Variant Rett Syndrome in a Girl with a Pericentric X-Chromosome Inversion Leading to Epigenetic Changes and Overexpression of the MECP2 Gene

Rett syndrome is a neurodevelopmental disorder caused by mutations in the MECP2 gene. We investigated the genetic basis of disease in a female patient with a Rett-like clinical. Karyotype analysis revealed a pericentric inversion in the X chromosome -46,X,inv(X)(p22.1q28), with breakpoints in the cytobands where the MECP2 and CDKL5 genes are located. FISH analysis revealed that the MECP2 gene is not dislocated by the inversion. However, and in spite of a balanced pattern of X inactivation, this patient displayed hypomethylation and an overexpression of the MECP2 gene at the mRNA level in the lymphocytes (mean fold change: 2.55±0.38) in comparison to a group of control individuals; the expression of the CDKL5 gene was similar to that of controls (mean fold change: 0.98±0.10). No gains or losses were detected in the breakpoint regions encompassing known or suspected transcription regulatory elements. We propose that the de-regulation of MECP2 expression in this patient may be due to alterations in long-range genomic interactions caused by the inversion and hypothesize that this type of epigenetic de-regulation of the MECP2 may be present in other RTT-like patients.

Propylthiouracil Induced Pulmonary-Renal Syndrome: a Case Report.

Propylthiouracil (PTU) is known to induce antineutrophil cytoplasmatic antibody (ANCA) seropositivity; however, small vessel vasculitis (SVV) with pulmonary and renal involvement is rare. We present the case of an 81-year-old woman on PTU treatment due to toxic nodular goitre who developed alveolar hemorrhage and rapidly progressive glomerulonephritis. The authors highlight the importance of early recognising drug-induced pulmonary-renal syndrome (PRS) in order to avoid unnecessary tests, a delay in the diagnosis and evolution to end-stage kidney disease or life-threatening conditions.

Rett Syndrome With and Without Detected MECP2 Mutations: an Attempt to Redefine Phenotypes

Background: The diagnosis of Rett syndrome (RTT) is based on a set of clinical criteria, irrespective of mutation status. The aims of this study were (1) to define the clinical differences existing between patients with Rett syndrome with (Group I) and without a MECP2 mutation (Group II), and (2) to characterize the phenotypes associated with the more common MECP2 mutations. Patients and Methods: We analyzed 87 patients fulfilling the clinical criteria for RTT. All were observed and videotaped by the same paediatric neurologist. Seven common mutations were considered separately, and associated clinical features analysed. Results: Comparing Group I and II, we found differences concerning psychomotor development prior to onset, acquisition of propositive manipulation and language, and evolving autistic traits. Based on age at observation, we found differences in eye pointing, microcephaly, growth, number of stereotypies, rigidity, ataxia and ataxic-rigid gait, and severity score. Patients with truncating differed from those with missense mutations regarding acquisition of propositive words and independent gait, before the beginning of the disease, and microcephaly, growth, foot length, dystonia, rigidity and severity score, at the time of observation. Patients with the R168X mutation had a more severe phenotype, whereas those with R133C showed a less severe one. Patients with R294X had a hyperactive behaviour, and those with T158M seemed to be particularly ataxic and rigid. Conclusion: A clear regressive period (with loss of prehension and language, deceleration of growth) and the presence of more than three different stereotypies, rigidity and ataxic-rigid gait seemed to be very helpful in differentiating Group I from Group II.

Analysis of Highly Conserved Regions of the 3'UTR of MECP2 Gene in Patients with Clinical Diagnosis of Rett Syndrome and Other Disorders Associated with Mental Retardation

In this work we explored the role of the 3'UTR of the MECP2 gene in patients with clinical diagnosis of RTT and mental retardation; focusing on regions of the 3'UTR with almost 100% conservation at the nucleotide level among mouse and human. By mutation scanning (DOVAM-S technique) the MECP2 3'UTR of a total of 66 affected females were studied. Five3'UTR variants in the MECP2 were found (c.1461+9G>A, c.1461+98insA, c.2595G>A, c.9961C>G and c.9964delC) in our group of patients. None of the variants found is located in putative protein-binding sites nor predicted to have a pathogenic role. Our data suggest that mutations in this region do not account for a large proportion of the RTT cases without a genetic explanation.

Burnout dos enfermeiros nos serviços de saúde em Portugal : um estudo de caso na Saúde 24 Porto

RESUMO - A síndrome de burnout, definida pela exaustão emocional, despersonalização e realização pessoal, designa um estado de fadiga física e emocional crónico dos profissionais, o qual pode comprometer as organizações. Neste estudo descritivo, pretende-se estudar a síndrome de burnout nos enfermeiros dos serviços de saúde, especialmente focado nos serviços de atendimento permanente telefónico, suas características, consequências e estratégias de prevenção. A população alvo serão todos os enfermeiros que trabalham em serviços de atendimento permanente telefónico e a amostra, não probabilística e de conveniência, os enfermeiros que desempenham funções no centro de atendimento da Saúde 24 Porto. Primeiramente aborda-se o conceito de burnout e a sua relação com a prática de Enfermagem, de seguida é realizada uma descrição sobre os centros de atendimento em saúde até à atual situação da Saúde 24. Na amostra em estudo, enfermeiros da Saúde 24 Porto, existe predominância do sexo feminino (66,99%) e a média de idades é de 32 anos (26 anos de idade mínima, 49 de idade máxima e desvio padrão de 4,59). Constatou-se que 94,26% desempenha funções de enfermeiro comunicador e os restantes 5,74% são enfermeiros supervisores, a média de anos de atividade profissional é de 5,67 anos e 36,4% dos enfermeiros desempenha funções na Saúde 24 há mais de 3 anos. Foi aplicado o Inventário de Burnout de Maslach e os resultados indicaram a ausência de síndrome de esgotamento profissional. Existem níveis médios de burnout, sustentados pelos valores obtidos na exaustão emocional no terço inferior (<19,10), e valores no terço inferior, na realização pessoal (<38,00) e nível baixo na despersonalização (<4,90). No que concerne à idade não foram encontradas correlações significativas em nenhuma das dimensões, contudo, no que refere ao tempo de serviço verificou-se que existem correlações significativas e negativas para a exaustão emocional e para a despersonalização ou seja, a tendência atual é a de que os enfermeiros com menos tempo de serviço têm maior tendência para scores mais altos de burnout. Existe uma relação entre as variáveis, grau académico, exaustão e despersonalização, a qual mostrou uma tendência para scores mais altos em relação a enfermeiros licenciados e pós graduados nas dimensões de exaustão e despersonalização contrariamente aos enfermeiros com o grau de mestre ou especialidade. Existe também uma relação entre as variáveis género e despersonalização, sendo o score baixo, aquele que apresenta maior expressão no sexo masculino, mas principalmente no sexo feminino. As mulheres têm scores mais baixos que os homens nesta dimensão, traduzindo-se na percentagem mais elevada obtida (67,1%, contra 53,6%). E em contrapartida nos resultados obtidos para o score alto relativo à despersonalização, os homens apresentam um resultado pior do que as mulheres, sendo 26,1% para os homens e 12,1% para as mulheres. Quando se examinam as funções desempenhadas distribuídas pelas dimensões de burnout, verifica-se a existência de uma relação entre a variável função desempenhada e a realização pessoal. Nos resultados percebeu-se que, quanto mais elevada a função desempenhada (enfermeiro supervisor), mais baixa é a realização pessoal. E esta dimensão tem o score inverso, logo a interpretação deverá ser feita no sentido de que, quanto mais elevada for a função, maior será a realização pessoal. Os resultados obtidos são animadores contudo a vulnerabilidade para este tipo de problema, entre enfermeiros, potencializada pelo tipo de trabalho realizado por estes profissionais de saúde será desejável estar atento e usar estratégias para enfrentar o burnout quando ele surgir. O fenómeno burnout não é apenas como um problema do individuo mas é principalmente um problema da organização.

Multiple Haemangiomas, Diaphragmatic Eventration and Beckwith-Wiedemann Syndrome: An Unusual Association

A 6-month-old girl with Beckwith-Wiedemann syndrome, multiple haemangiomas (axillary, laryngeal, pulmonary and hepatic) and diaphragmatic eventration was reported. All tumours responded to treatment with propranolol. The surgical correction of diaphragmatic eventration was crucial to a better outcome.

Validation of Two US Risk Scores for Percutaneous Coronary Intervention in a Single-Center Portuguese Population of Patients with Acute Coronary Syndrome

INTRODUCTION: New scores have been developed and validated in the US for in-hospital mortality risk stratification in patients undergoing coronary angioplasty: the National Cardiovascular Data Registry (NCDR) risk score and the Mayo Clinic Risk Score (MCRS). We sought to validate these scores in a European population with acute coronary syndrome (ACS) and to compare their predictive accuracy with that of the GRACE risk score. METHODS: In a single-center ACS registry of patients undergoing coronary angioplasty, we used the area under the receiver operating characteristic curve (AUC), a graphical representation of observed vs. expected mortality, and net reclassification improvement (NRI)/integrated discrimination improvement (IDI) analysis to compare the scores. RESULTS: A total of 2148 consecutive patients were included, mean age 63 years (SD 13), 74% male and 71% with ST-segment elevation ACS. In-hospital mortality was 4.5%. The GRACE score showed the best AUC (0.94, 95% CI 0.91-0.96) compared with NCDR (0.87, 95% CI 0.83-0.91, p=0.0003) and MCRS (0.85, 95% CI 0.81-0.90, p=0.0003). In model calibration analysis, GRACE showed the best predictive power. With GRACE, patients were more often correctly classified than with MCRS (NRI 78.7, 95% CI 59.6-97.7; IDI 0.136, 95% CI 0.073-0.199) or NCDR (NRI 79.2, 95% CI 60.2-98.2; IDI 0.148, 95% CI 0.087-0.209). CONCLUSION: The NCDR and Mayo Clinic risk scores are useful for risk stratification of in-hospital mortality in a European population of patients with ACS undergoing coronary angioplasty. However, the GRACE score is still to be preferred.

Novel FGFR1 Mutations in Kallmann Syndrome and Normosmic Idiopathic Hypogonadotropic Hypogonadism: Evidence for the Involvement of an Alternatively Spliced Isoform

OBJECTIVE: To determine the prevalence of fibroblast growth factor receptor 1 (FGFR1) mutations and their predicted functional consequences in patients with idiopathic hypogonadotropic hypogonadism (IHH). DESIGN: Cross-sectional study. SETTING: Multicentric. PATIENT(S): Fifty unrelated patients with IHH (21 with Kallmann syndrome and 29 with normosmic IHH). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Patients were screened for mutations in FGFR1. The functional consequences of mutations were predicted by in silico structural and conservation analysis. RESULT(S): Heterozygous FGFR1 mutations were identified in six (12%) kindreds. These consisted of frameshift mutations (p.Pro33-Alafs*17 and p.Tyr654*) and missense mutations in the signal peptide (p.Trp4Cys), in the D1 extracellular domain (p.Ser96Cys) and in the cytoplasmic tyrosine kinase domain (p.Met719Val). A missense mutation was identified in the alternatively spliced exon 8A (p.Ala353Thr) that exclusively affects the D3 extracellular domain of FGFR1 isoform IIIb. Structure-based and sequence-based prediction methods and the absence of these variants in 200 normal controls were all consistent with a critical role for the mutations in the activity of the receptor. Oligogenic inheritance (FGFR1/CHD7/PROKR2) was found in one patient. CONCLUSION(S): Two FGFR1 isoforms, IIIb and IIIc, result from alternative splicing of exons 8A and 8B, respectively. Loss-of-function of isoform IIIc is a cause of IHH, whereas isoform IIIb is thought to be redundant. Ours is the first report of normosmic IHH associated with a mutation in the alternatively spliced exon 8A and suggests that this disorder can be caused by defects in either of the two alternatively spliced FGFR1 isoforms.

Acute Sheehan's Syndrome Presenting as Central Diabetes Insipidus

Sheehan's syndrome occurs as a result of ischaemic pituitary necrosis due to severe postpartum haemorrhage. Improvements in obstetrical care have significantly reduced its incidence in developed countries, but postpartum pituitary infarction remains a common cause of hypopituitarism in developing countries. We report a case of severe postpartum haemorrhage followed by headache, central diabetes insipidus and failure to lactate, which prompted us to investigate and identify both anterior and posterior pituitary deficiency compatible with Sheehan's syndrome. A timely diagnosis allowed us to implement an adequate treatment and follow-up plan, which are known to improve clinical status and patient outcome.

Mitchell-Riley Syndrome: A Novel Mutation in RFX6 Gene

A novel RFX6 homozygous missense mutation was identified in an infant with Mitchell-Riley syndrome. The most common features of Mitchell-Riley syndrome were present, including severe neonatal diabetes associated with annular pancreas, intestinal malrotation, gallbladder agenesis, cholestatic disease, chronic diarrhea, and severe intrauterine growth restriction. Perijejunal tissue similar to pancreatic tissue was found in the submucosa, a finding that has not been previously reported in this syndrome. This case associating RFX6 mutation with structural and functional pancreatic abnormalities reinforces the RFX6 gene role in pancreas development and β-cell function, adding information to the existent mutation databases.

Mutations in the MECP2 Gene Are Not a Major Cause of Rett Syndrome-Like or Related Neurodevelopmental Phenotype in Male Patients

Rett syndrome is a genetic neurodevelopmental disorder that affects mainly girls, but mutations in the causative MECP2 gene have also been identified in boys with classic Rett syndrome and Rett syndrome-like phenotypes. We have studied a group of 28 boys with a neurodevelopmental disorder, 13 of which with a Rett syndrome-like phenotype; the patients had diverse clinical presentations that included perturbations of the autistic spectrum, microcephaly, mental retardation, manual stereotypies, and epilepsy. We analyzed the complete coding region of the MECP2 gene, including the detection of large rearrangements, and we did not detect any pathogenic mutations in the MECP2 gene in these patients, in whom the genetic basis of disease remained unidentified. Thus, additional genes should be screened in this group of patients.