Publications by authors named "Cees Noordam"

20 Publications

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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

Home to Hospital Live Streaming With Virtual Reality Goggles: A Qualitative Study Exploring the Experiences of Hospitalized Children.

JMIR Pediatr Parent 2018 Dec 13;1(2):e10. Epub 2018 Dec 13.

Amalia Children's Hospital, Department of Pediatrics, Radboud University Medical Center, Nijmegen, Netherlands.

Background: Being separated from home and relatives is a major stressor for children and adolescents when hospitalized. Children long for a manner to be distracted, pleasured, and socially connected during hospitalization. Different technological devices have been applied in health care to answer those needs. Both virtual reality (VR) and videoconferencing have proven their value in hospital wards and pediatrics. VisitU combines these 2 technologies innovatively. VisitU is a recently launched VR product enabling users to be virtually at home during hospitalization.

Objective: This study aims to explore the experiences of hospitalized patients with the VR intervention of VisitU in addition to standard care.

Methods: Over a 3-month period, a purposive sample of 10 patients hospitalized in the Radboudumc Amalia Children's Hospital was included in this qualitative study. Semistructured interviews were performed, one before and one after the use of the VR device. Patients were asked open-ended questions concerning their experiences with VisitU on practical, cognitive, emotional, and social domains. The interviews were audiorecorded and transcribed verbatim. Atlas.ti was used to support the qualitative analysis. Furthermore, the inductive thematic analysis was done according to the 6-step procedure described by Braun and Clarke.

Results: The following 6 main themes were the result of the qualitative analysis: "Being hospitalized," "Expectations of VisitU," "VisitU in use," "VisitU, the benefits," "The impact of VisitU," and "Barriers when using VisitU." The way VisitU was used by patients varied. The main benefits of VisitU were being somewhere else, being at home, and facilitating social connection. Limitations were experienced on the technical abilities, physical side effects, and complexity of use. Despite that, patients were positive about VisitU and unanimous in the view that they would like to use it again and advise other patients to use it.

Conclusions: This study shows the positive experiences of pediatric patients with VR live streaming. VisitU brings together the needs of patients and possibilities of VR and videoconferencing; it offers patients a way out of the hospital. Nevertheless, practical and technical obstacles must be overcome and side effects are an area of further research.
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http://dx.doi.org/10.2196/pediatrics.9576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716480PMC
December 2018

Ocular findings in Noonan syndrome: a retrospective cohort study of 105 patients.

Eur J Pediatr 2018 Aug 9;177(8):1293-1298. Epub 2018 Jun 9.

Department of Pediatrics, Radboud University Medical Center Amalia Children's hospital, P.O. Box, 9101, 6500 HB, Nijmegen, The Netherlands.

The aim of this retrospective study is to describe ocular findings in a large Noonan syndrome cohort and to detect associations between ocular features and genetic mutations that were not found in earlier studies. We collected ophthalmological and genetic data of 105 patients (median age, 12 years; range, 0-60 years) clinically diagnosed as Noonan syndrome. The ocular findings were linked to the genotypes. All patients with Noonan syndrome showed multiple abnormalities in the categories of vision and refraction, external ocular features, ocular alignment and motility, anterior ocular segment, and posterior ocular segment. In total, 50 patients have NS due to a mutation in PTPN11. Permanent visual impairment (bilateral best-corrected visual acuity < 0.3) was found in 7 patients, including patients with a mutation in RAF1, SHOC2, and KRAS. Keratoconus was found in 2 PTPN11 positive patients, and prominent corneal nerves were observed in a patient with a SOS1 mutation.

Conclusions: This study shows an overview of ocular abnormalities in Noonan syndrome, including permanent visual impairment caused by binocular optic nerve abnormalities and nystagmus. Delay in ophthalmological diagnosis is still present, also in patients with visual impairment. All Noonan syndrome patients should have a complete ophthalmological examination at the time of diagnosis. What is Known: • Although we discover more pathogenic mutations in patients with Noonan syndrome, Noonan syndrome still is a clinical diagnosis • Ocular features of Noonan syndrome are characterized by developmental anomalies of the eyelids and associated with other ocular abnormalities in childhood (including refractive errors, strabismus and amblyopia). What is New: • There seems to be a delay in the ophthalmological diagnosis and awareness of the broad variety ofophthalmological features including refractive errors and visual impairment in Noonan syndrome is needed. All children should have a full ophthalmological examination at the time of diagnosis. • Permanent visual impairment (best-corrected visual acuity < 0.3) is found in patients with mutations in RAF1, SHOC2, and KRAS and the cause is probably a developmental disorder of the optic nerves.
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http://dx.doi.org/10.1007/s00431-018-3183-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061046PMC
August 2018

First-year growth in children with Noonan syndrome: Associated with feeding problems?

Am J Med Genet A 2018 Apr;176(4):951-958

Department of Pediatrics, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands.

Children with Noonan syndrome show rapid decline of growth in the first year of life and feeding problems are present in over 50%. The aim of this study was to explore whether growth decelerates because of feeding problems or other Noonan syndrome-related factors. We performed a retrospective, longitudinal cohort study of clinically and genetically diagnosed subjects with Noonan syndrome (n = 143). Questionnaires about the phenotypic-genotypic profile and reported feeding problems were sent to eligible subjects. Data on first-year growth was obtained from growth charts. Ninety-one participants were excluded because of different criteria. A total of 52 subjects with Noonan syndrome were included. The largest decline in weight and length standard deviation score (SDS) occurred in the first 2.5 months after birth (-1.93 and -1.15, respectively), with feeding problems causing a decline of 0.57 SDS in the remaining months. At 1 year, children with feeding problems were on average 290 g lighter and 0.8 cm shorter than children without feeding problems. Weight gain was also negatively influenced by having a PTPN11 mutation (n = 39) and a higher gestational age, whereas children of parents with Noonan syndrome and with a higher birth weight gained more weight. Growth in length was reduced by having cardiac surgery and a higher gestational age, but positively influenced by birth length and maternal height. Growth in children with Noonan syndrome is impaired right after birth and only partially associated with feeding problems. In addition, several specific Noonan syndrome-related factors seem to influence growth in the first year.
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http://dx.doi.org/10.1002/ajmg.a.38649DOI Listing
April 2018

Sugarsquare, a Web-Based Patient Portal for Parents of a Child With Type 1 Diabetes: Multicenter Randomized Controlled Feasibility Trial.

J Med Internet Res 2017 08 22;19(8):e287. Epub 2017 Aug 22.

Department of Medical Psychology, Radboud University Medical Center, Nijmegen, Netherlands.

Background: Raising a child with type 1 diabetes (T1D) means combining the demands of the disease management with everyday parenting, which is associated with increased levels of distress. A Web-based patient portal, Sugarsquare, was developed to support parents, by providing online parent-professional communication, online peer support and online disease information.

Objective: The first aim of this study was to assess the feasibility of conducting a multicenter, randomized controlled trial in Dutch parents of a child with T1D. The second aim was to assess the feasibility of implementing Sugarsquare in clinical practice.

Methods: The parents of 105 children (N=105) with T1D below the age of 13 participated in a 6-month multicenter randomized controlled feasibility trial. They were randomly assigned to an experimental (n=54, usual care and Sugarsquare) or a control group (n=51, usual care). Attrition rates and user statistics were gathered to evaluate feasibility of the trial and implementation. To determine potential efficacy, the parenting stress index (PSI-SF) was assessed at baseline (T0) and after 6 months (T1).

Results: Of a potential population of parents of 445 children, 189 were willing to participate (enrollment refusal=57.5%, n=256), 142 filled in the baseline questionnaire (baseline attrition rate=25%, n=47), and 105 also filled in the questionnaire at T1 (post randomization attrition rate during follow-up=26%, n=32). As such, 24% of the potential population participated. Analysis in the experimental group (n=54) revealed a total of 32 (59%) unique users, divided into 12 (38%) frequent users, 9 (28%) incidental users, and 11 (34%) low-frequent users. Of the total of 44 professionals, 34 (77%) logged in, and 32 (73%) logged in repeatedly. Analysis of the user statistics in the experimental group further showed high practicability and integration in all users, moderate acceptability and demand in parents, and high acceptability and demand in health care professionals. Baseline parenting stress index scores were related to the parents' frequency of logging on (ρ=.282, P=.03) and page-views (ρ=.304, P=.01). No significant differences in change in parenting stress between experimental and control group were found (F=.49, P=.49).

Conclusions: The trial can be considered feasible, considering the average enrollment refusal rate, baseline attrition rate and postrandomization attrition rate, compared to other eHealth studies, although lower than hypothesized. Implementing Sugarsquare in clinical practice was partly feasible, given moderate demand and acceptability in parent users and lack of potential efficacy. Parents who reported higher levels of parenting stress used Sugarsquare more often than other parents, although Sugarsquare did not reduce parenting stress. These results indicate that Web-based interventions are a suitable way of providing parents of children with T1D with additional support. Future studies should determine how Sugarsquare could reduce parenting stress, for instance by adding targeted interventions. Factors potentially contributing to successful implementation are suggested.

Trial Registration: Nederlands Trial Register Number: NTR3643; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3643 (Archived by WebCite at http://www.webcitation.org/6qihOVCi6).
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http://dx.doi.org/10.2196/jmir.6639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5585595PMC
August 2017

Motor performance in children with Noonan syndrome.

Am J Med Genet A 2017 Sep 19;173(9):2335-2345. Epub 2017 Jun 19.

Department of Rehabilitation, Pediatric Physical Therapy, Radboud University Medical Center, Nijmegen, The Netherlands.

Although problems with motor performance in daily life are frequently mentioned in Noonan syndrome, the motor performance profile has never been systematically investigated. The aim of this study was to examine whether a specific profile in motor performance in children with Noonan syndrome was seen using valid norm-referenced tests. The study assessed motor performance in 19 children with Noonan syndrome (12 females, mean age 9 years 4 months, range 6 years 1 month to 11 years and 11 months, SDS 1 year and 11 months). More than 60% of the parents of the children reported pain, decreased muscle strength, reduced endurance, and/or clumsiness in daily functioning. The mean standard scores on the Visual Motor Integration (VMI) test and Movement Assessment Battery for Children 2, Dutch version (MABC-2-NL) items differed significantly from the reference scores. Grip strength, muscle force, and 6 min Walking Test (6 MWT) walking distance were significantly lower, and the presence of generalized hypermobility was significantly higher. All MABC-2-NL scores (except manual dexterity) correlated significantly with almost all muscle strength tests, VMI total score, and VMI visual perception score. The 6 MWT was only significantly correlated to grip strength. This is the first study that confirms that motor performance, strength, and endurance are significantly impaired in children with Noonan syndrome. Decreased functional motor performance seems to be related to decreased visual perception and reduced muscle strength. Research on causal relationships and the effectiveness of interventions is needed. Physical and/or occupational therapy guidance should be considered to enhance participation in daily life.
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http://dx.doi.org/10.1002/ajmg.a.38322DOI Listing
September 2017

Metabolic Health in Short Children Born Small for Gestational Age Treated With Growth Hormone and Gonadotropin-Releasing Hormone Analog: Results of a Randomized, Dose-Response Trial.

J Clin Endocrinol Metab 2015 Oct 10;100(10):3725-34. Epub 2015 Aug 10.

Dutch Growth Research Foundation (M.v.d.S., A.J.L., D.C.M.v.d.K., A.C.S.H.K.), Rotterdam, 3001 KB, The Netherlands; Children's Hospital Erasmus MC-Sophia (M.v.d.S., A.C.S.H.K.), 3000 CA, Rotterdam, The Netherlands; Department of Pediatrics (W.M.B.v.W.), University Medical Center Groningen, 9700 RB Groningen, The Netherlands; Department of Pediatrics (F.J.P.C.M.v.d.H.), Zaans Medisch Centrum, 1502 DV Zaandam, The Netherlands; Department of Pediatrics (F.S.N.), Rijnstate Hospital, 6815 AD Arnhem, The Netherlands; Department of Pediatrics (C.N.), Radboud University Medical Center, 6525 HP Nijmegen, The Netherlands; Department of Pediatrics (R.J.O.), Catharina Hospital, 5623 EJ Eindhoven, The Netherlands; Department of Pediatrics (W.O.), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; Amalia Department of Pediatrics (E.J.S.), Isala Clinics, 8025 AB Zwolle, The Netherlands; and Department of Pediatrics (C.W.), Canisius Hospital, 6532 SZ Nijmegen, The Netherlands.

Context: Previously we showed that pubertal children born small for gestational age (SGA) with a poor adult height (AH) expectation can benefit from treatment with GH 1 mg/m(2) per day (∼ 0.033 mg/kg/d) in combination with 2 years of GnRH analog (GnRHa) and even more so with a double GH dose. GnRHa treatment is thought to have negative effects on body composition and blood pressure. Long-term effects and GH-dose effects on metabolic health in children treated with combined GH/GnRHa are unknown.

Objective: This study aimed to investigate body composition, blood pressure, and lipid profile during GH treatment, either with or without 2 years of additional GnRHa. To assess whether GH 2 mg/m(2) per day (∼ 0.067 mg/kg/d) results in a similar or even more favorable metabolic health at AH than GH 1 mg/m(2) per day.

Methods: This was a longitudinal, randomized, dose-response GH trial involving 107 short SGA children (58 girls) treated with GH until AH (GH randomized 1 or 2 mg/m(2)/d during puberty). Sixty-four children received additional GnRHa. At AH, metabolic parameters were compared between children treated with combined GH/GnRHa and those with only GH. The GH dose effect on metabolic health was evaluated in a subgroup of 47 children who started GH treatment in early puberty (randomized 1 or 2 mg/m(2)/d) with 2 years of GnRHa.

Results: At AH, fat mass percentage (FM%) SD score (SDS), lean body mass (LBM) SDS, blood pressure SDS, and lipid profile were similar between children treated with combined GH/GnRHa and those with only GH. In the pubertal subgroup, FM% SDS was lower during treatment with GH 2 mg/m(2) per day. There was no GH dose-dependent effect on LBM SDS, blood pressure, and lipid profile.

Conclusions: Combined GH/GnRHa treatment has no long-term negative effects on metabolic health compared with only GH. Started in early puberty, a GH dose of 2 mg/m(2) per day results in a similar metabolic health at AH and a more favorable FM% than GH 1 mg/m(2) per day.
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http://dx.doi.org/10.1210/jc.2015-2619DOI Listing
October 2015

Parents' experiences, needs, and preferences in pediatric diabetes care: Suggestions for improvement of care and the possible role of the Internet. A qualitative study.

J Spec Pediatr Nurs 2015 Jul 15;20(3):218-29. Epub 2015 Jun 15.

Department of Medical Psychology, Radboud university medical center, Nijmegen, the Netherlands.

Purpose: To investigate the needs and preferences of parents of children with type 1 diabetes (T1D) concerning pediatric diabetes care and use of Internet in care.

Design And Methods: Parents of 34 children, aged 2-12, with T1D participated in seven focus group interviews.

Results: Analysis revealed provision of tailored care, disease information, peer support, and accessibility of healthcare professionals as major needs in parents. Internet could be used to satisfy these needs.

Practical Implications: According to parents, diabetes teams should focus on the impact of the disease, parents' experience, and the child's development, and provide online professional and peer support.
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http://dx.doi.org/10.1111/jspn.12118DOI Listing
July 2015

Assessment of psychosocial problems in children with type 1 diabetes and their families: the added value of using standardised questionnaires in addition to clinical estimations of nurses and paediatricians.

J Clin Nurs 2015 Aug 9;24(15-16):2143-51. Epub 2015 Mar 9.

Department of Paediatric Psychology, Tilburg University, Tilburg, The Netherlands.

Aims And Objectives: To investigate the assessment of psychosocial problems in children with type 1 diabetes by means of clinical estimations made by nurses and paediatricians and by using standardised questionnaires.

Background: Although children with type 1 diabetes and their parents show increased risk for psychosocial problems, standardised assessment of these problems lacks in diabetes care.

Design: By comparing these different modes of assessment, using a cross-sectional design, information about the additional value of using standardised questionnaires is provided.

Methods: Participants were 110 children with type 1 diabetes (aged 4-16), their parents, and healthcare professionals. Children filled out the Strengths and Difficulties Questionnaire and the Paediatric Quality of Life Inventory, Diabetes Module. Parents filled out the Strengths and Difficulties Questionnaire parent-report and the Parenting Stress Index. Independently, nurses and paediatricians filled out a short questionnaire, which assessed their clinical estimations of the children's psychosocial problems and quality of life, and parents' levels of parenting stress. Reports of children and parents were compared to clinical estimations.

Results: Children in our sample showed more psychosocial problems and lower health-related quality of life than their healthy peers. In approximately half of the children, dichotomous estimations by healthcare professionals and dichotomised reports by patients and parents were in agreement. In 10% of the children, no psychosocial problems were present according to professionals' estimations, although patients and parents-reported psychosocial problems. In 40%, psychosocial problems were present according to professionals' estimations, although parents and patients did not report psychosocial problems.

Conclusion: Children with type 1 diabetes show more psychosocial problems than healthy children. Professionals seem to tend towards overestimating psychosocial problems.

Relevance To Clinical Practice: Extending the assessment of psychosocial problems with routine screening on patient-reported outcomes, using validated questionnaires, could be of additional value in tailoring care to the needs of the individual child and parents.
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http://dx.doi.org/10.1111/jocn.12789DOI Listing
August 2015

The Sugarsquare study: protocol of a multicenter randomized controlled trial concerning a web-based patient portal for parents of a child with type 1 diabetes.

BMC Pediatr 2014 Jan 28;14:24. Epub 2014 Jan 28.

Department of Medical Psychology, Radboud university medical center, PO Box 9101, 6500 HB, Nijmegen, the Netherlands.

Background: Type 1 diabetes demands a complicated disease self-management by child and parents. The overwhelming task of combining every day parenting tasks with demands of taking care of a child with diabetes can have a profound impact on parents, often resulting in increased parenting stress. Tailored disease information, easy accessible communication with healthcare professionals and peer support are found to support parents to adequately cope with the disease and the disease self-management in everyday life. Internet can help facilitate these important factors in usual pediatric diabetes care. Therefore, we will develop a web-based patient portal in addition to usual pediatric diabetes care and subsequently evaluate its efficacy and feasibility. The web-based patient portal, called Sugarsquare, provides online disease information, and facilitates online parent-professional communication and online peer support. We hypothesize that parenting stress in parents of a child with type 1 diabetes will decrease by using Sugarsquare and that Sugarsquare will be feasible in this population.

Methods/design: We will test the hypotheses using a multicenter randomized controlled trial. Eligible participants are parents of a child with type 1 diabetes under the age of 13. Parents are excluded when they have no access to the internet at home or limited comprehension of the Dutch language. Participants are recruited offline from seven clinics in the Netherlands. Participants are randomly allocated to an intervention and a control group. The intervention group will receive access to the intervention during the twelve-month study-period; the control group will receive access in the last six months of the study-period. Self-reported parenting stress is the primary outcome in the present study. Data will be gathered at baseline (T0) and at six (T1) and twelve (T2) months following baseline, using online questionnaires. User statistics will be gathered throughout the twelve-month study-period for feasibility.

Discussion: Dependent on its feasibility and efficacy, the intervention will be implemented into usual pediatric diabetes care. Strengths and limitations of the study are discussed.

Trial Registration: NTR3643 (Dutch Trial Register).
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http://dx.doi.org/10.1186/1471-2431-14-24DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3909406PMC
January 2014

Teaming up: feasibility of an online treatment environment for adolescents with type 1 diabetes.

Pediatr Diabetes 2014 Aug 18;15(5):394-402. Epub 2013 Dec 18.

Department of Medical Psychology, Radboud university medical center, 6500 HE, Nijmegen, The Netherlands; Children's Diabetes Center Nijmegen, 6500 GS, Nijmegen, The Netherlands.

Objective: To evaluate the feasibility of an online interactive treatment environment for adolescents with type 1 diabetes, called Sugarsquare, to supplement usual care.

Research Design And Methods: Sugarsquare provides easily accessible contact with the diabetes team, peer support, and treatment overview. Of 120 eligible patients, 62 adolescents aged 11-21 (M = 15.23, SD = 2.00) were assigned to a usual-care group (n = 31) or a usual-care + intervention group (n = 31). Feasibility was assessed in terms of acceptability, demand, practicability, integration, and efficacy in a 9-month study-period.

Results: Assessment of acceptability and demand revealed that 20 adolescents in the intervention group (65%) logged in at least once; 16 adolescents (52%) logged in repeatedly. Usage resulted in 5795 page-views, 3580 chat-messages, 427 forum-messages, and in 40 private interactions between 11 adolescents (35%) and professionals. Assessment of practicability revealed that all 13 professionals (100%) accessed the intervention. Slow processing speed and security procedures formed obstacles for usage. Assessment of integration showed that international standards for diabetes care (International Diabetes Federation/International Society for Pediatric and Adolescent Diabetes/American Diabetes Association) were met. Assessment of efficacy revealed improvement in the intervention group in evaluation of care (Patients' Evaluation of Quality of Diabetes), F(1,30) = 5.35, p < 0.05, and quality of life, communication (PedsQL), F(1,30) = 11.65, p <0.05. The latter was correlated with posted chat-messages (r = 0.42, p < 0.05). No between-group differences were found.

Conclusions: This study shows that Sugarsquare is feasible in adolescents with type 1 diabetes. It meets a demand in adolescents and can support professionals when organizing on-going care according to international standards. Results are promising and next steps are a full-scale randomized controlled trial and subsequent implementation in daily care.
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http://dx.doi.org/10.1111/pedi.12103DOI Listing
August 2014

Copy number variants in patients with short stature.

Eur J Hum Genet 2014 May 25;22(5):602-9. Epub 2013 Sep 25.

Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.

Height is a highly heritable and classic polygenic trait. Recent genome-wide association studies (GWAS) have revealed that at least 180 genetic variants influence adult height. However, these variants explain only about 10% of the phenotypic variation in height. Genetic analysis of short individuals can lead to the discovery of novel rare gene defects with a large effect on growth. In an effort to identify novel genes associated with short stature, genome-wide analysis for copy number variants (CNVs), using single-nucleotide polymorphism arrays, in 162 patients (149 families) with short stature was performed. Segregation analysis was performed if possible, and genes in CNVs were compared with information from GWAS, gene expression in rodents' growth plates and published information. CNVs were detected in 40 families. In six families, a known cause of short stature was found (SHOX deletion or duplication, IGF1R deletion), in two combined with a de novo potentially pathogenic CNV. Thirty-three families had one or more potentially pathogenic CNVs (n=40). In 24 of these families, segregation analysis could be performed, identifying three de novo CNVs and nine CNVs segregating with short stature. Four were located near loci associated with height in GWAS (ADAMTS17, TULP4, PRKG2/BMP3 and PAPPA). Besides six CNVs known to be causative for short stature, 40 CNVs with possible pathogenicity were identified. Segregation studies and bioinformatics analysis suggested various potential candidate genes.
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http://dx.doi.org/10.1038/ejhg.2013.203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3992565PMC
May 2014

Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog: results of a randomized, dose-response GH trial.

J Clin Endocrinol Metab 2012 Nov 17;97(11):4096-105. Epub 2012 Aug 17.

Dutch Growth Research Foundation, P.O. Box 23068, 3001 KB Rotterdam, The Netherlands.

Context: GH treatment is effective in improving height in short children born small for gestational age (SGA). GH is thought to have limited effect when started during adolescence.

Objective: The aim of this study was to investigate GH treatment efficacy in short SGA children when treatment was started during adolescence; to assess whether GH 2 mg/m(2) · d during puberty improves adult height (AH) compared with 1 mg/m(2) · d; and to assess whether an additional 2-yr postponement of puberty by GnRH analog (GnRHa) improves AH in children who are short at the start of puberty (<140 cm), with a poor AH expectation.

Patients And Design: In this longitudinal, randomized, dose-response GH trial, we included 121 short SGA children (60 boys) at least 8 yr of age. We performed intention-to-treat analyses on all children and uncensored case analyses on 84 children who reached AH. Besides, we evaluated growth during 2 yr of combined GH/GnRHa and subsequent GH treatment until AH in a subgroup of 40 pubertal children with a height of less than 140 cm at the start.

Results: Short SGA children started treatment at a median age of 11.2 yr, when 46% had already started puberty. Median height increased from -2.9 at start to -1.7 sd score (SDS) at AH (P < 0.001). Treatment with GH 2 vs. 1 mg/m(2) · d during puberty resulted in significantly better AH (P = 0.001), also after correction for gender, age at start, height SDS at start, treatment years before puberty, and target height SDS. AH was similar in children who started puberty at less than 140 cm and received GH/GnRHa, compared with children who started puberty greater than 140 cm and received GH only (P = 0.795).

Conclusion: When started in adolescence, GH treatment significantly improves AH in short SGA children, particularly with GH 2 mg/m(2) · d during puberty. When SGA children are short at the start of puberty, they can benefit from combined GH/GnRHa treatment.
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http://dx.doi.org/10.1210/jc.2012-1987DOI Listing
November 2012

[Congenital hyperinsulinism in the north-east Netherlands. Clinical features and DNA diagnostics in 22 children].

Ned Tijdschr Geneeskd 2011 ;155(32):A3343

Universitair Medisch Centrum St Radboud, Afd. Kindergeneeskunde, Nijmegen, the Netherlands.

Objective: To describe the clinical features and relevant genetic mutations in 22 children with congenital hyperinsulinism in the north-east Netherlands.

Design: Retrospective, descriptive study.

Method: Children born between June 1988 and June 2009, who were presented at the academic medical centres of Nijmegen and Groningen were included. They were clinically suspected of having congenital hyperinsulinism and DNA diagnostics were carried out. Clinical course, laboratory results, genetic data, interventions, follow-up data and patient demographics were documented.

Results: A total of 22 children from 20 families were included. Of these 22 children, 5 were born macrosomic. In 16 children the disorder was picked up within the first 4 days of life either through glucose screening of premature children or because they had symptoms. All children were treated with diazoxide; 12 (55%) did not respond to this treatment. Ultimately, 9 children underwent pancreatectomy. Five children had focal type congenital hyperinsulinism. In 15 children 13 different mutations were identified in relevant genes. We found 9 different mutations in the ABCC8-gene, including 2 novel mutations (c.2117-2A>T and c.4076C>G), 1 in the KCNJ11 gene, 1 in the GCK gene, and 2 in the GLUD1 gene. In the villages of Aalten and Silvolde a high prevalence of congenital hyperinsulinism was observed (1 in 6930), probably due to a common ancestor.

Conclusion: The clinical characteristics of Dutch children with congenital hyperinsulinism were comparable with those reported in other study populations. We found two novel mutations in the ABCC8 gene. The mutations in the north-east Netherlands were diverse; no one mutation occurred more frequently than any other.
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November 2011

Mitochondrial dysfunction and organic aciduria in five patients carrying mutations in the Ras-MAPK pathway.

Eur J Hum Genet 2011 Feb 10;19(2):138-44. Epub 2010 Nov 10.

Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

Various syndromes of the Ras-mitogen-activated protein kinase (MAPK) pathway, including the Noonan, Cardio-Facio-Cutaneous, LEOPARD and Costello syndromes, share the common features of craniofacial dysmorphisms, heart defect and short stature. In a subgroup of patients, severe muscle hypotonia, central nervous system involvement and failure to thrive occur as well. In this study we report on five children diagnosed initially with classic metabolic and clinical symptoms of an oxidative phosphorylation disorder. Later in the course of the disease, the children presented with characteristic features of Ras-MAPK pathway-related syndromes, leading to the reevaluation of the initial diagnosis. In the five patients, in addition to the oxidative phosphorylation disorder, disease-causing mutations were detected in the Ras-MAPK pathway. Three of the patients also carried a second, mitochondrial genetic alteration, which was asymptomatically present in their healthy relatives. Did we miss the correct diagnosis in the first place or is mitochondrial dysfunction directly related to Ras-MAPK pathway defects? The Ras-MAPK pathway is known to have various targets, including proteins in the mitochondrial membrane influencing mitochondrial morphology and dynamics. Prospective screening of 18 patients with various Ras-MAPK pathway defects detected biochemical signs of disturbed oxidative phosphorylation in three additional children. We concluded that only a specific, metabolically vulnerable sub-population of patients with Ras-MAPK pathway mutations presents with mitochondrial dysfunction and a more severe, early-onset disease. We postulate that patients with Ras-MAPK mutations have an increased susceptibility, but a second metabolic hit is needed to cause the clinical manifestation of mitochondrial dysfunction.
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http://dx.doi.org/10.1038/ejhg.2010.171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3025797PMC
February 2011

Biosimilars: controversies as illustrated by rhGH.

Curr Med Res Opin 2010 May;26(5):1219-29

Faculty of Pharmaceutical Sciences, KU Leuven, Leuven, Belgium.

Unlabelled: Abstract Background and scope: Similar biological medicinal products, also called 'biosimilars', are copies of biopharmaceutical products whose patent has expired. Whether biosimilars are truly comparable and interchangeable with their reference biopharmaceutical products in terms of quality, efficacy and tolerability, is still a matter of debate. This review discusses the controversies related to the criteria for regulatory approval of biosimilars. These concerns are illustrated using recombinant human growth hormone (rhGH) biosimilars as an example.

Methods: Publications on the regulatory approval of biosimilars in general and rhGH biosimilars in particular were searched in MEDLINE by exploding and combining the medical subject heading terms 'human growth hormone', 'efficacy' or 'safety' and the free-text words 'biosimilar', 'biopharmaceutical', 'similar biological medicinal product', 'follow-up biologic' or 'biogeneric'. Searches were limited to full-text English-language articles. The websites from the European Medicines Agency (EMA) and from the American Food and Drug Administration were also consulted. Regulatory status: To obtain regulatory approval of a biosimilar product by EMA, demonstration of comparability with an approved reference biopharmaceutical product in terms of quality, efficacy and tolerability is needed. Thus, comparative quality studies, non-clinical and clinical efficacy and tolerability studies are required. However, in contrast to the reference product, comparative non-clinical pharmacokinetics, safety pharmacology, reproduction toxicology, mutagenicity and carcinogenicity studies are not mandatory to obtain approval of a biosimilar. In addition, comparable efficacy and tolerability only needs to be established by one study in a single population during a limited time interval (12 months) and often allows extrapolation to all other approved indications of the reference product. Consequently, for the currently approved rhGH biosimilars, long-term efficacy and tolerability in all indications has not been proven to the same degree as for the reference products.

Conclusions: The validity of the current criteria for comparability and interchangeability of biosimilars and their reference products remains controversial. The authors conclude that long-term clinical investigations and systematic monitoring of the efficacy and tolerability of rhGH biosimilars in all indications are needed. In addition, the medico-economical environment should allow physicians to take a free and informed decision about the type of rhGH to be prescribed.
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http://dx.doi.org/10.1185/03007991003719642DOI Listing
May 2010

[Clinical reasoning and decision making in clinical practice: a boy with fatigue and abdominal pain].

Ned Tijdschr Geneeskd 2009 ;153:B87

Universitair Medisch Centrum St Radboud, afd. Kindergeneeskunde, Nijmegen, The Netherlands.

A 14-year-old boy presented with fatigue and abdominal pain. Laboratory tests revealed a primary hypothyroidism with circulating auto-antibodies against thyroid peroxidase (TPO), anaemia and an elevated level of creatine kinase (CK). A diagnosis of auto-immune hypothyroidism with associated anaemia and myopathy was made. Thyroid hormone replacement therapy was started. However, six months later, he still complained of fatigue. He had unexpectedly varying thyroid function tests and the anaemia and the elevated level of CK persisted. Analysis of the other hormonal axes demonstrated a secondary adrenal insufficiency which was treated with hydrocortisone suppletion therapy. If a patient suffering from hypothyroidism does not respond appropriately to therapy or even deteriorates, adrenal insufficiency should always be considered. Patients with one type of auto-immune endocrinopathy have a greater risk at developing other types of auto-immune endocrinopathies.
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November 2009

[Clinical reasoning and decision making in clinical practice: a boy with fatigue and abdominal pain].

Ned Tijdschr Geneeskd 2009 May;153(21):1018-23

Afd. Kindergeneeskunde, Nijmegen.Universitair Medisch Centrum St Radboud.

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May 2009

Inactivating PAPSS2 mutations in a patient with premature pubarche.

N Engl J Med 2009 May;360(22):2310-8

Department of Pediatrics-Metabolic and Endocrine Disorders, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.

Dehydroepiandrosterone (DHEA) sulfotransferase, known as SULT2A1, converts the androgen precursor DHEA to its inactive sulfate ester, DHEAS [corrected], thereby preventing the conversion of DHEA to an active androgen. SULT2A1 requires 3'-phosphoadenosine-5'-phosphosulfate (PAPS) for catalytic activity. We have identified compound heterozygous mutations in the gene encoding human PAPS synthase 2 (PAPSS2) in a girl with premature pubarche, hyperandrogenic anovulation, very low DHEAS levels, and increased androgen levels. In vitro coincubation of human SULT2A1 and wild-type or mutant PAPSS2 proteins confirmed the inactivating nature of the mutations. These observations indicate that PAPSS2 deficiency is a monogenic adrenocortical cause of androgen excess.
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http://dx.doi.org/10.1056/NEJMoa0810489DOI Listing
May 2009

Reduced levels of GH during GnRH analogue treatment in pubertal short girls born small for gestational age (SGA).

Clin Endocrinol (Oxf) 2009 Jun 28;70(6):914-9. Epub 2008 Sep 28.

Department of Pediatrics, Division of Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands.

Context: Several studies showed a decrease in height velocity during GnRH analogue (GnRHa) treatment. No information is available on GH levels during GnRHa treatment in short SGA girls.

Objective: To study overnight GH profiles and IGF-I and IGFBP-3 levels in girls with Tanner stage 2 and stage 3, before and after 3 months of GnRHa treatment, and to compare levels with those found in prepubertal short SGA girls.

Patients: Twenty-four pubertal and 16 prepubertal short SGA girls.

Intervention: After baseline overnight GH profiles, pubertal girls received leuprorelide acetate depots of 3.75 mg subcutaneously every 4 weeks.

Outcome Measures: GH, IGF-I and IGFBP-3 levels.

Results: At baseline, GH levels were comparable to levels found in prepubertal short SGA girls and IGF-I and IGFBP-3 SDS were significantly below the population mean. After 3 months of GnRHa treatment, AUC(0) (P = 0.02), mean (P = 0.02) and maximum GH levels (P = 0.008) had significantly decreased. Mean GH levels were significantly lower than in prepubertal short SGA girls (P = 0.03). Eight girls with more than 40% decrease in mean GH levels also had a significantly greater decrease in IGF-I and IGFBP-3 levels. Mean and maximum GH levels at baseline correlated significantly with those after 3 months of GnRHa treatment.

Conclusion: Short SGA girls lack the normal increase in GH levels seen in puberty and have reduced IGF-I and IGFBP-3 levels, which might explain their reduced pubertal growth spurt. GnRHa treatment led to a significant reduction in GH levels. Therefore, combining GnRHa treatment with GH treatment might improve adult height of short SGA girls.
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http://dx.doi.org/10.1111/j.1365-2265.2008.03438.xDOI Listing
June 2009