Evaluation of flash glucose monitoring after long-term use: A pediatric survey.

AIMS: To understand the opinions of children with type 1 diabetes about their everyday use of flash glucose monitoring. (FGM). METHODS: Children with type 1 diabetes using the FreeStyle Libre® FGM system and/or their parents were surveyed in several French medical centers between December 2016 and June 2017, regardless of their treatment regimen and metabolic control. RESULTS: Of the 347 patients recruited, 79.5% had been using the sensor for more than three months (average usage time: 285 days). The main reported motivations for initiating this type of monitoring were to avoid finger prick pain (for 85.9% of patients) and to allow parents to check nocturnal glucose levels (60.8%). Two-thirds of respondents experienced difficulties, mainly the sensor falling off (47.6%), measurement discrepancies (25.1%) and cutaneous reactions (22.2%); 89.5% changed their habits: 70.6% took more scans, 37.2% corrected their hyperglycemia more promptly, and 37.5% used trends to adjust their insulin dosage. About one-third of the study group (35.1%) experienced lower HbA1c levels, and two thirds (67.1%) were satisfied with the device. CONCLUSIONS: Our results show that FGM is a widely accepted option for self-monitoring diabetes, but that specific training is required to improve its use for insulin dosage adjustment and metabolic results.

Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty.

CONTEXT AND OBJECTIVE: Idiopathic central precocious puberty (iCPP) is defined as early activation of the hypothalamic-pituitary-gonadal axis in the absence of identifiable central lesions. Mutations of the makorin RING finger 3 (MKRN3) gene are associated with iCPP. We aimed to assess the frequency of MKRN3 mutations in iCPP and to compare the phenotypes of patients with and without MKRN3 mutations. DESIGN: An observational study was carried out on patients recruited at pediatric hospitals in France and Italy. Forty-six index CPP cases were screened for mutations in the MKRN3 coding sequence: 28 index cases of familial cases and 18 cases did not report any familial history of CPP. The endocrine phenotype was compared between MKRN3 mutated and non-mutated patients. RESULTS: MKRN3 mutations were identified in one sporadic and 13 familial cases. We identified five new heterozygous missense mutations predicted to be deleterious for protein function and two frameshift mutations, one new and the other recurrent, predicted to result in truncated proteins. Age at puberty onset varied very little among patients with MKRN3 mutations and puberty occurred earlier in these patients than in those without MKRN3 mutations (6.0 years (5.4-6.0) vs 7.0 years (6.0-7.0), P=0.01). CONCLUSIONS: MKRN3 mutations are common in familial iCPP. MKRN3 is one of the gatekeepers of the postnatal activation of the gonadotropic axis.

PROKR2 variants in multiple hypopituitarism with pituitary stalk interruption.

CONTEXT: Pituitary stalk interruption represents a frequent feature of congenital hypopituitarism, but only rare cases have been assigned to a known genetic cause. OBJECTIVE: Using a candidate gene approach, we tested several genes as potential causes of hypopituitarism with pituitary stalk interruption. We hypothesized that ectopic posterior pituitary may be a consequence of defective neuronal axon projections along the pituitary stalk or defective angiogenesis of hypophyseal portal circulation. Considering the role of the prokineticin 2 pathway in angiogenesis and neuronal migration, we screened PROK2 and PROKR2 genes. DESIGN: PROK2 and PROKR2 and all genes previously known to be involved in hypopituitarism with pituitary stalk interruption (LHX4, HESX1, OTX2, and SOX3) were screened in 72 index cases with pituitary stalk interruption syndrome from the GENHYPOPIT database. In vitro studies were performed to assess the functional consequences of allelic variants. RESULTS: We identified two heterozygous PROKR2 mutations (p.Leu173Arg and p.Arg85His) previously reported in isolated hypogonadotroph hypogonadism and a novel PROKR2 variant (p.Ala51Thr) that, in contrast with both other mutations, did not impair receptor signaling activity. Three allelic variants of HESX1 were identified: the heterozygous p.Phe156Ser and the homozygous p.Arg109X mutations were functionally deleterious, whereas p.Ser67Thr was found as a rare allelic variant in association with p.Arg85His PROKR2 mutation in the same patient. CONCLUSIONS: We report PROKR2 variants in congenital hypopituitarism with pituitary stalk interruption, suggesting a potential role of the prokineticin pathway in pituitary development.

Microvascular diabetes complications in Wolfram syndrome (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness [DIDMOAD]): an age- and duration-matched comparison with common type 1 diabetes.

OBJECTIVE: Some previous studies suggested that patients suffering from Wolfram syndrome or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) might be relatively preserved from diabetic retinopathy and nephropathy. However, these data were not conclusive because either observations were only anecdotic or did not match with control type 1 diabetic populations. RESEARCH DESIGN AND METHODS: A group of 26 French diabetic patients with DIDMOAD was compared with a population of 52 patients with common type 1 diabetes matched for age at diabetes diagnosis (8.62 +/- 1.84 vs. 8.27 +/- 1.30 years; P = NS) and diabetes duration (12.88 +/- 1.58 vs. 12.87 +/- 1.13 years; P = NS) to study the quality of glycemic control and the incidence of microvascular complications. RESULTS: Glycemic control was significantly better in the DIDMOAD group than in the type 1 diabetic group (A1C: 7.72 +/- 0.21 vs. 8.99 +/- 0.25%, respectively; P = 0.002), with significant lower daily insulin requirements (0.71 +/- 0.07 vs. 0.88 +/- 0.04 UI x kg(-1) x day(-1), respectively; P = 0.0325). The prevalence of microvascular complications in the DIDMOAD group was half that observed in the type 1 diabetic group, but the difference was not significant. CONCLUSIONS: Diabetes in DIDMOAD patients is more easily controlled despite the presence of other handicaps. This better glycemic control could explain the trend to decreased microvascular diabetes complications observed in previous studies.

An uncommon phenotype with familial central hypogonadism caused by a novel PROP1 gene mutant truncated in the transactivation domain.

CONTEXT: PROP1 gene mutations are usually associated with childhood onset GH and TSH deficiencies, whereas gonadotroph deficiency is diagnosed at pubertal age. OBJECTIVES: We report a novel PROP1 mutation revealed by familial normosmic hypogonadotropic hypogonadism. We performed in vitro transactivation and DNA binding experiments to study functional consequences of this mutation. SETTING: Three brothers were followed in the Department of Endocrinology of a French university hospital. PATIENTS: These patients from a consanguineous kindred were referred for cryptorchidism and/or delayed puberty. RESULTS: Initial investigations revealed hypogonadotropic hypogonadism. One of the patients had psychomotor retardation, intracranial hypertension, and minor renal malformations. The brothers reached normal adult height and developed GH and TSH deficiencies after age 30. A novel homozygous nonsense mutation (W194X) was found in the PROP1 gene, indicating that the protein is truncated in its transactivation domain. Transfection studies confirmed the deleterious effect of this mutation, whose transactivation capacity was only 34.4% of that of the wild-type. Unexpectedly altered DNA-binding properties suggested that the C-terminal end of the factor plays a role in protein-DNA interaction. CONCLUSIONS: PROP1 mutations should be considered among the growing number of genetic causes of initially isolated hypogonadotropic hypogonadism. This report extends the phenotype variability associated with PROP1 mutations.

[Congenital hypopituitarism: when should transcription factor gene screenings be performed?]. / Hypopituitarisme congénital. Quand analyser les gènes de facteurs de transcription?

THE GENETIC ORIGIN INCREASINGLY INCRIMINATED: Congenital pituitary hormone deficiencies represent conditions of hypopituitarism resulting from abnormal pituitary ontogenesis. This group of genetically determined diseases has considerably widened with the development of molecular biology. Many transcription factors playing a role in pituitary development have been identified, and their mutations reported as causes of isolated or multiple pituitary hormone deficiencies. Isolated pituitary hormone deficiencies may affect somatotroph, gonadotroph, and corticotroph lineages. They result from mutations of the genes of hormones (such as growth hormone), of a factor that regulates their synthesis or secretion (such as TPIT for corticotrophics), or of their receptors (GHRH or GnRH receptor genes). Multiple (or combined) pituitary hormone deficiencies result in the concomitant or sequential onset of several anterior pituitary hormone deficiencies. They are due to mutations of transcription factors involved in the early steps of pituitary development (RIEG, HesX1, LHX4, LHX3, Prop1, POU1F1/Pit-1), and are associated with various phenotypes. FOR BETTER MANAGEMENT: Long-term follow-up of these patients and functional studies of the mutations identified in specialized research centers will help to determine phenotype-genotype correlations, hence providing a valuable help to the management of these orphan diseases.

Pronóstico de talla en pacientes con pubertad precoz tratadas con Triptorelin / Predict of size in patient with precocious puberty tried with triptorelin

La pubertad precoz no es una patología rara en la niñez. Una de las consecuencias observadas es la baja talla definitiva en niñas no tratadas. El objetivo del presente trabajo es mostrar los resultados obtenidos sobre el crecimiento de 30 pacientes tratadas con un análogo de Lh-Rh (Triptorelin)