bodies predicts the position of mutation.  Hämostaseologie. 31[1/2011], A32 2011;  Ref Type: Abstract
• 2 Anand A, Feffer SE. Hematocrit and bleeding time: an update.  South Med J. 1994;  87 299-301
• 3 Anderson NM, Berndl E, Berberovic Z. et al . Myh9Q1443L Is a Novel Mouse Model of MYH9-Related Disorders.  ASH Annual Meeting Abstracts. 2010;  116 2527
• 4 Behar DM, Rosset S, Tzur S. et al . African ancestry allelic variation at the MYH9 gene contributes to increased susceptibility to non-diabetic end-stage kidney disease in Hispanic Americans.  Hum Mol Genet. 2010;  19 1816-1827
• 5 Chiquet BT, Hashmi SS, Henry R. et al . Genomic screening identifies novel linkages and provides further evidence for a role of MYH9 in nonsyndromic cleft lip and palate.  Eur J Hum Genet. 2009;  17 195-204
• 6 Epstein CJ, Sahud MA, Piel CF. Hereditary macrothrombocytopathia, nephritis and deafness.  Am J Med. 1972;  299-310
• 7 Fabbro S, Kahr WH, Hinckley J. et al . Homozygosity mapping with SNP arrays confirms 3p21 as a recessive locus for gray platelet syndrome and narrows the interval significantly.  Blood. 2011;  epubl
• 8 Greinacher A, Nieuwenhuis HK, White JG. Sebastian platelet syndrome: a new variant of hereditary macrothrombocytopenia with leukocyte inclusions.  Blut. 1990;  61 282-288
• 9 Heath KE, Campos-Barros A, Toren A. et al . 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;  69 1033-1045
• 10 Hegglin R. Gleichzeitige konstitutionelle Veränderungen an Neutrophilen und Thrombozyten.  Helv Med Acta. 1945;  439-440
• 11 Heller PG, Pecci A, Glembotsky AC. et al . Unexplained recurrent venous thrombosis in a patient with MYH9-related disease.  Platelets. 2006;  17 274-275
• 12 Kunishima S, Kojima T, Matsushita T. et al . Mutations in the NMMHC-A gene cause autosomal dominant macrothrombocytopenia with leukocyte inclusions (May-Hegglin anomaly/Sebastian syndrome).  Blood. 2001;  97 1147-1149
• 13 Lalwani AK, Goldstein JA, Kelley MJ. et al . Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9.  Am J Hum Genet. 2000;  67 1121-1128
• 14 Leung TF, Tsoi WC, Li CK. et al . A Chinese adolescent girl with Fechtner-like syndrome.  Acta Paediatr. 1998;  87 705-707
• 15 Marigo V, Nigro A, Pecci A. et al . Correlation between the clinical phenotype of MYH9-related disease and tissue distribution of class II nonmuscle myosin heavy chains.  Genomics. 2004;  83 1125-1133
• 16 Maupin P, Phillips CL, Adelstein RS. et al . Differential localization of myosin-II isozymes in human cultured cells and blood cells.  J Cell Sci. 1994;  107 (Pt 11) 3077-3090
• 17 May R. Leukozyteneinschlüsse.  Dtch Arc Klin Med. 1909;  96 1-6
• 18 Mhatre AN, Li Y, Bhatia N. et al . Generation and characterization of mice with Myh9 deficiency.  Neuromolecular Med. 2007;  9 205-215
• 19 Mori K, Suzuki S, Sugai K. et al . Morphological changes of platelets during the process of platelet aggregation in gray platelet syndrome.  Tohoku J Exp Med. 1986;  149 425-436
• 20 Nurden AT, Fiore M, Pillois X. et al . Genetic testing in the diagnostic evaluation of inherited platelet disorders.  Semin Thromb Hemost. 2009;  35 204-212
• 21 Nurden AT, Nurden P. The gray platelet syndrome: clinical spectrum of the disease.  Blood Rev. 2007;  21 21-36
• 22 Pecci A, Granata A, Fiore CE. et al . Renin-angiotensin system blockade is effective in reducing proteinuria of patients with progressive nephropathy caused by MYH9 mutations (Fechtner-Epstein syndrome).  Nephrol Dial Transplant. 2008;  23 2690-2692
• 23 Pecci A, Gresele P, Klersy C. et al . Eltrombopag for the treatment of the inherited thrombocytopenia deriving from MYH9 mutations.  Blood. 2010;  116 5832-5837
• 24 Pecci A, Panza E, Pujol-Moix N. et al . Position of nonmuscle myosin heavy chain IIA (NMMHC-IIA) mutations predicts the natural history of MYH9-related disease.  Hum Mutat. 2008;  29 409-417
• 25 Peterson LC, Rao KV, Crosson JT. et al . Fechtner syndrome – a variant of Alport's syndrome with leukocyte inclusions and macrothrombocytopenia.  Blood. 1985;  65 397-406
• 26 Raslova H, Komura E, Le Couedic JP. et al . FLI1 monoallelic expression combined with its hemizygous loss underlies Paris-Trousseau/Jacobsen thrombopenia.  J Clin Invest. 2004;  114 77-84
• 27 Savoia A, Balduini A. MYH9-Related Disorders.. Pagon RA, Bird TC, Dolan CR, Stephens K, editors. GeneReviews [Internet] Seattle (WA): University of Washington, Seattle; 1993–2008 Nov 20 [updated 2009 Jun 25]. 2008
• 28 Selleng K, Lubenow LE, Greinacher A. et al . Perioperative management of MYH9 hereditary macrothrombocytopenia (Fechtner syndrome).  Eur J Haematol. 2007;  79 263-268
• 29 Suzuki N, Kunishima S, Ikejiri M. et al . R702C Mutation of the MYH9 Gene Provokes Impaired Platelet Formation, Renal Focal Segmental Glomerulosclerosis, and Hearing Disability In the Mice Model.  ASH Annual Meeting Abstracts. 2010;  116 482
• 30 Toren A, Rozenfeld-Granot G, Rocca B. et al . Autosomal-dominant giant platelet syndromes: a hint of the same genetic defect as in Fechtner syndrome owing to a similar genetic linkage to chromosome 22q11-13.  Blood. 2000;  96 3447-3451
• 31 White JG. Platelet pathology in carriers of the X-linked GATA-1 macrothrombocytopenia.  Platelets. 2007;  18 620-627

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