Lab Med Online.  2019 Oct;9(4):224-231. 10.3343/lmo.2019.9.4.224.

Frequently Delayed Diagnosis and Misdiagnosis in MYH9-related Disorders: Data from Genetically Confirmed Cases of Korean Patients

Affiliations
  • 1Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. heejinkim@skku.edu
  • 2Department of Laboratory Medicine & Genetics, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea.
  • 3Department of Laboratory Medicine, Hanyang University College of Medicine, Seoul, Korea.
  • 4Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.
  • 5Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
  • 6Department of Internal Medicine, School of Medicine, CHA University, Seongnam, Korea.

Abstract

MYH9-related disorders (MYH9RD) are autosomal-dominant disorders characterized by macrothrombocytopenia with or without leukocyte inclusion bodies or extra-hematological features, such as sensorineural deafness and renal impairment. MYH9RD can be misdiagnosed as an acquired form of thrombocytopenia including immune thrombocytopenic purpura (ITP). This leads to delayed diagnosis or administration of ineffective treatment. In the present study, we investigated the clinical and molecular characteristics of five unrelated Korean patients with MYH9RD and their family members, from four institutions. We reviewed clinical and laboratory data including extra-hematological manifestations. MYH9 pathogenic variants were detected by direct sequencing in all probands and the affected family members (N=10): two probands with c.5521G>A (p.Glu1841Lys) and one proband each with c.99G>T (p.Trp33Cys), c.287C>T (p.Ser96Leu), and c.3493C>T (p.Arg1165Cys). All patients had macrothrombocytopenia. Only the proband with Ser96Leu had extra-hematological manifestations. Past history revealed that two patients had been misdiagnosed with ITP and one of them had received a splenectomy. We validated the frequency of misdiagnosis (~20%) and genotype-phenotype correlations through a comprehensive review of previously reported cases of MYH9RD in Korea. It is important to suspect MYH9RD in patients with thrombocytopenia, and timely identification of macrothrombocytopenia and MYH9 pathogenic variants is required for early and accurate diagnosis of MYH9RD.

Keyword

MYH9; Pathogenic variant; Macrothrombocytopenia; Korean

MeSH Terms

Deafness
Delayed Diagnosis*
Diagnosis
Diagnostic Errors*
Genetic Association Studies
Humans
Inclusion Bodies
Korea
Leukocytes
Purpura, Thrombocytopenic, Idiopathic
Splenectomy
Thrombocytopenia

Figure

  • Fig. 1 Peripheral blood smears (×1,000, Wright Giemsa stain) of (A) Proband 1, (B) Proband 2, and (C) Proband 3, showing leukocyte inclusion bodies (arrow) and giant platelets (arrow head).

  • Fig. 2 Pedigree chart (A) and DNA sequences (B) of proband 4 and family members. The asterisks represent the members analyzed by genetic screening. The bottom panels show the nucleotide change of c.3493C>T in the affected individuals.

  • Fig. 3 Schematic representation of the genotype-phenotype correlations in 43 Korean patients with genetically confirmed MYH9-related disorders including 10 patients identified in this study. (A) The pathogenic variants detected in each exon are indicated in boxes. Our cases are indicated with asterisks (*). (B) Associations of the three domains affected by pathogenic variants with incidence of bleeding tendency. Pathogenic variants in the globular head domain correlated with bleeding tendency. (C) Associations of the three domains affected by pathogenic variants with extra-hematological features (deafness, renal impairment, cataracts, etc.). Pathogenic variants in the globular head and coiled-coil domains correlated with the incidence of extra-hematological features.


Reference

1. Pecci A, Klersy C, Gresele P, Lee KJ, De Rocco D, Bozzi V, et al. MYH9-related disease: a novel prognostic model to predict the clinical evolution of the disease based on genotype-phenotype correlations. Hum Mutat. 2014; 35:236–247.
Article
2. Balduini CL, Pecci A, Savoia A. Recent advances in the understanding and management of MYH9-related inherited thrombocytopenias. Br J Haematol. 2011; 154:161–174.
Article
3. Thakral B, Rojanapremsuk T, Saluja K, Eldibany M. Misdiagnosed MYH9 related inherited macrothrombocytopenia with an inadvertent splenectomy. Pathology. 2015; 47:377–379.
Article
4. Williamson DR, Albert M, Heels-Ansdell D, Arnold DM, Lauzier F, Zarychanski R, et al. Thrombocytopenia in critically ill patients receiving thromboprophylaxis: frequency, risk factors, and outcomes. Chest. 2013; 144:1207–1215.
Article
5. Savoia A, De Rocco D, Pecci A. MYH9 gene mutations associated with bleeding. Platelets. 2017; 28:312–315.
Article
6. Shiota M, Kunishima S, Hamabata T, Nakata M, Hata D. Early diagnosis improves the quality of life in MYH9 disorder. Pediatr Blood Cancer. 2012; 58:314–315.
7. Kim SJ, Lee S, Park HJ, Kang TH, Sagong B, Baek JI, et al. Genetic association of MYH genes with hereditary hearing loss in Korea. Gene. 2016; 591:177–182.
Article
8. Oh T, Seo HJ, Lee KT, Kim HJ, Kim HJ, Lee JH, et al. MYH9 nephropathy. Kidney Res Clin Pract. 2015; 34:53–56.
9. Min SY, Ahn HJ, Park WS, Kim JW. Successful renal transplantation in MYH9-related disorder with severe macrothrombocytopenia: first report in Korea. Transplant Proc. 2014; 46:654–656.
Article
10. Jang MJ, Park HJ, Chong SY, Huh JY, Kim IH, Jang JH, et al. A Trp33Arg mutation at exon 1 of the MYH9 gene in a Korean patient with May-Hegglin anomaly. Yonsei Med J. 2012; 53:662–666.
Article
11. Han KH, Lee H, Kang HG, Moon KC, Lee JH, Park YS, et al. Renal manifestations of patients with MYH9-related disorders. Pediatr Nephrol. 2011; 26:549–555.
Article
12. Kook H, Nam HS, Baek HJ, Kim YO, Eom GH, Kee HJ, et al. Clinical characteristics of autosomal dominant giant platelet syndromes and mutation analysis of MYH9. Korean J Hematol. 2006; 41:16–27.
Article
13. Kunishima S, Matsushita T, Kojima T, Amemiya N, Choi YM, Hosaka N, et al. Identification of six novel MYH9 mutations and genotype-phenotype relationships in autosomal dominant macrothrombocytopenia with leukocyte inclusions. J Hum Genet. 2001; 46:722–729.
Article
14. Song KS, Choi JR, Song JW, Ha SK. A nonsence C5797T (R1933X) mutation of MYH9 gene in a family with May-Hegglin anomaly. Korean J Hematol. 2001; 36:253–256.
15. Noris P, Biino G, Pecci A, Civaschi E, Savoia A, Seri M, et al. Platelet diameters in inherited thrombocytopenias: analysis of 376 patients with all known disorders. Blood. 2014; 124:e4–e10.
Article
16. Kunishima S, Matsushita T, Kojima T, Sako M, Kimura F, Jo EK, et al. Immunofluorescence analysis of neutrophil nonmuscle myosin heavy chain-A in MYH9 disorders: association of subcellular localization with MYH9 mutations. Lab Invest. 2003; 83:115–122.
Article
17. Seri M, Pecci A, Di Bari F, Cusano R, Savino M, Panza E, 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; 82:203–215.
18. Shim YJ, Kim UH, Suh JK, Lee KS. Natural course of childhood chronic immune thrombocytopenia using the revised terminology and definitions of the international working group: a single center experience. Blood Res. 2014; 49:187–191.
Article
19. Pecci A, Panza E, Pujol-Moix N, Klersy C, Di Bari F, Bozzi V, 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.
Article
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