Turner syndrome: French National Diagnosis and Care Protocol (NDCP; National Diagnosis and Care Protocol).

Turner syndrome (TS; ORPHA 881) is a rare condition in which all or part of one X chromosome is absent from some or all cells. It affects approximately one in every 1/2500 liveborn girls. The most frequently observed karyotypes are 45,X (40-50%) and the 45,X/46,XX mosaic karyotype (15-25%). Karyotypes with an X isochromosome (45,X/46,isoXq or 45,X/46,isoXp), a Y chromosome, X ring chromosome or deletions of the X chromosome are less frequent. The objective of the French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins) is to provide health professionals with information about the optimal management and care for patients, based on a critical literature review and multidisciplinary expert consensus. The PNDS, written by members of the French National Reference Center for Rare Growth and Developmental Endocrine disorders, is available from the French Health Authority website. Turner Syndrome is associated with several phenotypic conditions and a higher risk of comorbidity. The most frequently reported features are growth retardation with short adult stature and gonadal dysgenesis. TS may be associated with various congenital (heart and kidney) or acquired diseases (autoimmune thyroid disease, celiac disease, hearing loss, overweight/obesity, glucose intolerance/type 2 diabetes, dyslipidemia, cardiovascular complications and liver dysfunction). Most of the clinical traits of TS are due to the haploinsufficiency of various genes on the X chromosome, particularly those in the pseudoautosomal regions (PAR 1 and PAR 2), which normally escape the physiological process of X inactivation, although other regions may also be implicated. The management of patients with TS requires collaboration between several healthcare providers. The attending physician, in collaboration with the national care network, will ensure that the patient receives optimal care through regular follow-up and screening. The various elements of this PNDS are designed to provide such support.

Prenatal education of overweight or obese pregnant women to prevent childhood overweight (the ETOIG study): an open-label, randomized controlled trial.

BACKGROUND: We aimed to evaluate whether pre and perinatal education of pregnant women would reduce childhood overweight. METHODS: Four French centers included women at ≤21 gestational weeks (GWs) with body mass index (BMI) >25 kg/m2 before pregnancy. Patients were randomized to a control group (routine care including at least one dietary visit) or an intervention group (2 individuals (26 and 30 GW) and 4 group sessions (21, 28, 35 GW, 2 months postpartum)) aimed at educating the future mother regarding infant and maternal nutrition. The primary objective was to reduce post-natal excessive weight gain in the infant from birth to 2 years (NCT00804765). This project was funded by a grant from the National Programme for Hospital Research (PHRC-2007 French Ministry of Health). RESULTS: We included 275 women (BMI: 32.5 kg/m2). The rate of post-natal excessive weight gain was similar in the intervention (n = 132) and control (n = 136) groups by intention to treat (ITT: 59.1% vs 60.3% respectively, p = 0.84) in available data (AD, n = 206) and by per-protocol analysis (PP, n = 177). Two years after delivery, normalization of maternal BMI and number of infants with BMI < 19 kg/m2 were not significantly different in the interventional group in ITT and in the control group. Although not significantly different in ITT, normalization of maternal BMI was more frequent in AD (n = 149: 12.9% vs 3.8%, p = 0.04) and 2-year-old infant BMIs were less likely to be >19 kg/m2 in the intervention group in AD (n = 204: 0% vs 6.8%, p = 0.014) and PP (n = 176: 0% vs 6.4%, p = 0.03). CONCLUSIONS: An education and nutritional counseling program for overweight women, starting after 3 months of gestation, did not significantly change post-natal excessive weight gain of infants or prevent overweight in mothers and children 2 years after delivery.

AZP-531, an unacylated ghrelin analog, improves food-related behavior in patients with Prader-Willi syndrome: A randomized placebo-controlled trial.

CONTEXT AND OBJECTIVE: Prader-Willi syndrome (PWS) is characterized by early-onset hyperphagia and increased circulating levels of the orexigenic Acylated Ghrelin (AG) hormone with a relative deficit of Unacylated Ghrelin (UAG). AZP-531, a first-in-class UAG analog, was shown to inhibit the orexigenic effect of AG in animals, to improve glycemic control and decrease body weight in humans. We aimed to investigate the safety and efficacy of AZP-531 in patients with PWS for whom no approved treatment for hyperphagia is currently available. METHODS AND DESIGN: Multi-center, randomized, double-blind, placebo-controlled trial. Forty-seven patients with genetically confirmed PWS and evidence of hyperphagia received daily subcutaneous injections of AZP-531 (3 and 4 mg for 50-70 kg and >70 kg body weight, respectively) or matching placebo for 14 days. Assessments included adverse events, vital signs, safety laboratory tests, the Hyperphagia Questionnaire (HQ), patient-reported appetite, body composition and glycemic measures. RESULTS: AZP-531 was well tolerated. There was a significant improvement with AZP-531 versus placebo in the mean total score, the 9-item score and the severity domain score of the HQ (p < .05). The highest reduction in the total and 9-item scores was observed in AZP-531 subjects with the highest hyperphagia score at baseline. Findings were supported by a reduction in appetite scores observed with AZP-531 only. Body weight did not change in both groups while a significant reduction in waist circumference and fat mass was observed only with AZP-531. AZP-531 significantly decreased post-prandial glucose levels in a baseline glucose dependent fashion. CONCLUSIONS: AZP-531 may constitute a new treatment strategy to improve hyperphagia and metabolic issues in patients with PWS. These findings support further investigation in longer-term clinical trials.

Glucose Profiles in Pregnant Women After a Gastric Bypass : Findings from Continuous Glucose Monitoring.

BACKGROUND: The diagnosis of gestational diabetes mellitus (GDM) usually requires an oral glucose tolerance test, but this procedure seems inappropriate after gastric bypass surgery (Roux-en-Y gastric bypass (RYGB)) due to specific altered glycemic responses. We aimed here at describing continuous glucose monitoring (CGM) profile of pregnant women after RYGB. METHODS: CGM was performed in 35 consecutive pregnant women after RYGB at 26.2 ± 5 weeks of gestation. RESULTS: After RYGB, pregnant women display high postprandial interstitial glucose (IG) peaks and low IG before and 2 h after meals. The postprandial IG peak is reached early, within 54 ± 9 min. The maximum IG values reach 205 mg/dl, and the percentage of time above 140 mg/dl (6.6 ± 7 %) is similar to what is described in GDM women. CONCLUSIONS: This study is the first to describe CGM profile in pregnant women after RYGB. CGM features are similar to those of non-pregnant post-RYGB patients, characterized by wide and rapid changes in postprandial IG, and high exposure to hyperglycemia. The exposure to hyperglycemia is similar to what is reported in GDM although the time to postprandial peak is shorter. CGM could be an additional useful approach to screen for glucose intolerance during pregnancy after RYGB.

Highly restricted deletion of the SNORD116 region is implicated in Prader-Willi Syndrome.

The SNORD116 locus lies in the 15q11-13 region of paternally expressed genes implicated in Prader-Willi Syndrome (PWS), a complex disease accompanied by obesity and severe neurobehavioural disturbances. Cases of PWS patients with a deletion encompassing the SNORD116 gene cluster, but preserving the expression of flanking genes, have been described. We report a 23-year-old woman who presented clinical criteria of PWS, including the behavioural and nutritional features, obesity, developmental delay and endocrine dysfunctions with hyperghrelinemia. We found a paternally transmitted highly restricted deletion of the SNORD116 gene cluster, the shortest described to date (118 kb). This deletion was also present in the father. This finding in a human case strongly supports the current hypothesis that lack of the paternal SNORD116 gene cluster has a determinant role in the pathogenesis of PWS. Moreover, targeted analysis of the SNORD116 gene cluster, complementary to SNRPN methylation analysis, should be carried out in subjects with a phenotype suggestive of PWS.

New management strategy of pregnancies at risk of congenital adrenal hyperplasia using fetal sex determination in maternal serum: French cohort of 258 cases (2002-2011).

CONTEXT: Prenatal dexamethasone (DEX) treatment has been proposed since 1984 to prevent genital virilization in girls with congenital adrenal hyperplasia (CAH). DEX is effective in CAH females if initiated before the sixth week of gestation, but its safety in children treated in utero remains controversial regarding cognitive functions. OBJECTIVE: To avoid prenatal DEX in males and initiate DEX in due time in CAH females, we proposed in 2002 a protocol for fetal sex determination in the maternal serum (SRY test). DESIGN AND SETTING: We conducted a retrospective study of the management of 258 fetuses in the period 2002 through 2011 in pregnancies managed in referent medical centers with an institutional practice. PATIENTS: A total of 258 fetuses at risk of CAH (134 males and 124 females) were included. INTERVENTION: DEX was offered after informed consent to pregnant women. MAIN OUTCOME MEASURE: The sensitivity of an early SRY test was evaluated after data collection. RESULTS: The SRY test is sensitive from 4 weeks and 5 days of gestation. It avoided prenatal DEX in 68% of males, and this percentage increased over the years. DEX was maintained until prenatal diagnosis in non-CAH females. Virilization was prevented in 12 CAH girls treated at the latest at 6 weeks gestation and minimized in 3 girls treated between 6 and 7 weeks gestation. Maternal tolerance was correct. No fetal malformations were noted in the 154 children treated in utero. CONCLUSIONS: The SRY test is reliable to avoid prenatal DEX in males, but its application must be improved. Prenatal DEX should be maintained to prevent virilization and traumatic surgery in CAH girls after informed consent and information provided to families about the benefit to risk ratio in limiting hyperandrogenism during fetal life. Our large multicentric French cohort has helped to better assess the risks previously reported.

Growth hormone therapy for children and adolescents with Prader-Willi syndrome is associated with improved body composition and metabolic status in adulthood.

CONTEXT: Children with Prader-Willi syndrome (PWS) who receive GH treatment have improved growth and body composition; however, data are lacking for adults when treatment is discontinued after completion of growth. OBJECTIVES: Our aim was to compare body composition and metabolic status in adults with PWS according to GH treatment in childhood and adolescence. DESIGN: 64 adults (mean age: 25.4 years) with a genetic diagnosis of PWS were evaluated: 20 received GH in childhood (T), which had been discontinued at the time of this study, and 44 did not receive GH (C). Mean duration of treatment in the T group was 4.4 ± 2.7 years, age at baseline was 11.8 ± 2.7 years, mean time between the end of treatment and the current evaluation was 7.0 ± 4.4 years. MAIN OUTCOMES MEASURES: Dual-energy X-ray absorptiometry was used to assess body composition and fasting biological analyses evaluated metabolic status. RESULTS (MEAN ± SD): Body mass index and percentage of fat mass were significantly lower in the T group (32.4 ± 10.3 vs 41.2 ± 11.1 kg/m(2), P = 0.05 and 44.0 ± 9.6 vs 50.1 ± 7.2%, P = 0.02, respectively). Insulinemia and HOMA-IR in non-diabetic subjects were significantly lower in the T group (5.8 ± 5.9 vs 13.9 ± 11.6 µUI/ml, P = 0.03, and 1.6 ± 1.3 vs 2.7 ± 2.1, P = 0.04, respectively). Non-diabetic and diabetic subjects from the T group had a significantly lower HbA1c. Lipid profiles were similar between groups. CONCLUSIONS: GH treatment in childhood and adolescence is associated with significantly decreased body mass index and improved body composition and metabolic status in adults with PWS at several years after discontinuing treatment.

Hormonal contraception in women at risk of vascular and metabolic disorders: guidelines of the French Society of Endocrinology.

Hormonal contraceptive methods are widely used in France, including not only oral estrogen-progestin combinations but also non-oral estrogen-progestin delivery methods (patches, vaginal rings), as well as oral forms, implants and intra-uterine devices that deliver only a progestin. Hormonal contraception has only a modest impact on lipid and carbohydrate metabolism, but estrogen-progestin contraceptives have been linked to a variety of vascular risks. Overall, the risk of venous thrombosis is multiplied by a factor of about 4, depending on age, the compounds used, and other risk factors (including biological thrombophilia and a personal history of thrombosis), whereas the risk of arterial events is only increased in women with risk factors. Available data suggest there is no excess risk with progestin-based contraceptives, but far fewer studies have been conducted. At the initiative of the French Society of Endocrinology, an expert group met in 2010 in order to reach a consensus on the use of hormonal contraceptive methods in women with vascular or metabolic risk factors, based on available data and international guidelines published by WHO in 2009 and subsequently adapted to the United States context. The following text, intentionally limited to hormonal contraception, is intended to serve as a guide when prescribing in specific clinical situations, such as a family or personal history of arterial or venous thromboembolism, or the existence of cardiovascular risk factors (hypertension, smoking, diabetes, dyslipidemia, obesity).