Exome Sequencing has a high diagnostic rate in sporadic congenital hypopituitarism and reveals novel candidate genes.

CONTEXT: The pituitary gland is key for childhood growth, puberty, and metabolism. Pituitary dysfunction is associated with a spectrum of phenotypes, from mild to severe. Congenital Hypopituitarism (CH) is the most commonly reported pediatric endocrine dysfunction with an incidence of 1:4000, yet low rates of genetic diagnosis have been reported. OBJECTIVE: We aimed to unveil the genetic etiology of CH in a large cohort of patients from Argentina. METHODS: We performed whole exome sequencing of 137 unrelated cases of CH, the largest cohort examined with this method to date. RESULTS: Of the 137 cases, 19.1% and 16% carried pathogenic or likely pathogenic variants in known and new genes, respectively, while 28.2% carried variants of uncertain significance. This high yield was achieved through the integration of broad gene panels (genes described in animal models and/or other disorders), an unbiased candidate gene screen with a new bioinformatics pipeline (including genes high loss of function intolerance), and analysis of copy number variants. Three novel findings emerged. First, the most prevalent affected gene encodes the cell adhesion factor ROBO1. Affected children had a spectrum of phenotypes, consistent with a role beyond pituitary stalk interruption syndrome. Second, we found that CHD7 mutations also produce a phenotypic spectrum, not always associated with full CHARGE syndrome. Third, we add new evidence of pathogenicity in the genes PIBF1 and TBC1D32, and report 13 novel candidate genes associated with CH (e.g. PTPN6, ARID5B). CONCLUSION: Overall, these results provide an unprecedented insight into the diverse genetic etiology of hypopituitarism.

Ability of TyG Index as a Marker of Insulin Resistance in Argentinean School Children.

Objective: To determine if the triglycerides and glucose index (TyG) can be used as a marker for insulin resistance (IR) in Argentinean schoolchildren according to age and sex. Methods: Anthropometric data, blood glucose levels, lipid profiles, and insulin levels were measured. The TyG index was defined by Ln [fasting triglyceride (mg/dL)* fasting glucose (mg/dL)/2]. A comparison of the ability of TyG to identify children with IR was performed using receiver operating characteristic (ROC) curves and the area under the ROC (AUROC) curve. IR was defined as HOMA-IR > III quartile. Results: A total of 915 (528, 57.7% males) apparently healthy schoolchildren, aged 9.3 ± 2.2, were evaluated. The AUROC using the HOMA-IR > III quartile as the dichotomous variable showed that TyG was a fair marker to identify IR (0.65, 95% CI, 0.61-0.69; p < 0.01). There was a significantly higher TyG AUROC in males (0.69, 95% CI, 0.63-0.75; p < 001) than in females (0.60, 95% CI, 0.54-0.66; p < 0.01). When children were divided according to age into two groups (5.0-9.9 and 10.0-14.9-year-olds); younger children (0.64, 95% CI, 0.58-0.69; p < 0.011) and older children (0.62, 95% CI, 0.55-0.68; p = 0.01) had a similar and fair AUROC. However, when children were divided by age and sex, females older than ten had a non-significant AUROC (0.53, 95% CI, 0.42-0.63; p = 0.61). The TyG index compared with HOMA-IR had low sensitivity and specificity, ranging from 0.62 to 0.56. Conclusion: The TyG index had a fair AUROC with low sensitivity and specificity, indicating poor discrimination in identifying IR in apparently healthy Argentinean children. The ability to use TyG for screening purposes seems limited in Argentinean schoolchildren.

Association Between High Birth Weight and Later Central Obesity in 9-Year-Old Schoolchildren.

Background and Objective: Studies have suggested that birth weight (BW) is associated with body mass index (BMI), but its association with waist circumference (WC) in children should be further explored. To determine the association between central obesity (OB) in 9-year-old Argentinean schoolchildren and high BW. Methods: Schoolchildren (n = 2567, 1157 males) aged 8.7 ± 2.1 years from 10 elementary schools in 5 states in Argentina were examined between April 2017 and September 2019. Mothers submitted children's BW information. Pediatricians assessed anthropometric measures and blood pressure (BP). Central OB was defined for children as WC ≥90th percentile for age and gender. Results: The prevalence of overweight (OW) and OB (OW/OB) was 42.7% (1095) and that of central OB was 34.8% (856) in 9-year-old children. The prevalence of low BW (<2500 grams) and high BW (>4000 grams) was 6.6% (n = 169) and 7.4% (n = 190), respectively. BW (3.25 vs. 3.36 kg), weight (31.38 vs. 42.88 kg), BMI (17.29 vs. 22.25 kg/m2), BMI z-scores (z-BMI; 0.25 vs. 1.63), systolic BP (96 vs. 98 mmHg), and diastolic BP (59 vs. 60 mmHg) were significantly lower in 9-year-old children without central OB than in those with central OB, respectively. Multiple logistic regression analysis using central OB as the dependent variable showed that high BW [odds ratio, 1.98 (95% confidence interval 1.44-2.73)] was associated with central OB, adjusted for age, gender, and systolic and diastolic BP. Conclusion: This study shows that central OB in 9-year-old children was associated with high BW. Future longitudinal studies should be performed to confirm this finding. Clinical Registration number, IATIMET-08102019.

Asociación del peso al nacer con adiposidad en niños escolares de distintas regiones de argentina / Association of birth weight with adiposity in school children from different regions of argentina

Introducción: diversos estudios han sugerido que el bajo y alto peso al nacer (PN) se asocian a obesidad (OB) y sobrepeso (SP) durante la infancia y la edad adulta. Objetivos: determinar la asociación entre PN y OB en escolares de 9 años de tres regiones de Argentina. Materiales y métodos: las medidas antropométricas y la presión arterial (PA) se tomaron en 1.131 escolares (505 masculinos) de 8,8±2,1 años de edad promedio, en tres regiones de Argentina durante el año 2019. Se interrogó, además, acerca del peso al nacer y el estilo de vida. Resultados: el 21,1% (239) de los niños presentaba SP (IMC>85 <95 percentilo según CDC) y el 21,8% (246) OB (IMC>95 percentilo). La prevalencia de PN bajo (<2.500 g) fue de fue de 6,2% (n=70) y de PN alto (>4.000 g) de 7,3% (n=82). El puntaje z-IMC de los niños de 9 años aumentaba significativamente con el aumento del PN: PN bajo (z-IMC=0,33), normal (z-IMC=0,72) y alto (z-IMC=1,12). En modelos de regresión logística múltiple se observó que el PN bajo se asoció inversamente a la OB (OR, 0.41 [IC del 95%: 0,19-0,92]), mientras que el PN alto se asoció directamente con la OB ajustado por edad y sexo (OR, 2.48 [95% IC 1,53-4,02]). Conclusiones: nuestros datos indican que el alto PN, pero no el bajo PN, se asocia con OB en niños en edad escolar de 9 años, mientras que el bajo PN está inversamente asociado con OB.

Introduction: several studies have suggested that low and high birth weight are associated with obesity (OB) and overweight (OW) during childhood and adulthood. Objectives: to determine the association between birth weight and OB in 9-year-old schoolchildren from three areas of Argentina. Materials and methods: anthropometric measurements and blood pressure (BP) were taken in 1.131 schoolchildren (505 males) of an average age of 8.8±2.1 years in three areas of Argentina during 2019. Mothers were asked about their children's birth weight and lifestyle. Results: 21.1% (239) of the children had OW (BMI>85 <95 percentile according to the CDC) and 21.8% (246) OB (BMI>95 percentile). The prevalence of low birth weight (<2.500 g) was 6.2% (n=70) and of high birth weight (>4.000 g) was 7.3% (n=82). The 9-year-old z-BMI score increased significantly with increasing birth weight: low birth weight (z-BMI=0.33), normal (z-BMI=0.72) and high (z-BMI=1.12). In multiple logistic regression models, it was found that low birth weight was inversely associated with OB (OR, 0.41 [95% CI: 0.19-0.92]), while high birth weight was directly associated with OB adjusted for age and sex (OR, 2.48 [95% CI 1.53-4.02]). Conclusions: our data indicate that high birth weight, but not low birth weight, is associated with OB in 9-year-old schoolchildren, while low birth weight is inversely associated with OB

Adiposity, lifestyle behaviors, and cardiometabolic markers in Argentinean schoolchildren.

BACKGROUND: We determined the association between schoolchildren's OW/OB with age, sex, lifestyle behaviors, and cardiometabolic markers. METHODS: Age, sex, anthropometric measures, and BP (blood pressure) were recorded in 1249 (554 M) schoolchildren. OW/OB was defined as BMI > 85%ile and BMI > 95%ile respectively. A validated questionnaire for lifestyle behaviors was performed. We offered free laboratory testing to a subgroup of 168 children. RESULTS: Schoolchildren aged 8.8 ± 2.1 y from 9 elementary schools in 4 areas of Argentina were examined between April and September 2019. 265 (21.2%) of the children were OW, 265 (21.2%) were OB, and 425 (35%) had central OB. OW/OB was associated with low milk intake (OR = 1.92; 95% CI, 1.1-3.3), skipping breakfast (OR = 2.00; 95% CI, 1.2-3.4), a family history of hypertension (OR = 1.74; 95% CI, 1.1-2.9), and systolic BP (OR = 1.03; 95% CI, 1.01-1.05); adjusted for confounding variables. The subgroup analysis showed that OW/OB children had lower iron (83 vs. 94 ug/dl, respectively) and HDL-C (43 vs. 47 mg/dl) levels, but higher non-HDL-C (107 vs. 99 mg/dl) levels than normal-weight children. Multiple logistic regression analysis showed that OW/OB was inversely associated with iron (OR = 0.99; 95% CI, 0.98-0.998) and HDL-C (OR = 0.94; 95% CI, 0.91-0.97) levels; adjusted for confounding variables. CONCLUSION: Adiposity in schoolchildren was associated with unhealthy lifestyle behaviors, higher atherogenic risk, and lower iron concentrations, suggesting that OW/OB children are at increased risk for anemia and cardiometabolic disease.

Diabetes mellitus tipo 1: edad de comienzo y presencia en familiares de primer grado / Type 1 diabetes mellitus: age of onset and presence in first-degree relatives

Introducción: la diabetes mellitus tipo 1 (DM1) se considera una enfermedad de la infancia/adolescencia, pero puede ocurrir a cualquier edad. El riesgo de desarrollar DM1 es de ocho a 15 veces mayor en parientes de primer grado. La proporción de menores de 15 años con un pariente de primer grado afectado es ≈12%. Luego de años de seguimiento, esta frecuencia puede aumentar a más del 20%. Objetivos: determinar la edad de comienzo en pacientes adultos con DM1 y su frecuencia en familiares de primer grado. Materiales y métodos: en 414 sujetos se definió diagnóstico de DM1 por fenotipo, juicio clínico y requerimiento de insulina dentro del año de diagnóstico. Se determinó edad al diagnóstico y los sujetos se dividieron en mayores y menores de 30 años al momento del debut. En ellos se evaluó y comparó: DM1 en familiares de primer grado, índice de masa corporal (IMC), circunferencia de cintura, HbA1c e hipotiroidismo. Para la comparación de variables cuantitativas de los dos grupos se usó test de t y ANOVA para grupos múltiples, y para las variables categóricas se empleó chi cuadrado con corrección de Fisher. Resultados: el debut antes de los 10 años fue de 28,2%, entre los 10 y 20 años de 36,9%, entre los 20 y 30 años de 18,8% y por encima de los 30 años de 17,1%. Hubo similar frecuencia de hipotiroidismo y familiares de primer grado con DM1 en aquellos con diagnóstico antes o después de los 30 años. Se halló presencia de DM1 en familiares de primer grado en el 17,2% (padre 3,6%, madre 3,1%, hermano 10,2%, hijo 0,5%). Conclusiones: antes de los 30 años debutó el 82,9% de los pacientes, pero hubo un 17,1% que lo hizo después. El 17,2% tenía familiares de primer grado con DM1. A diferencia de los estudios en niños y adolescentes, y al igual que los estudios que evaluron poblaciones de DM1 adultos, encontramos el mayor antecedente de DM1 entre hermanos (10,2%). Dicho patrón familiar fue similar entre DM1 con comienzo antes o después de los 30 años

Introduction: type 1 diabetes mellitus (T1DM) is a childhood and adolescence disease, but it can occur at any age. The risk of developing T1DM is 8-15 times higher in first-degree relatives of patients with T1DM. The proportion of affected first-degree relatives in children under 15 with T1DM is ≈12%. This frequency may increase to more than 20% after years of follow-up. Objectives: to determine the age of onset of T1DM in adult patients and the frequency of T1DM in their first-degree relatives. Materials and methods: a diagnosis of T1DM was defined in 414 subjects by phenotype, clinical judgment and early insulin requirement within the year of diagnosis. Age at diagnosis was determined and subjects were divided into those with debut before or after 30. The following variables were recorded and compared: presence of T1DM in first-degree relatives, body mass index (BMI), waist circumference, HbA1c and association with hypothyroidism. t test and ANOVA for two or multiple subgroups comparison and chi square test with Fisher correction for quantitative or categorical variables were used. Results: the frequency of diabetes debut before the age of 10 was 28.2%, between 10 and 20 years 36.9%, between 20 and 30 years 18.8% and above 30 years 17.1%. The frequency of hypothyroidism and first-degree relatives with T1DM was similar in those diagnosed before or after 30 years. The presence of T1DM in first-degree relatives was found in 17.2% of the patients (father 3.6%, mother 3.1%, sibling 10.2%, son 0.5%). Conclusions: in 82.9% of patients debut was before the age of 30, but it was later in 17.1%. 17.2% of patients had first-degree relatives with T1DM. We found the highest frequency of T1DM association among siblings (10.2%) similar to studies in adult T1DM populations but contrary to studies in children and adolescents. This family pattern was similar between T1DM beginning before or after 30 years

Umbilical waist-to-height ratio and trunk fat mass index (DXA) as markers of central adiposity and insulin resistance in Argentinean children with a family history of metabolic syndrome.

Central adiposity is increasing in childhood. To find a simple index of central fatness that accurately predicts insulin resistance we studied 55 obese children and 53 siblings, aged 6-16 years. We recorded the family metabolic score, calculated clinical and DXA-derived fat distribution indexes and HOMA-IR. Umbilical waist-to-height ratio (W-to-Ht) had the best combination of ROC area (0.99, IC95: 0.93 to 1.0), Youden's index (0.976), coefficient of variation (4.9) and correlation with HOMA-IR (r = 0.58, p < 0.0001); it also correlated (p < 0.001) with BMI (r = 0.95) and DXA-trunk fat mass index (r = 0.93). It was the best predictor of insulin resistance in a multiple regression model (p < 0.0001). Odds ratios for insulin resistance were 9.33 when the family score was >10 (p < 0.01) and 14.35 when umbilical W-to-Ht was >0.54 (p < 0.0001). Umbilical W-to-Ht, a simple marker of central adiposity, strongly relates to children's DXA-trunk fat mass index and insulin resistance.

Parental hypertension and 24 h-blood pressure in children prior to diabetic nephropathy.

In a search for predictors of nephropathy development, albumin excretion rate (AER), ambulatory blood pressure, and parental hypertension were assessed in 40 type 1 diabetic patients and 27 normal siblings (age<18 years) during a 2-year follow-up period. A double-antibody kit and an automated device were used for measuring 24-h AER and ambulatory blood pressure monitoring (ABPM), respectively. Patients had higher 24-h and daytime diastolic blood pressure (DBP), diastolic load, and daytime heart rate than siblings. Patients with hypertensive parents had higher 24-h DBP and diastolic load than patients with normotensive parents and all siblings. Non-dipping was more frequent in children with hypertensive parents ( P<0.05). Both diabetes ( P<0.001) and parental hypertension ( P<0.05) had independent effects on longitudinal AER (average AER during follow-up). Patients with intermittent or persistent microalbuminuria showed a trend towards higher diastolic load ( P<0.05); the latter group had higher 24-h DBP ( P<0.01). Longitudinal AER correlated with 24-h DBP ( P<0.01) and maternal mean blood pressure ( P<0.05). Since changes in blood pressure preceded persistent microalbuminuria, ABPM might help to identify diabetic children prone to nephropathy.

Ioduria en escolares. Relacion con incidencia de bocio, nivel socioeconomico e ingesta de sal / Iodine in school children. Relationship with incidence of goiter, socioeconomic group and salt intake

Para valorar la ingesta diaria de iodo se midió la ioduria en 134 escolares de ambos sexos, de 5 - 14 años, de Luján de Cuyo (Mendoza). Los mismos fueron categorizados: a) según la existencia o no de bocio por palpación de 2 observadores; b) según el nivel socioeconómico y c) según la marca comercial de sal consumida. Las muestras provenían de un grupo examinado de 700 escolares. No hubo diferencias significativas en sexo, edad, peso o estatura entre los grupos mencionados. Se recolectaron m-uestras de escolares bociosos en mayor proporción que de normales. La ioduria media de los escolares sin bocio fue significativamente mayor que la de los bociosos, (p < 0,005). La prevalencia de bocio disminuyó en los escolares con ioduria de > 150 mug/24 h (p < 0,05). Los niveles de ioduria de escolares de distinto nivel socioeconómico fueron semejantes (p = 0,56). No se encontraron diferencias significativas entre consumidores de las dos marcas comerciales de sal más comunes (p = 0,07). Aunque los valores medios de ioduria en la población evaluada son aceptables, la amplia variabilidad observada sugiere la implementación de mejores medidas de control y de información a la población y, tal vez, la suplementación de iodo discriminada para optimizar la iodoprofilaxis.