Raquel Barrio

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.

LEOPARD syndrome (PTPN11, T468M) in three boys fulfilling neurofibromatosis type 1 clinical criteria.

Noonan syndrome (NS) and neurofibromatosis type 1 (NF1) are well-defined entities. The association of both disorders is called neurofibromatosis–Noonan syndrome (NFNS), a disorder that has been related to mutations in the NF1 gene. Both NS and NFNS display phenotypic overlapping with LEOPARD syndrome (LS), and differential diagnosis between these two entities often represents a challenge for clinicians. We report on three patients (two brothers and a not-related patient) diagnosed as having NFNS. They fulfilled NF1 diagnostic criteria and had some features of NS. The three of them had hypertophic cardiomyopathy while neurofibromas, Lisch nodules, and unidentified bright objects on MRI were absent. PTPN11 gene assays revealed a T468M mutation, typical of LS. Thorough clinical examinations of the patients revealed multiple lentigines, which were considered to be freckling in the initial evaluation. We conclude that NF1 clinical criteria should be used with caution in patients with features of NS. Patients with hyperpigmented cutaneous spots associated with cardiac anomalies, even if fulfilling the minimal NF1 criteria for diagnosis, should be strongly considered for LS diagnosis.

The majority of cases of neonatal diabetes in Spain can be explained by known genetic abnormalities

Background  Neonatal diabetes is a rare disease characterized by hyperglycaemia within the first 3 months of life and requiring insulin treatment; it can either be transient (TNDM) or permanent (PNDM). Alterations at band 6q24 and heterozygous activating mutations in KCNJ11, the gene encoding the pore‐forming subunit of the KATP channel, can cause neonatal diabetes.

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.

Impact of insulin pump therapy on long-term glycemic control in a pediatric Spanish cohort

AIMS To evaluate the efficacy and safety of Continuous Subcutaneous Insulin Infusion (CSII) in a pediatric cohort and to determine if the ISPAD/IDF/ADA criteria for good metabolic control are achieved during long periods of time. METHODS Retrospective longitudinal study including ninety patients [10.5 (6.5-13.9) years of age, 58% males]. Age at debut, type 1 diabetes mellitus duration, pubertal stage, HbA1c, insulin dose, mean number of glycemic controls, number of basal rates, % basal/total insulin, severe hypoglycemia and diabetic ketoacidosis events were analyzed. Subgroup analysis based on age and pubertal stage was performed. RESULTS HbA1c decreased from 6.9% [52 mmol/mol] to 6.7% [50 mmol/mol] after one year of CSII. Afterwards, it remained less than 7% during the follow-up period (median 3.5 ± 1.8 years (range 1-8). Prior to CSII, 76% of the subjects met ISPAD/ADA criteria. One year after initiating CSII, 96% of children had HbA1c<7.5%. Improvement in glycohemoglobin levels was most prominent in those patients with the highest HbA1c initial levels. Total insulin dose decreased from 0.89 to 0.73 UI/kg/day (p<0.001). Proportion of basal/total insulin changed significantly (47 to 42% (p<0.05)). Number of fractions of the basal rate increased from 5.6 ± 1.8 at one year of CSII to 6.7 ± 2.1 five years later. Incidence of severe hypoglycemic events decreased from 19 to 6.9 episodes/100 patient-year. Only 2 episodes of diabetic ketoacidosis occurred. CONCLUSIONS CSII allows reaching ISPAD/IDF/ADA goals safely during an extended follow-up period in a diabetic pediatric cohort.

New mutation type in pseudohypoparathyroidism type Ia

Context  The GNAS gene encodes the α‐subunit of the stimulatory G proteins, which play a crucial role in intracellular signal transduction of peptide and neurotransmitter receptors. Heterozygous inactivating maternally inherited mutations of GNAS (including translation initiation mutations, amino acid substitutions, nonsense mutations, splice site mutations and small insertions or deletions) lead to a phenotype in which Albright hereditary osteodystrophy is associated with pseudohypoparathyroidism type Ia.

Hypothalamic adipic hypernatraemia syndrome with normal osmoregulation of vasopressin

Adipsic hypernatraemia is an uncommon disorder in childhood caused by a defect in the osmoregulation of thirst, leading to impairment of water homeostasis and chronic hyperosmolality of body fluids. Adipsia is often associated with an abnormality in osmoregulated vasopressin secretion due to the close proximity of the hypothalamic osmoreceptors that control thirst with those regulating vasopressin secretion. Hypothalamic lesions of diverse aetiology (vascular abnormalities, neoplasms, granulomatous diseases, trauma etc.) have been described in this syndrome. We report a 12-year-old boy with evident weight loss due to hypernatraemic dehydration with a selective defect in osmoregulation of thirst and normal vasopressin secretion with no demonstrable structural lesion. To date, only six paediatric patients with this condition have been described in the literature. Conclusion:hypothalamic adipsic hypernatraemia syndrome must be suspected when a dehydrated patient denies thirst. The study of antidiuretic function is necessary because the osmoregulation of vasopressin secretion could be altered.

The syndrome of central hypothyroidism and macroorchidism: IGSF1 controls TRHR and FSHB expression by differential modulation of pituitary TGFβ and Activin pathways

IGSF1 (Immunoglobulin Superfamily 1) gene defects cause central hypothyroidism and macroorchidism. However, the pathogenic mechanisms of the disease remain unclear. Based on a patient with a full deletion of IGSF1 clinically followed from neonate to adulthood, we investigated a common pituitary origin for hypothyroidism and macroorchidism, and the role of IGSF1 as regulator of pituitary hormone secretion. The patient showed congenital central hypothyroidism with reduced TSH biopotency, over-secretion of FSH at neonatal minipuberty and macroorchidism from 3 years of age. His markedly elevated inhibin B was unable to inhibit FSH secretion, indicating a status of pituitary inhibin B resistance. We show here that IGSF1 is expressed both in thyrotropes and gonadotropes of the pituitary and in Leydig and germ cells in the testes, but at very low levels in Sertoli cells. Furthermore, IGSF1 stimulates transcription of the thyrotropin-releasing hormone receptor (TRHR) by negative modulation of the TGFβ1-Smad signaling pathway, and enhances the synthesis and biopotency of TSH, the hormone secreted by thyrotropes. By contrast, IGSF1 strongly down-regulates the activin-Smad pathway, leading to reduced expression of FSHB, the hormone secreted by gonadotropes. In conclusion, two relevant molecular mechanisms linked to central hypothyroidism and macroorchidism in IGSF1 deficiency are identified, revealing IGSF1 as an important regulator of TGFβ/Activin pathways in the pituitary.