Wave Fields and Nearshore Currents in the Coastal Region Opposite San Mauro Cilento (Italy)

In this paper in order to simulate nearshore currents in computational domains representing the complex morphology of real coastal regions we use a model based on a contravariant integral form of the fully nonlinear Boussinesq equations (FNBE). The contravariant integral form, in which Christoffel symbols are absent, of the continuity equation does not contain the dispersive term. The Boussinesq equation system is numerically solved by a hybrid finite volume-finite difference scheme. The wave breaking is represented by discontinuities of the weak solution of the integral form of the nonlinear shallow water equations (NSWE). The capacity of the proposed model to correctly simulate the wave train propagation on a highly distorted grid is verified against test case present in the literature. The simulation of wave fields and nearshore currents in the coastal region, opposite San Mauro Cilento (Italy) in presence of a system of T-head groins, is numerically reproduced by using the proposed model

Disorders of the RAS-MAPK pathway or Rasopathies: clinical, diagnostic and therapeutic aspects

Le “RASopatie” includono un gruppo di patologie congenito-malformative a trasmissione autosomica-dominante causate da mutazioni eterozigoti germinali in geni che codificano per proteine del pathway RAS-MAPKinasi. Sono caratterizzate da dismorfismi faciali, iposomia, cardiopatia congenita, anomalie ectodermiche e scheletriche, coinvolgimento cognitivo e suscettibilità tumorale. La bassa statura è uno dei principali elementi distintivi sul quale si può agire sotto il profilo terapeutico, mediante somministrazione di Ormone della Crescita biosintetico (GH). In questo studio è stato analizzato l’andamento accrescitivo in un ampio gruppo di 88 pazienti affetti da Rasopatia con diagnosi molecolare confermata. Sono stati valutati: distribuzione per genotipo, prevalenza delle caratteristiche fenotipiche e correlazione genotipo-fenotipo sull’intero gruppo di studio ed in particolare andamento accrescitivo spontaneo, proporzioni corporee, sviluppo puberale, e dati di statura finale (FH) in 33 soggetti, di cui 16 trattati con GH per deficit secretivo (GHD). Valutati inoltre efficacia e sicurezza della terapia con GH, definito il rischio oncologico e quantificato il coinvolgimento psico-cognitivo. 33 pazienti hanno mostrato GHD e sono stati trattati con GH per 6,8 ± 4,8 anni. Prima dell’ inizio della terapia, la velocità di crescita era - 2.6 ± 1.3 SDS e i livelli basali di IGF1 pari a - 2.0 ± 1.1 SDS. La terapia con GH a lungo termine, iniziata precocemente durante l’infanzia, ha determinato un guadagno staturale positivo rispetto ai pazienti non trattati (+1,3 SDS), normalizzando la FH per gli standards di condizione ma non per la popolazione generale e il Target staturale parentale. Il timing di sviluppo puberale ha influenzato negativamente lo scatto di crescita puberale. 1/88 soggetti, non sottoposta a terapia con GH, ha sviluppato neoplasia. Sono emersi ritardo mentale (41.1%), deficit visuo-spaziali (41.8%), ADHD (38.8%), anomalie del SNC (24.4%) e anomalie del tracciato elettroencefalografico (6.7%).RASopathies are developmental disorders caused by heterozygous germline mutations in genes encoding proteins in the RAS-MAPK signaling pathway. These conditions share facial dysmorphism, failure to thrive, congenital heart disease, ectodermal, and skeletal anomalies, variable cognitive involvement, and susceptibility to certain malignancies as major characteristics. This study analized clinical features, growth trend and body proportions in 88 patients affected by RASopathies with molecularly confirmed diagnosis, and FH reached in 33, including 16 treated with GH therapy for proven GH deficiency. Clinically, 69 patients (78.4%) had a diagnosis of Noonan syndrome (NS), seven of NS/Loose anagen hair (8.0%), six of CFC syndrome (6.8%), and two of Costello syndrome, Noonan syndrome with multiple lentigines (NSML) and Legius syndrome. Among them, 52 (59.1%) had PTPN11 mutations, while the other genotypes were less than 10%. Most patients were born at term, after a physiological pregnancy and presented regular neonatal adaptation. 75.9% patients had cardiac anomalies and 20.2% needed surgery for cardiac involvement. Thirty-three patients showed GH deficiency after pharmacological tests, and were GH-treated for an average period of 6.8±4.8 years. Before starting therapy, HV was -2.6±1.3 SDS, and mean basal IGF1 levels were -2.0±1.1 SDS. Long-term GH therapy, starting early during childhood, resulted in a positive height response compared with untreated patients (1.3 SDS in terms of height-gain), normalizing FH for Ranke standards but not for general population and Target Height. The delayed pubertal development and the inadequate pubertal catch-up growth could explain the impaired FH. Our patients on GH-therapy benefitted from the pharmacological treatment if started in pre-puberty and given for a long time. Probably, the prepubertal start of GH-treatment could compensate the lack of a pubertal growth. 1/88 patient had cancer, but she didn’t received GH. The patients presented cognitive impairment (41.1%), ADHD (38.8%), SNC anomalies (24.4%) and EEG alterations (6.7%)

Lipid profile in Noonan syndrome and related disorders: trend by age, sex and genotype

BackgroundRASopathies are developmental disorders caused by dysregulation of the RAS-MAPK signalling pathway, which contributes to the modulation of multiple extracellular signals, including hormones and growth factors regulating energetic metabolism, including lipid synthesis, storage, and degradation.Subjects and methodsWe evaluated the body composition and lipid profiles of a single-centre cohort of 93 patients with a molecularly confirmed diagnosis of RASopathy by assessing height, BMI, and total cholesterol, HDL, triglycerides, apolipoprotein, fasting glucose, and insulin levels, in the context of a cross sectional and longitudinal study. We specifically investigated and compared anthropometric and haematochemistry data between the Noonan syndrome (NS) and Mazzanti syndrome (NS/LAH) groups.ResultsAt the first evaluation (9.5 ± 6.2 years), reduced growth (-1.80 ± 1.07 DS) was associated with a slightly reduced BMI (-0.34 DS ± 1.15 DS). Lipid profiling documented low total cholesterol levels (< 5th percentile) in 42.2% of the NS group; in particular, in 48.9% of PTPN11 patients and in 28.6% of NS/LAH patients compared to the general population, with a significant difference between males and females. A high proportion of patients had HDL levels lower than the 26th percentile, when compared to the age- and sex-matched general population. Triglycerides showed an increasing trend with age only in NS females. Genotype-phenotype correlations were also evident, with particularly reduced total cholesterol in about 50% of patients with PTPN11 mutations with LDL-C and HDL-C tending to decrease during puberty. Similarly, apolipoprotein A1 and apolipoprotein B deficits were documented, with differences in prevalence associated with the genotype for apolipoprotein A1. Fasting glucose levels and HOMA-IR were within the normal range.ConclusionThe present findings document an unfavourable lipid profile in subjects with NS, in particular PTPN11 mutated patients, and NS/LAH. Further studies are required to delineate the dysregulation of lipid metabolism in RASopathies more systematically and confirm the occurrence of previously unappreciated genotype-phenotype correlations involving the metabolic profile of these disorders

Neuropsychiatric phenotype in a child with pseudohypoparathyroidism.

Pseudohypoparathyroidism (PHP) is a rare heterogeneous genetic disease characterized by end\u2011organ resistance to parathyroid hormone. In adulthood, heterogeneous neurological and psychiatric disorders have been reported which are associated with hypoparathyroidism in general and with PHP in particular, while for childhood, data are scanty. We report a case of a boy with PHP type 1b, in whom neurological signs at the onset prevailed, characterized by tic\u2011like dyskinesias associated with a series of heterogeneous not well\u2011defined neurological and behavioral features, describing the diagnostic work\u2011up performed and the follow\u2011up. We suggest that the diagnostic hypothesis of PHP might be considered when dealing with a child with tic\u2011like dyskinesias, especially if associated with a series of heterogeneous not well\u2011defined neurological and behavioral features. In these cases, treatment with calcitriol and calcium has to be started as soon as possible to achieve a prompt and persistent clinical improvement

The influence of gh treatment on glucose homeostasis in girls with turner syndrome: A 7-year study

Context: Growth hormone (GH) influences glucose homeostasis mainly by negatively affecting insulin sensitivity. Objective: To longitudinally study insulin sensitivity [via homeostasis model assessment of insulin sensitivity (HOMA-S)], insulin secretion [insulinogenic index (IGI)], and capacity of b cells to adapt to changes in insulin sensitivity [oral disposition index (ODI)] in girls with Turner syndrome (TS) undergoing GH treatment. Design and Setting: Longitudinal, retrospective, 7-year study conducted in a tertiary pediatric endocrine unit and university pediatric clinic. Patients and Methods:We studied 104 patientswith TS (mean age6standard deviation, 9.163.4 years) for a median of 7.2 years. Intervention: Every year, the children underwent an oral glucose tolerance test, which was used to calculate HOMA-S, IGI, and ODI. Results: HOMA-S, IGI, and ODI did not significantly change. Conclusion: The results are reassuring, showing no negative influence of GH treatment on insulin sensitivity and on b-cell secretory capacity in girlswith TS

The influence of growth hormone treatment on glucose homeostasis in growthhormone-deficient children: A six-year follow-up study

Background: Growth hormone (GH) influences glucose homeostasis by negatively affecting insulin sensitivity, leading to a compensatory increase in insulin secretion. It has recently been reported, in animals and humans, that GH might also stimulate insulin secretion by directly affecting the growth and function of pancreatic β-cells. The aim of this work was to longitudinally study the insulin sensitivity (HOMA-S), insulin secretion [insulinogenic index (IGI)] and capacity of β-cells to adapt to changes in insulin sensitivity [oral disposition index (ODI)] in GH-deficient (GHD) children under GH treatment. Methods: We studied 99 GHD (62 male, 37 female; age 8.9 ± 3.5 years) children for a median period of 6 years (range 1.5-16.2). Every year, our patients underwent an oral glucose tolerance test, which was used to calculate the HOMA-S, IGI and ODI. Results: Although HOMA-S remained unchanged, an increase in IGI and ODI was observed, becoming significant after 6 years of treatment (1.25 ± 1.28 vs. 2.35 ± 2.38, p < 0.05 and 0.57 ± 0.68 vs. 1.50 ± 1.92, p < 0.01, respectively). Conclusion: Our results suggest a positive influence of GH treatment on the β-cell secretory capacity in children with GH deficiency

Response to long-term growth hormone therapy in patients affected by RASopathies and growth hormone deficiency: Patterns of growth, puberty and final height data

RASopathies are developmental disorders caused by heterozygous germline mutations in genes encoding proteins in the RAS-MAPK signaling pathway. Reduced growth is a common feature. Several studies generated data on growth, final height (FH), and height velocity (HV) after growth hormone (GH) treatment in patients with these disorders, particularly in Noonan syndrome, the most common RASopathy. These studies, however, refer to heterogeneous cohorts in terms of molecular information, GH status, age at start and length of therapy, and GH dosage. This work reports growth data in 88 patients affected by RASopathies with molecularly confirmed diagnosis, together with statistics on body proportions, pubertal pattern, and FH in 33, including 16 treated with GH therapy for proven GH deficiency. Thirty-three patients showed GH deficiency after pharmacological tests, and were GH-treated for an average period of 6.8 ± 4.8 years. Before starting therapy, HV was -2.6 ± 1.3 SDS, and mean basal IGF1 levels were -2.0 ± 1.1 SDS. Long-term GH therapy, starting early during childhood, resulted in a positive height response compared with untreated patients (1.3 SDS in terms of height-gain), normalizing FH for Ranke standards but not for general population and Target Height. Pubertal timing negatively affected pubertal growth spurt and FH, with IGF1 standardized score increased from -2.43 to -0.27 SDS. During GH treatment, no significant change in bone age velocity, body proportions, or cardiovascular function was observed

Challenges in the clinical interpretation of small de novo copy number variants in neurodevelopmental disorders

In clinical genetics, the need to discriminate between benign and pathogenic variants identified in patients with neurodevelopmental disorders is an absolute necessity. Copy number variants (CNVs) of small size can enable the identification of genes that are critical for neurologic development. However, assigning a definite association with a specific disorder is a difficult task. Among 328 trios analyzed over seven years of activity in a single laboratory, we identified 19 unrelated patients (5.8%) who carried a small (< 500 kb) de novo CNV. Four patients had an additional independent de novo CNV. Nine had a variant that could be assigned as definitely pathogenic, whereas the remaining CNVs were considered as variants of unknown significance (VUS). We report clinical and molecular findings of patients harboring VUS. We reviewed the medical literature available for genes impacted by CNVs, obtained the probability of truncating loss-of-function intolerance, and compared overlapping CNVs reported in databases. The classification of small non-recurrent CNVs remains difficult but, among our findings, we provide support for a role of SND1 in the susceptibility of autism, describe a new case of the rare 17p13.1 microduplication syndrome, and report an X-linked duplication involving KIF4A and DLG3 as a likely cause of epilepsy