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BackgroundThe type 1 insulin-like growth factor receptor (IGF1R) is a keystone of fetal growth regulation by mediating the effects of IGF-I and IGF-II. Recently, a cohort of patients carrying an IGF1R defect was described, from which a clinical score was established for diagnosis. We assessed this score in a large cohort of patients with identified IGF1R defects, as no external validation was available. Furthermore, we aimed to develop a functional test to allow the classification of variants of unknown significance (VUS) in vitro.MethodsDNA was tested for either deletions or single nucleotide variant (SNV) and the phosphorylation of downstream pathways studied after stimulation with IGF-I by western blot analysis of fibroblast of nine patients.ResultsWe detected 21 IGF1R defects in 35 patients, including 8 deletions and 10 heterozygous, 1 homozygous and 1 compound-heterozygous SNVs. The main clinical characteristics of these patients were being born small for gestational age (90.9%), short stature (88.2%) and microcephaly (74.1%). Feeding difficulties and varying degrees of developmental delay were highly prevalent (54.5%). There were no differences in phenotypes between patients with deletions and SNVs of IGF1R. Functional studies showed that the SNVs tested were associated with decreased AKT phosphorylation.ConclusionWe report eight new pathogenic variants of IGF1R and an original case with a homozygous SNV. We found the recently proposed clinical score to be accurate for the diagnosis of IGF1R defects with a sensitivity of 95.2%. We developed an efficient functional test to assess the pathogenicity of SNVs, which is useful, especially for VUS.

The type 1 insulin-like growth factor receptor (IGF1R) is a keystone of fetal growth regulation by mediating the effects of IGF-I and IGF-II. Recently, a cohort of patients carrying anDNA was tested for either deletions or single nucleotide variant (SNV) and the phosphorylation of downstream pathways studied after stimulation with IGF-I by western blot analysis of fibroblast of nine patients.We detected 21We report eight new pathogenic variants of

Objective Non-idiopathic CPP is caused by acquired or congenital hypothalamic lesions visible on MRI or is associated with various complex genetic and/or syndromic disorders. This study investigated the different types and prevalence of non-isolated CPP phenotypes. Design and Methods This observational cohort study included all patients identified as having non-idiopathic CPP in the database of a single academic pediatric care center over a period of 11.5 years. Patients were classified on the basis of MRI findings for the CNS as having either hypothalamic lesions or complex syndromic phenotypes without structural lesions of the hypothalamus. Results In total, 63 consecutive children (42 girls and 21 boys) with non-isolated CPP were identified. Diverse diseases were detected, and the hypothalamic lesions visible on MRI (n = 28, 45% of cases) included hamartomas (n = 17; either isolated or with an associated syndromic phenotype), optic gliomas (n = 8; with or without neurofibromatosis type 1), malformations (n = 3) with interhypothalamic adhesions (n = 2; isolated or associated with syndromic CNS midline abnormalities, such as optic nerve hypoplasia, ectopic posterior pituitary) or arachnoid cysts (n = 1). The patients with non-structural hypothalamic lesions (n = 35, 55% of cases) had narcolepsy (n = 9), RASopathies (n = 4), encephalopathy or autism spectrum disorders with or without chromosomal abnormalities (n = 15) and other complex syndromic disorders (n = 7). Conclusion Our findings suggest that a large proportion (55%) of patients with non-isolated probable non-idiopathic CPP may have complex disorders without structural hypothalamic lesions on MRI. Future studies should explore the pathophysiological relevance of the mechanisms underlying CPP in these disorders.

Context: The unexpected observation of a normal GH peak in 22% of young adults with childhood-onset GH deficiency (GHD) and ectopic neurohypophysis has raised questions about the criteria defining GHD in young adults and whether patients with subsequent increases in GH secretion nonetheless have a subtle form of GHD.Objective: Our objective was to determine the characteristics of patients with childhood-onset nonacquired GHD who recover normal peak GH secretion when adult height has been achieved.Design and Setting: We conducted a university hospital-based observational follow-up study.Participants: Sixty-two patients with ectopic neurohypophysis (n = 24), isolated hypoplastic anterior pituitary (n = 14), or normal hypothalamic pituitary area (n = 24) on magnetic resonance imaging (MRI) at the time of GHD diagnosis underwent reevaluation of the GH-IGF-I axis at a mean age of 16.8 ± 1.6 yr.Main Outcome Measures: Outcome measures included clinical and MRI findings and serum IGF-I and peak GH levels.Results: On retesting, peak GH exceeded 10 μg/liter in 31 patients (50%): six (20%) patients with ectopic neurohypophysis, 10 (32%) patients with initially isolated hypoplastic anterior pituitary, and 15 (48%) patients with normal MRI findings. Among these patients, serum IGF-I levels were significantly lower in patients with ectopic neurohypophysis than in those without structural abnormalities of the hypothalamic pituitary axis (n = 25), but patients without structural abnormalities also had significantly lower serum IGF-I levels than control subjects, after controlling for age, sex, and body mass index (mean serum IGF-I levels of 374 ± 83 vs. 446 ± 108 μg/liter; β-coefficient = −72; P = 0.003).Conclusions: The severity of the disease seems to have decreased over time in these patients, who may nonetheless present persistent pituitary failure. The natural history and clinical implications of these findings remain to be clarified. The possibility of a deterioration in the secretion of GH and other pituitary hormones later in life in a subset of these patients warrants the careful long-term follow-up of this population.

Drug-based therapy is usually the initial treatment for Graves' disease (GD) hyperthyroidism in children, but there is some debate about treatment duration.Our objective was to assess the effect of long-term carbimazole therapy on GD remission in children and its determinants.This was an observational prospective multicenter follow-up cohort study.Participants included 154 children newly diagnosed with GD between 1997 and 2002. The intention was to treat patients with three consecutive courses of carbimazole, each lasting 2 yr. Definitive treatment was performed in cases of poor compliance with antithyroid drug (ATD) treatment, thyrotoxicosis relapse, or major adverse effects of ATD treatment.The main outcome measure was remission for at least 18 months after the completion of each course of ATD treatment.The median duration of follow-up was 10.4 (9.0-12.1) yr. Overall estimated remission rates (95% confidence interval) 18 months after the withdrawal of ATD treatment increased with time and were 20 (13-26), 37 (29-45), 45 (35-54), and 49 (40-57)% after 4, 6, 8, and 10 yr follow-up, respectively. A multivariate competing risk model revealed an independent positive effect of less severe forms of hyperthyroidism at diagnosis [subhazard ratio of 1 for patients with free T(4)35 pmol/liter vs. 0.4 (0.20-0.80) for free T(4) ≥ 35 pmol/liter; P = 0.01] and of the presence of other autoimmune conditions [subhazard ratio of 2.23 (1.19-4.18); P = 0.01] on remission rate after medical treatment.About half the patients achieved remission after carbimazole discontinuation, and there seems to be a plateau in the incidence of remission achieved after 8-10 yr ATD therapy.

Objective To analyze glycemic profile in children with congenital central hypoventilation syndrome, which is characterized by autonomic nervous system dysfunction. Study design We carried out a university hospital–based observational study. Participants included 14 patients assessed from 2007 to 2009 with a median age of 7.6 (25th-75th percentiles, 1.5-9.6) years at the time of the study. Glucose metabolism was assessed by calculating 24-hour plasma glucose (before and after meals) and fasting insulin concentrations and carrying out an oral glucose tolerance test (OGTT). The main outcome measure was the proportion of patients with abnormal glucose concentrations. Results Abnormal plasma glucose concentrations were found in 6 (43%) of the 14 patients with high fasting (n = 1) or postprandial (n = 5) hyperglycemia. OGTT was performed in 8 patients, of whom 3 (38%) had impaired glucose tolerance. Indices of insulin resistance and secretion were normal. No difference in clinical aspects relating to the presence of affected organs and/or systems related to central nervous system dysfunction, age, or auxology findings was found between patients with normal (43%) and abnormal (57%) glucose homeostasis over a 24-hour glycemia cycle or OGTT. Conclusion This study provides new information about glucose homeostasis in congenital central hypoventilation syndrome, revealing a high incidence of hyperglycemia and expanding the spectrum of the disease. It highlights the link between autonomic nervous system dysfunction and glycemic dysregulation. Regular, long-term monitoring of glucose metabolism is recommended in these patients.