RESUMEN
CONTEXT: Prader-Willi syndrome (PWS) is characterized by hypothalamic dysfunction. In children with PWS, stress-induced central adrenal insufficiency (CAI) has been described, however, daily life cortisol production may be normal. Hair cortisol concentration (HCC) is a marker of long-term systemic cortisol production. Cortisol awakening response (CAR) is the increase in cortisol level after awakening. A negative CAR might suggest hypothalamic-pituitary-adrenal (HPA)-axis reactivity problems. Little is known about HCC and CAR in children with PWS. OBJECTIVE: To investigate long-term cortisol levels in hair and CAR in children with PWS. DESIGN: Cross-sectional study. PATIENTS: 41 children with PWS. SETTING: Dutch PWS Reference Center. MAIN OUTCOME MEASURES: HCC and salivary cortisol measured by LCMS. RESULTS: Median (IQR) HCC was 1.90 (1.02-3.30) pg/mg at a median (IQR) age of 14.5 (8.20-19.0) years, with median HCC in age-matched references being 2.63 pg/mg. Five patients (13.2%) had HCC < 2.5th percentile for age and these patients had a repeatedly negative CAR. Median HCC was significantly lower in patients with negative CAR than in patients with normal CAR (1.00 (0.22-1.59) vs. 2.25 (1.47-3.26) pg/mg, p = 0.007). One patient had both HCC < 2.5th percentile and repeatedly low morning salivary cortisol levels and negative CAR, and was diagnosed with adrenal insufficiency by overnight metyrapone test. CONCLUSIONS: HCC were normal in the majority of children with PWS. Our data suggest that children with HCC < 2.5th percentile and (repeatedly) negative CAR might possibly have adrenal insufficiency or delayed HPA-axis responsiveness.
Asunto(s)
Cabello , Hidrocortisona , Síndrome de Prader-Willi , Adolescente , Insuficiencia Suprarrenal/epidemiología , Niño , Estudios Transversales , Cabello/química , Humanos , Hidrocortisona/análisis , Sistema Hipófiso-Suprarrenal/fisiopatología , Síndrome de Prader-Willi/metabolismo , Síndrome de Prader-Willi/fisiopatología , Adulto JovenRESUMEN
OBJECTIVE: Children with Prader-Willi syndrome (PWS) have mild to moderate cognitive impairment. Short-term studies showed positive effects of growth hormone (GH) on cognitive development. This study investigated the effects of 8 years of GH on cognitive development in children with PWS. We also investigated whether starting GH during infancy results in higher cognitive functioning after 8 years of GH. DESIGN: Longitudinal study in 43 children with PWS during 8 years of GH (median age at GH start 8.1 years). Cognitive functioning after 8 years was compared to another group of 22 children with PWS (median age at GH start 1.4 years). METHODS: Cognitive functioning was measured by Wechsler Intelligence Scale for Children. Vocabulary, Similarities and Block Design subtests were expressed as standard deviation scores (SDS) and total IQ (TIQ) calculated. RESULTS: Estimated mean (95%CI) Block Design SDS changed from -2.2 (-2.6; -1.8) at GH start to -1.8 (-2.2; -1.4) after 8 years of GH (P = 0.18), similarly SDS from -1.5 (-2.1; -0.9) to -1.3 (-1.9; -0.7, P = 0.66) and TIQ from 66 (60; 72) to 69 (63; 75, P = 0.57). Vocabulary SDS remained similar, being -1.9 (-2.3; -1.4) at GH start and -1.9 (-2.4; -1.5) after 8 years (P = 0.85). After 8 years of GH Vocabulary, SDS and TIQ were higher in the children who started GH during infancy, compared to those who started GH later in childhood (P < 0.01, P = 0.04, respectively). CONCLUSIONS: Cognitive functioning in children with PWS remains similar during long-term GH and develops at the same pace as healthy peers.
Asunto(s)
Disfunción Cognitiva/tratamiento farmacológico , Hormona de Crecimiento Humana/uso terapéutico , Síndrome de Prader-Willi/tratamiento farmacológico , Síndrome de Prader-Willi/psicología , Adolescente , Factores de Edad , Niño , Preescolar , Cognición/efectos de los fármacos , Estudios de Cohortes , Femenino , Genotipo , Hormona de Crecimiento Humana/administración & dosificación , Humanos , Lactante , Estudios Longitudinales , Masculino , Países Bajos , Síndrome de Prader-Willi/genética , Estudios Prospectivos , Resultado del Tratamiento , Escalas de WechslerRESUMEN
CONTEXT: Patients with Prader-Willi syndrome (PWS) have an increased fat mass and decreased lean body mass. GH-treated young adults with PWS who have attained adult height benefit from continuation of growth hormone (GH) treatment, as GH maintained their improved body composition, whereas fat mass increased during the placebo period. Adults with PWS are predisposed to T2DM and cardiovascular disease. Whether GH affects metabolic health profile of this patient group is unknown. OBJECTIVE: To investigate the effects of GH vs placebo on metabolic health, in young adults with PWS who were GH-treated for many years during childhood and had attained adult height (AH). METHOD: A 2-year, randomized, double-blind, placebo-controlled crossover study with stratification for gender and BMI in 27 young adults with PWS. Intervention with GH (0·67 mg/m2 /day) and placebo, both for 1-year duration. RESULTS: Compared to placebo, GH treatment resulted in similar glucose and insulin levels during oral glucose tolerance test. Only fasting glucose and insulin were slightly higher during GH vs placebo (+0·2 mmol/l and +18·4 pmol/l), although both remained within normal ranges in both phases. Blood pressure and lipid profile were similar after GH vs placebo. At baseline (AH) and during GH, no patients had metabolic syndrome, while 1 developed it during placebo treatment. CONCLUSIONS: Growth hormone treatment has no adverse effects on metabolic health profile. Thus, GH-treated young adults with PWS who have attained AH benefit from continuation of GH treatment without safety concerns regarding metabolic health.
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Hormona de Crecimiento Humana/uso terapéutico , Síndrome de Prader-Willi/tratamiento farmacológico , Adolescente , Glucemia/análisis , Estudios Cruzados , Femenino , Prueba de Tolerancia a la Glucosa , Hormona de Crecimiento Humana/efectos adversos , Humanos , Insulina/sangre , Masculino , Síndrome de Prader-Willi/fisiopatología , Adulto JovenRESUMEN
BACKGROUND: Patients with Prader-Willi syndrome (PWS) have a cognitive impairment. Growth hormone (GH) treatment during childhood improves cognitive functioning, while cognition deteriorates in GH-untreated children with PWS. Cessation of GH treatment at attainment of adult height (AH) might deteriorate their GH-induced improved cognition, while continuation might benefit them. We, therefore, investigated the effects of placebo versus GH administration on cognition in young adults with PWS who were GH-treated for many years during childhood and had attained AH. METHOD: Two-year, randomized, double-blind, placebo-controlled cross-over study in 25 young adults with PWS. Cross-over intervention with placebo and GH (0.67 mg/m2/day), both during 1 year. RESULTS: Total (TIQ), verbal (VIQ) and performance IQ (PIQ) did not deteriorate during 1 year of placebo, compared to GH treatment (p > 0.322). Young adults with a lower TIQ had significantly more loss of TIQ points during placebo versus GH, in particular VIQ decreased more in those with a lower VIQ. The effect of placebo versus GH on TIQ, VIQ and PIQ was not different for gender or genotype. CONCLUSIONS: Compared to GH treatment, 1 year of placebo did not deteriorate cognitive functioning of GH-treated young adults with PWS who have attained AH. However, patients with a lower cognitive functioning had more loss in IQ points during placebo versus GH treatment. The reassuring finding that 1 year of placebo does not deteriorate cognitive functioning does, however, not exclude a gradual deterioration of cognitive functioning on the long term. TRIAL REGISTRATION: ISRCTN24648386 , NTR1038 , Dutch Trial Register, www.trialregister.nl . Registered 16 August 2007.
Asunto(s)
Cognición/efectos de los fármacos , Hormona del Crecimiento/uso terapéutico , Síndrome de Prader-Willi/tratamiento farmacológico , Adolescente , Estatura , Estudios Cruzados , Método Doble Ciego , Femenino , Hormona del Crecimiento/administración & dosificación , Humanos , MasculinoRESUMEN
BACKGROUND: Prader-Willi syndrome (PWS) is known for hyperphagia with impaired satiety and a specific behavioural phenotype with stubbornness, temper tantrums, manipulative and controlling behaviour and obsessive-compulsive features. PWS is associated with hypothalamic and oxytocinergic dysfunction. In humans without PWS, intranasal oxytocin administration had positive effects on social and eating behaviour, and weight balance. OBJECTIVE AND HYPOTHESES: To evaluate the effects of intranasal oxytocin compared to placebo administration on social behaviour and hyperphagia in children with PWS. DESIGN: Randomized, double-blind, placebo-controlled, crossover study in a PWS Reference Center in the Netherlands. METHOD: Crossover intervention with twice daily intranasal oxytocin (dose range 24-48 IU/day) and placebo administration, both during 4 weeks, in 25 children with PWS (aged 6 to 14 years). RESULTS: In the total group, no significant effects of oxytocin on social behaviour or hyperphagia were found, but in the 17 children younger than 11 years, parents reported significantly less anger (P = 0·001), sadness (P = 0·005), conflicts (P = 0·010) and food-related behaviour (P = 0·011), and improvement of social behaviour (P = 0·018) during oxytocin treatment compared with placebo. In the eight children older than 11 years, the items happiness (P = 0·039), anger (P = 0·042) and sadness (P = 0·042) were negatively influenced by oxytocin treatment compared to placebo. There were no side effects or adverse events. CONCLUSIONS: This randomized, double-blind, placebo-controlled study suggests that intranasal oxytocin administration has beneficial effects on social behaviour and food-related behaviour in children with PWS younger than 11 years of age, but not in those older than 11 years of age.
Asunto(s)
Conducta Alimentaria/efectos de los fármacos , Oxitocina/farmacología , Síndrome de Prader-Willi/tratamiento farmacológico , Conducta Social , Administración Intranasal , Adolescente , Factores de Edad , Ira/efectos de los fármacos , Niño , Estudios Cruzados , Depresión/tratamiento farmacológico , Método Doble Ciego , Humanos , Síndrome de Prader-Willi/fisiopatologíaRESUMEN
OBJECTIVE: Short stature caused by point mutations or deletions of the short stature homeobox (SHOX) gene (SHOX haploinsufficiency (SHI)) is a registered indication for GH treatment. Patients with a SHOX enhancer deletion (SED) have a similar phenotype, but their response to GH is unknown. It is uncertain if duplications of SHOX or its enhancer (SDUP) cause short stature. This study aimed to describe the clinical characteristics and growth response to GH treatment in patients with aberrations of SHOX and its enhancers. DESIGN: In this retrospective multi-center study (2002-March 2014) clinical information was available from 130 patients (72 SHI, 44 SED, and 14 SDUP) of whom 52 patients were treated with GH. We evaluated height, sitting height (SH), arm span, dysmorphic features and indicators of the growth response to GH (delta height SDS, height velocity, and index of responsiveness). RESULTS: Patients with SEDs showed similar HtSDS to patients with SHI (-2.3 and -2.6, respectively, P=0.2), but they were less disproportionate (SH/height ratio SDS 2.0 vs 3.1 (P<0.01) and extremities/trunk ratio 2.57 vs 2.43 (P=0.03)). The 1st year growth response to GH treatment was significantly greater in prepubertal patients with SEDs than SHI. None of the patients with an SDUP was disproportionate and SDUP cosegregated poorly with short stature; their growth response to GH treatment (n=3) was similar to the other groups. CONCLUSIONS: Patients with SEDs are equally short, but less disproportionate than patients with SHI, and show a greater response to GH.