Epstein Syndrome Research Articles

Non-Muscle Myosin II A: Friend or Foe in Cancer?

Non-muscle myosin IIA (NM IIA) is a motor protein that belongs to the myosin II family. The myosin heavy chain 9 (MYH9) gene encodes the heavy chain of NM IIA. NM IIA is a hexamer and contains three pairs of peptides, which include the dimer of heavy chains, essential light chains, and regulatory light chains. NM IIA is a part of the actomyosin complex that generates mechanical force and tension to carry out essential cellular functions, including adhesion, cytokinesis, migration, and the maintenance of cell shape and polarity. These functions are regulated via light and heavy chain phosphorylation at different amino acid residues. Apart from physiological functions, NM IIA is also linked to the development of cancer and genetic and neurological disorders. MYH9 gene mutations result in the development of several autosomal dominant disorders, such as May-Hegglin anomaly (MHA) and Epstein syndrome (EPS). Multiple studies have reported NM IIA as a tumor suppressor in melanoma and head and neck squamous cell carcinoma; however, studies also indicate that NM IIA is a critical player in promoting tumorigenesis, chemoradiotherapy resistance, and stemness. The ROCK-NM IIA pathway regulates cellular movement and shape via the control of cytoskeletal dynamics. In addition, the ROCK-NM IIA pathway is dysregulated in various solid tumors and leukemia. Currently, there are very few compounds targeting NM IIA, and most of these compounds are still being studied in preclinical models. This review provides comprehensive evidence highlighting the dual role of NM IIA in multiple cancer types and summarizes the signaling networks involved in tumorigenesis. Furthermore, we also discuss the role of NM IIA as a potential therapeutic target with a focus on the ROCK-NM IIA pathway.

\u201cMYH9 mutation and squamous cell cancer of the tongue in a young adult: a novel case report\u201d

BackgroundThe incidence of tongue cancer in young adults is on the rise. This trend is more pronounced in females. Although the aetiology is still unclear, there is mounting evidence that genetic syndromes can play a key role in development of oral cancers in this patient group. We report the first case of oral squamous cell carcinoma (oSCC) in a young adult with an MYH9-related disorder (MYH9-RD).Case presentationA 19-year-old female with a germline MYH9 variant (missense variant in exon 2: c.287C > T, (p.Ser96Leu)) was referred to the head and neck surgery department for investigation of a painful, thick right tongue ulcer. She was diagnosed with Epstein syndrome, an MYH9-RD, at 12 years of age. Her main phenotypic features were profound thrombocytopenia and marked renal impairment. The tongue biopsy confirmed SCC. Preoperative positron emission tomography (PET) revealed avidity in the right tongue and ipsilateral level 2A neck lymph node. With substantial preoperative multidisciplinary input, she underwent cancer ablation and microvascular free flap reconstruction. Her pathology showed a 35 mm diameter, 14 mm thick moderately differentiated SCC with perineural and lymphovascular invasion. Two out of 38 right neck nodes were positive for metastasis with extranodal extension. None of the 34 left neck nodes was involved.She had an uneventful recovery and was discharged home on day 6 postoperative day. On day 15 postoperative day, she had catastrophic bleeding in the neck with a respiratory arrest after a forceful cough. She required an emergency tracheostomy and returned to the theatre for haemostasis. Following a short inpatient stay, she was again discharged home and underwent adjuvant therapy consisting of external beam radiotherapy of 60Gy in 30 fractions. On clinical examination and PET at 6 months after surgery, she had no evidence of disease recurrence.ConclusionsMYH9-RD can present with advanced locoregional oral cavity malignancy at an early age. The combination of profound thrombocytopenia and marked renal impairment can impact heavily on routine major head and neck cancer surgery and adjuvant treatment. This rare and challenging condition underlines the importance of early detection of cancer and multidisciplinary team input.

Successful cochlear implantation in a patient with Epstein syndrome during long-term follow-up

Epstein syndrome is a rare disease characterized by macrothrombocytopenia, nephritis and progressive sensorineural hearing loss (SNHL). This syndrome is presently recognized as an autosomal dominant disease caused by mutations of non-muscle myosin heavy chain 9 (MYH9). Little information is available about the progress of SNHL, the efficacy of cochlear implants (CI) or the perioperative management of thrombocytopenia in patients with Epstein syndrome. We herein report a case of a patient with Epstein syndrome with the MYH9:c.2105G>A:p.R702H variant who underwent cochlear implantation after 27 years of follow-up for her progressive SNHL. The deterioration rates of hearing were 3.48 dB/year on the right ear and 2.46 dB/year on the left ear. The patient derived benefits from CI and had a speech recognition test result (for sentences) of 93% at 6-months postoperatively. Thrombocytopenia was successfully managed without any bleeding complications by using eltrombopag, an oral thrombopoietic agent, making transfusion of platelets unnecessary. The accurate diagnosis of Epstein syndrome was made only after long-term follow-up as the thrombocytopenia was initially diagnosed as idiopathic thrombocytopenic purpura. This case report highlights the perioperative management of thrombocytopenia, the progress of SNHL and the potential pitfalls of diagnosis.

Linking the Landscape of MYH9-Related Diseases to the Molecular Mechanisms that Control Non-Muscle Myosin II-A Function in Cells.

The MYH9 gene encodes the heavy chain (MHCII) of non-muscle myosin II A (NMII-A). This is an actin-binding molecular motor essential for development that participates in many crucial cellular processes such as adhesion, cell migration, cytokinesis and polarization, maintenance of cell shape and signal transduction. Several types of mutations in the MYH9 gene cause an array of autosomal dominant disorders, globally known as MYH9-related diseases (MYH9-RD). These include May-Hegglin anomaly (MHA), Epstein syndrome (EPS), Fechtner syndrome (FTS) and Sebastian platelet syndrome (SPS). Although caused by different MYH9 mutations, all patients present macrothrombocytopenia, but may later display other pathologies, including loss of hearing, renal failure and presenile cataracts. The correlation between the molecular and cellular effects of the different mutations and clinical presentation are beginning to be established. In this review, we correlate the defects that MYH9 mutations cause at a molecular and cellular level (for example, deficient filament formation, altered ATPase activity or actin-binding) with the clinical presentation of the syndromes in human patients. We address why these syndromes are tissue restricted, and the existence of possible compensatory mechanisms, including residual activity of mutant NMII-A and/or the formation of heteropolymers or co-polymers with other NMII isoforms.

Providing Primary Care to Children Diagnosed with Myosin Heavy Chain 9-Related Platelet Disorder: A Case Report and Review of Literature

Introduction:Myosin-heavy chain 9 (MYH9)-related platelet disorders are a group of rare inherited thrombocytopenias, encompassing four syndromes, such as May-Hegglin anomaly, Epstein syndrome, Fechtner syndrome and Sebastian platelet syndrome. Typically diagnosed in adulthood, this disorder presents with chronic thrombocytopenia in all affected individuals with varying bleeding tendencies. Other clinical manifestations may include nephritis leading to end-stage renal disease, sensorineural hearing impairment and presenile cataracts. It is often misdiagnosed as autoimmune thrombocytopenia, which can lead to inappropriate treatment with corticosteroids or intravenous immunoglobulin for many years before the correct diagnosis is made.1 This case report describes the unique role of a pediatric hematologist to facilitate multidisciplinary care and services for a child diagnosed with MYH9-related disorder and illustrates the complex health care needs of this rare diagnosis in the pediatric populations.Case description:A 4-year-old girl of Mexican origin with a history of bilateral hearing loss and speech delay was first evaluated by audiology. Upon referral for a genetic evaluation, she was incidentally found to have asymptomatic thrombocytopenia. In the next four months, she received an extensive hematologic and infectious disease workup for the unexplained thrombocytopenia, while she was treated simultaneously for immune thrombocytopenia with corticosteroids or intravenous IgG. Neither of the interventions helped to normalize her persistently low platelet count (6,000-31,000), but instead led to sporadic intervals of undesirable weight gain and mood irritability. Further genetic testing with whole genome sequencing revealed a heterozygous pathogenic variant of MYH-9 mutation in the patient, who inherited the polymorphism from her father. Specifically, her variant exhibits complete penetrance for early-onset renal failure.As a result of the patient's platelet disorder and her frequent clinic visits to hematology, a close physician-patient relationship was developed thereafter. Her pediatric hematologist assumes the role of a primary care provider and coordinates multiple specialist visits to address her complex health care issues, including general pediatrics, speech therapy, audiology, otolaryngology, nephrology and medical genetics. Longitudinal care for this patient is mostly supportive: (1) platelet transfusion is required if she experiences any prolonged bleeding episodes; (2) prophylaxis with desmopressin is provided for dental and surgical procedures; (3) parents are counseled on child safety and limitations on major contact sports. Lastly, due to the identification of a pathogenic variant in both the patient and father, patient's brother and sister are both at increased risk of inheriting the platelet disorder. In our patient's case, since her family is limited by financial means for an evaluation with molecular testing, her siblings' platelet counts and sizes can be assessed instead with a CBC and peripheral blood smear.Discussion:The complexity of an inherited hematologic disorder involves multidisciplinary, longitudinal and lifelong care for optimal health care delivery and improved clinical outcomes. When approaching a pediatric patient diagnosed with a rare platelet disorder, the role of a hematologist becomes essential to be the primary care provider and to coordinate specialist visits for the patient without delays. Efficient care coordination with a focus on the patient's needs can avoid unnecessary duplication of tests and services.2 Children affected by rare genetic disorders, such as MYH-9 disorders, have complex unmet health needs and frequently experience unique barriers to care. Longitudinal surveillance is necessary to assess the progress of the MYH9 disease, and supportive care should be provided accordingly.

MYH9-ASSOCIATED SYNDROME EPSTEIN: MACROTHROMBOCYTOPENIA, SENSORINEURAL HEARING LOSS, NEPHROPATHY IN CHILDREN (ACCORDING TO THE LITERATURE)

The article presents literature data on clinical and morphological manifestations of MYH9-associated Epstein syndrome, flowing with macrothrombocytopenia, sensorineural hearing loss, nephropathy. The pathogenetic foundations, clinical features, course, treatment and prognosis of MYH9-associated Epstein syndrome in children are discussed. The paper presents clinical observation confirmed by molecular genetic study MYH9-associated Epstein syndrome in an 8-year-old boy.

A Sporadic Case of Epstein Syndrome: A Rare Cause of Refractory Thrombocytopenia

A Sporadic Case of Epstein Syndrome: A Rare Cause of Refractory Thrombocytopenia

Наследственная тромбоцитопения, ассоциированная с мутацией в гене MYH9

Inherited thrombocytopenia caused by mutations in MYH9 gene, is one of the forms of inherited platelet disorders. Currently, it comprises a group of diseases previously known as: Mey–Hegglin anomaly, Epstein syndrome, Fechtner syndrome, Sebastian syndrome. These syndromes are characterized by macrothrombocytopenia, and development of non-hematological manifestations such as sensorineural hearing loss, cataract and progressive nephropathy. Finding of large forms of platelets in blood smears and specific inclusions in neutrophils in immunofluorescence staining are simple methods for early diagnosis of this form of inherited thrombocytopenia, molecular-genetic analysis helps to detect the specific mutations. This article is described a clinical case of a 9-years old child with MYH9-related inherited thrombocytopenia, having typical clinical picture and confirmed by molecular-genetic analysis. It illustrated that the administration of agonist TPO-receptors may be effective for prevention of bleeding in this form of inherited thrombocytopenia.

Successful Kidney Transplantation in Epstein Syndrome With Antiplatelet Antibodies and Donor-specific Antibodies: A Case Report

An autosomal dominant hereditary disease, Epstein syndrome (ES) is characterized by sensorineural hearing impairment, macrothrombocytopenia, and hereditary nephritis, and can progress to end-stage kidney disease after puberty. Generally, kidney transplantation is difficult to perform in Epstein syndrome owing to the high risk of perioperative bleeding. Additionally, due to previous platelet transfusions, ES patients sometimes have antihuman leukocyte antigen (HLA) antibodies, including antiplatelet antibodies and donor-specific anti-HLA antibodies (DSA), which may result in refractoriness to platelet transfusion and antibody-mediated rejection (AMR). We report a case of successful kidney transplantation in a patient with ES who had DSA and antiplatelet antibodies. To prevent AMR, we used a desensitization protocol (a combination of plasmapheresis, rituximab, and basiliximab induction). Surveillance biopsy performed at 4 months and 1 year after transplantation showed no pathological findings suggesting AMR. To prevent perioperative bleeding complications, we infused the patient with HLA-matched platelets, thereby maintaining the platelet count at >10.0 × 104/μL, and no postoperative episodes of bleeding occurred.

Successful Renal Transplant in Epstein Syndrome: A Rare Cause of Thrombocytopenia Diagnosed During Pre-transplant Evaluation

Successful Renal Transplant in Epstein Syndrome: A Rare Cause of Thrombocytopenia Diagnosed During Pre-transplant Evaluation

Congenital thrombocytopenia with nephritis: The first case of MYH9 related disorder in Serbia

The group of autosomal dominant disorders - Epstein syndrome, Sebastian syndrome, Fechthner syndrome and May-Hegglin anomaly - are characterised by thrombocytopenia with giant platelets, inclusion bodies in granulocytes and variable levels of deafness, disturbances of vision and renal function impairment. A common genetic background of these disorders are mutations in MYH9 gene, coding for the nonmuscle myosin heavy chain IIA. Differential diagnosis is important for the adequate treatment strategy. The aim of this case report was to present a patient with MYH9 disorder in Serbia. A 16-year-old boy was referred to our hospital with the diagnosis of resistant immune thrombocytopenia for splenectomy. Thrombocytopenia was incidentally discovered at the age of five. The treatment with corticosteroids on several occasions was unsuccessful. Although the platelet count was below 10 x 10(9)/L, there were no bleeding symptoms. Besides thrombocytopenia with giant platelets, on admission the patient also suffered sensorineuronal hearing loss and proteinuria. The diagnosis was confirmed with immunofluorescence and genetic analyses. Early recognition of MYH9-related diseases is essential to avoid unnecessary and potentially harmful treatments for misdiagnosed immune thrombocytopenia, and also for timely and proper therapy in attempt to delay end-stage renal failure and improve quality of life.

Familial cases with MYH9 disorders caused by MYH9 S96L mutation

We report familial cases with MYH9 disorders: a 1-year-old Japanese boy who presented only with macrothrombocytopenia, and his 33-year-old father who had been diagnosed with refractory chronic idiopathic thrombocytopenic purpura, and suffered from hearing loss and chronic renal failure. Peripheral blood smears revealed giant platelets but no Döhle body-like cytoplasmic inclusion bodies in neutrophils. Heterozygous MYH9 S96L mutations were found in the patient and his father, resulting in the diagnosis of a familial case with MYH9 disorders. The possibility of MYH9 disorders including Epstein syndrome should be assessed in cases of thrombocytopenia through the careful examination of hematological features.

Report of a Young Girl With MYH9 Mutation and Review of the Literature

MYH9 mutations cause the inherited macro-thrombocytopenic syndromes of May-Hegglin anomaly, Fechtner syndrome, Sebastian syndrome, and Epstein syndrome, collectively referred to as MYH9-related disease. We present the case of a girl with MYH9-related disease whose diagnosis was facilitated by platelet electron microscopy and MYH9 sequencing. We discuss our patient's clinical presentation, now with 12 years of follow-up. We also discuss management and her possible prognosis given her specific MYH9 mutation.

Genetics of familial forms of thrombocytopenia

The joint application of clinical and genetic investigation to patients with inherited thrombocytopenias, as well as the availability of new methods for studying megakaryopoiesis, has greatly expanded the knowledge of these disorders in the last few years with regard to their etiology, pathogenesis and clinical aspects. In particular, new diseases have been described, as deriving from mutations in the genes FLNA, TUBB1, ITGA2/ITGB3, ANKRD26, CYCS, and ABCG5 or ABCG8. Moreover, forms previously considered separate entities were found to be different clinical aspects of a single disease. For instance, identification of MYH9 as the gene whose mutations cause the May-Hegglin anomaly led to the recognition that Sebastian platelet syndrome, Epstein syndrome, and Fechtner syndrome derive from mutations of the same gene and describe overlapping disorders. Despite these advances, knowledge of hereditary thrombocytopenias is still far from satisfactory because for approximately half of the patients it is not possible to formulate a definite diagnosis in that their illnesses has not yet been described. In this review, we provide a systematic description of hereditary thrombocytopenias as we know them today, giving special attention to genetic aspects.

Cochlear implantation in a patient with Epstein syndrome

Epstein syndrome is a rare disease which is accompanied by nephritis, sensorineural hearing impairment and macrothrombocytopenia. It has been suggested that this syndrome is a hereditary disease associated with mutations in MYH9, which encodes non-muscle myosin heavy chain IIA. We report a case of a patient with Epstein syndrome in whom bilateral profound hearing impairment developed and who had undergone cochlear implantation 9 years previously. Prior to this, the patient showed progressive sensorineural hearing impairment and had become completely deaf by the age of 25. A cochlear implant was successfully used with a speech discrimination score of 98% (sentence test). However, in the present case, peri- and postoperative complications occurred: tympanic perforation remained after a promontory stimulation test, followed by transitory otitis with purulent discharge. Therefore, tympanoplasty was performed simultaneously with cochlear implantation. These complications were considered to be caused by platelet dysfunction and delayed wound healing. Furthermore, cochlear destruction was observed 8 years postoperatively. In Epstein syndrome, the mechanism of osseous change remains uncertain. To the best of our knowledge, this is the first case report of Epstein syndrome in a patient with long-term use of a CI.

MYH9 Related Platelet Disorders - Often Unknown and Misdiagnosed

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.

Glomerular pathology in autosomal dominant MYH9 spectrum disorders: what are the clues telling us about disease mechanism?

Genetic variation in MYH9, encoding non-muscle heavy chain IIA, has been recognized for over a decade as the cause of an autosomal dominant syndrome characterized by macrothrombocytopenia, neutrophil inclusions, and glomerular pathology. More recently, genetic variation in the MYH9 region on chromosome 22 has been associated with chronic kidney disease in African-descent individuals. A better understanding of the disease mechanisms responsible for glomerular injury in autosomal dominant MYH9 syndromes will lead to fuller appreciation of the role of this gene in glomerular biology.

ABO‐incompatible renal transplantation in Epstein syndrome

Epstein syndrome (ES) is an autosomal dominant hereditary disease characterized by hereditary nephritis, sensory deafness, and thrombocytopenia. We herein report the case of a 20-yr-old man with ES who underwent ABO blood type-incompatible living-donor kidney transplantation from his mother. He was given platelet transfusion, and his pre-operative number of platelets were 108 x 10(3)/microL. After transplantation, urine output and the decrease in serum creatinine (sCr) were within the acceptable ranges. On the seventh post-operative day (POD), sCr had risen and urine output decreased. Anti-type A antibody rapidly elevated from <2 times (x2) just before transplantation to 64 times (x64), and the patient required hemodialysis again. Resistance index (RI) by ultrasound increased from an average of 0.5 approximately 0.6 on POD 1 to an average of 0.7 approximately 0.8 on POD 7. However, several biopsies (POD 4, 7, and 10) showed no obvious findings of acute rejection except for intense C4d deposition. Because acute antibody-mediated rejection was not completely ruled out, he was treated with methyl-prednisolone pulse therapy, plasma exchange, cyclophosphamide, and immunoglobulin. Regardless, his titer of anti-type A antibody was still high, and he still presented oliguria. We performed an emergent splenectomy. Consequently, the levels of anti-type A antibody decreased, the RI also dropped to an average of 0.6. However, on POD 19 and 25 (platelets were 27 x 10(3)/microL and 36 x 10(3)/microL), he developed a massive intraperitoneal hematoma around the graft and region of the removed spleen, which pushed the graft out and caused acute tubular necrosis, resulting in anuria. The RI rose to an average of 0.8 approximately 1.0 after these episodes. He also experienced bleeding from a duodenal ulcer on POD 21. However, his renal function has fully recovered after acute hemodialysis for 35 d. The latest sCr was 1.5 mg/dL with a recovery in RI to 0.6. Although his platelet count was maintained at a minimum of 50 x 10(3)/microL, he had several severe bleeding episodes, concluding that sufficient platelets are necessary after transplantation in ES.

Introduction

This supplement contains the proceedings of the 13th Japanese Clinico-Pathological Conference on Renal Allograft Pathology, which was held on July 18, 2009, in Tokyo, Japan. The importance of kidney transplant pathology to evaluate graft condition and select optimal therapy has been widely acknowledged. The conference on renal allograft pathology has been held every year since 1997, and clinical nephrologists, transplant surgeons, urologists, and renal and general pathologists in Japan discuss renal transplant cases and topics related to renal transplantation. Every year’s conference has included unique topics concerning renal transplantation and provided an opportunity for debate from residents and fellows to specialists in pathology, internal medicine, and surgical fields. This year’s conference consisted of four special mini-lectures and 22 scientific studies and case presentations. Before the session, attendees could view all of the renal allograft case samples via a virtual microscope system at the front of the conference room. In addition, the histopathological features of two cases were discussed using virtual slides and a high-definition television system. The theme of the special mini-lectures in this meeting was “New therapeutic strategy for renal transplantation: Induction of tolerance in clinical and preclinical kidney transplantation.” In particular, the lecture “Induction of tolerance in clinical kidney transplantation” presented by Dr. Kawai from Massachusetts General Hospital/Harvard Medical School, Boston, USA, was quite educational for us in terms of the next practical and ideal strategy for kidney transplantation. Drs. Bashuda (Juntendo University, Tokyo, Japan) and Yamashita (Hokkaido University School of Medicine, Hokkaido, Japan) presented new strategies using adoptive transfer of regulatory T-cell-like cells (anergic cells) or anti-CD40 monoclonal antibody in preclinical studies, using non-human primates. For scientific studies and case presentations, we prepared five topics for detailed discussion: ABO-incompatible transplantation, acute antibody-mediated rejection, acute T-cell-mediated rejection, post-transplant glomerulonephritis, and pathology of surgical complications and others. Within each heading, four to five cases or studies were presented and discussed clinico-pathologically. Under the topic “ABO-incompatible transplantation,” pathology within 90 d of transplantation was characterized, and the very rare cases that show hyperacute rejection and acute antibody-mediated rejection in Epstein syndrome with thrombocytopenia were reported. Other topics included acute antibody or cell-mediated rejection. The clinico-pathological characterization of acute vascular rejection was discussed, and cases showing BK virus infection and plasma cell-rich acute rejection were reported. Under the topic “post-transplant glomerulonephritis,” the pathology and treatment of recurrence or de novo focal glomerulosclerosis (FSGS) and essential cryoglobulinemia were discussed. “Pathology of surgical complications and others” covered cases of pregnancy-induced thrombotic thrombocytopenic purpura and anemia-associated progressive interstitial fibrosis after transplantation, and the usefulness of baseline renal biopsy in the evaluation of the condition of living donor kidneys was reported. From the discussion of the scientific studies and transplant cases, we reconfirm that the examination of renal morphology in allograft patients is essential to evaluation of graft condition and achieving appropriate therapy. We believe that the reports appearing in this supplement address the above-mentioned issues that are important to the field of renal transplantation. The guest editors thank all authors and participants for their contributions. We also gratefully acknowledge the outstanding effort and support of Novartis Pharma K.K. (Japan) in holding this meeting. In addition, the sponsorship of the many cooperating firms listed on the title page made it possible to hold the meeting and publish this supplement. Finally, I express my sincere appreciation to Dr. Morozumi and Dr. Yamaguchi for their dedication to this meeting.

The May-Hegglin anomaly in a kidney transplant recipient.

We report a 37-year-old renal transplanted patient with thrombocytopaenia. He had May–Hegglin anomaly (MHA) inherited from his father, who died due to myocardial infarction subsequent to two renal transplantations. At the age of 15 years, proteinuria was found, but he was not biopsied. In 1982, he underwent splenectomy because of trauma. In 1989, when he was 17, renal function was found to be decreased. Five years later, he started haemodialysis and at 24 years he underwent live related kidney transplantation. Serum creatinine was always found stable around 1.9 mg/dl on cyclosporine, azathioprine and steroids. Automated blood count reported a number of platelets around 8000/μl with a mean volume of 20.3 fl (normal range 7.2– 11.1 fl). However, blood cell counters have a defined volume window for platelet counting and large macrothrombocytes are classified as red blood cells, meaning that platelet number is underestimated (Figure 1). The true value of platelets after count with the microscope was around 30 000/μl. He was completely asymptomatic, without any bleeding tendency. MHA is a rare autosomal dominant platelet disorder, characterized by macrothrombocytopaenia and granulocyte inclusion bodies. The mutation involves the MYH9 gene, localized in chromosome 22q, which encodes a heavy chain of non-muscle myosin IIA. MYH9-related hereditary macrothrombocytopaenia disorders include: MHA, Ebstein, Fechtner and Sebastian syndromes, which are characterized by nephritis, hearing loss and cataract [1]. In 1992, Nel et al. [2] reported two cases of MHA incidentally discovered in a patient and his brother during investigation for end-stage renal failure and workup for renal transplantation. Alhindawi and Al-Jbour [3] described an association between Epstein syndrome and chronic nephropathy. Recently, Singh et al. [4] suggested that MYH9 gene alterations are associated with a greater risk of focal segmental glomerulosclerosis and hypertensive nephrosclerosis in African Americans.