MYH9-related Disorder Research Articles

A Case of Thrombocytopenia with <italic>MYH9</italic> Gene Mutation Found in Siblings

Myosin heavy chain 9 (MYH9) related diseases are autosomal dominant diseases characterized by macrothrombocytopenia and inclusion bodies in leukocyte, which can be accompanied by extra-hematologic symptoms such as sensorineural hearing loss, renal dysfunction, and cataract. They are often diagnosed incidentally in adulthood or misdiagnosed as idiopathic thrombocytopenic purpura (ITP), leading to unnecessary treatment with intravenous high-dose gamma-globulin, steroids, or splenectomy. Here, we report the case of a brother and sister confirmed to have a MYH9 gene mutation during follow-up. An 8-year-old boy was confirmed to have thrombocytopenia at birth and treated with intravenous gamma-globulin under suspicion of ITP or sepsis. He was discharged after showing an increase in platelet count. Subsequently, during outpatient workup, he exhibited thrombocytopenia, large platelets, and neutrophilic inclusion bodies. His 10-year-old sister also presented with the same findings. In 2021, DNA analysis revealed that they share a mutation (c.4270G> A, p. Asp1424Asn), a pathogenic variant associated with MYH9-related disorder.

MYH9-related disorder with sole presentation of end-stage kidney disease and long-term, recurrence-free living after living donor renal transplantation: a case report.

MYH9-related disorders are a group of autosomal dominant disorders caused by mutations in MYH9, and are characterized by thrombocytopenia, sensorineural hearing loss, cataracts, and renal failure. Here, we report a case of chronic renal failure due to MYH9-related disorder with renal symptoms in a patient who underwent living-donor renal transplantation. The patient was diagnosed with proteinuria during a health checkup at the age of 12years. Her renal function gradually deteriorated, and hemodialysis was initiated at 34years of age. No definitive diagnosis of renal disease was made through renal biopsy. At the age of 35, she underwent living-donor renal transplantation from her mother as the donor. Six years after transplantation, her renal function remained stable, and no evidence of recurrent nephritis was found during renal biopsies. The family history revealed that her father, uncle, and younger brother had end-stage kidney disease. Genetic testing revealed a mutation (p.E1653D) related to the MYH9 gene. As her father had a history of renal biopsy and was diagnosed with focal segmental glomerulosclerosis (FSGS), we diagnosed chronic renal failure due to FSGS associated with MYH9 disorder. There were no findings suggestive of hearing loss, cataracts, or thrombocytopenia in the recipient or their family members with renal failure, and no symptoms other than renal failure were noted.

Diagnostic delay of MYH9-related disorder in Japan.

MYH9-related disorder (MYH9-RD) is characterized by congenital macrothrombocytopenia and granulocyte inclusion bodies. MYH9-RD is often misdiagnosed as chronic immune thrombocytopenia. In this study, we investigated age at definitive diagnosis and indicative thrombocytopenia in 41 patients with MYH9-RD from the congenital thrombocytopenia registry in Japan. Our cohort comprises 54.8% adults over 18 years at confirmed diagnosis. We found a significant difference (p < 0.0001) between the median age at definitive diagnosis of 25.0 years and for indicative thrombocytopenia it was 9.0 years. Our findings strongly suggest diagnostic delay of MYH9-RD in Japan. Our registry system will continue to contribute to this issue.

Analysis of clinical phenotype and gene mutation characteristics of MYH9-related disorder

Objective: To investigate the clinical phenotype and gene mutation characteristics of MYH9-related disorder (MYH9-RD). Methods: The clinical data of 66 patients with MYH9-RD in the First Affiliated Hospital of Soochow University from January 2010 to December 2022 were retrospectively analyzed. According to the bleeding symptom, the patients were divided into bleeding and non-bleeding group, and according to the mutation sites, the patients were divided into non-muscle myosin heavy chain ⅡA head region (MD) and tail region (TD) mutation group. Statistical analysis was made to explore the clinical features in different groups such as platelet counts, bleeding, renal function, cataracts and hearing as well as MYH9 gene mutations. Results: A total of 66 MYH9-RD patients were included, with 28 males and 38 females, diagnosis age of 1-63(26±2) years. And 41% (27/66) of the patients had no family history. All patients presented with macrothrombocytopenia and normal platelet aggregation(10/10), 92% (54/59) of the patients had visible blue inclusion bodies in neutrophils, 30% (20/66) had bleeding symptoms, 45% (22/49) had proteinuria or glomerulonephropathy, 20% (8/41) had bilateral hearing impairment, and 10% (4/42) had bilateral cataracts. 18 mutation sites were identified in total, including 15 missense, 1 splicing and 2 termination mutations. Among them, p.Asp1424Asn, p.Arg1933* and p.Arg702His/Cys mutations were identified in 56% (29/52) of the patients, and p.Ser96Leu, Arg1165Cys and p.Glu1841Lys mutations were recurrent mutations, while p.Ala44Thr, p.Asp1447Ala and c.3838-2A>G mutations were novel mutations. The average platelet count of patients in bleeding group was (19±3)×109/L, which was significantly less than (36±3)×109/L in non-bleeding group (P<0.001). Compared with TD mutation group, patients of MD mutation group were presented with lower platelet count and higher risk of bleeding, as well as more severe clinical presentations including renal and hearing impairment and cataracts (all P<0.05). Conclusion: Mutations of p.Asp1424Asn, p.Arg1933* and p.Arg702His/Cys in MYH9 gene are hotspot mutations for MYH9-RD patients, Compared with TD mutation group, patients of MD mutation group were presented with lower platelet count and higher risk of bleeding, as well as more severe clinical presentations including renal and hearing impairment and cataracts.

Successful living-related kidney transplantation in MYH9-related disorder with macrothrombocytopenia: lessons for the clinical nephrologist.

Successful living-related kidney transplantation in MYH9-related disorder with macrothrombocytopenia: lessons for the clinical nephrologist.

Hereditary thrombocytopenia with familial novel mutation in MYH9 gene: A familial case report

One of the rarest types of hereditary thrombocytopenia is the MYH9-related disorder. This spectrum of disorders is characterized by large platelets with or without leukocyte inclusion bodies, a decrease in the total number of platelets, and autosomal dominant inheritance. Proteinuric nephropathy that frequently progresses to end-stage renal failure, as well as the beginning of progressive high-frequency sensorineural hearing loss in young adults, is also associated with MYH9-related disorder. In this case report, we presented three family members who had thrombocytopenia and in whom a heterozygous novel 22 bp deletion (c.4274_4295del) was detected which is located in exon 31 of the MYH9 gene. There was no evidence of bleeding in the family members we presented and thrombocytopenia was detected incidentally. Additionally, renal failure, hearing loss, presenile cataracts, and clinical symptoms were not detected in these family members. This novel mutation detected in the MYH9 gene has not been reported in the literature before.

\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.

Pure Smooth Endoplasmic Reticulum (SER) Inclusions in Granulocytes of MYH9-Related Disorder Patients

MYH9-related disorders are a group of disorders (May-Hegglin anomaly, Fechtner syndrome, Sebastian syndrome) characterized by macrothrombocytopenia and ribosome inclusions in granulocytes. They are caused by mutations in the MYH9 gene and, depending on the location of the mutation, are associated with extrahematological pathologies (sensorineural hearing loss, progressive nephropathy, presenile cataracts) of variable intensity.The inclusions are formed by single and clustered ribosomes and are partially surrounded by segments of rough endoplasmic reticulum (RER). Typical inclusions in May-Hegglin anomaly are spindle-shaped, well-defined, and contain longitudinal filaments. Those found in Sebastian and Fechter syndromes are round or oval, have no filaments and, sometimes, show cross-striated arrangement of the ribosome aggregates.When reviewing the electron micrographs of the granulocyte inclusions of 10 patients with MYH9-related disorders previously published (Pujol-Moix et al. Haematologica 2004;89:330-337) we observed a special type of inclusion not described in the article. This inclusion has the typical appearance of smooth endoplasmic reticulum (SER) clusters, that is, a meshwork of branching tubules of SER without limiting membranes and no other structures such as ribosomes or RER. In 3 of the patients reviewed, in addition to the typical inclusions of MYH9-related disorder, some granulocytes with SER clusters were observed. These clusters were rounded or oval in shape and, when present, were 1 or 2 per cell (Fig. 1).The patients who presented granulocyte SER clusters are those identified as B4, C6 and D8 in the Haematologica article and are briefly described in Table 1. The patients presenting with SER clusters showed different characteristics such as age, bleeding, platelet counts, and proportion of giant platelets. Therefore, we cannot relate the presence of SER clusters to any clinical or biological characteristic of patients. It should be noticed that we did not find SER clusters in any patient with May-Hegglin anomaly. However, the small number of cases studied does not allow any conclusions to be drawn.SER clusters have been described in different types of cells such as hepatocytes or kidney tubular epitelial cells (Ghadially FN. Ultrastructural Pathology of the Cell and Matrix. Butterwords. London, 1988, pp 422-427). Normal granulocytes (neutrophils, eosinophils, and basophils) besides their own specific granules, also contain other general subcellular structures, including dispersed SER membranes. However, SER membranes forming clusters in these cells have not been previously described. In addition, SER clusters do not seem to correspond to evolved forms of typical MYH9 inclusions, for example by degranulation of the RER, based on the observations that typical inclusions show abundant ribosomes but few RER segments, no appreciable ribosomes are observed in the SER clusters, and the morphology of the tubules forming the SER and RER is different.We suggest that SER clusters could be considered a new type of inclusion in MYH9-related disorders. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Role of Thrombopoietin Receptor Agonists in Inherited Thrombocytopenia.

In the last decade, improvements in genetic testing have revolutionized the molecular diagnosis of inherited thrombocytopenias (ITs), increasing the spectrum of knowledge of these rare, complex and heterogeneous disorders. In contrast, the therapeutic management of ITs has not evolved in the same way. Platelet transfusions have been the gold standard treatment for a long time. Thrombopoietin receptor agonists (TPO-RA) were approved for immune thrombocytopenia (ITP) ten years ago and there is evidence for the use of TPO-RA not only in other forms of ITP, but also in ITs. We have reviewed in the literature the existing evidence on the role of TPO-RAs in ITs from 2010 to February 2021. A total of 24 articles have been included, 4 clinical trials, 3 case series and 17 case reports. A total of 126 patients with ITs have received TPO-RA. The main diagnoses were Wiskott–Aldrich syndrome, MYH9-related disorder and ANKRD26-related thrombocytopenia. Most patients were enrolled in clinical trials and were treated for short periods of time with TPO-RA as bridging therapies towards surgical interventions, or other specific approaches, such as hematopoietic stem cell transplantation. Here, we have carried out an updated and comprehensive review about the efficacy and safety of TPO-RA in ITs.

Cisplatin-Mediated Upregulation of APE2 Binding to MYH9 Provokes Mitochondrial Fragmentation and Acute Kidney Injury.

Cisplatin chemotherapy is standard care for many cancers but is toxic to the kidneys. How this toxicity occurs is uncertain. In this study, we identified apurinic/apyrimidinic endonuclease 2 (APE2) as a critical molecule upregulated in the proximal tubule cells (PTC) following cisplatin-induced nuclear DNA and mitochondrial DNA damage in cisplatin-treated C57B6J mice. The APE2 transgenic mouse phenotype recapitulated the pathophysiological features of C-AKI (acute kidney injury, AKI) in the absence of cisplatin treatment. APE2 pulldown-MS analysis revealed that APE2 binds myosin heavy-Chain 9 (MYH9) protein in mitochondria after cisplatin treatment. Human MYH9-related disorder is caused by mutations in MYH9 that eventually lead to nephritis, macrothrombocytopenia, and deafness, a constellation of symptoms similar to the toxicity profile of cisplatin. Moreover, cisplatin-induced C-AKI was attenuated in APE2-knockout mice. Taken together, these findings suggest that cisplatin promotes AKI development by upregulating APE2, which leads to subsequent MYH9 dysfunction in PTC mitochondria due to an unrelated role of APE2 in DNA damage repair. This postulated mechanism and the availability of an engineered transgenic mouse model based on the mechanism of C-AKI provides an opportunity to identify novel targets for prophylactic treatment of this serious disease. SIGNIFICANCE: These results reveal and highlight an unexpected role of APE2 via its interaction with MYH9 and suggest that APE2 has the potential to prevent acute kidney injury in patients with cisplatin-treated cancer. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/3/713/F1.large.jpg.

A family with an MYH9-related disorder with different phenotypes masquerading as immune thrombocytopaenia: an underreported disorder in Taiwan.

A 66-year-old woman had experienced abnormal bleeding since the age of 7. Thrombocytopenia was not detected until she was 48, and immune thrombocytopenia was diagnosed at age 66. She also reported experiencing hearing disturbance since the age of 30 and acute renal failure since the age of 61 but reported no visual disturbance. Her younger son, who was 40 years old, also experienced abnormal bleeding since the age of 6, but immune thrombocytopenia was diagnosed as late as age 35. He had no other associated disorders. Laboratory examinations of both mother and son revealed a low platelet count (8000 and 29,000µL, respectively), giant platelets and Döhle body-like granulocyte inclusion bodies. The mother had a high creatinine level (15.4mg/dL) and normal liver enzyme levels. MYH9 genetic analysis identified a heterozygous mutation, c.101T>A, p.Val34Glu at exon 2 in both patients. These clinical and laboratory findings were consistent with a diagnosis of an MYH9-related disorder with different phenotypes observed in the same family. MYH9-related disorders were recognised in 2003, but were often misdiagnosed as immune thrombocytopenia, and hence, they have rarely been reported in Taiwan.

Renal transplantation in a patient with MHY9-related disease; a case report

MYH9-related diseases (MYH9-RD) are clinically represented by thrombocytopenia, large platelets, proteinuria and various degrees of renal dysfunction. We present a 25-year-old male with thrombocytopenia, large platelets, renal dysfunction and proteinuria. Gene sequencing of whole exons of MYH9 gene confirmed the diagnosis of MYH9-related disorder and revealed single nucleotide polymorphisms (SNPs) in the introns 13 (rs3752462) and 14 (rs2413396) and a mutation in exon 26 of MYH9 gene. Our result supported the possibility of non-coding SNPs involvement in the pathogenicity of the MYH9-RD disease and successful renal transplant in this patient.

Rare inherited kidney diseases: an evolving field in Nephrology.

There are more than 150 different rare genetic kidney diseases. They can be classified according to diagnostic findings as (i) disorders of growth and structure, (ii) glomerular diseases, (iii) tubular, and (iv) metabolic diseases. In recent years, there has been a shift of paradigm in this field. Molecular testing has become more accessible, our understanding of the underlying pathophysiologic mechanisms of these diseases has evolved, and new therapeutic strategies have become more available. Therefore, the role of nephrologists has progressively shifted from a mere spectator to an active player, part of a multidisciplinary team in the diagnosis and treatment of these disorders. This article provides an overview of the recent advances in rare hereditary kidney disorders by discussing the genetic aspects, clinical manifestations, diagnostic, and therapeutic approaches of some of these disorders, named familial focal and segmental glomerulosclerosis, tuberous sclerosis complex, Fabry nephropathy, and MYH-9 related disorder.

Next-generation sequencing for the diagnosis of MYH9-RD: Predicting pathogenic variants.

The heterogeneous manifestations of MYH9‐related disorder (MYH9‐RD), characterized by macrothrombocytopenia, Döhle‐like inclusion bodies in leukocytes, bleeding of variable severity with, in some cases, ear, eye, kidney, and liver involvement, make the diagnosis for these patients still challenging in clinical practice. We collected phenotypic data and analyzed the genetic variants in more than 3,000 patients with a bleeding or platelet disorder. Patients were enrolled in the BRIDGE‐BPD and ThromboGenomics Projects and their samples processed by high throughput sequencing (HTS). We identified 50 patients with a rare variant in MYH9. All patients had macrothrombocytes and all except two had thrombocytopenia. Some degree of bleeding diathesis was reported in 41 of the 50 patients. Eleven patients presented hearing impairment, three renal failure and two elevated liver enzymes. Among the 28 rare variants identified in MYH9, 12 were novel. HTS was instrumental in diagnosing 23 patients (46%). Our results confirm the clinical heterogeneity of MYH9‐RD and show that, in the presence of an unclassified platelet disorder with macrothrombocytes, MYH9‐RD should always be considered. A HTS‐based strategy is a reliable method to reach a conclusive diagnosis of MYH9‐RD in clinical practice.

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.

The Transition from Childhood to Adulthood in Chronic Immune Thrombocytopenia Patients: Clinical Management and the Role of Splenectomy and Thrombopoietin Receptor Agonists in a Single Center Experience

Introduction. Children diagnosed with Immune thrombocytopenia (ITP) will develop a chronic disease (plt < 100 x 109/L lasting >12 months since the onset) in 20-30% of cases. The transition from ITP started in childhood to adulthood has been scarcely studied and no specific studies have been publishedAims.To present the results of a single center retrospective survey on ITP pts diagnosed in childhood who were sent in an adult setting to continue the managementMethods. Charts of ITP pts diagnosed in childhood (1-17 yrs) in our Pediatric Dept who developed a chronic disease, need at least one line of therapy and were sent to our adult ITP office from Jan 2013 to Feb 2018, were retrospectively reviewed. Demographic and clinical data were collected and outcome was assessed based on established guidelinesResults. Our Pediatric Dept accounts for a mean of 37 newly ITP diagnosis/year in children aged 1-17 yrs, with 32.8% of pts developing a chronic disease. During the selected observation time, 60 pts was expected to become > 18 yrs old with a chronic ITP. Overall 28 pts (14 female) pts were sent to our Adult ITP office at pediatrician's discretion (46.6% of expected). Table 1 summarizes demographic and clinical characteristics of pts. Median age at ITP diagnosis was 9.5 yrs (12 moths to 17 yrs). Median age of pts coming to the adult ITP office was 21 yrs (18 to 37 yrs) and the reason they were sent for was the need to continue a pharmacological treatment in 8 cases (eltrombopag-Elt-), bleeding in 3 cases, pregnancy in 4 cases, plt count < 50 x 109/L in 13 cases. The median n of lines of treatment already received in childhood was 1 (1 to 4). 16 pts have received only steroid since diagnosis (on demand treatment for bleedings), 8 pts were treated with thrombopoietin receptor agonists (TPO-RA) and 1 also with rituximab. One patient, 8 yrs old, was splenectomized because of grade 3 multiple bleedings, with complete response (CR). He was sent to adult ITP office at 37 yrs when ITP relapsed, with grade 3 bleeding. Overall the median follow up from diagnosis, after the transition to adult ITP office is 18 yrs (4-39 yrs), the median n of lines at data cut-off was 2.5 (1-5) and the overall outcome is summarized in Fig 1. 11 patients were treated with TPO-RA (8 pts received Elt since childhood, 2 pts started Elt and 1 Rom in adulthood), ORR was 81.8% (CR=7). Since the transition 4 patients switched the TPO-RA because response to the first TPO-RA was suboptimal or minor side effect (headache) was reported or limited compliance was suspected. Splenectomy was offered to all patients treated with TPO-RA to avoid chronic pharmacological treatment, and to other selected patients with a low plt count and a history of bleeding. 8/11 patients accepted splenectomy. Median time since diagnosis to splenectomy was 8 yrs (1 to 18 yrs) and in all pts a stable CR (plt > 100 x 109/L) was achieved, with a median follow up after surgery of 36.5 months (10-48 months). Surgery was performed also in the previous splenectomized pt (29 yrs later) because an accessory spleen was detected, and a CR was achieved (follow up 40 months). 2 patients stopped TPO-RA on a personal decision, refused splenectomy or other treatments: their plt count is < 30 x 109/L without bleeding. 15 pts were on active follow up without therapy (median plt count 58 x 109/L) and without any bleeding. One patient is waiting for splenectomy, taking prednison. The 4 pregnant patients were treated with steroids and IVIG, had natural labour without adverse events and their babies had a normal plt count. After pregnancy one pt was treated with Elt for 1 year, then she refused treatment and splenectomy. All 4 women returned to a number of plts similar to pre-gestational count. In 1 pt a MYH9 related-disorder was confirm at 21 yrs.Overall a CR was achieved during TPO-RA treatment in 9/11 pts and 9/28 (32%) achieved a stable CR after splenectomyConclusions. The transition from childhood to adulthood in chronic ITP pts leads clinicians to challenges related to growing age, especially in female pts approaching the fertility and pregnancy specific needs. However only a minority of children with ITP developed a chronic disease which required a prolonged treatment. TPO-RA seems to be effective and well tolerated but chronic administration has limited compliance. Splenectomy, even if performed in adulthood after many yrs since diagnosis, allows to achieve a stable CR sparing young adults from chronic pharmacological treatment. DisclosuresGambacorti-Passerini:Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy.

Bone marrow morphology and disease progression in congenital thrombocytopenia: a detailed clinicopathologic and genetic study of eight cases

Patients with congenital thrombocytopenia have an increased risk of developing myeloid neoplasms. In these cases, the morphologic distinction between disease at baseline and at progression is challenging. This report analyzes clinicopathologic features of congenital thrombocytopenia with long-term follow-up at one referral center. Records from the last 20 years were searched for cases of congenital thrombocytopenia with bone marrow biopsies and peripheral blood smears. The clinical, morphologic, immunophenotypic, and molecular features were analyzed. Six adult and two pediatric patients were identified (six male, two female). Age range at first biopsy was 1–47 (median, 31) years. Underlying diseases included thrombocytopenia-absent radius syndrome, congenital thrombocytopenia with radial–ulnar synostosis, MYH9-related disorder, shortened telomere syndrome, congenital thrombocytopenia with ANKRD26 mutation, and familial platelet disorder with predisposition to acute myeloid leukemia. Four patients had myelodysplastic/myeloproliferative neoplasm-like marrow changes such as hypercellularity, increased myeloid to erythroid ratio, numerous micromegakaryocytes (highlighted by CD42b), and marrow fibrosis. Two patients had marrow hypoplasia and two had unremarkable marrow morphology. Three patients—all in the myelodysplastic/myeloproliferative neoplasm-like group—developed disease progression characterized by erythroid and myeloid dysplasia, elevated bone marrow blasts, and new cytogenetic abnormalities. Unlike non-familial myeloid neoplasms, congenital thrombocytopenia patients in the myelodysplastic/myeloproliferative neoplasm-like group had a long and indolent clinical course (average age at disease progression, 47 years). In summary, three distinct morphologic types of congenital thrombocytopenia were identified: a hyperplastic myelodysplastic/myeloproliferative neoplasm-like group, a hypoplastic bone marrow failure-like group, and a group with relatively normal marrow morphology. Emergence of cytogenetic abnormalities and dysplasia in non-megakaryocyte lineages correlated with disease progression.

MYH9-related disorder, a probable May–Hegglin anomaly case series: A tertiary care experience

Objective/backgroundMay–Hegglin anomaly (MHA) is a rare familial bleeding disorder characterized by a triad of thrombocytopenia, giant platelets, and Döhle-like inclusion bodies within the leukocytes. The clinical spectrum as well as the pathophysiology of this entity is not well defined. The objective of this work is to present a series of three cases of MHA diagnosed in our hospital, where the patients presented with variable bleeding manifestations, thrombocytopenia, and giant platelets. Materials and MethodsWe studied three cases of possible MHA. In addition to the clinical examination, complete hemogram, and peripheral blood smear examination, these patients were also subjected to coagulation studies. Although bleeding symptoms varied among these patients, platelet aggregation tests with various agonists showed a normal response. ResultsConsistent findings of this entity noted in our patients were mild-to-moderate thrombocytopenia, giant platelets, and Döhle-like inclusions within the leukocytes. ConclusionA diagnosis of MHA could be made based on a thorough peripheral blood smear examination, which also helps to avoid a misdiagnosis of immune thrombocytopenia.

Renal Failure Due to MYH9-Related Disorder (Macro-Thrombocytopenia): Peritoneal Dialysis as a First Choice Therapy and Kidney Transplant from Living Donor

Renal Failure Due to MYH9-Related Disorder (Macro-Thrombocytopenia): Peritoneal Dialysis as a First Choice Therapy and Kidney Transplant from Living Donor

Successful Renal Transplantation in MYH9-Related Disorder With Severe Macrothrombocytopenia: First Report in Korea

MYH9-related disorders (MYH9 RD) are genetic disorders by the variation of MYH9 gene that encodes for the nonmuscle myosin heavy chain IIA. The clinical and laboratory findings of Fechtner syndrome, an MYH9 RD, are macrothrombocytopenia, basophilic cytoplasmic inclusion bodies in leukocytes, glomerulopathy, sensorineural deafness, and cataracts. Fechtner syndrome is a rare cause of chronic kidney disease. To our knowledge, this is first report of successful renal transplant in MYH9 RD in Korea. We report the two cases with a brief review of literatures since we experienced successful living donor kidney transplantation in Fechtner syndrome with end-stage renal disease, showing very serious thrombocytopenia due to MYH9 mutation.