Macrothrombocytopenia, renal dysfunction and nephrotic syndrome in a young male patient: a case report of MYH9-related disease

ABSTRACT MYH9-related disease is an autosomal dominant disorder caused by mutations of the MYH9 gene, which encodes the non-muscle myosin heavy chain IIA on chromosome 22q12. It is characterized by congenital macrothrombocytopenia, bleeding tendency, hearing loss, and cataracts. Nephropathy occurs in approximately 30% of MYH9-related disease in a male patient carrier of a de novo missense mutation in exon 1 of the MYH9 gene [c.287C > T; p.Ser(TCG)96(TTG)Leu]. He presented all phenotypic manifestations of the disease, but cataracts. Renal alterations were microhematuria, nephrotic-range proteinuria (up to 7.5 g/24h), and rapid loss of renal function. The decline per year of the glomerular filtration rate was 20 mL/min/1.73m2 for five years. Blockade of the renin-angiotensin system, the only recommended therapy for slowing the progression of this nephropathy, was prescribed. Although MYH9-related disease is a rare cause of glomerulopathy and end-stage renal disease, awareness of rare genetic kidney disorders is essential to ensure accurate diagnosis and proper management of orphan disease patients.

MYH9-related disease is an autosomal dominant disorder caused by mutations of the MYH9 gene, which encodes the non-muscle myosin heavy chain IIA on chromosome 22q12. It is characterized by congenital macrothrombocytopenia, bleeding tendency, hearing loss, and cataracts. Nephropathy occurs in approximately 30% of MYH9-related disease in a male patient carrier of a de novo missense mutation in exon 1 of the MYH9 gene [c.287C > T; p.Ser(TCG)96(TTG) Leu]. He presented all phenotypic manifestations of the disease, but cataracts. Renal alterations were microhematuria, nephrotic-range proteinuria (up to 7.5 g/24h), and rapid loss of renal function. The decline per year of the glomerular filtration rate was 20 mL/min/1.73m 2 for five years. Blockade of the renin-angiotensin system, the only recommended therapy for slowing the progression of this nephropathy, was prescribed. Although MYH9-related disease is a rare cause of glomerulopathy and end-stage renal disease, awareness of rare genetic kidney disorders is essential to ensure accurate diagnosis and proper management of orphan disease patients. MYH9-RD is characterized by congenital macrothrombocytopenia, leading to bleeding tendency, along with cytoplasmic inclusion bodies within leukocytes (Döhle-like inclusions), sensorineural deafness, cataracts, and nephropathy. The latter usually presents at a juvenile age with proteinuria, sometimes causing nephrotic syndrome, with or without microhematuria. It often progresses to endstage renal disease (ESRD). 1 Herein, we sought to describe the case of a young male patient affected by MYH9-RD that developed nephrotic-range proteinuria, microhematuria, and rapid loss of kidney function.

Case desCRiption
A twenty-year-old male has been followed up at the Clinic Hospital of Federal University of Paraná due to medical history of epistaxis, ecchymosis, and petechiae since infancy. At first, Bernard-Soulier syndrome was suspected due to macrothrombocytopenia and tendency of bleeding. When he was 17 years old, hearing loss and hypertension were detected along with mild renal failure, microhematuria and nephrotic-range proteinuria. Renal biopsy could not be performed due to risk of bleeding (platelets count: 7000/μL). Cataracts were excluded by ophthalmological evaluation. Due to the clinical suspicion of MYH9-RD, genotyping of the patient and of his parents was performed. A de novo missense mutation in exon 1 of the MYH9 gene [c.287C > T; p.Ser(TCG)96(TTG)Leu] was detected ( Figure 1). Actually, neither his parents nor his brother and sister had clinical manifestation of MYH9-RD. Enalapril (20 mg/day) was initiated for renal protection. The patient did not adhere to treatment and was lost to follow-up. Two years later, he returned to the outpatient clinic complaining of foamy urine, peripheral edema, and hypertension (160/120 mmHg). Laboratory tests detected worsening of renal function and persistent proteinuria. Table 1 shows the evolution of laboratory parameters during the follow-up.

dIscussIon
MYH9-RD is characterized by congenital macrothrombocytopenia associated with variable degrees of sensorineural hearing loss, pre-senile cataract, and renal disease. Nephropathy occurs in approximately 30% of the patients with MYH9-RD and has a progressive and severe evolution. It usually presents at a juvenile age with proteinuria, sometimes causing nephrotic syndrome, with or without microhematuria. Our patient presented all clinical manifestation of MYH9-RD, but cataract. In most patients, nephropathy progresses to ESRD before the fourth decade of life. 1 A genotype-phenotype correlation has been recognized in MYH9-RD. A higher incidence and a worse prognosis of kidney impairment have been associated with mutations affecting the head domain of NMMHC-IIA, compared with mutations in tail domain. 2 Most patients with MYH9-RD present an autosomal dominant inheritance, and around 30% of them have a de novo mutation. 1 Our patient presented a de novo missense mutation in exon 1 of MYH9 [c.287C > T; p.Ser(TCG)96(TTG)Leu] in the head domain. To date, more than 30 mutations within the 40 exons of the MYH9 gene have been detected, among them the one of our patient. 3 In agreement with the genotype-phenotype correlation, our patient developed a rapid deterioration of renal function. The decline per year of the glomerular filtration rate was 20 mL/min/1.73m 2 during the last five years.
Due to the overlap of clinical manifestations, MYH9-RD associated with renal impairment was considered a variant of Alport syndrome, designated as Fechtner syndrome. Recently, these syndromes were recognized as distinct disorders. They can be distinguished by the presence of thrombocytopenia, the hallmark of MYH9-RD and not a feature of Alport syndrome. Moreover, the latter is caused by mutations in the COL4A3, COL4A4, and COL4A5  genes, leading mainly to alterations in the glomerular basement membrane. 4 The clinical features together with the presence of a pathogenic mutation in the MYH9 gene allowed a prompt and reliable diagnosis of MYH9-RD. Renal biopsy is not usually performed in MYH9nephropathy because of the risk of bleeding, reserved for cases in which the differential diagnosis is necessary. Renal histopathological findings are variable and unspecific, encompassing mesangial expansion or proliferation and segmental glomerulosclerosis. Electron microscopy commonly reveals glomerular basement membrane thickening and podocyte foot process effacement 1 . The pathogenesis of MYH9-nephropathy is not completely understood. NMMHC-IIA is an important component of podocyte foot process. Thus, MYH9-nephropathy may result from an alteration in the podocyte cytoskeleton. 5 Blockade of the renin-angiotensin system might be effective in reducing proteinuria and slowing the progression of MYH9 nephropathy. 6 As our patient did not adhere to the treatment, we could not evaluate the efficacy of this strategy, though.
To the best of our knowledge, this is the first case of MYH9-nephropathy described in Brazil. The learning points of this case need to be highlighted. In case of macrothrombocytopenia of uncertain diagnosis, urinalysis must be performed and proteinuria should be monitored to start renin-angiotensin system blockage as early as possible. Genotyping is a valuable tool for guiding diagnosis and prognosis. Finally, awareness of rare genetic kidney disorders is essential to ensure accurate diagnosis and proper management of orphan disease patients.