Prevalencia del síndrome metabólico en una población de niños obesos en el País Vasco, su relación con la resistencia a la insulina, las adipoquinas y grhelina

274 p. : graf.Introducción: El síndrome metabólico es un conjunto de alteraciones antropométricas, clínicas y bioquímicas que predisponen al desarrollo de la enfermedad cardiovascular arterioesclerótica y a la diabetes mellitus tipo 2 a lo largo de la vida. En la asociación entre la obesidad y el síndrome metabólico, la resistencia a la insulina es clave porque constituye el sustrato fisiopatológico sobre el cual se desarrolla el síndrome. Igualmente las adipoquinas y citoquinas pueden influir para el desarrollo del mismo. Objetivo: Este trabajo tiene como objetivo conocer la prevalencia del síndrome metabólico y observar la relación que existe entre los componentes del síndrome con la resistencia a la insulina, las adipoquinas y la ghrelina en una población de niños obesos del País Vasco y observar si tras la disminución del IMC existen diferencias en la prevalencia del SM y en los niveles plasmáticos de las adipoquinas, ghrelina e insulina. Diseños, población y métodos: Se han estudiado 136 pacientes con edades entre los 6-15 años con el diagnóstico de obesidad. El criterio de inclusión fue la presencia de una obesidad primaria definida como un índice de masa corporal (IMC) ¿ 2 SDS. La obesidad además se clasificó en obesidad leve (¿ 2 y <3 SDS), obesidad moderada (¿ 3 y <4 SDS) y obesidad severa (¿ 4SDS). Para la definición del síndrome metabólico se utilizaron los criterios propuestos por la International Diabetes Federation (IDF) para la población pediátrica. Resultados: La edad media de los niños participantes fue de 10,3 ± 2,3 años (r: 6,2-14,5). Con un IMC de 3,8 ± 1,4 SDS (r: 2-11,9). La distribución de los niños según la severidad de la obesidad fue obesidad leve 31%, obesidad moderada 37% y obesidad severa 32%. La distribución por sexo fue 57% varones (77 pacientes) con edad media de 10,5 ± 2,3 años (r: 6,2-14,2) y 43% mujeres (59 pacientes) con edad media de 10,1 ± 2,3 años (r: 6,2-14,5). No se observaron diferencias en la edad según el sexo. La prevalencia del síndrome metabólico en la población estudiada fue del 2,9% (cuatro pacientes). Observamos que el 24,3% de los niños presentaron dos criterios, el 70% un criterio y el 2,9% ningún criterio. Cuando consideramos exclusivamente la población de niños mayores de 10 años (n= 77), la prevalencia del SM fue del 5,2%. En el análisis de los criterios que componen el síndrome metabólico el HDL-c estaba disminuido en el 14% de los pacientes y estaban aumentados, la glucemia en ayunas en un paciente, los triglicéridos en el 4,4% de los pacientes, la tensión arterial sistólica en el 11,8 % de los pacientes y la tensión arterial diastólica en 2 pacientes. Igualmente el 96,3% de los pacientes presentaron un perímetro abdominal igual o mayor al percentil 90. Tras la realización de un TTOG que consideramos como un criterio adicional, encontramos alteración del metabolismo hidrocarbonado en el 9,6% de los pacientes (13 niños) presentando todos ellos intolerancia a la glucosa (ITG), sólo un niño presentó además alteración de la glucemia en ayunas (AGA). Cuando comparamos la frecuencia de los criterios del SM según el sexo, no se observaron diferencias La prevalencia de la resistencia a la insulina fue 13,5% (18 niños). Con una frecuencia mayor en los puberales (72%) frente a los prepuberales (28%). Así mismo el índice de resistencia a la insulina realizado por medio del índice HOMA aumentó según la severidad de la obesidad. Además los niños con resistencia a la insulina fueron mayores, con un mayor IMC-z, con una tensión sistólica y diastólica aumentada. Con niveles más elevado de la glucemia basal y en el minuto 120 en un TTOG y de los triglicéridos. Igualmente los niños con resistencia a la insulina tenían disminuidos los niveles de adiponectina y ghrelina y estaban aumentados los niveles de leptina, insulina, IGF-1 y IGF-BP3 y no había diferencias significativas con la resistina. También observamos las múltiples correlaciones que existían entre los criterios que componen el síndrome metabólico, las adipoquinas y la insulina con los índices de insulinoresistencia HOMA-IR y de insulinosensibilidad QUICKI-IS. La evolución de los niños en conjunto fue favorable. En el control anual se objetivó una disminución del IMC-z en 0,95 ± 1 SDS (r: -1,12 a 4,4 SDS) y el 30% de los niños que seguían en el estudio presentaron un peso adecuado o sobrepeso. Entre los niños obesos la severidad de la obesidad también había disminuido, así el 32% presentaron obesidad leve, el 18% obesidad moderada y el 20% seguía con una obesidad severa. Cuando existió una disminución del IMC ¿ 0,5 SDS observamos que se modificaron favorablemente los criterios del SM. Así el número de niños con dos criterios para el diagnostico disminuyó y aumentó el numero de niños sin criterios para el SM. Además aumentaron los niveles plasmáticos de la adiponectina y disminuyeron la leptina, ghrelina e insulina y no se observó diferencia con la resistina. En síntesis con la modificación del estilo de vida en los niños se consigue la disminución del IMC-z y la mejoría metabólica de los mismos.Este proyecto fue financiado con ayudas del: Proyecto TRIGR (Trial to Reduce IDDM in Genetically at Risk) National Institut of Health 5UO1- HD040364-10 CIBERDEM. (Ciber de Diabetes y enfermedades metabólicas asociadas) Proyecto: Evaluación del síndrome metabólico en niños obesos, estudio genético y su relación con la enfermedad. Departamento de Sanidad del Gobierno Vasco (2005111059) Beca del Departamento de Educación, Universidad e Investigación de la Universidad del País Vasco IT-472-07 Fundación IKERTU Hay que destacar la contínua y generosa ayuda económica de PFIZER. S.A

Variable phenotype in HNF1B mutations: extrarenal manifestations distinguish affected individuals from the population with congenital anomalies of the kidney and urinary tract

Background: Mutations in hepatocyte nuclear factor 1B (HNF1B) have been associated with congenital anomalies of the kidney and urinary tract (CAKUT) in humans. Diabetes and other less frequent anomalies have also been described. Variable penetrance and intrafamilial variability have been demonstrated including severe prenatal phenotypes. Thus, it is important to differentiate this entity from others with similar clinical features and perform confirmatory molecular diagnosis. Methods: This study reports the results of HNF1B screening in a cohort of 60 patients from 58 unrelated families presenting with renal structural anomalies and/or non-immune glucose metabolism alterations, and other minor features suggesting HNF1B mutations. Results: This study identified a pathogenic variant in 23 patients from 21 families. The most frequent finding was bilateral cystic dysplasia or hyperechogenic kidneys (87% of patients). Sixty percent of them also fulfilled the criteria for impaired glucose metabolism, and these were significantly older than those patients with an HNF1B mutation but without diabetes or prediabetes (14.4 versus 3.3years, P<0.05). Furthermore, patients with HNF1B mutations had higher frequency of pancreatic structural anomalies and hypomagnesaemia than patients without mutations (P<0.001 and P = 0.003, respectively). Hyperuricaemia and increased liver enzymes were detected in some patients as well. Conclusions: Renal anomalies found in patients with HNF1B mutations are frequently unspecific and may resemble those found in other renal pathologies (CAKUT, ciliopathies). Active searching for extrarenal minor features, especially pancreatic structural anomalies or hypomagnesaemia, could support the indication for molecular diagnosis to identify HNF1B mutations

Incidence of Diabetes Mellitus and Associated Risk Factors in the Adult Population of the Basque Country, Spain

The aim of this study was to estimate the incidence of diabetes mellitus in the Basque Country and the risk factors involved in the disease by reassessing an adult population after 7 years of follow-up. In the previous prevalence study, 847 people older than 18 years were randomly selected from all over the Basque Country and were invited to answer a medical questionnaire, followed by a physical examination and an oral glucose tolerance test. In the reassessment, the same variables were collected and the resulting cohort comprised 517 individuals of whom 43 had diabetes at baseline. The cumulative incidence of diabetes was 4.64% in 7 years and the raw incidence rate was 6.56 cases/1000 person-years (95%CI: 4.11-9.93). Among the incident cases, 59% were undiagnosed. The most strongly associated markers by univariate analyses were age >60 years, dyslipidaemia, prediabetes and insulin resistance. We also found association with hypertension, obesity, family history of diabetes and low education level. Multivariate analysis adjusted for age and sex showed that a set of risk factors assessed together (dyslipidaemia, waist-to-hip-ratio and family history of diabetes) had great predictive value (AUC-ROC=0.899, 95%CI: 0.846-0.953, p=0.942), which suggests the need for early intervention before the onset of prediabetesThis work was partially supported by grants from the Department of Health of the Basque Country Government (2015111020); ISCIII (PI14/01104), co-funded by ERDF/ESF, "A way to make Europe"/"Investing in your future"; UPV/EHU (IT1281-19); Menarini Group Spain (BCA16/029); Endocrine-European Reference Network (EndoERN 739527); and CIBERDEM (Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders). The study funders were not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of the report

Novel Variant in the CNNM2 Gene Associated with Dominant Hypomagnesemia

The maintenance of magnesium (Mg2+) homeostasis is essential for human life. The Cystathionine-beta-synthase (CBS)-pair domain divalent metal cation transport mediators (CNNMs) have been described to be involved in maintaining Mg2+ homeostasis. Among these CNNMs, CNNM2 is expressed in the basolateral membrane of the kidney tubules where it is involved in Mg2+ reabsorption. A total of four patients, two of them with a suspected disorder of calcium metabolism, and two patients with a clinical diagnosis of primary tubulopathy were screened for mutations by Next-Generation Sequencing (NGS). We found one novel likely pathogenic variant in the heterozygous state (c.2384C>A; p.(Ser795*)) in theCNNM2gene in a family with a suspected disorder of calcium metabolism. In this family, hypomagnesemia was indirectly discovered. Moreover, we observed three novel variants of uncertain significance in heterozygous state in the other three patients (c.557G>C; p.(Ser186Thr), c.778A>T; p.(Ile260Phe), and c.1003G>A; p.(Asp335Asn)). Our study shows the utility of Next-Generation Sequencing in unravelling the genetic origin of rare diseases. In clinical practice, serum Mg2+ should be determined in calcium and PTH-related disorders.This study was supported by three grants from the Department of Health (2017111014, 2018111097 and 2019111052) and one grant from the Department of Education (IT1281-19) of the Basque Government. This work is generated within the Endocrine European Reference Network (Project ID number of Endo-ERN: 739527). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Five Patients with Disorders of Calcium Metabolism Presented with GCM2 Gene Variants

The GCM2 gene encodes a transcription factor predominantly expressed in parathyroid cells that is known to be critical for development, proliferation and maintenance of the parathyroid cells. A cohort of 127 Spanish patients with a disorder of calcium metabolism were screened for mutations by Next-Generation Sequencing (NGS). A targeted panel for disorders of calcium and phosphorus metabolism was designed to include 65 genes associated with these disorders. We observed two variants of uncertain significance (p.(Ser487Phe) and p.Asn315Asp), one likely pathogenic (p.Val382Met) and one benign variant (p.Ala393_Gln395dup) in the GCM2 gene in the heterozygous state in five families (two index cases had hypocalcemia and hypoparathyroidism, respectively, and three index cases had primary hyperparathyroidism). Our study shows the utility of NGS in unravelling the genetic origin of some disorders of the calcium and phosphorus metabolism, and confirms the GCM2 gene as an important element for the maintenance of calcium homeostasis. Importantly, a novel variant in the GCM2 gene (p.(Ser487Phe)) has been found in a patient with hypocalcemia.This study was supported by three grants from the Department of Health (2017111014, 2018111097 and 2019111052) and one grant from the Department of Education (IT1281-19) of the Basque Government. This work is generated within the Endocrine European Reference Network (Project ID number of Endo-ERN: 739527). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscrip

Rare Germline DICER1 Variants in Pediatric Patients With Cushing's Disease: What Is Their Role?

Context: The DICER1 syndrome is a multiple neoplasia disorder caused by germline mutations in the DICER1 gene. In DICER1 patients, aggressive congenital pituitary tumors lead to neonatal Cushing's disease (CD). The role of DICER1 in other corticotropinomas, however, remains unknown. Objective: To perform a comprehensive screening for DICER1 variants in a large cohort of CD patients, and to analyze their possible contribution to the phenotype. Design, setting, patients, and interventions: We included 192CD cases: ten young-onset (age <30 years at diagnosis) patients were studied using a next generation sequencing panel, and 182 patients (170 pediatric and 12 adults) were screened via whole-exome sequencing. In seven cases, tumor samples were analyzed by Sanger sequencing. Results: Rare germline DICER1 variants were found in seven pediatric patients with no other known disease-associated germline defects or somatic DICER1 second hits. By immunohistochemistry, DICER1 showed nuclear localization in 5/6 patients. Variant transmission from one of the parents was confirmed in 5/7 cases. One patient had a multinodular goiter; another had a family history of melanoma; no other patients had a history of neoplasms. Conclusions: Our findings suggest that DICER1 gene variants may contribute to the pathogenesis of non-syndromic corticotropinomas. Clarifying whether DICER1 loss-of-function is disease-causative or a mere disease-modifier in this setting, requires further studies.This work was supported by the Intramural Research Programs of Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and National Institute for Neurological Diseases and Stroke, National Institutes of Health, a grant from the Basque Department of Education (IT795-13), a grant from the Basque Department of Health (GV2018111082), the Merck Serono Research award from Fundacion Salud 2000 (15-EP-004) and the Jose Igea 2018 grant, sponsored by Pfizer, from Fundacion Sociedad Espanola de Endocrinologia Pediatrica (SEEP)

Negative autoimmunity in a Spanish pediatric cohort suspected of type 1 diabetes, could it be monogenic diabetes?

Objective Monogenic diabetes can be misdiagnosed as type 1 or type 2 diabetes in children. The right diagnosis is crucial for both therapeutic choice and prognosis and influences genetic counseling. The main objective of this study was to search for monogenic diabetes in Spanish pediatric patients suspected of type 1 diabetes with lack of autoimmunity at the onset of the disease. We also evaluated the extra value of ZnT8A in addition to the classical IAA, GADA and IA2A autoantibodies to improve the accuracy of type 1 diabetes diagnosis. Methods Four hundred Spanish pediatric patients with recent-onset diabetes (mean age 8.9 +/- 3.9 years) were analyzed for IAA, GADA, IA2A and ZnT8A pancreatic-autoantibodies and HLA-DRB1 alleles. Patients without autoimmunity and those with only ZnT8A positive were screened for 12 monogenic diabetes genes by next generation sequencing. Results ZnT8A testing increased the number of autoantibody-positive patients from 373 (93.3%) to 377 (94.3%). An isolated positivity for ZnT8A allowed diagnosing autoimmune diabetes in 14.8% (4/27) of pediatric patients negative for the rest of the antibodies tested. At least 2 of the 23 patients with no detectable autoimmunity (8%) carried heterozygous pathogenic variants: one previously reported missense variant in the INS gene (p.Gly32Ser) and one novel frameshift variant (p.Val264fs) in the HNF1A gene. One variant of uncertain significance was also found. Carriers of pathogenic variants had HLA-DRB1 risk alleles for autoimmune diabetes and clinical characteristics compatible with type 1 diabetes except for the absence of autoimmunity. Conclusion ZnT8A determination improves the diagnosis of autoimmune diabetes in pediatrics. At least 8% of pediatric patients suspected of type 1 diabetes and with undetectable autoimmunity have monogenic diabetes and can benefit from the correct diagnosis of the disease by genetic study.This work was partially supported by grants from Menarini Group Spain (BCA/16/030), University of the Basque Country, UPV/EHU (IT795-13), Department of Health of the Basque Government (GV2016111035) and ISCIII (PI14/01104) integrated into the National R&D&I Plan 2013-2016 and co-financed by FEDER (European Funds for Regional Development). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript