Multidisciplinary Outpatient Clinic of Neurocutaneous Diseases: Five-year Experience of a Pediatric Tertiary Hospital in Portugal.

INTRODUCTION: Neurocutaneous syndromes (NCS) are a heterogeneous group of conditions with multiorgan involvement and diverse manifestations, evolving throughout life with significant morbidity. A multidisciplinary approach to NCS patients has been advocated, although a specific model is not yet established. The aim of this study was 1) to describe the organization of the recently created Multidisciplinary Outpatient Clinic of Neurocutaneous Diseases (MOCND) at a Portuguese pediatric tertiary hospital; 2) to share our institutional experience focusing on the most common conditions, neurofibromatosis type 1 (NF1) and tuberous sclerosis complex (TSC); 3) to analyze the advantages of a multidisciplinary center and approach in NCS. METHODS: Retrospective analysis of 281 patients enrolled in the MOCND over the first five years of activity (October 2016 to December 2021), reviewing genetics, family history, clinical features, complications, and therapeutic strategies for NF1 and TSC. RESULTS: The clinic works weekly with a core team of pediatricians and pediatric neurologists supported by other specialties as needed. Of the 281 patients enrolled, 224 (79.7%) had identifiable syndromes such as NF1 (n = 105), TSC (n = 35), hypomelanosis of Ito (n = 11), Sturge-Weber syndrome (n = 5), and others. In NF1 patients, 41.0% had a positive family history, all manifested café-au-lait macules, 38.1% neurofibromas with 45.0% being large plexiform neurofibromas. Sixteen were under treatment with selumetinib. Genetic testing was performed in 82.9% of TSC patients with pathogenic variants found in TSC2 gene in 72.4% patients (82.7% if considered contiguous gene syndrome). Family history was positive in 31.4%. All TSC patients presented hypomelanotic macules and fulfilled diagnostic criteria. Fourteen patients were being treated with mTOR inhibitors. CONCLUSION: Offering a systematic and multidisciplinary approach to NCS patients enables timely diagnosis, promotes a structured follow-up, and encourages discussion to outline management plans for optimal care to every patient, with significant impact on the quality of life of patients and families.

Minimally invasive surgery for pilonidal disease: Outcomes of the Gips technique-A systematic review and meta-analysis.

BACKGROUND: Pilonidal disease is a common inflammatory condition that significantly impacts quality of life. Currently, there is a tendency to favor minimally invasive procedures. The present review aims to summarize the evidence and assess the outcomes of the Gips procedure. METHODS: A systematic review was conducted on MEDLINE/Pubmed, Scopus, Web of Science, and Cochrane Library databases until December 2022. Eligible studies included patients with pilonidal disease submitted to the Gips procedure, reporting at least 1 of the following outcomes: wound complications, wound healing time, time to resume daily activities, and recurrence (International Prospective Register of Systematic Reviews protocol: CRD42023389269). The National Institutes of Health assessment tool was used for risk of bias evaluation. Meta-analysis was performed using OpenMeta[Analyst] and R software, and a subgroup analysis was performed when applicable. RESULTS: Thirteen observational studies with a total of 4,286 patients submitted to Gips were included. The pooled wound complications rate was 7.8% (95% confidence interval: 5.1-10.6), the median time to resume daily activities was 1 day (95% confidence interval: 1-2), and the mean wound healing time was 4.7 weeks (95% confidence interval: 3.0-6.4). Subgroup analysis showed that pooled recurrence rate was 6.5% (95% confidence interval: 5.2-7.8) up to 2 years and 38.9% (95% confidence interval: 27.1-50.7) after more than 2 years of surgery. Most results showed substantial heterogeneity across studies. CONCLUSION: Despite apparent favorable outcomes of the Gips procedure, there is a high recurrence rate over time. Because included studies had an observational nature and unstandardized methodologies, comparative randomized controlled trials with longer follow-ups are needed for high-level evidence regarding these outcomes.

Benzodiazepine use and mortality in chronic heart failure.

INTRODUCTION: The prognostic implications of using benzodiazepines (BZD) in heart failure (HF) patients are still unknown. OBJECTIVES: This study aimed to assess the association of BZD use with all­cause death in ambulatory, chronic HF patients. PATIENTS AND METHODS: We investigated a retrospective cohort of ambulatory HF patients with left ventricular systolic dysfunction (LVSD). The patients were followed up from their first medical appointment until January 2021 and all­cause mortality was the primary end point. The Cox regression analysis was used to assess the association between BZD use and all­cause mortality. Subgroup analyses were performed considering age, sex, body mass index (BMI), respiratory disease, chronic kidney disease (CKD), and New York Heart Association (NYHA) class. Multivariable models were built to account for confounders. RESULTS: We studied 854 patients (69% men), of mean (SD) age 71 (13) years, of whom 51% had severe LSVD, and 242 (28.3%) regularly used BZD. During a median follow­up of 46 months, 443 patients (51.9%) died. BZD use predicted no crude survival disadvantage in the entire investigated group and in the subgroup analysis according to sex, respiratory disease, BMI, and NYHA class. BZD use was not mortality­associated among patients aged 75 years and younger. However, in those older than 75 years the hazard ratio (HR) of all­cause death was 1.3 (95% CI, 0.99-1.69; P = 0.06). BZD use seemed safe in the patients without CKD, but in those with CKD it was associated with worse survival (HR, 1.33; 95% CI, 1.02-1.73). In a multivariable­adjusted analysis, the use of BZD was independently associated with increased death risk (HR, 1.36; 95% CI, 1.06-1.75). CONCLUSIONS: The patients medicated with BZD presented a 36% higher risk of dying. BZD should probably be used with caution, particularly in older HF patients and in those with CKD.

A novel variant of DeSanto-Shinawi Syndrome with joint manifestations.

The clinical features associated with WAC haploinsufficiency include recognizable dysmorphic facial features, variable degrees of developmental delay and intellectual disability that were recently delineated as DeSanto-Shinawi syndrome (OMIM 616708). We describe a patient with DeSanto-Shinawi syndrome caused by a novel frameshift variant in WAC gene (NM_016628.4(WAC):c.1689del (p.Phe563Leufs*6)). As noted in cases previously reported, our patient phenotype included facial dysmorphism, intellectual disability, behavioral problems, feeding difficulties, hirsutism, constipation and astigmatism. She also had limited range of motion of joints since birth and Juvenile Idiopathic Arthritis diagnosed at eleven years old. Although in the last years some additional features were reported in DeSanto-Shinawi syndrome, joint manifestations have not been previously described. As limited range of motion of joints was reported since birth with no correlation with arthritis onset, it could be a new clinical feature. Polyarthritis in this patient can be only a coincidence, since there is a first degree relative with psoriasis, or might be related to WAC mutation. Indeed, WAC encodes a protein that plays a vital role in autophagy. It has already been demonstrated that WAC haploinsufficiency leads to increased autophagy and, according to different authors, increased autophagy may display a pathogenic role in several autoimmune disorders such as Rheumatoid Arthritis and Juvenile Idiopathic Arthritis. Thus, WAC haploinsufficiency may have contributed to autoimmune disorder in this patient.

The ratio of furosemide dosage to urinary sodium concentration predicts mortality in patients with chronic stable heart failure.

INTRODUCTION: The urinary sodium (UNa) concentration is associated with outcomes in patients with acute heart failure (HF). Its impact in individuals with chronic HF is unknown. OBJECTIVES: This study examined the combined effect of diuretic dosage and UNa concentration in chronic HF. PATIENTS AND METHODS: The research sample for this retrospective cohort study consisted of ambulatory patients receiving optimized therapy and followed in an HF clinic. The patients were recruited between 2009 and 2012. The exclusion criteria were therapeutic adjustments or hospital admissions in the previous 2 months and renalreplacement therapy. The patients were followed for 5 years; the endpoint was all­cause mortality. The association between the ratio of furosemide dosage to UNa concentration and 5­year mortality was studied using a receiver operating characteristic (ROC) curve. The  patients were cross­classified according to daily furosemide dosage (with the cutoff set at 80 mg) and UNa concentration (80 mEq/l). Multivariable Cox regression analysis was used to assess the prognostic impact of the ratio. RESULTS: We analyzed 283 patients with chronic HF (70.3% male; mean age, 69 years). During follow­up, 134 patients died. The median furosemide dosage was 80 mg/day and the mean UNa concentration was 85 mEq/l. Based on the ROC curve, the best cutoff for the ratio of daily furosemide dosage to UNa concentration was 0.8. Patients with a ratio of 0.8 or higher had an adjusted hazard ratio for 5­year mortality of 2.85 (95% CI, 1.78-4.58). Patients with a UNa excretion rate of less than 80 mEq/l who wereadministered 80 mg or more of furosemide per day were found to have a worse prognosis (HR, 4.15; 95% CI, 2.31-7.45) when compared with those with a UNa excretion rate of 80 mEq/l or more and less than 80 mg furosemide per day. CONCLUSIONS: Combining the diuretic dosage and measurement of UNa excretion can be used to refine risk stratification in chronic HF. The furosemide­to­UNa ratio can be a surrogate marker for diuretic resistance and has a prognostic impact in chronic HF.

Hypogonadotropic hypogonadism due to compound heterozygous mutations TACR3 in siblings.

The authors present a new association of two heterozygous TACR3 mutations (p.Arg230His and p.Trp275*) responsible for a clinical trait of normosmic congenital hypogonadotropic hypogonadism in a family.

Age affects the prognostic impact of diabetes in chronic heart failure.

AIMS: Increasing age is an established prognostic determinant in chronic heart failure (HF). Diabetes often complicates HF in its course and appears to worsen HF prognosis. A differential impact of diabetes depending on patients' age was not yet studied. We evaluated the impact of diabetes in the mortality of HF patients according to their age. METHODS: We studied a cohort of chronic ambulatory HF patients prospectively recruited. Patients were on optimized evidence-based therapy, and they were excluded if on renal replacement therapy or if they had any therapy modification or hospitalizations in the previous 2 months. Patients were followed for up to 5 years; all-cause mortality was analyzed. Mortality predictors were assessed using a Cox regression. Analysis was stratified according to patient's age: cutoff 75 years. Multivariate models were built. Interaction between diabetes and age was formally tested. RESULTS: We studied 283 chronic HF patients; mean age was 69 years and 70.3% were male; 58.0% had severe systolic dysfunction; 105 (37.1%) were diabetic. In patients with less than 75 years, the coexistence of diabetes predicted a multivariate adjusted 1.98 (95% CI 1.13-3.46) 5-year death risk while in older patients (≥ 75 years) no significant association was reported. Age interacted with the prognostic impact of diabetes, p for interaction = 0.04. CONCLUSIONS: The prognostic impact of diabetes in chronic HF depends on patient's age. In patients < 75 years, the coexistence of diabetes predicts an almost double risk of 5-year mortality; no such association exists in patients with 75 years or above. Diabetes predicts mortality only in younger HF patients.

Prognostic prediction in acute heart failure patients with extreme BNP values.

BACKGROUND: Some patients have good prognosis despite elevated B-type natriuretic peptide (BNP), while others have ominous outcome with low BNP. We aimed at characterising these groups of patients. METHODS: We analysed patients prospectively included in an acute HF registry. Vital status within 1-year post discharge was ascertained. A receiver-operating characteristic curve was used to define discharge BNP cut-offs for 1-year death prediction. Among survivors, we compared patients with low and not-low BNP (cut-off 400 pg/mL); and among non-survivors those with high vs not-high BNP (cut-off 2000 pg/mL). In the specific subgroups of patients with low and high BNP, mortality predictors were assessed with multivariate Cox-regression analysis. RESULTS: We studied 584 patients, median age 78 years, 62.5% had HF with reduced ejection fraction; and 199 (34.1%) died during the first year. Non-survivors were very homogeneous irrespective of BNP, survivors were substantially different. In patients discharged with BNP <400 pg/mL, increasing age independently predicted death; when BNP ≥2000 pg/mL death predictors were higher NYHA class, and non-use of evidence-based therapy. BNP was outcome associated in both groups. CONCLUSIONS: Different prognostic predictors may play a role in different BNP levels. We suggest that risk stratification in HF would probably be more accurate if made on top of BNP knowledge.

Molecular characterization of a rare analphoid supernumerary marker chromosome derived from 7q35 → qter: a case report.

BACKGROUND: Analphoid supernumerary marker chromosomes (aSMC) constitute one of the smallest groups of SMC, and are characterized by a centromeric constriction but no detectable alpha-satellite DNA. These marker chromosomes cannot be properly identified by conventional banding techniques alone, and molecular cytogenetic methods are necessary for a detailed characterization. Analphoid SMC derived from chromosome 7 are extremely rare, with only five cases reported so far. CASE PRESENTATION: In this work we report an aSMC involving the terminal long arm of chromosome 7 in a 10-year-old boy with multiple dysmorphic features and severe development delay. Cytogenetic analysis revealed a mosaic karyotype with the presence of an extra SMC, de novo, in 20% of lymphocytes and 73% of fibroblast cells. Next, we performed FISH analysis with multiple DNA probes and cCGH analysis. This identified the origin of the SMC as an analphoid marker resulting of invdup rearrangement of 7q35-qter region. Affimetrix CytoScan HD array analysis redefined the aSMC as a 15.42 Mb gain at 7q35-q36.3 (minimum tetraplicated region-chr7: 143,594,973-159,119,707; GRCh37/hg19) of maternal origin that encloses 67 OMIM genes, 16 of which associated to disease. Uniparental disomy of chromosome 7 (UPD 7) has been excluded. CONCLUSIONS: We report the first patient with an aSMC(7) derived from the terminal 7q region who has been molecularly and clinically full characterized. The use of SNParray in the characterization of SMC reveals to be a powerful tool, giving information not only about copy number variation but also about loss-of-heterozygosity and parental origin. We conclude that an integrated genome-wide copy number variation analysis, if possible associated to FISH and gene expression studies, could facilitate in the future the difficult task of establishing accurate genotype-phenotype correlations and help to improve genetic counselling.

Sound Levels and Risk Perceptions of Music Students During Classes.

It is well recognized that professional musicians are at risk of hearing damage due to the exposure to high sound pressure levels during music playing. However, it is important to recognize that the musicians' exposure may start early in the course of their training as students in the classroom and at home. Studies regarding sound exposure of music students and their hearing disorders are scarce and do not take into account important influencing variables. Therefore, this study aimed to describe sound level exposures of music students at different music styles, classes, and according to the instrument played. Further, this investigation attempted to analyze the perceptions of students in relation to exposure to loud music and consequent health risks, as well as to characterize preventive behaviors. The results showed that music students are exposed to high sound levels in the course of their academic activity. This exposure is potentiated by practice outside the school and other external activities. Differences were found between music style, instruments, and classes. Tinnitus, hyperacusis, diplacusis, and sound distortion were reported by the students. However, students were not entirely aware of the health risks related to exposure to high sound pressure levels. These findings reflect the importance of starting intervention in relation to noise risk reduction at an early stage, when musicians are commencing their activity as students.

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 ß-cell function, adding information to the existent mutation databases.

Low prealbumin is strongly associated with adverse outcome in heart failure.

OBJECTIVE: Prealbumin is one of the best indicators of nutritional status. We previously showed that prealbumin predicted in-hospital mortality in heart failure (HF) patients. We evaluated if a low discharge prealbumin after admission with acute HF would predict morbidity and mortality. METHODS: We conducted a prospective observational study. Patients admitted with a primary diagnosis of HF were studied. Follow-up was up to 6 months. Endpoints analysed were: all-cause and HF-death; all-cause and worsening HF hospitalisation. Patients with discharge prealbumin ≤15.0 mg/dL and those with prealbumin >15 mg/dL were compared. A Cox-regression analysis was used to evaluate the prognostic impact of low prealbumin. RESULTS: We studied 514 patients. Mean age was 78 years and 45.7% were male. During follow-up, 101 patients died (78 for HF) and 209 patients were hospital readmitted (140 for worsening HF). Median prealbumin was 20.1 (15.3-25.3) mg/dL. Patients with lower prealbumin were more often women, older aged and with non-ischaemic HF; they had lower albumin, haemoglobin and total cholesterol; and higher glomerular filtration rate, C-reactive protein, B-type natriuretic peptide and length of hospital stay. Lower prealbumin associated with less ß-blocker and statin use. Patients with discharge prealbumin ≤15 mg/dL had a multivariate adjusted HR of 6-month all-cause and HF death of 1.67 (1.00 to 2.80) and 2.12 (1.19 to 3.79) respectively and of all-cause and HF readmission of 1.47 (1.01 to 2.14) and 1.58 (1.01 to 2.47). CONCLUSIONS: Patients with discharge prealbumin ≤15 mg/dL have an higher risk of 6 months morbidity and mortality. The unbalance between protein-energy demands and its availability predicts ominous HF outcome.

Prognostic value of neutrophil gelatinase-associated lipocalin in acute heart failure.

BACKGROUND: The identification of patients at risk for worse outcome is still a challenge. We hypothesized that cystatin C, a marker of renal function, and neutrophil gelatinase-associated lipocalin (NGAL), a marker of acute renal injury, would have a role in the prognostic stratification of these patients. METHODS: We prospectively evaluated 121 patients admitted for acute HF. Serum NGAL and cystatin C levels were measured on the first morning after admission. The outcome measures used were the occurrence of death from all causes, and the combined endpoint defined as the first occurrence of either death or hospital admission. Patients were followed for up to 3 months. RESULTS: The variables associated with a higher occurrence of death in a univariate approach were older age and higher levels of BNP, cystatin C and NGAL, and those associated with the occurrence of the combined endpoint were older age, Diabetes mellitus, lower GFR, type 1 cardio-renal syndrome, BNP, cystatin C and NGAL. BNP and NGAL remained independent predictors of the occurrence of both all-cause death and the combined endpoint. NGAL levels in the 75th percentile (>167.5 ng/mL) were associated with a 2.7-fold increase in the risk of death and a 2.9-fold increase in the risk of the first occurrence of either death or hospitalization. CONCLUSIONS: Serum NGAL, a marker of acute renal injury, is an independent predictor of worse short term prognosis in patients with acute HF. This suggests a role of renal damage, apart from renal function, in the prognosis of these patients.

De novo mutations of SETBP1 cause Schinzel-Giedion syndrome.

Schinzel-Giedion syndrome is characterized by severe mental retardation, distinctive facial features and multiple congenital malformations; most affected individuals die before the age of ten. We sequenced the exomes of four affected individuals (cases) and found heterozygous de novo variants in SETBP1 in all four. We also identified SETBP1 mutations in eight additional cases using Sanger sequencing. All mutations clustered to a highly conserved 11-bp exonic region, suggesting a dominant-negative or gain-of-function effect.

Tetra-amelia and lung hypo/aplasia syndrome: new case report and review.

Tetra-amelia is a rare malformation that may be associated with other anomalies and is usually inherited in an autosomal recessive pattern. We describe a fetus, born to a nonconsanguineous couple, with tetra-amelia, bilateral cleft lip and palate and bilateral lung agenesis, without other anomalies. Karyotype was normal (46,XX) and premature centromere separation was excluded. No mutation was identified upon molecular analysis of WNT3, HS6ST1, and HS6ST3. We reviewed the literature and the differential diagnosis to clarify the clinical delineation of conditions associated with tetra-amelia. The present report describes the sixth family with this pattern of malformations and reinforces the evidence that the "tetra-amelia and lung hypo/aplasia syndrome" is a distinct autosomal recessive condition, with no identified gene thus far.