Publications by authors named "Urs Eiholzer"

24 Publications

  • Page 1 of 1

Prader-Willi Syndrome and Hypogonadism: A Review Article.

Int J Mol Sci 2021 Mar 8;22(5). Epub 2021 Mar 8.

Centre for Paediatric Endocrinology Zurich (PEZZ), 8006 Zurich, Switzerland.

Prader-Labhart-Willi syndrome (PWS) is a rare genetic disorder characterized by intellectual disability, behavioural problems, hypothalamic dysfunction and specific dysmorphisms. Hypothalamic dysfunction causes dysregulation of energy balance and endocrine deficiencies, including hypogonadism. Although hypogonadism is prevalent in males and females with PWS, knowledge about this condition is limited. In this review, we outline the current knowledge on the clinical, biochemical, genetic and histological features of hypogonadism in PWS and its treatment. This was based on current literature and the proceedings and outcomes of the International PWS annual conference held in November 2019. We also present our expert opinion regarding the diagnosis, treatment, care and counselling of children and adults with PWS-associated hypogonadism. Finally, we highlight additional areas of interest related to this topic and make recommendations for future studies.
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http://dx.doi.org/10.3390/ijms22052705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962179PMC
March 2021

The increase in child obesity in Switzerland is mainly due to migration from Southern Europe - a cross-sectional study.

BMC Public Health 2021 01 29;21(1):243. Epub 2021 Jan 29.

Center for Paediatric Endocrinology Zurich (PEZZ), Moehrlistrasse 69, CH-8006, Zurich, Switzerland.

Background: Novel height, weight and body mass index (BMI) references for children in Switzerland reveal an increase in BMI compared to former percentile curves. This trend may be the result of children with parents originating from Southern European countries having a higher risk of being overweight compared to their peers with parents of Swiss origin. We examined the association of generational, migration-related and socioeconomic factors on BMI in Switzerland and expect the results to lead to more targeted prevention programs.

Methods: From contemporary cross-sectional data, we calculated subgroup-specific BMI percentiles for origin. Results for children of Swiss origin were compared with historical BMI data from Zurich. We tested for the association of overweight and obesity with origin and compared the distributions of BMI percentile ranks. Logistic regression analyses were applied to predict probabilities of being overweight or obese by origin and the Swiss neighborhood index of socioeconomic position (SSEP).

Results: Compared to the BMI from two generations ago, the newly calculated BMI increased only slightly for children with both parents from Switzerland; 1.2% of these girls and 1.6% of these boys are obese. In the Swiss population, 13% of the children have parents from Southern Europe and the proportion of obesity is 57 and 42% in these boys and girls, respectively. Their BMI medians correspond to those of their parents' countries of origin. For the probability of being overweight or obese, the SSEP differences are less important than the status of origin.

Conclusion: We identified children with both parents from Southern Europe as the main influence driving the increase in BMI in Switzerland over the past 50 years. A differentiated consideration of the proportions of various migrant groups within cross-sectional samples is essential when monitoring BMI. Ignoring fluctuations can lead to false conclusions.
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http://dx.doi.org/10.1186/s12889-021-10213-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845097PMC
January 2021

Contemporary height, weight and body mass index references for children aged 0 to adulthood in Switzerland compared to the Prader reference, WHO and neighbouring countries.

Ann Hum Biol 2019 Sep 31;46(6):437-447. Epub 2019 Oct 31.

Centre for Paediatric Endocrinology Zurich (PEZZ), Zurich, Switzerland.

In 2011, WHO growth curves replaced those of Prader and colleagues (First Zurich longitudinal study) in Switzerland. To present contemporary height-, weight- and body mass index (BMI)-for-age references reflecting children's growth in modern Switzerland. Cross-sectional sample comprising 30,141 boys and girls aged 0-20 years measured between 2012 and 2019. Height, weight and BMI reference curves were created using the LMS method. Derived percentiles were compared with those of Prader, WHO and neighbouring countries. Growth in the first 5 years is almost identical with Prader curves. Thereafter children are taller, yet their final height is only about 1 cm higher. Today's children, in particular boys, are considerably heavier. In comparison with WHO growth references, Swiss children are taller from the second year until adulthood; the WHO 3rd percentiles lie about 4 cm below those of our updated references. Weight and BMI median percentiles from our sample are similar to those of WHO and higher than the Prader curves. However, the course of the 97th BMI percentile WHO curves extends well below the 97th percentile of the updated Swiss curves. This study provides contemporary reference data for assessing individual growth based on height, weight and BMI of Swiss children.
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http://dx.doi.org/10.1080/03014460.2019.1677774DOI Listing
September 2019

Letter regarding "Prevalence of growth hormone deficiency in previously GH-treated young adults with Prader-Willi syndrome" by Donze et al.

Clin Endocrinol (Oxf) 2019 10 26;91(4):578-579. Epub 2019 Jun 26.

President IPWSO, Department of Psychiatry, University of Cambridge, Cambridge, UK.

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http://dx.doi.org/10.1111/cen.14047DOI Listing
October 2019

Less physically active children are shorter.

Minerva Pediatr 2017 Apr 19;69(2):135-140. Epub 2015 Nov 19.

Center for Pediatric Endocrinology Zürich (PEZZ), Zurich, Switzerland -

Background: Current concepts of linear growth include genetic, endocrine and nutritional factors. Limited and controversial results exist regarding the effect of physical activity (PA) on linear growth. In 2009, we showed that PA promotes foot length in hypoactive children with Prader-Willi-Syndrome. In the present study we tested the hypothesis that PA related epiphyseal loading has a positive modulating effect on linear growth in healthy school children.

Methods: In 99 healthy schoolchildren, we measured height, foot length and PA by tri-axial accelerometry. PA related epiphyseal loading was expressed as the product between mass (body weight) and acceleration (vector magnitude). Correlation between height, foot length and PA were calculated taking into account co-variables age, sex, parental height, lean and fat mass measured by DEXA.

Results: Height SDS (P<0.015, r=0.245) as well as foot length SDS (P<0.001, r=0.363) correlated with PA. Multiple linear regression models showed that muscle mass expressed by lean body mass has higher correlation with PA, height SDS and foot length SDS than fat mass.

Conclusions: This study shows that physically less active children are shorter and have shorter feet. In analogy to the "muscle bone unit", we propose a "muscle epiphyseal unit" which regulates local bone growth as long as epiphyseal plates are still open.
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http://dx.doi.org/10.23736/S0026-4946.16.04287-0DOI Listing
April 2017

Parent preference in Switzerland for easy-to-use attributes of growth hormone injection devices quantified by willingness to pay.

Expert Rev Med Devices 2014 Jan 2;11(1):31-8. Epub 2013 Dec 2.

Growth Clinic, PEZZ Center for Pediatric Endocrinology Zurich, Moehrlistrasse 69, Zurich, Switzerland.

Sustained treatment adherence, usually over long periods of time, is critical to the success of growth hormone (GH) therapy. However, adherence rates are often poor which may result in suboptimal clinical outcomes. The type of device used by patients to administer their GH can influence adherence. Offering patients a choice of device maximizes the chance of adherence to treatment. Multiple factors will influence a patient's choice of device, depending on individual priorities. This study evaluated the most preferred features of GH injection devices by parents using a web-based questionnaire and as assessed by their willingness to pay for specific device features. The results show that parents are willing to pay for device features facilitating ease of use.
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http://dx.doi.org/10.1586/17434440.2014.856754DOI Listing
January 2014

Strength training and physical activity in boys: a randomized trial.

Pediatrics 2013 Dec 4;132(6):1105-11. Epub 2013 Nov 4.

Head of the Center for Pediatric Endocrinology Zurich, Moehrlistrasse 69, CH-8006 Zurich, Switzerland.

Background: In developed societies levels of daily physical activity (PA) among school-age children are decreasing. This implies risk factors for cardiovascular and metabolic diseases. Specific strategies to improve levels of PA are needed. In prepubertal boys there is evidence that strength training increases spontaneous PA outside of training.

Methods: A total of 102 schoolchildren (age 10-14 years) in Switzerland were randomly assigned to physical education classes or to participate twice weekly at a guided strength training program for 19 weeks. Spontaneous PA energy expenditure (PAEE; 3axial accelerometry for 7 days), leg and arm strength, and body composition (dual energy radiograph absorptiometry) were measured at baseline, after 19 weeks of training intervention, and after 3 months of washout.

Results: There were no significant differences between the groups at baseline. In the intervention group, PAEE increased by 10% from baseline to end of training in boys (P = .02), but not in girls. Leg and arm strength were increased owing to training intervention in both boys and girls. All other variables were unchanged. Baseline PAEE was significantly negatively correlated with changes of PAEE.

Conclusions: Targeted strength training significantly increases daily spontaneous PA behavior in boys. The less active children showed the greatest increase in spontaneous PAEE. Girls showed a similar increase in strength, but not in spontaneous PAEE. This may be explained by their earlier pubertal development. Strength training may be a promising strategy in schools to counteract decreasing levels of PA.
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http://dx.doi.org/10.1542/peds.2013-1343DOI Listing
December 2013

High-intensity training increases spontaneous physical activity in children: a randomized controlled study.

J Pediatr 2010 Feb 20;156(2):242-6. Epub 2009 Oct 20.

Center for Pediatric Endocrinology Zurich, Mohrlistrasse 69, CH-8006 Zurich, Switzerland.

Objective: To test the hypothesis that resistance training may increase spontaneous physical activity in children.

Study Design: Two junior ice hockey teams were randomly assigned to unchanged training schedules (team ZSC, 21 boys; mean age, 13.2 years) or to participate twice weekly in guided resistance training for 4 months (team GCK, 25 boys; mean age, 13.4 years). Spontaneous physical activity energy expenditure (SpAEE; 3-axial accelerometry for 7 days), muscle strength, and body composition (dual energy x-ray absorptiometry) were measured at 0, 4, and 12 months.

Results: Baseline measures did not differ in the groups, except for higher leg and trunk strength in team ZSC. In the intervention group compared with the control group, SpAEE significantly (P < or = .02) increased at 4 months (+25.5% versus 0%) and 12 months (+13.5% versus -9.5%). Leg and arm strength increased because of training intervention; all other variables were unchanged. None of these variables correlated with changes in SpAEE.

Conclusion: In boys who play ice hockey, spontaneous physical activity is inducible with resistance training; this effect seems to be independent of changes in body composition and strength. If this was confirmed in unselected children, resistance training might be a new strategy for childhood obesity prevention programs.
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http://dx.doi.org/10.1016/j.jpeds.2009.08.039DOI Listing
February 2010

Association between foot growth and musculoskeletal loading in children with Prader-Willi syndrome before and during growth hormone treatment.

J Pediatr 2009 Feb 25;154(2):225-9. Epub 2008 Sep 25.

Center for Pediatric Endocrinology Zurich, Zurich, Switzerland.

Objective: To explore how foot growth relates to musculoskeletal loading in children with Prader-Willi syndrome (PWS).

Study Design: In 37 children with PWS, foot length (FL) before and after 6 years of growth hormone therapy (GHT) was retrospectively evaluated with parental and sibling's FL, height, and factors reflecting musculoskeletal loading, such as weight for height (WfH), lean body mass (LBM; dual energy X-ray absorptiometry, deuterium labeled water), physical activity (accellerometry), and walk age. Because of the typically biphasic evolution of body mass and the late walk age in PWS, 2 age groups were separated (group 1, >2.5 years; group 2, < or =2.5 years).

Results: Children with PWS normalized height, but not FL after 6 years of GHT. Parental FL correlation with PWS's FL was lower than with sibling's FL. In group 1, FL positively correlated with WfH, LBM, and physical activity. In group 2, FL negatively correlated with age at onset of independent ambulation. Foot catch-up growth with GHT was slower in group 2 compared with group 1.

Conclusion: In PWS, FL is positively associated with musculoskeletal loading. Small feet in children with PWS before and during long-term GHT may be more than just another dysmorphic feature, but may possibly reflect decreased musculoskeletal loading influencing foot growth and genetic and endocrine factors.
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http://dx.doi.org/10.1016/j.jpeds.2008.08.008DOI Listing
February 2009

Association between short sleeping hours and physical activity in boys playing ice hockey.

J Pediatr 2008 Nov 27;153(5):640-5, 645.e1. Epub 2008 Jun 27.

Center for Pediatric Endocrinology PEZZ, Zurich, Switzerland.

Objectives: To determine physical activity in healthy boys and how physical activity relates to training and daily awake hours.

Study Design: In 66 boys (5 to 15 years) affiliated with an ice-hockey club, we measured total daily energy expenditure (TDEE, doubly-labeled water) and basal metabolic rate (ventilated-hood method). Physical activity energy expenditure for the whole day (DAEE), during training, and during spontaneous physical activity was measured by accelerometry and activity protocols. Univariate (UA) and multivariate (MA) correlation analysis was applied.

Results: Physical activity level, DAEE, and TDEE for prepubertal (2.0 and 2.2 Mcal/d) and pubertal (bone age >or=13 years; 1.8 and 2.8 Mcal/d) boys were matched to literature data from normal boys of equal age. In prepubertal boys DAEE correlated positively with awake hours (r(UA) = 0.55, r(MA) = 0.39, P < .01). In pubertal boys this correlation was not significant, the slopes between the 2 groups being significantly different (P = .025). In prepubertal boys spontaneous physical activity expenditure correlated significantly positively with training activity expenditure (r(UA) = 0.72, r(MA) = 0.52, P < .001).

Conclusion: Contrary to findings in adults, where short sleepers had lower physical activity and intensive training was negatively compensated reducing spontaneous physical activity, in physically active prepubertal boys, total daily and spontaneous physical activity relate positively to awake hours and training; suggesting child-specific control of physical activity.
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http://dx.doi.org/10.1016/j.jpeds.2008.05.015DOI Listing
November 2008

Developmental profiles in young children with Prader-Labhart-Willi syndrome: effects of weight and therapy with growth hormone or coenzyme Q10.

Am J Med Genet A 2008 Apr;146A(7):873-80

Center for Pediatric Endocrinology Zurich (PEZZ), Zurich, Switzerland.

Muscle hypotonia and failure to thrive are key symptoms of Prader-Willi syndrome (PWS) allowing diagnosis during infancy already. Improved general care as well as Coenzyme Q(10) (CoQ(10)) and growth hormone (GH) are administered to improve PWS children's outcome. This study aims to investigate psychomotor development of young PWS children in relation to body weight and body composition at baseline as well as to the effects of GH or CoQ(10) therapy. Twenty-six young children (age 1.0 +/- 0.1 years, mean +/- SEM) with PWS genetically proven at age 0.1 +/- 0.1 years (17 deletions, 8 maternal disomy) were divided into three groups: Group 1 on GH therapy (started in 1994-1996, 6 mg/kg/week) tolerating low body weight (<50th centile), group 2 on GH (1997-2000) and group 3 on CoQ(10) (2001-2002, 2.5 mg/kg/day orally), both combined with active early weight management to achieve weight >50th centile. Anthropometry, body composition and Griffith's developmental scores (DQs) were assessed before therapy and after 12 months. DQs were not related to infants' weight, lean mass or genetic background. DQs improved significantly with chronological age and were best in the most recently diagnosed group. Improved psychomotor development, mainly due to progress in locomotor development, did not differ between GH and CoQ(10) treated groups. In conclusion, while only GH has significant effects on growth and body composition, GH and CoQ(10) therapy act equally on psychomotor development of PWS infants. However, improving psychomotor development may merely reflect an age-related phenomenon additionally depending on early diagnosis and introduction of appropriate care.
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http://dx.doi.org/10.1002/ajmg.a.32137DOI Listing
April 2008

Three novel missense mutations within the LHX4 gene are associated with variable pituitary hormone deficiencies.

J Clin Endocrinol Metab 2008 Mar 11;93(3):1062-71. Epub 2007 Dec 11.

University Children's Hospital, Leipzig, Germany.

Context: The LHX4 LIM-homeodomain transcription factor has essential roles in pituitary gland and nervous system development. Heterozygous mutations in LHX4 are associated with combined pituitary hormone deficiency.

Objectives: Our objectives were to determine the nature and frequency of LHX4 mutations in patients with pituitary hormone deficiency and to examine the functional outcomes of observed mutations.

Design: The LHX4 gene sequence was determined from patient DNA. The biochemical and gene regulatory properties of aberrant LHX4 proteins were characterized using structural predictions, pituitary gene transcription assays, and DNA binding experiments.

Patients: A total of 253 patients from 245 pedigrees with GH deficiency and deficiency of at least one additional pituitary hormone was included in the study.

Results: In five patients, three types of heterozygous missense mutations in LHX4 that result in substitution of conserved amino acids were identified. One substitution is between the LIM domains (R84C); the others are in the homeodomain (L190R; A210P). The patients have GH deficiency; some also display reductions in TSH, LH, FSH, or ACTH, and aberrant pituitary morphology. Structural models predict that the aberrant L190R and A210P LHX4 proteins would have impaired DNA binding and gene activation properties. Consistent with these models, EMSAs and transfection experiments using pituitary gene promoters demonstrate that whereas the R84C form has reduced activity, the L190R and A210P proteins are inactive.

Conclusions: LHX4 mutations are a relatively rare cause of combined pituitary hormone deficiency. This report extends the range of phenotypes associated with LHX4 gene mutations and describes three novel exonic mutations in the gene.
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http://dx.doi.org/10.1210/jc.2007-1525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2266965PMC
March 2008

Clinical effects of treatment for hypogonadism in male adolescents with Prader-Labhart-Willi syndrome.

Horm Res 2007 19;68(4):178-84. Epub 2007 Mar 19.

Institute Growth Puberty Adolescence, Zürich, Switzerland.

Background: In boys with Prader-Labhart-Willi syndrome (PWS), hypogonadism causes pubertal arrest and reduces pubertal muscle growth. Formerly, it was assumed that therapy with gonadal hormones accentuates behaviour abnormalities in PWS. Our aim was to assess the clinical effects of human chorionic gonadotropin (hCG) therapy on pubertal development, muscle mass and behaviour in adolescents with PWS.

Methods: 6 peripubertal boys with PWS undergoing long-term treatment with growth hormone were examined 6-monthly for at least 2 years before and after pubertal arrest (13.5 +/- 0.3 years, mean +/- SEM) and the beginning of hCG therapy (500-1,500 IU twice weekly, intramuscularly). Height, weight, pubertal stage, bone age, body composition (by dual-energy X-ray absorptiometry), testosterone levels and behaviour abnormalities (obtained from parents) were assessed.

Results: Testicular volume and lean mass were reduced in pubertal boys with PWS. During hCG therapy, testosterone levels and lean mass significantly increased (at the beginning and after 2 years of hCG therapy: 2.3 +/- 0.9 and 10.7 +/- 1.3 nmol/l, -3.1 +/- 0.3 and -1.4 +/- 0.6 SD, respectively), and fat mass stabilized at 38%. The characteristically observed PWS-associated problems, mood instability, aggressiveness and difficulties in social interaction, did not deteriorate during therapy.

Conclusion: In the present study, timely application of hCG to treat hypogonadism in boys with PWS promoted virilization and normalized muscle mass without detrimental effects on behaviour. Larger studies comparing hCG therapy with testosterone replacement would be useful.
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http://dx.doi.org/10.1159/000100925DOI Listing
October 2007

A daily comprehensive muscle training programme increases lean mass and spontaneous activity in children with Prader-Willi syndrome after 6 months.

J Pediatr Endocrinol Metab 2006 Jan;19(1):65-74

Institute Growth Puberty Adolescence, Zürich, Switzerland.

Unlabelled: The reduction of spontaneous physical activity (PA) and of muscle tissue are thought to be major causes of fat accretion and metabolic deterioration in Prader-Labhart-Willi syndrome (PWS). We investigated whether a generalized physical training programme in a home setting improves these parameters. The prospective study included 11 prepubertal children (mean age 8.7 years, range 5.9-11.8) with documented PWS and under continuous growth hormone treatment for at least 2.8 years. Seven children were enrolled in a training programme for several muscle groups during 4-10 minutes daily. Twelve matched children with PWS served as controls (average age 8.8 years, 6.1-11.3). Before and after training, at 6 months, PA was assessed by measuring walking distance by pedometer registration and by an activity score, and body composition by DEXA expressed as standard deviation scores (SDS) related to height. After training, lean mass (LM) increased from -1.83 to -1.48 SDS, p <0.05, whereas the controls showed no change. In the training group, walking distance and PA increased from 4.2 to 4.7 km/d and from 255 to 266 points, respectively, and these rises significantly exceeded those observed in controls.

Conclusion: Children with PWS can be motivated by their families to follow a short daily training, which has general effects on PA and does increase, but not normalize LM.
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http://dx.doi.org/10.1515/jpem.2006.19.1.65DOI Listing
January 2006

Hypothalamic and gonadal components of hypogonadism in boys with Prader-Labhart- Willi syndrome.

J Clin Endocrinol Metab 2006 Mar 13;91(3):892-8. Epub 2005 Dec 13.

Institute Growth Puberty Adolescence, Moehrlistrasse 69, CH-8006 Zurich, Switzerland.

Context: The specific form of hypogonadism in Prader-Labhart-Willi syndrome (PWS), central or peripheral, remains unexplained.

Objectives: The objectives of this study were to investigate the cause of hypogonadism in PWS and determine whether human chorionic gonadotropin (hCG) treatment can restore pubertal development.

Design: This was a clinical follow-up study, divided into two samples, over a duration of 1.5 and 4.5 yr.

Patients: Eight male infants and six peripubertal boys (age at start of observation, 0.06-0.93 and 8.1-10.8 yr, respectively) with genetically confirmed PWS were studied.

Intervention: hCG (500-1500 U twice weekly) was given from age 13.5 yr to the present.

Main Outcome Measures: Serum FSH, LH, inhibin B, and testosterone levels and pubertal development were the main outcome measures.

Results: Infants with PWS presented normal LH (2.3 +/- 0.7 U/liter) and testosterone (2.5 +/- 0.9 nmol/liter) levels (mean +/- sem at 5 months) compared with the reference range. However, two thirds of the boys displayed cryptorchidism. Inhibin B levels were at the lowest level of the normal range and decreased significantly between infancy and puberty (at 13 yr, 72 +/- 17 pg/ml), whereas FSH secretion increased (9.9 +/- 2.6 U/liter). Pubertal maturation stopped at an average bone age of 13.9 yr. hCG therapy increased testosterone (11 +/- 2 nmol/liter) and reduced FSH (at 16 yr, 1.1 +/- 0.9 U/liter) levels. Testicular volume (5.6 +/- 1 ml) and inhibin B (26.5 +/- 11.9 pg/ml) remained low.

Conclusion: Children with PWS display a specific form of combined hypothalamic (low LH) and peripheral (low inhibin B and high FSH) hypogonadism, suggesting a primary defect in Sertoli and/or germ cell maturation or an early germ cell loss. hCG therapy stimulates testosterone production and virilization.
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http://dx.doi.org/10.1210/jc.2005-0902DOI Listing
March 2006

Deaths in children with Prader-Willi syndrome. A contribution to the debate about the safety of growth hormone treatment in children with PWS.

Authors:
Urs Eiholzer

Horm Res 2005 13;63(1):33-9. Epub 2004 Dec 13.

Foundation Growth Puberty Adolescence, Zurich, Switzerland.

Irrespective of GH treatment, children with Prader-Willi syndrome (PWS) suffer more frequently and more seriously from respiratory problems than healthy children. The pathogenesis of such respiratory problems in PWS seems to be multifactorial in origin, but mainly related to insufficiency of respiratory muscles and pharyngeal narrowness. Deaths of children with PWS are reported among GH treated as well as untreated children. Our data show that also disturbed body composition plays an important role in fatal outcomes, possibly enhancing the ventilation disorder. For several years, in our recommendations we have pointed out the secondary risks of increasing obesity. In addition, it is recommended for all children with PWS, in particular before institution of GH therapy, to have polysomnography and an otorhinolaryngologic examination performed, and tonsillectomy in the case of enlarged tonsils. Furthermore, upper airway infections should be treated aggressively.
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http://dx.doi.org/10.1159/000082745DOI Listing
May 2005

A comprehensive team approach to the management of patients with Prader-Willi syndrome.

J Pediatr Endocrinol Metab 2004 Sep;17(9):1153-75

Foundation Growth Puberty Adolescence, Zurich, Switzerland.

Prader-Willi syndrome (PWS) is a genetic disorder characterized by extreme obesity accompanied by other, multisystem clinical manifestations encompassing both physical and behavioral/cognitive abnormalities. The multi-dimensional problems of patients with PWS cannot be treated with a single intervention and benefit from a team approach to management to optimize outcomes. Childhood stature below target height and reduced final height are some defining characteristics of PWS, and compelling evidence from growth hormone (GH) treatment trials suggests that hypothalamic GH deficiency exists. Treatment with GH has been shown to increase height velocity in children with PWS, decrease weight-for-height index values and body fat mass, and have a positive effect on lean body mass during at least the first year of therapy. In addition to medical concerns, the behavioral manifestations, including an uncorrectable deficit in appetite control, and cognitive limitations associated with PWS, require long-term multidisciplinary management.
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http://dx.doi.org/10.1515/jpem.2004.17.9.1153DOI Listing
September 2004

Growth hormone and body composition in children younger than 2 years with Prader-Willi syndrome.

J Pediatr 2004 Jun;144(6):753-8

Department of Biostatistics, University of Zürich, Switzerland.

Objectives: To assess body composition of infants with Prader-Willi syndrome (PWS) by using deuterium dilution and investigating the efficacy of early institution of growth hormone (GH) therapy in increasing lean mass (LM) and preventing massive obesity.

Study Design: One group of 11 children with PWS <2 years before and during 30-month GH therapy (GH group) was compared with 6 infants administered only coenzyme Q(10) for 1 year (Q10 group). LM adjusted for height (LM(Ht)) and relative fat mass (%FM(Age)) standard deviation scores (SDS) were calculated from data of 95 healthy children.

Results: Initially, LM(Ht) of all patients was below the normal average. LM(Ht) decreased by -0.46 +/- 0.3 SD (P=.03) per year in the Q10 group but rose by 0.25 +/- 0.3 SD (P=.02) per year during GH therapy, normalizing after 30 months (-0.70 +/- 1.0 SD). Despite low to normal weight for height (WfH), %FM(Age) was above the normal average (GH group, 31.0% +/- 4.5%, Q10 group, 32.4% +/- 9.5%). In the Q10 infants, %FM(Age) increased by 0.71 +/- 0.7 SD per year, whereas in the GH group, %FM(Age) remained more stable up to 30 months.

Conclusions: Diminished LM(Ht) found in infants with PWS further declines during the early years. Early institution of GH therapy lifts LM(Ht) into the normal range and delays fat tissue accumulation.
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http://dx.doi.org/10.1016/j.jpeds.2004.03.005DOI Listing
June 2004

Carbohydrate metabolism is not impaired after 3 years of growth hormone therapy in children with Prader-Willi syndrome.

Horm Res 2003 ;59(5):239-48

Foundation Growth Puberty Adolescence, Zürich, Switzerland.

Background/aim: In children with Prader-Labhart-Willi syndrome (PWS), the insulin secretion is reduced, despite obesity, being ascribed to the growth hormone (GH) deficiency of hypothalamic origin. Besides, an increased prevalence of diabetes mellitus was described in this syndrome. Hence, we addressed the questions of how body composition and insulin secretion are interrelated and what impact GH therapy has on the carbohydrate metabolism in PWS.

Methods: We measured weight, lean and fat mass (by dual-energy X-ray absorptiometry), triglycerides, HbA(1c), and fasting insulin and glucose levels in 17 children (age range 1.5-14.6 years) with PWS to examine whether the carbohydrate metabolism is altered during 36 months of therapy with 8 mg GH/m(2) body surface/week. In a subgroup of 8 children, the insulin secretion was longitudinally assayed during oral glucose tolerance at 0 and 12 months of therapy.

Results: Before therapy, the insulin secretion was lower and markedly delayed as compared with reference data and did not rise during therapy. The glucose tolerance was impaired in 2 of 12 children examined by oral glucose tolerance test before therapy and normalized during therapy. Fasting insulin and insulin resistance being normal at the beginning, significantly increased at 12 months and returned to initial levels at 36 months of GH therapy. Fasting glucose as well as HbA(1c) and triglyceride levels were always normal. The fat mass before GH therapy was increased (39.5%) and dropped into the upper normal range (28.3%) during 3 years of therapy, being correlated with fasting insulin concentration and indices of insulin sensitivity before and after 1 year of therapy.

Conclusions: Children with PWS are characterized by an intact insulin sensitivity with a decrease and a delay of insulin secretion, regardless of moderate obesity or GH treatment. In the present setting, the carbohydrate metabolism is not impaired by GH therapy, but by the excessively increased fat mass.
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http://dx.doi.org/10.1159/000070224DOI Listing
October 2003

Improving body composition and physical activity in Prader-Willi Syndrome.

J Pediatr 2003 Jan;142(1):73-8

Foundation Growth Puberty Adolescence Zurich, Prevmedic, Bethanien Private Clinic, Zurich, Switzerland.

Objective: To determine if muscle training in Prader-Willi Syndrome (PWS) can improve local body composition, physical capacity, and activity.

Study Design: Seventeen children and adolescents with PWS and 18 control children were enrolled in a daily short calf muscle training program for 3 months. Before (t(0)) and after 3 months of training (t(3m)), spontaneous physical activity and exercise capacity were assessed by pedometer registrations and activity protocols. Local body composition was determined by calf circumference and skinfold measurements at t(0), t(3m), and 3 months after t(3m) (t(6m)).

Results: During training, calf skinfold decreased from 1.1 to 0.8 SD (P <.01) and calf circumference in PWS increased from 1.4 to 1.9 SD (P <.05), reflecting improved muscle mass. At t(3m), a significant increase in spontaneous physical activity (from 45% to 71%, compared with baseline data of control children, P <.05) and physical capacity (from 31%-78%, P <.01) was found.

Conclusions: In persons with PWS, a well-defined and easy-to-accomplish training program improves local body composition and has generalized effects on physical activity and capacity, opening up a new therapeutic option to improve metabolic conditions.
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http://dx.doi.org/10.1067/mpd.2003.mpd0334DOI Listing
January 2003

Fatal outcome of sleep apnoea in PWS during the initial phase of growth hormone treatment. A case report.

Horm Res 2002 ;58 Suppl 3:24-6

Foundation Growth Puberty Adolescence, Zürich, Switzerland.

The case of a boy with Prader-Willi syndrome (PWS) who suffered from respiratory problems since birth and suddenly died at the age of 6.5 years, 4 months after initiation of GH therapy, is presented. This case indicates the possibility of fatal courses in infants and children with PWS as a consequence of respiratory problems and raises the question as to a causal connection between the initiation of GH therapy and the sudden death of this child.
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http://dx.doi.org/10.1159/000066478DOI Listing
June 2003

Increased adrenal androgen levels in patients with Prader-Willi syndrome are associated with insulin, IGF-I, and leptin, but not with measures of obesity.

Horm Res 2002 ;58(5):215-22

Foundation Growth Puberty Adolescence, Zürich, Switzerland.

Background/aim: Since hyperandrogenism in simple obesity is assumed to arise from hyperinsulinism and/or increased insulin-like growth factor I (IGF-I) or leptin levels, we examined how in patients with Prader-Willi syndrome (PWS), the most frequent form of syndromal obesity, the accelerated adrenarche can be explained despite hypothalamic-pituitary insufficiency with low levels of insulin and IGF-I.

Methods: In 23 children with PWS and a mean age of 5.6 years, height, weight, fat mass, fasting insulin concentration, insulin resistance (by HOMA-R; see text), and leptin and IGF-I levels were determined to test whether they explain the variance of the levels of dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), of androstenedione, and of cortisol before and during 42 months of therapy with growth hormone.

Results: The baseline DHEAS, DHEA, and androstenedione concentrations were increased as compared with age-related reference values, whereas the cortisol level was always normal. During growth hormone treatment, the DHEA concentration further rose, and the cortisol level decreased significantly. The insulin and IGF-I concentrations were low before therapy, while fat mass and leptin level were elevated. The hormonal covariates provided alone or together between 24 and 60% of the explanation for the variance of adrenal androgen levels, but the anthropometric variables did not correlate with them.

Conclusions: In children with PWS, elevated androgen levels correlate with hormones that are usually associated with adiposity. However, the lack of direct correlations between disturbed body composition and androgen levels as well as the increased sensitivity to insulin and IGF-I are abnormalities specific to PWS, potentially caused by the underlying hypothalamic defect.
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http://dx.doi.org/10.1159/000066263DOI Listing
May 2003

Behavioral phenotypes in four mental retardation syndromes: fetal alcohol syndrome, Prader-Willi syndrome, fragile X syndrome, and tuberosis sclerosis.

Am J Med Genet 2002 Sep;111(4):381-7

Department of Child and Adolescent Psychiatry, University of Zurich, Switzerland.

Behavioral phenotypes were studied in four mental retardation syndromes using the Developmental Behavior Checklist (DBC). The four samples comprised fetal alcohol syndrome (FAS), Prader-Willi syndrome (PWS), fragile X syndrome (FRAX), and tuberosis sclerosis (TSC). Both on the item and the subscale level, there were clear behavioral differentiations across the four syndromes. FAS and FRAX proved to be most clearly differentiated from the other two samples, with PWS and TSC showing lower scores and less abnormal behavior profiles. Neither intelligence nor gender nor age contributed to variations in the number of behavior abnormalities. It was concluded that the DBC as a quantitative approach contributes significantly to the differentiation of behavioral phenotypes in various mental retardation syndromes.
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http://dx.doi.org/10.1002/ajmg.10627DOI Listing
September 2002

Sudden death of an infant with Prader-Willi syndrome--not a unique case?

Biol Neonate 2002 Aug;82(2):139-41

Foundation Growth Puberty Adolescence, Zürich, Switzerland.

Only in the recent past has Prader-Willi syndrome (PWS) also been diagnosed in newborns and infants, and the first descriptions of respiratory disturbances in young, not yet obese patients have been published only recently. We report an infant with PWS and respiratory problems, who suffered sudden death. To our knowledge, this is the first such case. In order to avoid fatalities, it seems mandatory to monitor respiratory function in infants with PWS and to suspect PWS in all hypotonic newborns to determine the frequency of the syndrome more accurately, and, more importantly, to diagnose PWS at an earlier stage in order to take appropriate measures.
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http://dx.doi.org/10.1159/000063097DOI Listing
August 2002