Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy.

The RASopathies are a group of genetic syndromes caused by upregulated RAS signaling. Noonan syndrome (NS), the most common entity among the RASopathies, is characterized mainly by short stature, cardiac anomalies and distinctive facial features. Mutations in multiple RAS-MAPK pathway-related genes have been associated with NS and related phenotypes. We describe two unrelated patients presenting with hypertrophic cardiomyopathy (HCM) and dysmorphic features suggestive of NS. One of them died in the neonatal period because of cardiac failure. Targeted sequencing revealed de novo MRAS variants, c.203C > T (p.Thr68Ile) and c.67G > C (p.Gly23Arg) as causative events. MRAS has only recently been related to NS based on the observation of two unrelated affected individuals with de novo variants involving the same codons here found mutated. Gly23 and Thr68 are highly conserved residues, and the corresponding codons are known hotspots for RASopathy-associated mutations in other RAS proteins. Functional analyses documented high level of activation of MRAS mutants due to impaired GTPase activity, which was associated with constitutive plasma membrane targeting, prolonged localization in non-raft microdomains, enhanced binding to PPP1CB and SHOC2 protein, and variably increased MAPK and PI3K-AKT activation. This report provides additional evidence that a narrow spectrum of activating mutations in MRAS represents another rare cause of NS, and that MRAS has to be counted among the RASopathy genes predisposing to HCM. Moreover, our findings further emphasize the relevance of the MRAS-SHOC2-PPP1CB axis in the control of MAPK signaling, and the contribution of both MAPK and PI3K-AKT pathways in MRAS functional upregulation.

Alarming increase in ketoacidosis in children and adolescents with newly diagnosed type 1 diabetes during the first wave of the COVID-19 pandemic in Israel.

OBJECTIVE: To evaluate the incidence and severity of ketoacidosis (DKA) at type 1 diabetes diagnosis during the first wave of the coronavirus disease 2019 (COVID-19) pandemic in Israel. RESEARCH DESIGN AND METHODS: A population-based study the product of a national collaboration of Israeli pediatric diabetes centers investigated the presentation of childhood-onset type 1 diabetes. The frequencies of DKA and severe DKA observed during the COVID-19 period from March 15, 2020 (commencement of the first nationwide lockdown) until June 30, 2020 were compared with the same periods in 2019, 2018, and 2017 using multivariable logistic regression, adjusting for age, sex, and socioeconomic position. RESULTS: During the COVID-19 period, DKA incidence was 58.2%, significantly higher than in 2019 (adjusted OR [aOR] 2.18 [95% CI, 1.31-3.60], P = 0.003); 2018 (aOR 2.05 [95% CI, 1.26-3.34], P = 0.004); and 2017 (aOR, 1.79 [95% CI, 1.09-2.93], P = 0.022). The incidence of severe DKA was 19.9%, significantly higher than in 2018 (aOR, 2.49 [95% CI, 1.20-5.19], P = 0.015) and 2017 (aOR, 2.73 [95% CI, 1.28-5.82], P = 0.009). In 2020, admissions and duration of stay in the intensive care unit were higher than in previous years (P = 0.001). During the COVID-19 pandemic, children aged 6-11 years had higher incidences of DKA (61.3% vs. 34.0%, 40.6%, and 45.1%, respectively, P = 0.012), and severe DKA (29.3% vs. 15.1%, 10.9%, and 5.9%, respectively, P = 0.002). CONCLUSIONS: The dramatic increase in DKA at presentation of childhood-onset type 1 diabetes during the COVID-19 pandemic mandates targeted measures to raise public and physician awareness.

A novel truncating variant in the FGD1 gene associated with Aarskog-Scott syndrome in a family previously diagnosed with Tel Hashomer camptodactyly.

Tel Hashomer camptodactyly syndrome is a long-known entity characterized by camptodactyly with muscular hypoplasia, skeletal dysplasia, and abnormal palmar creases. Currently, the genetic basis for this disorder is unknown, thus there is a possibility that this clinical presentation may be contained within another genetic diagnosis. Here, we present a multiplex family with a previous clinical diagnosis of Tel Hashomer camptodactyly syndrome. Whole exome sequencing and pedigree-based analysis revealed a novel hemizygous truncating variant c.269_270dup (p.Phe91Alafs*34) in the FGD1 gene (NM_004463.3) in all three symptomatic patients, congruous with a diagnosis of Aarskog-Scott syndrome. Our report adds to the limited data on Aarskog-Scott syndrome, and emphasizes the importance of unbiased comprehensive molecular testing toward establishing a diagnosis for genetic syndromes with unknown genetic basis.

Environmental rather than genetic factors determine the variation in the age of the infancy to childhood transition: a twins study.

OBJECTIVE: Using a twins study, we sought to assess the contribution of genetic against environmental factor as they affect the age at transition from infancy to childhood (ICT). STUDY DESIGN: The subjects were 56 pairs of monozygotic twins, 106 pairs of dizygotic twins, and 106 pairs of regular siblings (SBs), for a total of 536 children. Their ICT was determined, and a variance component analysis was implemented to estimate components of the familial variance, with simultaneous adjustment for potential covariates. RESULTS: We found substantial contribution of the common environment shared by all types of SBs that explained 27.7% of the total variance in ICT, whereas the common twin environment explained 9.2% of the variance, gestational age 3.5%, and birth weight 1.8%. In addition, 8.7% was attributable to sex difference, but we found no detectable contribution of genetic factors to inter-individual variation in ICT age. CONCLUSIONS: Developmental plasticity impacts much of human growth. Here we show that of the ∼50% of the variance provided to adult height by the ICT, 42.2% is attributable to adaptive cues represented by shared twin and SB environment, with no detectable genetic involvement.

Predicting pubertal development by infantile and childhood height, BMI, and adiposity rebound.

BACKGROUND: Despite substantial heritability in pubertal development, children differ in maturational tempo. HYPOTHESES: (i) puberty and its duration are influenced by early changes in height and adiposity. (ii) Adiposity rebound (AR) is a marker for pubertal tempo. METHODS: We utilized published prospective data from 659 girls and 706 boys of the Study of Early Child Care and Youth Development. We investigated the age of pubarche-thelarche-gonadarche-menarche as a function of early height, BMI, and AR. RESULTS: In girls, height standard deviation scores correlated negatively with thelarche and pubarche from 15 mo of age and with menarche from 54 mo. BMI correlated negatively with thelarche from 36 mo of age and menarche from 54 mo. In boys, age at gonadarche correlated negatively with height from 36 mo of age. An AR was detected in 47% of girls and 55% of boys, who became heavier and had earlier and faster puberty than those with no AR. CONCLUSION: The onset and tempo of puberty are influenced by a two-hit program. The first is exerted during the infancy-childhood transition (ICT; 6-12 mo) and includes height, as an early predictor of maturational tempo. The second hit occurs at the childhood-juvenility transition (5-7 y) and is based on adiposity and its rebound.

The Natural Course of Newborns with Transient Congenital Hypothyroidism.

OBJECTIVES: The incidence of congenital hypothyroidism (CH) has increased worldwide over the last decades mainly due to the lowering of screening thresholds, resulting in an increased identification of newborns with transient CH. Several studies reported the prevalence and the predictive parameters of transient CH but reports on the long-term outcome are rare. This study aimed to assess the long-term course of neonates with transient CH. DESIGN: Neonates diagnosed with transient and permanent CH between the years 1998 to 2018 at the Pediatric Endocrine Institute of Ha'Emek Medical Center were enrolled in the study. Data were retrieved retrospectively from medical files. RESULTS: Included in the study were 76 newborns (45M,59%) with transient CH and 53 (25M,47%) with permanent CH. The major cause of transient CH was prematurity (29%) and subclinical hypothyroidism (30%). During retrospective follow-ups of up to 23 years, reinitiation of LT4 therapy was not required apart from four patients with underlying syndromic etiologies. Neurodevelopmental impairment occurred in 16% of children with transient CH compared with 29.4% in the permanent CH group. CONCLUSIONS: Transient CH is frequent among preterm infants but is limited to infancy. SCH frequently presents as overt hypothyroidism at birth but in most cases the requirement for LT4 supplemental therapy is limited to the first years of life, suggesting that long-term follow-up of thyroid function tests may be unnecessary for non-syndromic children. The high rate of neurodevelopmental impairment in newborns with transient CH emphasizes the need for neurodevelopmental monitoring in these patients.

Insights into Central Congenital Hypothyroidism: A Multicenter Retrospective Analysis.

CONTEXT: Central congenital hypothyroidism (CCH) is a thyroid hormone deficiency at birth caused by inadequate pituitary stimulation of the thyroid gland. Although primary CH has been studied extensively, studies on CCH are sparse. OBJECTIVES: To assess the prevalence of CCH in Israel and describe its clinical features, neonatal screening results, and outcomes. DESIGN: Multicenter cross-sectional retrospective chart review. SETTING: Nine pediatric endocrine units throughout Israel. PATIENTS: Patients diagnosed with CCH in 1987-2021 were categorized into early (within 14 days of life) and late (after 14 days) diagnosis groups. Newborn screening (NBS) results were retrospectively retrieved from the national NBS program dataset. RESULTS: CCH prevalence in Israel was about 1:42,800 live births. Subjects were 94 patients (54 males), of these, 84% had multiple pituitary hormone deficiencies and 16% had isolated CCH. The median age at diagnosis was 50 days (range, 1-8760), with 66% having moderate to severe hypothyroidism. NBS detected only three infants. Early diagnosis occurred in 34% due to hypopituitarism, while 66% were diagnosed later due to growth and developmental delays. Neurodevelopmental sequelae included mental retardation (12%), learning difficulties (18%), delayed speech (27%), and motor clumsiness (19%), with no significant differences in outcomes between early and late diagnosis. CONCLUSIONS: Despite high rates of neurodevelopmental sequelae, no differences were found between early and late diagnosis groups. Further research is needed to assess the impact of delayed diagnosis on neurological outcomes in newborns with CCH. Improved strategies for detecting CHH in newborns are also necessary.

Energy Trade-off and 4 Extreme Human Body Types.

BACKGROUND: Resource trade-off theory suggests that increased performance on a given trait comes at the cost of decreased performance on other traits. METHODS: Growth data from 1889 subjects (996 girls) were used from the GrowUp1974 Gothenburg study. Energy Trade-Off (ETO) between height and weight for individuals with extreme body types was characterized using a novel ETO-Score (ETOS). Four extreme body types were defined based on height and ETOI at early adulthood: tall-slender, short-stout, short-slender, and tall-stout; their growth trajectories assessed from ages 0.5-17.5 years.A GWAS using UK BioBank data was conducted to identify gene variants associated with height, BMI, and for the first time with ETOS. RESULTS: Height and ETOS trajectories show a two-hit pattern with profound changes during early infancy and at puberty for tall-slender and short-stout body types. Several loci (including FTO, ADCY3, GDF5, ) and pathways were identified by GWAS as being highly associated with ETOS. The most strongly associated pathways were related to "extracellular matrix," "signal transduction," "chromatin organization," and "energy metabolism." CONCLUSIONS: ETOS represents a novel anthropometric trait with utility in describing body types. We discovered the multiple genomic loci and pathways probably involved in energy trade-off.

Family Size and the Age at Infancy-Childhood Transition Determine a Child's Compromised Growth in Large Families.

Background: Data on growth of Israeli school children show that children from Jewish ultra-orthodox Haredi and Bedouin Arab families have a higher prevalence of stature below the 3rd percentile. While these populations are usually from lower socioeconomic strata, they also have larger families. This study aimed to evaluate if family structure and the timing of a child's infancy-childhood transition (ICT) are central to variations in stature. Study Design: We analyzed the association between family size, birth order and inter-birth interval with child growth and the age at ICT in 3 groups of children, 148 high birth order children from large families (LF ≥ 6), 118 low birth order children from large families (LF ≤ 3) and 150 children from small families (SF). Results: High birth order children from large families were shorter in childhood than children from small families with a difference of 0.5 SDS in length. We found that birth length and birth order explained 35% of the total variance in infancy length whereas ICT age and infancy length explained 72% of the total variance in childhood length. Conclusion: Infancy and childhood length are compromised in children from large families. As the family grows larger the younger children tend to be shorter. Reduced length gain in the period between infancy to childhood is when growth is most affected.

Periorbital inflammation associated with craniofacial fibrous dysplasia: Report of three cases and review of the literature.

Fibrous dysplasia (FD) is a mosaic skeletal disorder in which the craniofacial bones are commonly affected. Normal structures are replaced by expansile, highly vascular, fibro-osseous tissue. The typical clinical course is a gradual, asymptomatic expansion of the osseous structures. However, in the periorbital region, even minor structural changes may cause functional impairment, such as diplopia and hyposmia. Furthermore, rapidly evolving secondary lesions, such as fluid-filled cysts, can sometimes develop. In the midface and periorbital regions, such acute change may be associated with severe pain, vision loss, and, signs of inflammation. Here we describe three patients with craniofacial FD who presented with recurrent episodes of periorbital inflammation mimicking orbital cellulitis. All presented with pain, edema, erythema, and warmth, with varying degrees of functional impairment. On imaging, all had cystic changes in the FD lesion, including two with aneurysmal bone cysts (ABCs). Two were initially diagnosed with periorbital cellulitis and treated with antibiotics; in two, the radiographic findings were misdiagnosed as osteomyelitis. Recurrent episodes were recognized as not infectious and effectively managed with corticosteroids. Given the vascular nature of FD and the association of ABCs, it is likely the findings in these patients represent inflammation associated with vascular leak in the relatively confined space of the tissues overlying the periorbital bones. Recognition of this entity can lead to more rapid and appropriate treatment.

Prediction of Adult Height by Machine Learning Technique.

CONTEXT: Prediction of AH is frequently undertaken in the clinical setting. The commonly used methods are based on the assessment of skeletal maturation. Predictive algorithms generated by machine learning, which can already automatically drive cars and recognize spoken language, are the keys to unlocking data that can precisely inform the pediatrician for real-time decision making. OBJECTIVE: To use machine learning (ML) to predict adult height (AH) based on growth measurements until age 6 years. METHODS: Growth data from 1596 subjects (798 boys) aged 0-20 years from the longitudinal GrowUp 1974 Gothenburg cohort were utilized to train multiple ML regressors. Of these, 100 were used for model comparison, the rest was used for 5-fold cross-validation. The winning model, random forest (RF), was first validated on 684 additional subjects from the 1974 cohort. It was additionally validated using 1890 subjects from the GrowUp 1990 Gothenburg cohort and 145 subjects from the Edinburgh Longitudinal Growth Study cohort. RESULTS: RF with 51 regression trees produced the most accurate predictions. The best predicting features were sex and height at age 3.4-6.0 years. Observed and predicted AHs were 173.9 ±â€…8.9 cm and 173.9 ±â€…7.7 cm, respectively, with prediction average error of -0.4 ±â€…4.0 cm. Validation of prediction for 684 GrowUp 1974 children showed prediction accuracy r = 0.87 between predicted and observed AH (R2 = 0.75). When validated on the 1990 Gothenburg and Edinburgh cohorts (completely unseen by the learned RF model), the prediction accuracy was r = 0.88 in both cases (R2 = 0.77). AH in short children was overpredicted and AH in tall children was underpredicted. Prediction absolute error correlated negatively with AH (P < .0001). CONCLUSION: We show successful, validated ML of AH using growth measurements before age 6 years. The most important features for prediction were sex, and height at age 3.4-6.0. Prediction errors result in over- or underestimates of AH for short and tall subjects, respectively. Prediction by ML can be generalized to other cohorts.

Human Type 1 Iodothyronine Deiodinase (DIO1) Mutations Cause Abnormal Thyroid Hormone Metabolism.

Background: Iodothyronine deiodinase-1 (D1) selenoenzyme regulates the systemic supply of active thyroid hormone (TH). Transient decrease in D1 enzymatic activity is clinically relevant and adaptive in nonthyroidal illness such as fasting or acute illness. However, DIO1 gene defects have not been reported in humans. Methods: Genetic analysis was performed using whole-exome sequencing in members of two unrelated families presenting with abnormal serum thyroid function tests. Plasmid constructs containing the two pathogenic DIO1 variants were used for in vitro studies assessing the kinetics of their enzymatic activity. Thyroid function tests were measured in Dio1 heterozygous-null mice. Results: We report the novel identification and characterization of two missense DIO1 pathogenic variants (resulting in p.Asn94Lys and p.Met201Ile) in two unrelated families presenting with abnormal TH metabolism with elevated serum reverse triiodothyronine (rT3) levels and rT3/T3 ratios. These characteristic in vivo parameters are also present in Dio1 heterozygous-null mice. Kinetic studies of the resulting mutant D1 proteins demonstrate two- to threefold higher Km indicating lower substrate affinity and slower enzyme velocity. Conclusions: We report the identification and characterization of two missense DIO1 pathogenic variants identified in families with abnormal TH metabolism. This is the first demonstration of inherited D1 deficiency in humans.

Sexual Dimorphism of Size Ontogeny and Life History.

Background: Ecological and physiological factors and social and economic constraints affect sex-specific body size. Here, we used the male/female (M/F) height ratio as an indicator of the combined effect of genetic and sex characteristics. We hypothesized that (1) sexual dimorphism in body size will be established during infancy and adolescence when growth velocity is maximal, (2) living standards and health are important factors which can affect sexual dimorphism in body size, (3) variations in sexual dimorphism in body size are due to the differential response of boys and girls to environmental cues, and (4) sexual dimorphism in body size will be more pronounced in those populations whose average height and weight are the greatest. Methods: To study the ontogeny of sexual dimorphism from birth until the age of 18 years, we used the 2000 CDC growth data. Data on height by country, life expectancy, and gross domestic product (GDP) per capita based on purchasing power parity were extracted from the national accounts data of NCD Risk Factor Collaboration, the World Bank, Eurostat: Demographic Statistics, Secretariat of the Pacific Community: Statistics and Demography Program, and the US Census Bureau. Results: We found that sexual dimorphism in body size starts at age 1 month, peaks at age 3 months, and diminishes by age 24 months. During childhood, there is no sexual difference in body size, and it is gradually established when the boys enter puberty. The M/F height ratio correlates positively with the average male and female height and weight by country. Conclusion: Sexual dimorphism in body size occurs when (a) the growth velocity is maximal during infancy and adolescence, (b) living standards are high, and health correlate positively with male/female height ratio. Anthropological studies and our results emphasize mostly the female resiliency hypothesis: shorter male heights in times of environmental stress lead to smaller sexual dimorphism in body size.

People Are Taller in Countries With Better Environmental Conditions.

Background: Height is considered an indicator of health and well-being of an individual and population. Height variation results from a complex interaction of genetic, environmental, socioeconomic, and cultural influences. In order to understand the contribution of environmental stress associated with the child's growth, we correlated indicators of a stressful environment with adult height. Methods: We utilized seven equally weighted indicators of a stressful environment: homicide rates, GDP per capita, income inequality (GINI index), corruption perception index (CPI), unemployment rate, urban air pollution, and life expectancy (LE). Data on male and female height by country from 1992 to 1996 were obtained from the NCD Risk Factor Collaboration dataset. We assessed separately data from the 31 member countries of the Organization for Economic Co-operation and Development (OECD). In order to establish whether the indicators reflected a single conceptual dimension, we conducted an exploratory analysis and principal component analysis (PCA) with orthogonal transformation of the original variables. The relationships between male and female heights and the z-transformed principal components: Quality of life (QoL) and the Social factor (SF) that were derived after the PCA was assessed. Results: Male and female heights strongly correlated (p < 0.0001) with each of the seven indicators. In the PCA, the indicators clustered into "Quality of Life" factors (QoL), which comprised the CPI, GDP, air pollution, LE, and "Social factors" (SF), which comprised homicide rate and GINI index. For males and females, the average height by country strongly correlated with QoL (p < 0.0001) and SF (p < 0.0001). Within OECD countries, male and female height strongly and negatively correlated with the SF, but not with QoL. Conclusion: Growth attenuation is a tradeoff adaptive response: a calorie used for growth cannot be used for fighting stress. Here we show that: (1) Adult height, when used as a measure of child's growth, is an indicator of a stressful environment in context with the genetic background and spatial factors; (2) Stressful QoL factors and the SF exert a greater effect on men's height than women's height; and (3) The ranking of the indicators of short stature are income inequality > air pollution > GDP > CPI > homicide rate > LE > unemployment.

Primary Ovarian Insufficiency Nationwide Incidence Rate and Etiology Among Israeli Adolescents.

PURPOSE: The aim of the study was to estimate the current incidence and the distribution of etiologies of primary ovarian insufficiency (POI) in a nationwide study. The prevalence of POI in young adult women has recently increased, but the data cited for adolescents are more than three decades old. METHODS: Data regarding females aged <21 years diagnosed with POI during the years 2000-2016 were collected from all the pediatric endocrinology units in Israel. POI was defined by at least 4 months of amenorrhea in association with menopausal levels of follicle-stimulating hormone. Iatrogenic cases were excluded. RESULTS: For the 130 females aged <21 years included in the study, the distribution of POI etiologies was Turner syndrome/mosaicism in 56 (43%), idiopathic in 35 (27%), and other (developmental, genetic, metabolic, adrenal, and autoimmune) in 39 (30%) females. During the years 2009-2016, compared with 2000-2008, the incidence rate of new POI diagnoses per 100,000 person-years doubled (4.5 vs. 2.0; p value <.0001), and incidence rates of idiopathic and other etiologies increased by 2.6 (p value = .008) and 3.0 (p value = .002), respectively. In contrast, the incidence of Turner syndrome was constant (p value = .2). In the age group of 15-21 years, the current incidence of non-Turner POI in adolescents is one per 100,000 person-years. CONCLUSIONS: In this nationwide study, the incidence rate of POI in youth aged <21 years was one tenth of the rate that is commonly cited. A significant increase in the rate of POI in non-Turner females was observed over the last decade. Contributions of environmental and epigenetic factors should be studied.

Combined Gestational Age- and Birth Weight-Adjusted Cutoffs for Newborn Screening of Congenital Adrenal Hyperplasia.

CONTEXT: Congenital adrenal hyperplasia (CAH) was among the first genetic disorders included in newborn screening (NBS) programs worldwide, based on 17α-hydroxyprogesterone (17-OHP) levels in dried blood spots. However, the success of NBS for CAH is hampered by high false positive (FP) rates, especially in preterm and low-birthweight infants. OBJECTIVE: To establish a set of cutoff values adjusting for both gestational age (GA) and birthweight (BW), with the aim of reducing FP rates. DESIGN: This cross-sectional, population-based study summarizes 10 years of experience of the Israeli NBS program for diagnosis of CAH. Multitiered 17-OHP cutoff values were stratified according to both BW and GA. PARTICIPANTS: A total of 1,378,132 newborns born between 2008 and 2017 were included in the NBS program. RESULTS: Eighty-eight newborns were ultimately diagnosed with CAH; in 84 of these, CAH was detected upon NBS. The combined parameters-adjusted approach significantly reduced the recall FP rate (0.03%) and increased the positive predictive value (PPV) (16.5%). Sensitivity among those referred for immediate attention increased significantly (94%). There were four false negative cases (sensitivity, 95.4%), all ultimately diagnosed as simple-virilizing. Sensitivity and specificity were 95.4% and 99.9%, respectively, and the percentage of true-positive cases from all newborns referred for evaluation following a positive NBS result was 96%. CONCLUSIONS: The use of cutoff values adjusted for both GA and BW significantly reduced FP rates (0.03%) and increased overall PPV (16.5%). Based on our 10 years of experience, we recommend the implementation of this two parameter-adjusted approach for NBS of classic CAH in NBS programs worldwide.

Control of childhood congenital adrenal hyperplasia and sleep activity and quality with morning or evening glucocorticoid therapy.

CONTEXT: Traditionally, hydrocortisone (HC) replacement therapy in congenital adrenal hyperplasia (CAH) is given by three daily doses, albeit not necessarily of equal quantity. Although a higher dose in the morning better imitates the physiological diurnal variation, a late-night higher dose was suggested to better suppress early morning hypothalamic-pituitary-adrenal axis peak activity. Yet, increased night cortisol has been claimed to be associated with sleep disturbances and insomnia. OBJECTIVE: Our objective was to evaluate evening vs. morning high-HC dose with respect to disease control, sleep pattern, and daytime activity in children with CAH. DESIGN: An open-label, cross-over, randomized trial of 15 children with classical CAH was performed. Patients were randomized to receive 50% of the daily HC in the morning or evening for 2 wk; the other two doses included 25% of the daily dose each. OUTCOME MEASURES: Disease control was assessed by 0800-h 17-hydroxyprogesterone, testosterone, androstenedione, and dehydroepiandrosterone sulfate on the last day of each treatment schedule. Sleep and daytime activity were assessed by a 7-d actigraph. RESULTS: Basal morning androstenedione, 17-hydroxyprogesterone, dehydroepiandrosterone sulfate, and testosterone levels during the high-morning and high-evening HC treatment schedules were comparable. There were no significant differences in sleep or daytime activity. CONCLUSIONS: With respect to disease control, sleep quality and daytime activity were not affected by treatment schedules. We recommend the high-morning dose schedule in replacement therapy of children with CAH.

Global Application of the Assessment of Communication Skills of Paediatric Endocrinology Fellows in the Management of Differences in Sex Development Using the ESPE E-Learning.Org Portal.

BACKGROUND: Information sharing in chronic conditions such as disorders of/differences in sex development (DSD) is essential for a comprehensive understanding by parents and patients. We report on a qualitative analysis of communication skills of fellows undergoing training in paediatric endocrinology. Guidelines are created for the assessment of communication between health professionals and individuals with DSD and their parents. METHODS: Paediatric endocrinology fellows worldwide were invited to study two interactive online cases (www.espe-elearning.org) and to describe a best practice communication with (i) the parents of a newborn with congenital adrenal hyperplasia and (ii) a young woman with 46,XY gonadal dysgenesis. The replies were analysed regarding completeness, quality, and evidence of empathy. Guidelines for structured assessment of responses were developed by 22 senior paediatric endocrinologists worldwide who assessed 10 selected replies. Consensus of assessors was established and the evaluation guidelines were created. RESULTS: The replies of the fellows showed considerable variation in completeness, quality of wording, and evidence of empathy. Many relevant aspects of competent clinical communication were not mentioned; 15% (case 1) and 17% (case 2) of the replies were considered poor/insufficient. There was also marked variation between 17 senior experts in the application of the guidelines to assess communication skills. The guidelines were then adjusted to a 3-level assessment with empathy as a separate key item to better reflect the qualitative differences in the replies and for simplicity of use by evaluators. CONCLUSIONS: E-learning can play an important role in assessing communication skills. A practical tool is provided to assess how information is shared with patients with DSD and their families and should be refined by all stakeholders, notably interdisciplinary health professionals and patient representatives.

Validation of a Novel Assay to Distinguish Bacterial and Viral Infections.

BACKGROUND: Reliably distinguishing bacterial from viral infections is often challenging, leading to antibiotic misuse. A novel assay that integrates measurements of blood-borne host-proteins (tumor necrosis factor-related apoptosis-inducing ligand, interferon γ-induced protein-10, and C-reactive protein [CRP]) was developed to assist in differentiation between bacterial and viral disease. METHODS: We performed double-blind, multicenter assay evaluation using serum remnants collected at 5 pediatric emergency departments and 2 wards from children ≥3 months to ≤18 years without (n = 68) and with (n = 529) suspicion of acute infection. Infectious cohort inclusion criteria were fever ≥38°C and symptom duration ≤7 days. The reference standard diagnosis was based on predetermined criteria plus adjudication by experts blinded to assay results. Assay performers were blinded to the reference standard. Assay cutoffs were predefined. RESULTS: Of 529 potentially eligible patients with suspected acute infection, 100 did not fulfill infectious inclusion criteria and 68 had insufficient serum. The resulting cohort included 361 patients, with 239 viral, 68 bacterial, and 54 indeterminate reference standard diagnoses. The assay distinguished between bacterial and viral patients with 93.8% sensitivity (95% confidence interval: 87.8%-99.8%) and 89.8% specificity (85.6%-94.0%); 11.7% had an equivocal assay outcome. The assay outperformed CRP (cutoff 40 mg/L; sensitivity 88.2% [80.4%-96.1%], specificity 73.2% [67.6%-78.9%]) and procalcitonin testing (cutoff 0.5 ng/mL; sensitivity 63.1% [51.0%-75.1%], specificity 82.3% [77.1%-87.5%]). CONCLUSIONS: Double-blinded evaluation confirmed high assay performance in febrile children. Assay was significantly more accurate than CRP, procalcitonin, and routine laboratory parameters. Additional studies are warranted to support its potential to improve antimicrobial treatment decisions.

Consecutive mutational events in a TSHR allele of Arab families with resistance to thyroid stimulating hormone.

BACKGROUND: Our laboratory identified six distinct inactivating TSHR gene mutations in Arab tribes living in Israel. We recently reported three nucleotide substitutions in exon 3 producing p.[L89L;Q90P] and one in exon 9 of the same allele producing p.P264S in Family A. Family B, reported herein, harbors the identical mutation in exon 3 only. We set to determine whether the mutations have common ancestral origin. METHODS: Coding regions of the TSHR were sequenced and flanking microsatellite markers spanning 5.3 cM were used for haplotyping. RESULTS: Two siblings of Family B were compound heterozygous for TSHR gene mutations. The paternal allele contained the exon 3 mutation and the maternal allele harbored a mutation in exon 10 (p.L653V). We investigated the possibility of a founder effect with subsequent mutational events for the presence of the same exon 3 mutation in different families. The haplotype of the allele harboring the exon 3 mutation in Family B was identical to that of Family A, also harboring the exon 9 mutation on the same allele, indicating that the latter occurred subsequently. The ancestral wild-type TSHR was present in Family B, suggesting that the mutation in exon 3 was also new in the history of that population. CONCLUSIONS: It is more likely that two consecutive mutational events occurred on the ancestral wild-type allele instead of a recombination bringing exon 3 and exon 9 mutations together on the same allele. New mutational events contribute to the high prevalence of TSHR mutations in this population in addition to a founder effect and limited gene pool due to inbreeding.