Novel MYH9 Gene Variant Identified in Chinese Child with Rare Hereditary Thrombocytopenia
核心洞察
Researchers identified a previously unreported MYH9 (搜索) gene variant (c.2440C>T, p.Arg814Trp) in an 8-year-old Chinese boy with MYH9-related disease (搜索), marking the first case of this specific mutation in the neck region of the protein.
The patient presented with macrothrombocytopenia (搜索), proteinuria (搜索), liver dysfunction (搜索), and hearing loss (搜索), taking seven years from symptom onset to accurate diagnosis due to the rarity and complexity of MYH9-RD (搜索).
Treatment with compound glycyrrhizin and benazepril hydrochloride showed promising results, with decreased liver enzymes and reduced proteinuria (搜索) after one year of therapy.
An 8-year-old Chinese boy with a seven-year history of abnormal liver function and three years of proteinuria (搜索) has been diagnosed with MYH9-related disease (搜索) (MYH9-RD (搜索)) caused by a novel gene variant, according to a case report published in Frontiers in Pediatrics. The discovery represents the first reported case of the specific MYH9 (搜索) c.2440C>T (p.Arg814Trp) variant located in the neck region of the non-muscle myosin heavy chain IIA (搜索) protein.
Clinical Presentation and Diagnostic Journey
The patient's complex medical history began at 11 months of age with patent ductus arteriosus, thrombocytopenia (搜索), and liver dysfunction (搜索). By age 4, he developed bilateral hearing loss (搜索) and continued to show persistent thrombocytopenia and elevated liver enzymes. At age 5, proteinuria (搜索) was detected, and by age 8, he was admitted to Sichuan Provincial Maternity and Child Health Care Hospital (搜索) for comprehensive evaluation.
Laboratory findings revealed significant abnormalities including a platelet count of 106 × 10⁹/L with an average platelet volume of 14.0 fL, indicating macrothrombocytopenia (搜索). Liver function tests showed elevated alanine aminotransferase (111.0 U/L) and aspartate aminotransferase (188.0 U/L). Urinalysis demonstrated proteinuria (搜索) with a protein-to-creatinine ratio of 218.45 mg/g and 24-hour urinary protein concentration of 547.5 mg/d.
Peripheral blood smear examination revealed macrothrombocytopenia (搜索) with medium and large platelets (4-7 μm) accounting for 40%-65% and giant platelets (>7 μm) representing 9%-15% of the total platelet population. Notably, no abnormal granulocyte inclusions were visible under standard Wright staining.
Genetic Analysis and Diagnostic Confirmation
Whole-exome sequencing identified the heterozygous MYH9 (搜索) gene variant c.2440C>T (p.Arg814Trp) in exon 20, which was absent in both parents, confirming this as a sporadic case. According to the American College of Medical Genetics and Genomics guidelines, this variant was classified as potentially pathogenic but had not been previously described in the literature.
To confirm the diagnosis, researchers performed immunofluorescence assays to detect non-muscle myosin heavy chain IIA (搜索) (NMMHC-IIA (搜索)) in neutrophils. While the patient's parents and a normal control showed dispersed and homogeneous distribution of NMMHC-IIA, the patient exhibited dotted type III inclusions scattered throughout the neutrophil cytoplasm, confirming the MYH9-RD (搜索) diagnosis.
Pathological Findings
Renal biopsy revealed focal segmental glomerulosclerosis (搜索) (FSGS (搜索)) with segmental sclerosis identified in two of ten examined glomeruli. Immunofluorescence showed IgA deposits in the mesangial region, an unusual finding that differs from previous MYH9-RD (搜索) cases and may have prognostic significance requiring further investigation.
Liver biopsy indicated mild liver injury with inflammatory necrosis activity and fibrotic enlargement in the portal area, corresponding to a modified Scheuer score of G2S1. This finding contributes to the understanding of liver involvement in MYH9-RD (搜索), as previous literature lacked detailed liver pathology data.
Treatment Response and Clinical Outcomes
The patient was treated with compound glycyrrhizin (25 mg three times daily) and benazepril hydrochloride (5 mg once daily) for one year. Follow-up examination showed encouraging results with serum transaminase levels decreasing to approximately 100 U/L, protein-to-creatinine ratio reducing to 113.20 mg/g, and platelet count improving to 129 × 10⁹/L. Renal function remained normal, and hearing impairment showed no progression.
Clinical Significance and Diagnostic Challenges
MYH9-RD (搜索) affects an estimated 1-9 per 1,000,000 individuals, with 20%-35% of cases occurring sporadically. The condition is frequently misdiagnosed as immune thrombocytopenic purpura (搜索), IgA nephropathy (搜索), or Alport syndrome (搜索), potentially leading to inappropriate treatments including glucocorticoids (搜索), immunosuppressive agents (搜索), and splenectomy.
The researchers emphasize that patients with unexplained macrothrombocytopenia (搜索), particularly those with concurrent eye, ear, or liver involvement, should be evaluated for MYH9-RD (搜索). A mean platelet diameter greater than 3.7 μm and/or more than 40% of platelets exceeding 3.9 μm serve as highly sensitive and specific indicators for differentiating MYH9-RD from other forms of thrombocytopenia (搜索).
Genotype-Phenotype Correlations
The MYH9 (搜索) gene contains 41 exons encoding NMMHC-IIA (搜索), with variants distributed across different protein regions. As of July 2023, 219 MYH9 gene variants related to MYH9-RD (搜索) have been documented, with 79.4% being missense variants. The neck region, where this novel variant is located, accounts for only 2.7% of all pathogenic variants, making this case particularly rare.
Previous studies suggest that patients with neck region variants typically exhibit elevated liver enzymes, hearing loss (搜索), mild thrombocytopenia (搜索), and FSGS (搜索), consistent with the clinical presentation observed in this case. However, the relationship between genotype and phenotype remains complex, with protein conservation loss and patient age potentially being more predictive of clinical outcomes than variant location alone.
Implications for Clinical Practice
This case underscores the importance of comprehensive genetic testing and immunofluorescence analysis in diagnosing MYH9-RD (搜索). The researchers recommend routine blood analysis and blood smear microscopy as essential screening methods, followed by immunofluorescence detection of abnormal NMMHC-IIA (搜索) localization in neutrophils and genetic testing for definitive diagnosis.
The successful treatment response to angiotensin system blockers in this case supports previous research indicating that these medications can significantly reduce proteinuria (搜索) in early-stage MYH9-RD (搜索) nephropathy. However, long-term monitoring remains crucial, as kidney involvement is associated with poor prognosis and potential progression to end-stage renal disease.
The identification of this novel MYH9 (搜索) variant expands the genetic spectrum of MYH9-RD (搜索) and contributes to better understanding of this rare disorder. Early recognition and appropriate management may help prevent unnecessary treatments and improve long-term outcomes for affected patients.