ZDHHC15 as a candidate gene for autism spectrum disorder.

The phenotypic repercussion of ZDHHC15 haploinsufficiency is not well-known. This gene was initially suggested as a candidate for X-linked mental retardation, but such an association was later questioned. We studied a multiplex family with three members with autism spectrum disorder (ASD) by array CGH, karyotype, exome sequencing and X-chromosome inactivation patterns. Medical history interviews, cognitive and physical examinations, and sensory profiling were also assessed. The three family members with ASD (with normal cognitive abilities and an abnormal sensory profile) were the only carriers of a 1.7 Mb deletion in the long arm of chromosome X, involving: ZDHHC15, MAGEE2, PBDC1, MAGEE1, MIR384 and MIR325. The normal chromosome X was preferentially inactivated in female carriers, and the whole exome sequencing of an affected family member did not reveal any additional genetic variant that could explain the phenotype. Thus, in the present family, ASD segregates with a deletion on chromosome X that includes ZDHHC15. Considering our results together with gene data (regarding function, expression, conservation and animal/cellular models), ZDHHC15 is a candidate gene for ASD. Emerging evidence also suggests that this gene could be associated with other neurodevelopmental disorders, with incomplete penetrance and variable expressivity.

Pulmonary barotrauma in SCUBA diving-related fatalities: a histological and histomorphometric analysis.

Arterial gas embolism following pulmonary barotrauma occurs in 13-24% of cases of diving deaths. The study aimed to evaluate the usefulness of a histomorphometric digital analysis in the detection of air space over-distension due to pulmonary barotrauma. The study was performed on lung parenchyma specimens of 12 divers: six had died due to arterial gas embolism following pulmonary barotrauma (mean age at death of 54 years, range of 41-61 years), and six had drowned in saltwater without a diagnosis of pulmonary barotrauma (mean age at death of 54 years, range of 41-66 years) (positive controls). For negative controls, six cases of non-SCUBA divers (mean age of death of 42 years, range of 23-55 years) who died of intracerebral haemorrhage were evaluated. No significant differences were observed in the characteristics of the air spaces between control groups (positive and negative). However, differences were observed in the area occupied by air spaces and the percentage of air space area when we compared the case group to the controls (p < 0.01); and there was a slight difference in the maximum and minimum diameters of air space (p < 0.05). The mean area occupied by air spaces and the mean percentage of air space were the most useful for discriminating pulmonary barotrauma from other causes of death (100% sensitivity and 91.7% specificity). Based on our study, inclusion of an increased pattern of air spaces as a possible diagnostic criterion for pulmonary barotrauma would be useful in discerning the cause of diving death.

Thromboembolism and bleeding in patients with cancer and mechanical heart valves.

Mechanical heart valves (MHV) require life-long anticoagulation with vitamin K antagonists (VKA), but anticoagulation management is complex in patients with cancer due to a high risk of thrombosis and bleeding. This is a retrospective, single-center study to assess anticoagulation management and thrombotic (stroke/valve thrombosis) and bleeding events in patients with active cancer and MHV. The incidence of thrombotic complications was compared to a control group (matched 1:1) of patients with MHV but without cancer. We included 48 patients, 60% of whom had aortic prostheses, 23% mitral prostheses and 17% both types. All patients received VKA as anticoagulant. With a median follow-up of 5.12 years, we observed two arterial thrombotic events (two strokes and no heart valve thrombosis). The 5-year incidence (95% confidence interval [CI]) of stroke/valve thrombosis was 5.7% (0.9-17.9%). The control group had a similar incidence of stroke/valve thrombosis (5-year incidence 7.9% [95%CI 2-19.8], p = 0.16). There were also 15 major bleeding episodes in the cancer group, 11 of which were related to a surgical procedure. The 5-year incidence (95% CI) of major bleeding was 32.9% (18.5-48%), and that of major bleeding unrelated to any procedure was 10.3% (3-23%). We found a low incidence of thrombotic events in this series of patients with active cancer and MHV who were anticoagulated with VKA. However, the incidence of bleeding was high, particularly in relation to invasive procedures.

The Glucocorticoid Resistance Syndrome. Two Cases of a Novel Pathogenic Variant in the Glucocorticoid Receptor Gene.

Glucocorticoid resistance syndrome is a rare genetic condition characterized by generalized or partial target-tissue insensitivity to glucocorticoids and a consequent hyperactivation of the hypothalamic-pituitary-adrenal axis. Clinical manifestations may include mineralocorticoid and/or androgen excess without manifestations of Cushing syndrome. At a cellular level, glucocorticoid actions are mediated by the nuclear glucocorticoid receptor encoded by the NR3C1 gene. To date, only 33 glucocorticoid receptor loss-of-function pathogenic variants have been associated with glucocorticoid resistance syndrome. The NR3C1 gene has 2 known disease-causing mechanisms: haploinsufficiency and negative dominance. We describe a mother and her son with a mild hyperandrogenic phenotype and a novel genetic variant of the NR3C1 gene predicting a truncated protein and causing glucocorticoid resistance syndrome. To date, no accurate genotype-phenotype correlation has been found.

Detection of giant cytoplasmic inclusions in a pediatric patient with recurrent infections: a case report.

Objectives: Giant inclusions in leukocytes is a common feature that can be observed in some infections but can be also related to rare genetic disorders such as Chédiak-Higashi syndrome (CHS). A differential diagnosis between these groups of diseases has to be performed using specific genetic tests. Clinical and pathological history is relevant for a diagnostic orientation due to the difficulty and specificity of the diagnostic confirmation. Case presenation: We present the case of a 3-years-old male patient with recurrent respiratory infections. It is important to highlight the presence of a lock of white hair on the front of the head and some hypopigmentation of the skin. In the blood smear, the presence of big cytoplasm granules in all the leukocytes, especially in neutrophils. Conclusions: CHS is an uncommon genetic disorder caused by the mutation in the LYST gene situated in chromosome 1q42.3 which codified for LYST protein. Molecular genetic testing also can be done to detect the biallelic variants in the LYST gene. It is essential to perform peripheral blood smears in the presence of changes in quantitative and/or qualitative values in the complete blood count as a first step in the diagnosis algorithm.

Evaluation of the New Beckmann Coulter Analyzer DxH 900 Compared to Sysmex XN20: Analytical Performance and Flagging Efficiency.

Efficiency and accuracy in automated hematology analyzers are very important for clinical laboratories. The purpose was to evaluate the flags and results reported by the newest Beckman Coulter analyzer DxH 900 compared to the Sysmex XN20 system. Samples were analyzed on the XN20 (Sysmex, Kobe, Japan) and on the Beckman Coulter DxH 900 (Beckman Coulter, Miami, Florida, USA). Slide reviews were performed microscopically. Morphologic criteria were used to identify abnormal cells as recommended by International Consensus Group for Hematology (ICSH): blasts, immature granulocytes (IG%), abnormal lymphocytes (ALs) and plasma cells. Results: there was a strong correlation between the analyzers in almost all clinical parameters tested. Both DxH 900 and XN20 showed an excellent degree of association for the leukocyte differential compared to the reference method (manual microscopy). When it comes to IG%, XN20 showed a positive bias for higher results. Related to platelets, there are no differences between the two methods for PLT count. For mean platelet volume (MPV), DxH 900 provided 100% results of the samples analyzed while XN20 while in the XN20 analyzer, 16% of the results were missing. From our results we came to the conclusion that both analyzers, DxH 900 and XN20 were clinically accurate and efficient. Abnormal Lymphocyte detection highlighted the differences between the two technologies as only minimal agreement was obtained. DxH 900 demonstrated higher sensitivity in detecting IG with good correlation with microscopic review. The DxH 900 for platelet clumps identification provides an excellent flag (PLT Clumps) with the highest sensitivity observed in our evaluation.

Positive predictive value of CD200 positivity in the differential diagnosis of chronic lymphocytic leukemia.

BACKGROUND: The role of CD200 in the differential diagnosis of chronic lymphocytic leukemia (CLL) and classical mantle cell lymphoma (MCL) is well established. Its role in the differential diagnosis of CLL and other lymphoproliferative disorders (LPD) is less clear, in particular its positive predictive value (PPV). MATERIALS AND METHODS: We conducted a systematic review of the use of CD200 in the differential diagnosis of CLL, MCL, and other predominantly leukemic, typically CD103-negative LPD. With the results, we then derived a curve to determine the PPV based on the prevalence of the disorders included in the differential diagnosis. RESULTS: Of 43 publications screened, 27 were included in the systematic review (5,764 patients). The median CD200 positivity rate in all studies and the percentage of CD200-positive (pooled) patients was 100% and 95% (3,061/3,208) in CLL, 4 and 8% (86/1112) in MCL and 56 and 62% (425/689) in other LPD. CONCLUSION: CD200 is suboptimal for the differential diagnosis of CLL and disorders other than nodal MCL.