Epstein Syndrome Presenting as Renal Failure in Young Patients

Abstract

Two young Chinese patients presented with renal failure and thrombocytopenia. Further investigations showed the presence of large platelets and high-frequency sensorineural hearing deficit. Genetic studies confirmed mutations in the gene encoding the myosin heavy chain (MYH-9), and Epstein Syndrome was diagnosed. One patient underwent deceased-donor kidney transplantation with satisfactory graft function. Epstein Syndrome is a rare genetic disorder with autosomal dominant inheritance. Clinicians should be aware of this entity when a young patient presents with renal failure and thrombocytopenia.

Keywords:

• Epstein Syndrome
• renal failure
• thrombocytopenia

INTRODUCTION

One should be alerted to the possibility of a genetic or familial disorder when a young patient presents with renal abnormalities. We describe two patients who presented with renal impairment, macrothrombocytopenia, and high-frequency sensory-neural hearing loss. Further investigations confirmed the diagnosis of Epstein Syndrome, a rare genetic disease due to defective myosin heavy chain (MYH-9). They are the first reported cases of Epstein Syndrome in China, including the first successfully transplanted patient.

CASE REPORTS

Patient 1

A 17-year-old male from southern China presented in 2004 with hypertension, renal impairment (serum creatinine 200 umol/L), and nephrotic syndrome (proteinuria 4.5 g/day). There were no red cells in the urine, and serological markers including the level of antinuclear antibodies, complement components, and C-reactive protein were all normal. Renal biopsy showed globally sclerosed glomeruli with marked interstitial fibrosis and tubular atrophy, and the patient was given a diagnosis of focal segmental glomeruloses (FSGS) (see Figure 1). A history of thrombocytopenia (platelet count in the range of 30 to 50 × 10⁹/L) was noted. Bone marrow biopsy showed megakaryocytic hyperplasia. The patient was treated for idiopathic thrombocytopenic purpura (ITP) with corticosteroid and intravenous immunoglobulin, without any significant response. His renal function continued to deteriorate, and he was started on peritoneal dialysis in 2005. Kidney transplantation from a deceased-donor was performed the next year, with satisfactory graft function. At this point, the diagnoses were reviewed. Examination of the peripheral blood film showed macrothrombocytopathy (see Figure 2). Although the patient did not complain about hearing abnormality, pure tone audiogram revealed high frequency sensorineural deafness (see Figure 3). Gene sequencing showed G to A substitution at nucleotide 2105 (R702H) in exon 16 of the myosin heavy chain MYH9 gene, and the diagnosis of Epstein Syndrome was established. Family screening did not show abnormal MYH9 gene in other family members, suggesting that the defect was a result of mutation.

Figure 1. Renal biopsy of Patient 1 showing a globally sclerosed glomerulus with interstitial fibrosis and tubular atrophy (PAS stain; Magnification 200x).

Figure 2. Blood film of Patient 1 showing macrothrombocytopathy (arrow).

Figure 3. Audiogram of Patient 1 showing bilateral sensori-neural hearing loss.

Patient 2

A 19-year-old male from southern China on long-term peritoneal dialysis was referred for the assessment of thrombocytopenia prior to a surgical procedure. He presented at nine months of age with thrombocytopenia (platelet count in the range of 20 to 30 × 10⁹/L), which did not respond to treatment with corticosteroid and intravenous immunoglobulin. At the age of 16, he presented with hypertension, microscopic hematuria, non-nephrotic proteinuria, and renal impairment. Renal biopsy was not performed in view of the thrombocytopenia. Despite empirical treatment with corticosteroid and mycophenolate mofetil, renal function continued to deteriorate, and he reached end-stage renal failure three years later. Examination of peripheral blood film showed thrombocytopenia and the presence of giant platelets, suggestive of congenital macrothrombocytopathy. Bone marrow examination showed megakaryocytic hyperplasia. Further questioning revealed hearing difficulty since childhood, and pure tone audiogram confirmed bilateral high tone sensorineural deafness. Gene sequencing confirmed the diagnosis of Epstein Syndrome, with C to T substitution at nucleotide 2104 (R702C) in exon 16 of MYH9 gene.

DISCUSSION

Epstein Syndrome is characterized by the triad of renal impairment, macrothrombocytopenia, and high-frequency sensorineural hearing loss. Although previously classified as an Alport's Syndrome variant, it is now known to be a rare genetic condition with autosomal dominant inheritance due to mutations affecting the myosin heavy chain (MYH-9) gene.

Diseases arising from myosin heavy chain (MYH-9) defects encompass an array of syndromes inherited in an autosomal dominant fashion, namely, Epstein Syndrome, Fetchner Syndrome, May-Hegglin Syndrome, and Sebastian Syndrome. Historically, these syndromes have been regarded as separate entities until the discovery of MYH-9 gene brought them together. The renal manifestations of this clinical spectrum were first described in 1972, when Epstein Syndrome was coined to describe familial cases of renal impairment, macrothrombocytopenia, and high-frequency hearing deficit.[1] Thirteen years later, Fetchner Syndrome was named after a patient who presented with cataract and leucocyte inclusion bodies in addition to the above three clinical features.[2] For patients with hematological manifestations such as macrothrombocytopenia and leucocyte inclusion bodies, but without renal or hearing problems, the terms May Hegglin anomaly and Sebastian Syndrome (inclusion bodies are inconspicuous) were used, respectively.[3]

The MYH-9 gene encodes the non-muscle myosin heavy chain IIA (NMM-IIA), which is a hetero-hexameric complex composed of a pair of heavy chains (NMMHC-IIA) and two pairs of light chains. NMMHC-IIA is responsible for cell spreading, cell motility, and maintenance of cell morphology and cytokinesis. The gene is located on chromosome 22q12-13 and comprises 44 exons, 40 of which contain the coding sequence. MYH-9 is present in various cell types, including hematological lineages (platelets, granulocytes, and monocytes), resident kidney cells (podocytes, mesangial cells, and tubular epithelial cells), and those in the auditory system (cochlear cells).[4,5]

Epstein Syndrome presents as hereditary nephritis together with hearing deficit. Although its phenotypic features may simulate those of Alport's Syndrome, there are important differences. Alport's Syndrome is characterized by abnormal type IV collagen in the glomerular basement membrane, which is normal in Epstein Syndrome.[6] Alport's Syndrome typically transmits in an X-linked recessive manner (though autosomal dominant and autosomal recessive forms do exist), while Epstein Syndrome is inherited in autosomal dominant fashion. In Epstein Syndrome, there is intra-familial variability in which some affected subjects may only show macrothrombocytopenia and deafness while their offspring may develop full-blown renal failure. In contrast, all affected males in X-linked Alport Syndrome inevitably progress to end stage kidney disease.[7-9]

Data from genotype-phenotype correlation studies suggest that mutations in the head ATPase domain are frequently associated with nephropathy and hearing impairment, as in Epstein and Fetchner Syndrome, while mutations in the C-terminal coiled region or truncation of the tailpiece is preferentially associated with hematological abnormalities only, as in May-Hegglin anomaly and Sebastian Syndrome.[5,10] Thrombocytopenia in these patients usually does not respond to treatment with corticosteroid or splenectomy.[11,12] Reduction of GP1b/IX/V in large platelets may contribute to bleeding diathesis, but the risk of bleeding is not high.[13]

Renal involvement typically presents with variable degrees of proteinuria or microscopic hematuria in young individuals, although patients can also present with severe renal impairment and histological findings of global glomerulosclerosis, interstitial fibrosis, and marked tubular atrophy. The exact mechanism that leads to renal failure is not defined. Non-specific changes such as podocyte effacement and loss of slit diaphragm have been described. Altered NMMHC-IIA distribution in the renal tubular cells and glomerular cells can be demonstrated by immunohistochemistry, with characteristic apical NMMHC-IIA staining at the renal tubules and reduced staining intensity in podocytes and mesangial areas.[3] Proteinuria could further contribute to the progression of renal damage. Deterioration of renal function progresses relentlessly, while the outcome after kidney transplantation appears to be favourable, and recurrence has not been reported.

Alertness to the characteristic clinical features, followed by examination of the blood film, audiogram, renal biopsy, and genetic diagnosis, are prerequisite to the correct diagnosis of Epstein Syndrome. Nucleotide sequencing is the most commonly used confirmatory test. However, the availability and cost of gene sequencing could preclude correct diagnosis in some patients. Furthermore, details on diagnostic accuracy and its role in genetic counseling remain to be defined. The correlation between genotypic abnormalities and phenotypic manifestations also requires further evaluation.[5]

Our two patients are the first cases of Epstein Syndrome ever reported in Chinese patients. Genetic screening of their families did not show any additional affected members, suggesting that these cases might have arisen from sporadic mutations. It is important to note the absence of significant peri-operative hemorrhage and the favorable clinical course after transplantation, albeit with a short follow-up.

In summary, nephrologists and hematologists should be alerted to the entity of MYH-9 gene related disorders in young patients who present with proteinuria, renal failure, hearing deficit, and/or thrombocytopenia, which have important implications on management and genetic counseling. The preliminary experience suggested that this condition is not a contraindication for kidney transplantation.[14,15]

DECLARATION OF INTEREST

The authors of this manuscript do not have any conflict of interest. No funding was received.

ACKNOWLEDGMENT

The authors would like to acknowledge the efforts of Dr. R. Leung, Department of Pathology, Queen Mary Hospital, Hong Kong, and Drs. K. W. Chan and G. Chan, Department of Pathology, Queen Mary Hospital, Hong Kong. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.