C. Noordam

Short Stature Associated with a Novel Heterozygous Mutation in the Insulin-Like Growth Factor 1 Gene

CONTEXTnHomozygous IGF1 deletions or mutations lead to severe short stature, deafness, microcephaly, and mental retardation. Heterozygosity for an IGF-I defect may modestly decrease height and head circumference.nnnOBJECTIVEnThe objective of the study was to investigate the clinical features of heterozygous carriers of a novel mutation in the IGF1 gene in comparison with noncarriers in a short family and to establish the effect of human GH treatment.nnnSUBJECTSnTwo children, their mother, and their maternal grandfather carried the mutation and were compared with two relatives who were noncarriers.nnnRESULTSnThe two index cases had severe short stature (height sd score -4.1 and -4.6), microcephaly, and low IGF-I levels. Sequencing of IGF1 revealed a heterozygous duplication of four nucleotides, resulting in a frame shift and a premature termination codon. The mother and maternal grandfather had the same IGF1 mutation. Adult height (corrected for shrinking and secular trend) and head circumference sd score of carriers of the paternally transmitted mutation was -2.5 and -1.8, in comparison with -1.6 and 0.3 in noncarriers, respectively. After 2 yr of GH treatment, both index cases exhibited increased growth.nnnCONCLUSIONSnHeterozygosity for this novel IGF1 mutation in children born from a mother with the same mutation, presumably in combination with other genetic factors for short stature, leads to severe short stature, which can be successfully treated with GH.

Homozygous and heterozygous expression of a novel mutation of the acid-labile subunit

CONTEXTnAcid-labile subunit (ALS) deficiency due to homozygous inactivation of the ALS gene (IGFALS) is associated with moderate short stature, and in few cases pubertal delay. The clinical expression of heterozygosity is unknown.nnnOBJECTIVEnTo investigate the clinical, laboratory, and radiological features of homozygous and heterozygous carriers of a novel mutation in the ALS gene in comparison with non-carriers.nnnSUBJECTSnThree short Kurdish brothers and their relatives.nnnRESULTSnThe index cases presented with short stature, microcephaly, and low circulating IGF-I and IGF-binding protein-3 (IGFBP-3), and undetectable ALS levels. Two were known with a low bone mineral density and one of them had suffered from two fractures. We found a novel homozygous ALS gene mutation resulting in a premature stop codon (c.1490dupT, p.Leu497PhefsX40). The IGF-I, IGFBP-3, and ALS 150 kDa ternary complex was absent, and ALS proteins in serum were not detected with western blot. IGFPB-1 and IGFPB-2 were low and there was a mild insulin resistance. Five heterozygous carriers tended to have a lower height and head circumference than five non-carriers, and had low plasma ALS and IGFBP-3 levels. Bone mineral (apparent) density was low in two out of three homozygous carriers, and also in four out of nine relatives.nnnCONCLUSIONSnThe clinical presentation of homozygous ALS mutations may, besides short stature, include microcephaly. Heterozygous carriers may have less statural and head growth, suggestive for a gene dosage effect.

Adult Height in Short Children Born SGA Treated with Growth Hormone and Gonadotropin Releasing Hormone Analog: Results of a Randomized, Dose-Response GH Trial

CONTEXTnGH 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.nnnOBJECTIVEnThe 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.nnnPATIENTS AND DESIGNnIn 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.nnnRESULTSnShort 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).nnnCONCLUSIONnWhen 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.

Genetic Analysis of Short Children with Apparent Growth Hormone Insensitivity

Background/Aims: In short children, a low IGF-I and normal GH secretion may be associated with various monogenic causes, but their prevalence is unknown. We aimed at testing GH1, GHR, STAT5B, IGF1, and IGFALS in children with GH insensitivity. Subjects and Methods: Patients were divided into three groups: group 1 (height SDS <–2.5, IGF-I <–2 SDS, n = 9), group 2 (height SDS –2.5 to –1.9, IGF-I <–2 SDS, n = 6) and group 3 (height SDS <–1.9, IGF-I –2 to 0 SDS, n = 21). An IGF-I generation test was performed in 11 patients. Genomic DNA was used for direct sequencing, multiplex ligation-dependent probe amplification and whole-genome SNP array analysis. Results: Three patients in group 1 had two novel heterozygous STAT5B mutations, in two combined with novel IGFALS variants. In groups 2 and 3 the association between genetic variants and short stature was uncertain. The IGF-I generation test was not predictive for the growth response to GH treatment. Conclusion: In severely short children with IGF-I deficiency, genetic assessment is advised. Heterozygous STAT5B mutations, with or without heterozygous IGFALS defects, may be associated with GH insensitivity. In children with less severe short stature or IGF-I deficiency, functional variants are rare.

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

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

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

CONTEXTnPreviously 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.nnnOBJECTIVEnThis 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.nnnMETHODSnThis 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.nnnRESULTSnAt 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.nnnCONCLUSIONSnCombined 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.

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

AIMS AND OBJECTIVESnTo 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.nnnBACKGROUNDnAlthough children with type 1 diabetes and their parents show increased risk for psychosocial problems, standardised assessment of these problems lacks in diabetes care.nnnDESIGNnBy comparing these different modes of assessment, using a cross-sectional design, information about the additional value of using standardised questionnaires is provided.nnnMETHODSnParticipants 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 childrens psychosocial problems and quality of life, and parents levels of parenting stress. Reports of children and parents were compared to clinical estimations.nnnRESULTSnChildren 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.nnnCONCLUSIONnChildren with type 1 diabetes show more psychosocial problems than healthy children. Professionals seem to tend towards overestimating psychosocial problems.nnnRELEVANCE TO CLINICAL PRACTICEnExtending 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.

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

BackgroundType 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/DesignWe 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.DiscussionDependent on its feasibility and efficacy, the intervention will be implemented into usual pediatric diabetes care. Strengths and limitations of the study are discussed.Trial registrationNTR3643 (Dutch Trial Register)

Successful treatment of severe subcutaneous insulin resistance with inhaled insulin therapy

van Alfen‐van der Velden AAEM, Noordam C, de Galan BE, Hoorweg‐Nijman JJG, Voorhoeve PG, Westerlaken C. Successful treatment of severe subcutaneous insulin resistance with inhaled insulin therapy.

New insights into factors influencing adult height in short SGA children: Results of a large multicentre growth hormone trial

Growth hormone (GH) treatment is effective in improving adult height (AH) in short children born SGA. However, there is a wide variation in height gain, even after adjustment for predictive variables. It is therefore important to investigate new factors which can influence the response to GH.