Long-term cortisol levels in hair of children and adolescents with Prader-Willi Syndrome

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 &lt; 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 &lt; 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 &lt; 2.5th percentile and (repeatedly) negative CAR might possibly have adrenal insufficiency or delayed HPA-axis responsiveness.</p

Reduced cortical complexity in children with prader-willi syndrome and its association with cognitive impairment and developmental delay

Background: Prader-Willi Syndrome (PWS) is a complex neurogenetic disorder with symptoms involving not only hypothalamic, but also a global, central nervous system dysfunction. Previously, qualitative studies reported polymicrogyria in adults with PWS. However, there have been no quantitative neuroimaging studies of cortical morphology in PWS and no studies to date in children with PWS. Thus, our aim was to investigate and quantify cortical complexity in children with PWS compared to healthy controls. In addition, we investigated differences between genetic subtypes of PWS and the relationship between cortical complexity and intelligence within the PWS group.Methods: High-resolution structural magnetic resonance images were acquired in 24 children with genetically confirmed PWS (12 carrying a deletion (DEL), 12 with maternal uniparental disomy (mUPD)) and 11 age- and sex-matched typically developing siblings as healthy controls. Local gyrification index (lGI) was obtained using the FreeSurfer software suite.Results: Four large clusters, two in each hemisphere, comprising frontal, parietal and temporal lobes, had lower lGI in children with PWS, compared to healthy controls. Clusters with lower lGI also had significantly lower cortical surface area in children with PWS. No differences in cortical thickness of the clusters were found between the PWS and healthy controls. lGI correlated significantly with cortical surface area, but not with cortical thickness. Within the PWS group, lGI in both hemispheres correlated with Total IQ and Verbal IQ, but not with Performance IQ. Children with mUPD, compared to children with DEL, had two small clusters with lower lGI in the right hemisphere. lGI of these clusters correlated with cortical surface area, but not with cortical thickness or IQ.Conclusions: These results suggest that lower cortical complexity in children with PWS partially underlies cognitive impairment and developmental delay, probably due to alterations in gene networks that play a prominent role in early brain development

Polymorphism in the IGF-I gene: clinical relevance for short children born small fos gestational age (SGA)

Low birth weight is associated with an increased risk in adult life of type 2 diabetes, hypertension and cardiovascular disease (CVD). The fetal insulin hypothesis postulates that genes involving insulin resistance could effect birth weight and disease in later life (Hattersley, 1999). Besides insulin, there is extensive evidence that insulin-like growth factor-I and -II (IGF-I, IGF-II) play an important role in fetal growth. We hypothesized that minor genetic variation in the IGF-I gene could influence pre- and postnatal growth. Three microsatellite markers located in the IGF-I gene in 124 short children (height &amp;lt; −1.88 SDS) who were born small for gestational age (SGA) and their parents were studied. SGA was defined as both a birth weight and birth length below −1.88 SDS for gestational age. Two polymorphic markers showed transmission disequilibrium. Allele 191 of the IGF1.PCR1 marker was transmitted more frequently from parent to child (χ2 = 4.8 and p = 0.02) and allele 198 of the 737/738 marker was transmitted less frequently from parent to child (χ = 4.5 and p = 0.03). Children carrying the 191-allele had significantly lower IGF-1 levels than children not carrying this allele (−1.1 SDS vs.− 0.05 SDS; p = 0.03). Also, head circumference SDS remained smaller in children with allele 191 compared to children without allele 191 (−2.1 SDS vs. −0.9 SDS; p = 0.003). Our results show that genetically determined low IGF-I levels may lead to a reduction in birth weight, length and head circumference and to persistent short stature and small head circumference in later life (proportionate small). Since low IGF-I levels are associated with type 2 diabetes and CVD, we propose that the IGF-I gene may provide a link between low birth weight and such diseases in later life.</jats:p

Pathophysiological aspects of hyperglycemia in children with meningococcal sepsis and septic shock: a prospective, observational cohort study

Introduction: The objective of this study was to investigate the occurrence of hyperglycemia and insulin response in critically ill children with meningococcal disease in the intensive care unit of an academic children's hospital.Methods: Seventy-eight children with meningococcal disease were included. The group was classified into shock non-survivors, shock survivors and sepsis survivors. There were no sepsis-only non-survivors. The course of laboratory parameters during 48 hours was assessed. Insulin sensitivity and β-cell function on admission were investigated by relating blood glucose leve

Anti-Müllerian hormone levels in girls and adolescents with Turner syndrome are related to karyotype, pubertal development and growth hormone treatment

STUDY QUESTION In girls and adolescents with Turner syndrome (TS), is there a correlation between serum AMH levels and karyotype, spontaneous puberty and other biochemical markers of ovarian function, or growth hormone (GH) therapy? SUMMARY ANSWER Serum anti-Müllerian hormone (AMH) correlates with karyotype, pubertal development, LH, FSH and are measurable in a higher percentage of TS patients under GH therapy. WHAT IS KNOWN ALREADY Most girls with TS suffer from incomplete sexual development, premature ovarian failure and infertility due to abnormal ovarian folliculogenesis. Serum AMH levels reflect the ovarian reserve in females, even in childhood. STUDY DESIGN, SIZE, DURATION Cross-sectional study investigating 270 karyotype proven TS patients aged 0-20 years between 2009 and 2010. PARTICIPANTS/MATERIALS, SETTINGS, METHODS Studies were conducted at three University Children's hospitals in Europe. Main outcome measures were clinical data concerning pubertal development as well as laboratory data including karyotype, serum AMH, LH, FSH, estradiol (E2), inhibin B and IGF. RESULTS AND THE ROLE OF CHANCE Serum AMH was detectable in 21.9% of all TS girls and correlated strongly with karyotypes. A measurable serum AMH was found in 77% of TS girls with karyotype 45,X/46,XX, in 25% with ‘other' karyotypes and in only 10% of 45,X TS girls. A strong relationship was also observed for measurable serum AMH and signs of spontaneous puberty such as breast development [adjusted odds ratio (OR) 19.3; 95% CI 2.1-175.6; P = 0.009] and menarche (crude OR 47.6; 95% CI 4.8-472.9; P = 0.001). Serum AMH correlated negatively with FSH and LH, but did not correlate with E2 and inhibin B. GH therapy increased the odds of having measurable AMH in TS (adjusted OR 4.1; 95% CI 1.9-8.8; P < 0.001). LIMITATIONS, REASONS FOR CAUTION The cross-sectional design of the study does not allow longitudinal interpretation of the data; for that further studies are needed. High percentage of non-measurable AMH levels in the cohort of TS require categorized analysis. WIDER IMPLICATIONS OF THE FINDINGS Serum AMH levels are a useful marker of the follicle pool and thus ovarian function in pediatric patients with TS. These findings are in line with the published literature. The finding that GH therapy may affect AMH levels is novel, but must be confirmed by future longitudinal studie

Response to GH Treatment After Radiation Therapy Depends on Location of Irradiation

OBJECTIVES: Cancer survivors with GH deficiency (GHD) receive GH therapy (GHT) after 1+ year observation to ensure stable tumor status/resolution. HYPOTHESIS: Radiation therapy (RT) to brain, spine, or extremities alters growth response to GHT. AIM: Identify differences in growth response to GHT according to type/location of RT. METHODS: The Pfizer International Growth Database was searched for cancer survivors on GHT for ≥5 years. Patient data, grouped by tumor type, were analyzed for therapy (surgery, chemotherapy, RT of the focal central nervous system, cranial, craniospinal, or total body irradiation [TBI] as part of bone marrow transplantation), sex, peak stimulated GH, age at GHT start, and duration from RT to GHT start. Kruskal-Wallis test and quantile regression modeling were performed. RESULTS: Of 1149 GHD survivors on GHT for ≥5 years (male 733; median age 8.4 years; GH peak 2.8 ng/mL), 431 had craniopharyngioma (251, cranial RT), 224 medulloblastoma (craniospinal RT), 134 leukemia (72 TBI), and 360 other tumors. Median age differed by tumor group (P < 0.001). Five-year delta height SD score (SDS) (5-year ∆HtSDS; median [10th-90th percentile]) was greatest for craniopharyngioma, 1.6 (0.3-3.0); for medulloblastoma, 5-year ∆HtSDS 0.9 (0.0-1.9); for leukemia 5-year ∆HtSDS, after TBI (0.3, 0-0.7) versus without RT (0.5, 0-0.9), direct comparison P < 0.001. Adverse events included 40 treatment-related, but none unexpected. CONCLUSIONS: TBI for leukemia had significant impact on growth response to GHT. Medulloblastoma survivors had intermediate GHT response, whereas craniopharyngioma cranial RT did not alter GHT response. Both craniospinal and epiphyseal irradiation negatively affect growth response to GH therapy compared with only cranial RT or no RT

Altered functional resting-state hypothalamic connectivity and abnormal pituitary morphology in children with Prader-Willi syndrome

Background: Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder, characterized by endocrine problems and hyperphagia, indicating hypothalamic-pituitary dysfunction. However, few studies have explored the underlying neurobiology of the hypothalamus and its functional connectivity with other brain regions. Thus, the aim of this study was to examine the anatomical differences of the hypothalamus, mammillary bodies, and pituitary gland as well as resting state functional connectivity of the hypothalamus in children with PWS. Methods: Twenty-seven children with PWS (13 DEL, 14 mUPD) and 28 typically developing children were included. Manual segmentations by a blinded investigator were performed to determine the volumes of the hypothalamus, mammillary bodies, and pituitary gland. In addition, brain-wide functional connectivity analysis was performed using the obtained masks of the hypothalamus. Results: Children with PWS showed altered resting state functional connectivity between hypothalamus and right and left lateral occipital complex, compared to healthy controls. In addition, children with PWS had on average a 50% smaller pituitary volume, an irregular shape of the pituitary, and a longer pituitary stalk. Pituitary volume did not increase in volume during puberty in PWS. No volumetric differences in the hypothalamus and mammillary bodies were found. In all subjects, the posterior pituitary bright spot was observed. Conclusions: We report altered functional hypothalamic connectivity with lateral occipital complexes in both hemispheres, which are implicated in response to food and reward system, and absence of connectivity might therefore at least partially contribute to the preoccupation with food in PWS

Use of national and international growth charts for studying height in european children: Development of up-to-date european height-for-age charts

Background: Growth charts based on data collected in different populations and time periods are key tools to assess children's linear growth. We analyzed the impact of geographic factors and the secular trend on height-for-age charts currently used in European populations, developed up-to-date European growth charts, and studied the effect of u

Insulin VNTR and IGF-1 promoter region polymorphisms are not associated with body composition in early childhood: The generation R study

Objective: The objective of this study was to examine the associations between insulin gene variable number of tandem repeats (INS VNTR) and insulin-like growth factor 1 (IGF1) gene promoter region polymorphisms with body composition in early childhood. Methods: This study was embedded in an ongoing prospective cohort study. Growth in early childhood (body mass index, total subcutaneous fat mass and waist-hip ratio) was assessed at birth and at the ages of 6 weeks and 24 months. DNA for genotyping was available in 738 children. Results: The genotype distribution of the INS VNTR gene was I/I 50.4%, I/III 40.4%, and III/III 9.2%. IGF1 genotypes were categorized in the following categories based on their 192-bp allele: homozygous (wild-type) 43.1%, heterozygous 45.8%, and noncarrier 11.2%. No differences were found in body mass index, total subcutaneous fat mass and waist-hip ratio in early childhood between the three groups for both the INS VNTR and IGF1 genotypes. We also did not find interactions between these genotypes and gender or birth weight on the effects of body composition measures. Conclusions: Our results do not support previous studies showing associations between INS VNTR and IGF1 promoter region polymorphisms with body composition in early childhood. Copyrigh