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Aggressive arterial aneurysms, such as thoracic aortic aneurysms and aortic dissection, were found to be caused by mutations in the genes encoding the transforming growth factor β (TGF-β) receptor I or II, which are characteristic of the Loeys–Dietz syndrome. Screening for these mutations in persons at risk may allow preventive measures to be taken. Aggressive arterial aneurysms were found to be caused by mutations in the genes encoding the transforming growth factor β receptor I or II. Screening for these mutations in persons at risk may allow preventive measures to be taken. Mutations in the genes encoding transforming growth factor β (TGF-β) receptors 1 and 2 ( TGFBR1 and TGFBR2, respectively) have recently been found in association with a continuum of clinical features. On the mild end, the mutations have been found in association with a presentation similar to that of Marfan's syndrome or with familial thoracic aortic aneurysm and dissection, 1 , 2 and on the severe end, they are associated with a complex phenotype in which aortic dissection or rupture commonly occurs in childhood. 3 This complex phenotype is characterized by the triad of widely spaced eyes (hypertelorism); a bifid uvula, cleft palate, . . .

Background Joubert syndrome (JBTS) is a genetically heterogeneous group of neurodevelopmental syndromes caused by primary cilia dysfunction. Usually the neurological presentation starts with abnormal neonatal breathing followed by muscular hypotonia, psychomotor delay, and cerebellar ataxia. Cerebral MRI shows mid- and hindbrain anomalies including the molar tooth sign. We report a male patient with atypical presentation of Joubert syndrome type 23, thus expanding the phenotype. Case presentation Clinical features were consistent with JBTS already from infancy, yet the syndrome was not suspected before cerebral MRI later in childhood showed the characteristic molar tooth sign and ectopic neurohypophysis. From age 11 years seizures developed and after few years became increasingly difficult to treat, also related to inadequate compliance to therapy. He died at 23 years of sudden unexpected death in epilepsy (SUDEP). The genetic diagnosis remained elusive for many years, despite extensive genetic testing. We reached the genetic diagnosis by performing whole genome sequencing of the family trio and analyzing the data with the combination of one analysis pipeline for single nucleotide variants (SNVs)/indels and one for structural variants (SVs). This lead to the identification of the most common variant detected in patients with JBTS23 (OMIM# 616490), rs534542684, in compound heterozygosity with a 8.3 kb deletion in KIAA0586 , not previously reported. Conclusions We describe for the first time ectopic neurohypophysis and SUDEP in JBTS23, expanding the phenotype of this condition and raising the attention on the possible severity of the epilepsy in this disease. We also highlight the diagnostic power of WGS, which efficiently detects SNVs/indels and in addition allows the identification of SVs.

Neonates with hypoplastic left heart syndrome (HLHS) were identified from the National Inpatient Sample dataset for the years 1998–2014. These patients were stratified into two chronological groups, past group (1998–2005) and recent group (2006–2014). A total of 20,649 neonates with HLHS were identified. Of them, 9179 (44.5%) were born in the past group and 11,470 (55.5%) in the recent group. Median birth weight was significantly less in the recent group (2967 g vs. 3110 g, p = 0.005). The patients in the recent group had more patients with low birth weight ( < 2.5 kg) and prematurity (8.7% vs 7.6% and 12.7% vs. 4.3%., respectively). In addition, recent group had more comorbidities including chromosomal anomalies, total anomalous pulmonary venous return, and kidney anomalies (5.6% vs. 3.6%, 2.3% vs. 1.7%, and 5.6% vs. 3.6%, respectively, p < 0.001); these were associated with a higher rate of extracorporeal membrane oxygenation utilization (9.2% vs. 4.5%, p < 0.001). Consequently, median length of stay was longer in the recent group (8 vs. 6 days, p < 0.001).Conclusion: Despite the higher frequency of comorbidities in recent group, the mortality rates decreased by 20% (from 25.3% to 20.6%, p < 0.001). Balloon atrial septostomy was performed less frequently in the recent group (23.3% vs. 16.1%, p < 0.001).What is known:• Hypoplastic left heart syndrome has the highest mortality among congenital cardiac defects during the first year of life.• Limited studies on patients’ comorbidities and mortality rates trends over last two decades.What is new:• The study utilized a national database to compare in-hospital mortality and length of stay between the two time periods 1998–2005 and 2006–2014.• The recent group had more comorbidities (prematurity, chromosomal anomalies, total anomalous pulmonary venous return, and kidney anomalies), and there was higher rate of ECMO and longer length of stay, while mortality rates decreased by 20%.

Background The T gene (brachyury gene) is the founding member of the T-box family of transcription factors and is vital for the formation and differentiation of the mesoderm and the axial development of all vertebrates. Results We report here on four patients from three consanguineous families exhibiting sacral agenesis, a persistent notochordal canal and abnormal ossification of the vertebral bodies, and the identification and characterisation of their underlying genetic defect. Given the consanguineous nature and the similarity of the phenotypes between the three families, we performed homozygosity mapping and identified a common 4.1 Mb homozygous region on chromosome 6q27, containing T, brachyury homologue (mouse) or T. Sequencing of T in the affected individuals led to the identification of a homozygous missense mutation, p.H171R, in the highly conserved T-box. The homozygous mutation results in diminished DNA binding, increased cell growth, and interferes with the normal expression of genes involved in ossification, notochord maintenance and axial mesoderm development. Conclusions We have identified a shared homozygous mutation in three families in T and linked it to a novel syndrome consisting of sacral agenesis, a persistent notochordal canal and abnormal ossification of the vertebral bodies. We suggest that screening for the ossification of the vertebrae is warranted in patients with sacral agenesis to evaluate the possible causal involvement of T.

We aimed to review symptoms, findings, surgical treatment options, short- and mid-term outcomes, and reoperation rate of patients diagnosed with of left coronary artery from the pulmonary artery (ALCAPA) of an anomalous origin in our institution. From May 2000 to March 2018, 33 patients who had left coronary artery originating from the pulmonary artery were retrospectively examined. The clinical features of patients, diagnostic tools and their efficacy, outcomes of surgical repair, and problems during follow-up were evaluated. Thirty-three patients (22 females, 11 males) were included in the study. At the time of surgery, the median age and weight of patients were 6 months (minimum/maximum, 1-166 months) and 6.5 kg (minimum/maximum, 3-38.5 kg), respectively. The mean follow-up was 5±3.5 years (range, 1-16 years). Dyspnea, tachypnea, diaphoresis, prolonged feeding time, and developmental delay were common presenting signs and symptoms. It was determined that all the patients who were diagnosed at another center reached our center for surgical treatment within 1 month. Twenty-three (69.7%) patients had pathologic Q wave with anterior and/or anterolateral myocardial infarction signs on an electrocardiogram (ECG), whereas 22 (66.6%) patients had ST-T segment changes. Twenty-one (63.6%) patients had cardiomegaly on the telecardiogram. A reimplantation surgery was performed to 22 patients and 10 patients underwent the Takeuchi procedure. In addition to ALCAPA repair, 5 patients needed mitral valve plasty. Atrial septal defect (ASD) and ventricular septal defect (VSD) were closed in one patient, and Tetralogy of Fallot was totally corrected in another. At discharge, there was a significant improvement in left ventricular (LV) systolic functions. At the last visit, all patients had normal LV systolic functions except four who had mild dysfunction. The mean follow-up of the four patients was 2.8 years. In the early postoperative period, complications were seen in 10 patients. Five patients died in the early postoperative period, while one patient died 9 months after the ALCAPA surgery because of low cardiac output syndrome that developed after mitral repair. Patients with ALCAPA commonly present with congestive heart failure symptoms. When the diagnosis is confirmed in these patients, surgical treatment should not be delayed. The availability of surgical center and surgery outcomes for ALCAPA diagnosed patients are comparable with other countries, but the delay in the diagnosis of disease is still a problem in our country.

BackgroundGermline mutations in the CHRNG gene that encodes the γ subunit of the embryonal acetylcholine receptor may cause the non-lethal Escobar variant (EVMPS) or the lethal form (LMPS) of multiple pterygium syndrome (MPS). In addition CHRNG mutations and mutations in other components of the embryonal acetylcholine receptor may present with fetal akinesia deformation sequence (FADS) without pterygia.MethodsIn order to elucidate further the role of CHRNG mutations in MPS/FADS, this study evaluated the results of CHRNG mutation analysis in 100 families with a clinical diagnosis of MPS/FADS.ResultsCHRNG mutations were identified in 11/41 (27%) of families with EVMPS and 5/59 (8%) with LMPS/FADS. Most patients with a detectable CHRNG mutation (21 of 24 (87.5%)) had pterygia but no CHRNG mutations were detected in the presence of central nervous system anomalies.DiscussionThe mutation spectrum was similar in EVMPS and LMPS/FADS kindreds and EVMPS and LMPS phenotypes were observed in different families with the same CHRNG mutation. Despite this intrafamilial variability, it is estimated that there is a 95% chance that a subsequent sibling will have the same MPS phenotype (EVMPS or LMPS) as the proband (though concordance is less for more distant relatives). Based on these findings, a molecular genetic diagnostic pathway for the investigation of MPS/FADS is proposed.

Background Sex chromosomal abnormalities are relatively common, yet many aspects of these syndromes remain unexplored. For instance epidemiological data in 47,XYY persons are still limited. Methods Using a national Danish registry, we identified 208 persons with 47,XYY or a compatible karyotype, whereof 36 were deceased; all were diagnosed from 1968 to 2008. For further analyses, we identified age matched controls from the male background population (n = 20,078) in Statistics Denmark. We report nationwide prevalence data, data regarding age at diagnosis, as well as total and cause specific mortality data in these persons. Results The average prevalence was 14.2 47,XYY persons per 100,000, which is reduced compared to the expected 98 per 100,000. Their median age at diagnosis was 17.1 years. We found a significantly decreased lifespan from 77.9 years (controls) to 67.5 years ( 47,XYY persons). Total mortality was significantly increased compared to controls, with a hazard ratio of 3.6 (2.6-5.1). Dividing the causes of deaths according to the International Classification of Diseases, we identified an increased hazard ratio in all informative chapters, with a significantly increased ratio in cancer, pulmonary, neurological and unspecified diseases, and trauma. Conclusion We here present national epidemiological data regarding 47,XYY syndrome, including prevalence and mortality data, showing a significantly delay to diagnosis, reduced life expectancy and an increased total and cause specific mortality.

Recent reports suggest that specific care strategies improve survival of infants with congenital diaphragmatic hernia (CDH). This review presents details of care from centers reporting high rates of survival among CDH infants. We conducted a MEDLINE search (1995 to 2006) and searched all citations in the Cochrane Central Register of Controlled Trials. Studies were included if they contained reports of >20 infants with symptomatic CDH, and >75% survival of isolated CDH. Thirteen reports from 11 centers met inclusion criteria. Overall survival, including infants with multiple anomalies, was 603/763 (79%; range: 69 to 93%). Survival for isolated CDH was 560/661 (85%; range: 78 to 96%). The frequency of extracorporeal membrane oxygenation (ECMO) use for isolated CDH varied widely among reporting centers 251/622 (40%; range: 11 to 61%), as did survival for infants with isolated CDH placed on ECMO: 149/206 (73%; range: 33 to 86%). There was no suggestion of benefit from use of antenatal glucocorticoids given after 34 weeks gestation or use of postnatal surfactant. Low mortality was frequently attributed to minimizing lung injury and adhering to center-specific criteria for ECMO. Use of strategies aimed at minimizing lung injury, tolerance of postductal acidosis and hypoxemia, and adhering to center-specific criteria for ECMO were strategies most consistently reported by successful centers. The literature lacks randomized clinical trials of these or other care strategies in this complex patient population; prospective studies of safety and long-term outcome are needed.

During end stage renal disease (ESRD) inflammatory pathways are activated which may lead to malnutrition inflammation syndrome (MIS). In the present study, 257 ESRD patients and 200 controls were included. Cytokine levels and genotyping was done by polymerase chain reaction–restriction fragment length polymorphism and enzyme-linked immunosorbent assay (ELISA). Risk was estimated through binary logistic regression. Cox proportional hazards regression and Kaplan–Meier were used for survival analysis. Tumor necrosis factor TNF-α-308 AA conferred 3.6-fold higher susceptibility (P=0.001) and higher TNF-α levels (P=0.05). TNF-α-238 AA was associated with 3.3-fold higher susceptibility to ESRD (P=0.002). IL-6-174 CC genotype conferred 3-fold risk to disease (P=0.001) along with higher IL-6 levels (P=0.001). IL-10-1082 GG genotype exhibited 2.2-fold higher susceptibility to disease (P=0.013). IL-10-592 AA/-819 TT genotypes were associated with high C reactive protein (P=0.02) and low IL-10 (P=0.03) levels. TNF-α-308 A allele was significantly associated with 2.3-fold higher risk of malnutrition. TNF-α-GAC, AGC and IL-6-CC were risk haplotypes associated with higher disease susceptibility. Combined analysis revealed 1.6-fold higher susceptibility to disease (P=0.02), there was 2-fold higher susceptibility to malnutrition (P=0.02) in high inflammation group. TNF-α-238 AA genotype was associated with 2.5-fold higher death hazard risk (P=0.02). Our study suggests that TNF-α and its genetic variants are major contributors to susceptibility to MIS in ESRD patients.

Trisomy 18 syndrome is a common autosomal aneuploidy chromosomal abnormality caused by the presence of extra chromosome 18 that leads to malformations of various parts of the body. In this study, we retrospectively investigated the effect of the medical progression and prognosis of 44 cases of trisomy 18, admitted to our neonatal intensive care unit between 1992 and 2013. The patients were divided into group A (n=20, 1992-2002) and group B (n=24, 2003-2012). Following delivery, karyotype, gender, gestational weeks, birth place, cesarean section, Apgar score and birth weight were analyzed using the Fisher's exact test, unpaired t-test and Mann-Whitney U test. Based on the statistical results, a comparison was made of the two groups and no significant differences were observed. Clinical data of major complications, mechanical ventilation, discharge from hospital and survival days were reviewed for the cases of trisomy 18. Of the 44 patients, 42 had cardiac anomaly, 16 had esophageal atresia, and 3 patients had brain anomaly. Ventilation treatment was performed in 29 cases (65.9%) and an increased percentage was identified in group B patients. The percentage survival was estimated using Kaplan-Meier curves and the two groups were analyzed using the generalized Wilcoxon test. Improvement in life prognosis was observed in group B as compared to group A. The log-rank test was used to assess survey periods of 180 days, 1 year, and the entire observation period. Although significant differences were observed for the prognosis of trisomy 18 at 180 days after birth, after 1 year and the entire survey period after birth, the significant differences were not confirmed. In conclusion, results of the present study provide information concerning genetic counseling for parents/guardians and life prognosis, prior to applying intensive management to newborns with trisomy 18.