DIAPH1 Mutation as a Novel Cause of Autosomal Dominant Macrothrombocytopenia and Hearing Loss.

Macrothrombocytopenia (MTP) is a group of rare disorders characterized by giant platelets, thrombocytopenia, and variable association with abnormal bleeding. Inherited MTP are frequently misdiagnosed as immune thrombocytopenia. Associated second-organ manifestation can help narrow down syndromic MTPs. We describe a case of autosomal dominant sensorineural hearing loss and MTP caused by a gain of function mutation in DIAPH1. This mutation causes altered megarkaryopoiesis and platelet cytoskeletal deregulation. Although hearing loss and MTP were likely progressive, clinically significant bleeding was not observed. DIAPH1-related MTP can be distinguished clinically from MYH9 mutation by the absence of cataracts and glomerular disease.

Anesthetic management without perioperative platelet transfusion for cervical laminectomy and laminoplasty in a case of May-Hegglin anomaly.

May-Hegglin anomaly (MHA) is an inherited autosomal dominant disorder characterized by giant platelets and inclusion bodies in granulocytes, and thrombocytopenia. There is no consensus on the perioperative management of this disorder. We report a case involving a patient with MHA who was perioperatively managed without platelet transfusion for cervical laminectomy and laminoplasty. In our case, the platelet count was measured to be 0.6 × 104/µL using an automatic blood cell counter. Peripheral blood smear and genetic test analyses were performed, leading to a definitive diagnosis of MHA. However, clot retraction, serotonin release, and platelet aggregation were normal. Total intravenous anesthesia with propofol and remifentanil, in combination with intermittent injection of fentanyl, was administered. The total blood loss volume was 300 mL, and perioperative course was uneventful. Visual platelet count and platelet function were preserved in this case, although platelet or red blood cell transfusion was not performed. No bleeding tendency was observed during perioperative management.

Bengal macrothrombocytopenia is not totally an innocuous condition.

Inherited macrothrombocytopenia is a subgroup of thrombocytopenias, and is characterised by the presence of giant platelets and decreased platelet count with variable bleeding manifestations. Bengal macrothrombocytopenia is a newly described entity, previously called asymptomatic constitutional macrothrombocytopenia (ACMT), presented with variable bleeding tendencies; with mild to severe thrombocytopenia and macro-platelets in their peripheral blood smear and it is not totally an innocuous condition as described previously.

A diagnostic approach that may help to discriminate inherited thrombocytopenia from chronic immune thrombocytopenia in adult patients.

Inherited thrombocytopenia (IT) is a heterogeneous group of rare diseases that are often confused with immune thrombocytopenia (ITP). The objective of this study was to supply clinicobiological elements that allow a distinction to be drawn between IT and chronic ITP. We then compared 23 adult patients with IT and 9 patients with chronic ITP. Our study revealed six discriminating criteria: (i) an age of discovery <34 years: positive predictive value (PPV) = 88.2% [63.6; 98.5], (ii) a family history of thrombocytopenia: PPV = 100.0% [82.4; 100.0], (iii) a personal history of bleeding: PPV = 100% [76.8; 100.0], (iv) a mean platelet volume >11 fL: PPV = 93.3% [68.1; 99.8], (v) an excess of giant platelets on blood smear: 100.0% [76.8; 100.0], and (vi) a percentage >44% of platelets with a surface area >4 µm(2) in electron microscopy: PPV = 83.3% [58.6; 96.4]. If at least three of these criteria were combined, it was possible to distinguish IT from chronic ITP with 91.3% [72.0; 98.9] sensitivity and PPV = 100.0% [66.4; 100.0] specificity. The secondary objective of this study was to assess the prevalence of potential IT diagnosis in patients with chronic thrombocytopenia of uncertain origin. Applying our diagnostic approach to a series of 20 cases allowed us to estimate that 40% of them could be suffering from IT. Finally, our diagnostic approach may help to correctly distinguish IT from chronic ITP, particularly in the context of macrothrombocytopenia.

R1933X mutation in the MYH9 gene in May-Hegglin anomaly mimicking idiopathic thrombocytopenic purpura.

May-Hegglin anomaly (MHA) is a rare autosomal dominant disorder characterized by the triad of thrombocytopenia, giant platelets, and inclusion bodies in leukocytes. Recent evidence links MHA to mutations in the MYH9 gene. MHA has not been reported in Taiwan before. We report a 25-year-old Taiwanese man who presented with prolonged bleeding after dental extraction. Examination of peripheral blood smear revealed thrombocytopenia (platelet = 35,000/µL), giant platelets, and Döhle-like cytoplasmic inclusions in neutrophils. A strong family history of thrombocytopenia favored hereditary macrothrombocytopenia over idiopathic thrombocytopenic purpura (ITP). Electron microscopy revealed a spindle shape and parallel order of filaments in the inclusions, consistent with the diagnosis of MHA. We performed mutational analysis using polymerase chain reaction followed by direct sequence of the MYH9 gene for the patient, his maternal uncle and cousin, and all showed the same heterozygous R1933X mutation in exon 40. MHA should be considered when a young patient has thrombocytopenia, frequently misdiagnosed as ITP. Morphological examination of peripheral blood smear, family history tracing and genetic studies are required to make an accurate diagnosis and avoid unnecessary and even harmful therapies such as corticosteroids and splenectomy.

Macrothrombocytopenia with leukocyte inclusions in a patient with Wilson disease: a case report and literature review.

BACKGROUND: Wilson disease (WD) is an autosomal recessive disorder caused by homozygous or compound heterozygous mutations in ATP7B. Clinical manifestations primarily involve liver and nervous system lesions, with rarely observed hematologic manifestations. CASE PRESENTATION: In the present case, a patient with WD presented with thrombocytopenia, giant platelets, and Döhle-like cytoplasmic inclusions in the leukocytes. Initially, the May-Hegglin anomaly was considered; however, whole-exome sequencing did not reveal any mutation in the MYH9 gene but a heterozygous mutation was found in (C.2804 C > T, p.T935M) in the ATP7B gene. After two years, the patient developed tremors in his hands, lower limb stiffness, and foreign body sensation in the eyes. Additionally, Kayser-Fleischer rings in the corneal limbus were detected by slit-lamp examination. Copper metabolism test indicated a slight decrease in serum ceruloplasmin. Transmission electron microscopy revealed that the inclusion bodies of leukocytes were swollen mitochondria. Mass spectrometry analysis showed that the copper levels were almost 20-fold higher in the leukocytes of the patient than in those of the control group. Based on the Leipzig scoring system, a diagnosis of WD was confirmed. Zinc sulfate treatment ameliorated the patient's symptoms and enhanced platelet, serum ceruloplasmin, and albumin levels. CONCLUSIONS: In conclusion, this case represents the first documented instance of WD presenting as thrombocytopenia, giant platelets, and Döhle-like cytoplasmic inclusions in the leukocytes. Excessive cellular copper accumulation likely underlies these findings; however, understanding precise mechanisms warrants further investigation.

Hemizygosity for the gene encoding glycoprotein Ibß is not responsible for macrothrombocytopenia and bleeding in patients with 22q11 deletion syndrome.

Essentials How thrombocytopenia relates to bleeding in 22q11 deletion syndrome (22q11DS) is not clear. Bleeding severity, platelet count and volume, and GPIBB were examined in patients with 22q11DS. Macrothrombocytopenia and bleeding typified imperfectly overlapping subsets of 22q11DS patients. GPIBB hemizygosity does not cause macrothrombocytopenia or bleeding in patients with 22q11DS. SUMMARY: Background and objectives Macrothrombocytopenia and bleeding are frequently associated with 22q11 deletion syndrome (22q11DS). GPIBB, which encodes the glycoprotein (GP) Ibß subunit of GPIb-IX-V, is commonly deleted in patients with 22q11DS. Absence of functional GPIb-IX-V causes Bernard-Soulier syndrome, which is a severe bleeding disorder characterized by macrothrombocytopenia. Patients with 22q11DS are often obligate hemizygotes for GPIBB, and those with only a pathogenically disrupted copy of GPIBB present with Bernard-Soulier syndrome. The objective of this study was to determine how GPIBB hemizygosity and sequence variation relate to macrothrombocytopenia and bleeding in patients with 22q11DS who do not have Bernard-Soulier syndrome. Patients/methods We thoroughly characterized bleeding severity, mean platelet volume, platelet count and GPIBB copy number and sequence in patients with 22q11DS. Results and conclusions Macrothrombocytopenia and mild bleeding were observed in incompletely overlapping subsets of patients, and GPIBB copy number and sequence variation did not correlate with either macrothrombocytopenia or bleeding in patients with 22q11DS. These findings indicate that GPIBB hemizygosity does not result in either macrothrombocytopenia or bleeding in these patients. Alternative genetic causes of macrothrombocytopenia, potential causes of acquired thrombocytopenia and bleeding and ways in which platelet size, platelet count and GPIBB sequence information can be used to aid in the diagnosis and management of patients with 22q11DS are discussed.

[Renal diseases related to MYH9 disorders].

Mutations in MYH9 gene encoding the nonmuscle myosin heavy chain IIA (NMMHC-IIA) are related to a number of rare autosomal-dominant disorders which has been known as May-Hegglin disease, Sebastian syndrome, Fechtner syndrome and Epstein syndrome. Their common clinical features are congenital macrothrombocytopaenia and polymorphonuclear inclusion bodies, in addition to a variable risk of developing proteinuria, chronic kidney disease progressing toward end stage, sensorineural deafness and presenile cataracts. The term MYH9 related disease (MYH9-RD) describes the variable expression of a single illness encompassing all previously mentioned hereditary disorders. Renal involvement in MYH9- RD has been observed in 30% of patients. Mutant MYH9 protein, expressed in podocytes, mesangial and tubular cells, plays a main role in foot process effacement and in development of nephropathy. Interestingly, the MYH9 gene is currently under investigation also for his possible contribution to many other non-hereditary glomerulopathies such as focal global glomerulosclerosis (hypertensive nephrosclerosis), idiopathic focal segmental glomerulosclerosis, C1q nephropathy and HIV-associated nephropathy. In this review we are aimed to describe renal diseases related to MYH9 disorders, from the hereditary disease to the acquired disorders, in which MYH9-gene acts as a "renal failure susceptibility gene".

New Alert Message Settings for the XN-series Automated Hematology Analyzer Are Useful for Avoiding Falsely High WBC Counts and to Detect Specimens with Giant Platelets.

We encountered blood specimens from a patient with MYH9 related diseases, which gave falsely high white blood cell (WBC) counts during laboratory analysis using Sysmex XN-series automated hematology analyzers. This overcount was revealed to be caused by the overlapping of platelet (PLT) distribution with the WBC area in the WNR channel, which was used for routine WBC count with the XN-series. On the other hand, the WBC count obtained through the WDF channel of the XN-series seemed more accurate in such a case. We then created and introduced alert message settings for such rare but critical specimens, which gives a warning when the discrepancy in WBC counts between the WNR and WDF channels is higher than 1.0×109/L. By using the alert message setting, we were able to detect some specimens which gave falsely high WBC counts with the routine WNR channel from three other cases of giant PLTs. In conclusion, our alert message setting seems useful in avoiding false reporting of WBC count due to abnormal cells, including giant PLTs.

Macrothrombocytopenia With Döhle Body-Like Granulocyte Inclusions: A Case Report of May-Hegglin Anomaly in a 33-Year-Old White Woman With an Update on the Molecular Findings of MYH9-Related Disease.

A 33-year-old white woman arrived at the hospital to undergo a hysterectomy due to uterine fibroids. Blood smear review identified macrothrombocytopenia and Döhle body-like cytoplasmic leukocyte inclusions. Genetic testing identified a mutation in exon 39 of the myosin heavy chain gene (MHY9; OMIM 160775), which confirmed the diagnosis of May-Hegglin anomaly. May-Hegglin anomaly is one of a spectrum of MYH9 disorders that also includes Sebastian, Epstein, and Fechtner syndromes. Herein, we describe the clinical and laboratory presentation of a patient with May-Hegglin anomaly and provide an update on the molecular findings and a discussion of the genotypic-phenotypic correlations in this potentially underdiagnosed disorder.

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

OBJECTIVE/BACKGROUND: May-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 METHODS: We 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. RESULTS: Consistent findings of this entity noted in our patients were mild-to-moderate thrombocytopenia, giant platelets, and Döhle-like inclusions within the leukocytes. CONCLUSION: A diagnosis of MHA could be made based on a thorough peripheral blood smear examination, which also helps to avoid a misdiagnosis of immune thrombocytopenia.