Milagros Alonso

Induction of puberty with human chorionic gonadotropin and follicle-stimulating hormone in adolescent males with hypogonadotropic hypogonadism

OBJECTIVE To evaluate the clinical and hormonal responses of adolescent males with hypogonadotropic hypogonadism (HH) in response to gonadotropin replacement with the use of long-term combined hCG and FSH therapy. DESIGN Prospective clinical study. SETTING Clinical pediatric department providing tertiary care. PATIENT(S) Seven prepubertal males with isolated HH with a mean (+/-SD) age of 15.44+/-1.97 years and seven prepubertal males with panhypopituitarism-associated HH with a mean (+/-SD) age of 18.1+/-3.24 years were studied. INTERVENTION(S) Human chorionic gonadotropin (1,000-1,500 IU IM) and FSH (75-100 IU SC) were administered every alternate day of the week until the total induction of puberty and spermatogenesis was achieved. MAIN OUTCOME MEASURE(S) Serum testosterone levels, testicular volume, penis length, and sperm count were evaluated after the administration of hCG and FSH. RESULT(S) All patients achieved normal sexual maturation and normal or nearly normal adult male levels of testosterone. The increase in testicular size was significant in both groups. Positive sperm production was assessed in four of five patients with isolated HH and in three of three patients with panhypopituitarism-associated HH. CONCLUSION(S) Long-term combined hCG and FSH therapy is effective in inducing puberty, increasing testicular volume, and stimulating spermatogenesis in adolescent males with isolated HH and panhypopituitarism-associated HH.

Diagnostic value of serological markers for celiac disease in diabetic children and adolescents.

OBJECTIVE To determine the accuracy of antigliadin and antiendomysium antibodies for the diagnosis of celiac disease in diabetic children and adolescents with and without digestive symptoms. STUDY DESIGN 177 children and adolescents with IDDM aged 15.4 +/- 5.4 years (mean +/- SD). Antigliadin (ELISA) and antiendomysium (IFI) antibodies were measured in 177 and 35 patients, respectively. RESULTS Seven of 177 patients (3.9%; 95% confidence interval: 1.1-6.7) had celiac disease. The specificities of antiendomysium antibodies test (83%), IgA-antigliadin antibodies test (80%) and IgG-antigliadin antibodies test (90%) and the positive predictive values of these antibodies (55-75%) were lower than those obtained with the combined determination of these antibodies (100%). Negative antibodies and normal mucosa in one determination did not rule out the development of celiac disease later. CONCLUSIONS The combined determination of antigliadin and antiendomysium antibodies is the test of choice in screening for celiac disease in diabetic patients. The yearly investigation of these antibodies is a reliable method for detecting silent celiac disease in this population.

HELICOBACTER PYLORI INFECTION WITH PARIETAL CELL ANTIBODIES IN CHILDREN AND ADOLESCENTS WITH INSULIN DEPENDENT DIABETES MELLITUS

One hundred and seventy-seven patients with insulin dependent diabetes mellitus (IDDM) diagnosed at the pediatric age were investigated for the presence of gastric parietal cell autoantibodies (PCA). The objective was to evaluate the prevalence of PCA seropositivity and to know whether Helicobacter pylori could be a reason for a higher presence of PCA in IDDM children and adolescents. Twelve of 177 patients (6.77%; confidence interval: 3.1-10.3) had detectable PCA. Gastric pathology was studied in eight of these patients and in seven patients without PCA. Diagnosis of H. pylori infection was made on antral biopsies. None of the patients had an atrophic gastritis. Six of the eight patients with PCA had gastric mucosa colonization by H. pylori and/or chronic gastritis. According to these results, we suggest that H. pylori can be the cause of the presence of PCA positive results in diabetic children and adolescents, and diabetic patients with detectable PCA should be screened for H. pylori.

Obesidad y síndrome metabólico en la infancia

La obesidad esta aumentando de manera ostensible en el nino y en el adolescente en la ultima decada en todos los paises. En estos pacientes, sobre todo los de ciertas etnias, se han comenzado a encontrar alteraciones del metabolismo hidrocarbonado y se ha llegado incluso a presentar diabetes tipo 2. Tambien muestran signos precoces de insulinorresistencia y factores de riesgo cardiovascular. La presencia de diferentes factores de riesgo tiene un efecto aditivo.

Alteraciones de los genes de la vía RAS-MAPK en 200 pacientes españoles con síndrome de Noonan y otros síndromes neurocardiofaciocutáneos. Genotipo y cardiopatía

INTRODUCTION AND OBJECTIVES Molecular characterization of congenital heart diseases now includes the not infrequent dysmorphic Noonan syndrome. A study of 6 genes of the RAS-MAPK pathway in Spanish patients is presented: the impact of heart disease, clinical expressivity, and diagnostic yield are investigated. METHODS The study included 643 patients (and 182 family members) diagnosed by dysmorphologists, cardiologists, and pediatric endocrinologists from 74 tertiary hospitals. Bidirectional sequencing analysis of PTPN11, SOS1, RAF1, BRAF, KRAS and HRAS focused on exons carrying recurrent mutations accounting for 80% to 95% of previously described mutations. RESULTS Mutations were detected in 230 patients (91 women and 139 men) in 200 (31%) families (172 PTPN11+, 14 SOS1+, 9 RAF1+, 5 BRAF+). There was specific reference to the heart defect suffered in 156 index cases: 103 patients had shown pulmonary stenosis, 12 pulmonary stenosis with hyperthrophic cardiomyopathy, 18 hypertrophic cardiomiopathy, and 14 other cardiopathies; heart disease was absent in 9 index cases. Heart disease had not been documented in 23 of 30 family members with positive genotype and compatible clinical signs. Diagnostic yield was higher (P=.016) for samples from some centers (53%; 14/32) and even from certain professionals (64%; 9/14; P=.019). Characterization rate was 18% in patients for whom clinical data were not available. Genotyping led to a more precise diagnosis in 26 patients. CONCLUSIONS Most patients (94%) with a positive genotype had known congenital heart disease, 79% pulmonary stenosis and 12% hyperthrophic cardiomyopathy. Cardiopathy had not been documented in 76% of family members carrying the mutation. Molecular study is a useful tool in these syndromes but a more rigorous clinical diagnosis should be intended as well.

An Activating Mutation in STAT3 Results in Neonatal Diabetes through Reduced Insulin Synthesis.

Neonatal diabetes mellitus (NDM) is a rare form of diabetes diagnosed within the first 6 months of life. Genetic studies have allowed the identification of several genes linked to the development of NDM; however, genetic causes for ∼20% of the cases remain to be clarified. Most cases of NDM involve isolated diabetes, but sometimes NDM appears in association with other pathological conditions, including autoimmune diseases. Recent reports have linked activating mutations in STAT3 with early-onset autoimmune disorders that include diabetes of autoimmune origin, but the functional impact of STAT3-activating mutations have not been characterized at the pancreatic β-cell level. By using whole-exome sequencing, we identified a novel missense mutation in the binding domain of the STAT3 protein in a patient with NDM. The functional analyses showed that the mutation results in an aberrant activation of STAT3, leading to deleterious downstream effects in pancreatic β-cells. The identified mutation leads to hyperinhibition of the transcription factor Isl-1 and, consequently, to a decrease in insulin expression. These findings represent the first functional indication of a direct link between an NDM-linked activating mutation in STAT3 and pancreatic β-cell dysfunction.

Pulmonary function in children with type 1 diabetes mellitus

Abstract Aim: To assess lung function in children and adolescents with type 1 diabetes mellitus (T1DM). Patients and methods: We conducted a case-control study of 100 patients with T1DM [median age 13 (10.6–14.7), 44% men, 23% prepubertal, and all nonsmokers] and 77 controls. None had evidence of lung disease or any other comorbidity. We performed pulmonary function tests, including spirometry [forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and FEV1/FVC ratio], plethysmography [total lung capacity (TLC), residual volume (RV), RV/TLC ratio, and airway resistance (Raw)], and diffusing capacity of carbon monoxide in the lung (TLCO), alveolar volume (AV), and TLCO/AV ratio. The duration of diabetes, degree of metabolic control, insulin dose, and presence of diabetic complications were registered. The χ2-test and analysis of variance were used to compare categorical and quantitative variables, respectively. Results: The duration of diabetes was 6.2±3.8 years with a median HbA1c of 7.08±0.4%. FEV1/FVC ratio was found to be significantly higher in patients with TIDM than in controls. Patients with diabetes also had a nonsignificant trend towards lower FVC, FEV1, Raw, and TLCO, and higher RV, TLC, and RV/TLC than controls. There were no differences in pulmonary function based on duration of disease or metabolic control. We found differences in pulmonary evaluation when pubertal stage was analyzed. Conclusions: The lung is functionally involved in children with T1DM. Pubertal development stage influences the evaluation of lung function.

An XX male with an intratubular undifferentiated germ cell neoplasia

OBJECTIVE To report a case of a 46,XX male with an intratubular undifferentiated germ cell neoplasia within an extra-abdominal gonad. DESIGN Case report. SETTING Molecular, cytogenetic, pathologic, and clinical units of three tertiary hospitals. PATIENT(S) A male with ambiguous genitalia at birth and descended testes observed in a pediatric endocrinology setting. INTERVENTION(S) Physical examination, hormonal assays, cytogenetic investigation, molecular analysis, surgical intervention for biopsies and bilateral orchiectomy, and pathologic evaluation. MAIN OUTCOME MEASURE(S) Pathologic evaluation with immunostaining for placental alkaline phosphatase and C-kit. RESULT(S) Conventional chromosome analysis revealed a 46,XXq- karyotype, and fluorescence in situ hybridization experiments with the SRY probe found a signal at the short arm of the deleted X chromosome. Molecular analysis indicated the presence of a portion of the short arm of the Y chromosome including the proto-oncogene TSPY. Pathologic evaluation of the gonads revealed an intratubular undifferentiated germ cell neoplasia. CONCLUSION(S) This is the first case of a 46,XX male with descended testes in whom an intratubular undifferentiated germ cell neoplasia developed. When proposals of management in this subgroup of disorders of sexual differentiation are formulated, the risk of germ cell malignancy must be taken into account.

Factores predisponentes al desarrollo de diabetes tipo 2 y riesgo cardiovascular en la infancia. Obesidad, insulinorresistencia, dislipemia e hipertensión: síndrome dismetabólico

La dislipemia, hipertension, insulinorresistencia, alteracion hidrocarbonada y obesidad son potentes factores de riesgo de la enfermedad cardiovascular en el adulto. Esta constelacion de situaciones patologicas se conoce como sindrome dismetabolico. La obesidad tiene un papel central en este sindrome. Aunque el impacto de la enfermedad cardiovascular y la muerte se ve en el adulto, el proceso patologico y los factores de riesgo asociados comienzan durante la infancia. Se han encontrado componentes del sindrome dismetabolico en el nino y en el adolescente. La obesidad en estas edades tambien se asocia con insulinorresistencia, junto a anomalias lipidicas y alteracion de la presion arterial en el adulto joven. La diabetes tipo 2 se ha vuelto muy prevalente entre los adolescentes obesos, y el mejor predictor de la alteracion de la tolerancia a la glucosa es la evidencia de insulinorresistencia. Debido al gran incremento de la incidencia de obesidad en la edad pediatrica, sobre todo en algunos paises y en ciertas etnias, tiene una gran importancia conocer y controlar estos factores de riesgo en las edades tempranas de la vida. Hay que prevenir e intervenir precozmente en los ninos y adolescentes con sobrepeso y obesidad, sobre todo en los que pertenecen a los grupos de riesgo.