Congenital amegakaryocytic thrombocytopenia: clinical and biological consequences of five novel mutations

BACKGROUND AND OBJECTIVES: Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare, autosomal recessive disorder induced by mutations of the gene coding for thrombopoietin (TPO) receptor (c-MPL). Patients initially present with isolated thrombocytopenia that subsequently progresses into pancytopenia. Although the mechanisms leading to aplasia are unknown, the age of onset has been reported to depend on the severity of the c-MPL functional defect. To improve our knowledge in this field, we studied clinical and biological features of five new patients. DESIGN AND METHODS: We diagnosed five CAMT patients, identified c-MPL mutations, including five novel alterations and investigated relationships between mutations and their clinical-biological consequences. RESULTS: In all cases, platelet c-MPL and bone marrow colonies were reduced, while serum TPO levels were elevated. We also documented that the percentage of bone marrow cells expressing tumor necrosis factor-a and interferon-g was increased during pancytopenia as compared to in controls, suggesting that, as in other bone marrow failure diseases, these inhibitory cytokines contributed to the pancytopenia. Contrary to previously published data, we found no evidence of correlations between different types of mutations and the clinical course. INTERPRETATION AND CONCLUSIONS: These results suggest that therapies, such as hematopoietic stem cell transplantation, which are potentially curative although associated with a risk of treatment-related mortality, should not be postponed even in those CAMT patients whose c-MPL mutations might predict residual activity of the TPO receptor

May-Hegglin Anomaly, Sebastian Syndrome, Fechtner Syndrome, and Epstein Syndrome Are not Distinct Entities but Represent a Variable Expression of a Single Illness

May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are autosomal dominant macrothrombocytopenias distinguished by different combinations of clinical and laboratory signs, such as sensorineural hearing loss, cataract, nephritis, and polymorphonuclear Döhle-like bodies. Mutations in the MYH9 gene encoding for the nonmuscle myosin heavy chain IIA (NMMHC-IIA) have been identified in all these syndromes. To understand the role of the MYH9 mutations, we report the molecular defects in 12 new cases, which together with our previous works represent a cohort of 19 families. Since no genotype-phenotype correlation was established, we performed an accurate clinical and biochemical re-evaluation of patients. In addition to macrothrombocytopenia, an abnormal distribution of NMMHC-IIA within leukocytes was observed in all individuals, including those without Döhle-like bodies. Selective, high-tone hearing deficiency and cataract was diagnosed in 83% and 23%, respectively, of patients initially referred as having May-Hegglin anomaly or Sebastian syndrome. Kidney abnormalities, such as hematuria and proteinuria, affected not only patients referred as Fechtner syndrome and Epstein syndrome but also those referred as May-Hegglin anomaly and Sebastian syndrome. These findings allowed us to conclude that May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but rather a single disorder with a continuous clinical spectrum varying from mild macrothrombocytopenia with leukocyte inclusions to a severe form complicated by hearing loss, cataracts, and renal failure. For this new nosologic entity, we propose the term "MHY9-related disease," which better interprets the recent knowledge in this field and identifies all patients at risk of developing renal, hearing, or visual defects

Cleft lip with or without cleft palate: implication of the heavy chain of non‐muscle myosin IIA

Non‐syndromic cleft lip with or without palate (CL/P) is one of the most common malformations among live births, but most of the genetic components and environmental factors involved remain to be identified. Among the different causes, MYH9, the gene encoding for the heavy chain of non‐muscle myosin IIA, was considered a potential candidate, because it was found to be abundantly and specifically expressed in epithelial cells of palatal shelves before fusion. After fusion, its expression level was shown to decrease and to become limited to epithelial triangles before disappearing, as fusion is completed

Association between hospitalization-related outcomes, dynapenia and body mass index: The Glisten Study

Objective: To compare the prognostic value of dynapenia, as evaluated by handgrip, and body mass index (BMI) on length of stay (LOS), days of bed rest, and other hospitalization-related outcomes in a population of older adults admitted to 12 italian acute care divisions. Methods: Data on age, weight, BMI, comorbidities, ADL, physical activity level, muscle strength, were recorded at hospital admission. LOS, days of bed rest, intrahospital falls, and discharge destination were also recorded during the hospitalization. Subjects with BMI <18.5 kg/m 2 were classified as underweight, subjects with BMI 18.5–24.9 as normal weight, subjects with BMI ≥25 as overweight-obese. Results: A total of 634 patients, mean age 80.8 ± 6.7 years and 49.4% women, were included in the analysis. Overall dynapenic subjects (D) showed a longer period of LOS and bed rest compared with non-dynapenic (ND). When the study population was divided according to BMI categories, underweight (UW), normal weight (NW), and overweight-obese (OW-OB), no significant differences were observed in hospital LOS and days of bed rest. When analysis of covariance was used to determine the difference of LOS across handgrip/BMI groups, D/OW-OB and D/UW subjects showed significantly longer LOS (11.32 and 10.96 days, both p 0.05) compared to ND/NW subjects (7.69 days), even when controlling for age, gender, baseline ADL, cause of hospitalization and comorbidity. After controlling for the same confounding factors, D/OW-OB, D/NW and D/UW subjects showed significantly longer bed rest (4.7, 4.56, and 4.05 days, respectively, all p 0.05, but D/OW-OB p 0.01) compared to ND/NW subjects (1.59 days). Conclusion: In our study population, LOS is longer in D/UW and D/OW-OB compared to ND/NW subjects and days of bed rest are mainly influenced by dynapenia, and not by BMI class