Prevalence and course of mood and anxiety disorders, and correlates of symptom severity in adolescents with type 1 diabetes: Results from diabetes LEAP.

OBJECTIVES: We aim to determine the prevalence and the course of anxiety and mood disorders in Dutch adolescents (12-18 years old) with type 1 diabetes, and to examine correlates of symptom severity, including parental emotional distress. METHODS: Participants were 171 adolescents and 149 parents. The Diagnostic Interview Schedule for Children-IV was used to assess current, past year and lifetime anxiety and mood disorders in adolescents. Symptom severity and diabetes distress were measured with validated questionnaires. Correlates of these symptoms were examined using hierarchical regression analyses and included demographics (adolescent sex and age), clinical factors (diabetes duration, treatment modality, most recent glycated hemoglobin A1c ; all extracted from medical charts), adolescent diabetes distress, and parent emotional distress. RESULTS: Twenty-four (14%) adolescents met the criteria for ≥1 disorder(s) in the previous 12 months. Anxiety disorders were more prevalent than mood disorders (13% vs. 4%). Lifetime prevalence of anxiety and mood disorders was 29% (n = 49). The presence of any of these disorders earlier in life (from 5 years old up to 12 months prior to assessment) was associated with disorders in the past 12 months (OR = 4.88, p = 0.001). Higher adolescent diabetes distress was related to higher symptoms of anxiety (b = 0.07, p = 0.001) and depression (b = 0.13, p = 0.001), while demographics, clinical characteristics, and parental emotional distress were not related. CONCLUSIONS: Anxiety and mood disorders are common among adolescents and related to earlier disorders. Higher diabetes distress was related to higher symptom severity. Clinicians are advised to address past psychological problems and remain vigilant of these problems.

Study protocol of Diabetes LEAP: a longitudinal study examining emotional problems in adolescents with type 1 diabetes and their parents/caregivers.

BACKGROUND: Type 1 diabetes (T1D) is a chronic metabolic condition requiring intensive daily self-care to avoid both high and low blood glucose levels. Self-care and glycemic outcomes are particularly problematic in adolescence, a period known for its increased risk of emotional problems. However, the true scope of mood and anxiety disorders in adolescents with T1D is unknown. Earlier studies are limited by a small sample size, lack of diagnostic interview data, a focus on depression only, non-adolescent specific estimates, lack of information about parental emotional problems and/or a cross-sectional design. Diabetes LEAP is a two-year prospective observational cohort study examining (a) the prevalence and course of depression and anxiety in adolescents with T1D and their parents/caregivers, (b) the risk factors predicting the presence of these emotional problems, (c) their longitudinal relation with diabetes outcomes, and (d) the psychosocial care currently in place. METHODS: Adolescents (12-18 years) from 8 Dutch pediatric diabetes clinics are interviewed using the DISC-IV to establish the presence of mood and anxiety disorders in the previous 4 weeks, the previous 12 months, and lifetime. They also complete questionnaires, including CDI-2, GAD-7, and PAID-T. Parents/caregivers complete PHQ-9, GAD-7, and PAID-PR. Follow-up assessments take place after 1 and 2 years. DISCUSSION: This longitudinal study with diagnostic interviews in a large cohort of adolescents with T1D in the Netherlands will provide much needed information regarding the prevalence and course of depression and anxiety in this group, thereby opening avenues for proper recognition, prevention and timely treatment.

Disturbed eating behaviors in adolescents with type 1 diabetes. How to screen for yellow flags in clinical practice?

BACKGROUND: Adolescents with type 1 diabetes are at an increased risk of disturbed eating behaviors (DEBs). OBJECTIVE: The aims of this study are to (i) explore the prevalence of DEBs and associated 'yellow flags', and (ii) establish concordance between adolescents-parents and adolescents-clinicians with respect to DEBs. METHODS: Adolescents (11-16 yr) and parents completed questionnaires. A stepwise approach was used to assess DEBs: only adolescents whose answers raised psychological yellow flags for DEBs completed the Diabetes Eating Problems Scale - Revised and questions from the AHEAD study. Parents and clinicians shared their observations regarding possible DEBs. Kruskal-Wallis tests, post hoc Mann-Whitney U test, and chi-squared tests were utilized to examine clinical yellow flags. Cohen's kappa was used to assess concordance. RESULTS: Of 103 adolescents participated (51.5% girls), answers of 47 (46.5%) raised psychological yellow flags, indicating body and weight concerns. A total of 8% scored above cut-off for DEBs. Clinical yellow flags were elevated glycated hemoglobin A1c (p = 0.004), older age (p = 0.034), dieting frequency (p = 0.001), reduced quality of life (p = 0.007), less diabetes self-confidence (p = 0.015), worsened diabetes management (p < 0.001), and body dissatisfaction (p < 0.001). Body Mass Index (BMI) z-scores and gender were no yellow flags. Concordance between parents and adolescents was slight (k = 0.126 and 0.141), and clinicians and adolescents was fair (k = 0.332). DISCUSSION: Half of the adolescents reported body and weight concerns, less than 1 in 10 reported DEBs. Screening for yellow flags for DEBs as a part of clinical routine using a stepwise approach and early assistance is recommended to prevent onset or deterioration of DEBs.

Overnight levels of luteinizing hormone, follicle-stimulating hormone and growth hormone before and during gonadotropin-releasing hormone analogue treatment in short boys born small for gestational age.

AIMS: To evaluate if 3 months of gonadotropin-releasing hormone analogue (GnRHa) treatment results in sufficient suppression of pubertal luteinizing hormone (LH) and follicle-stimulating hormone (FSH) profile patterns in short pubertal small for gestational age (SGA) boys. To compare growth hormone (GH) profiles and fasting insulin-like growth factor (IGF)-I and IGF-binding protein-3 (IGFBP-3) levels after 3 months of GnRHa treatment with those at baseline. METHODS: After measurement of baseline overnight profiles and IGF-I and IGFBP-3 levels, 14 short pubertal SGA boys received leuprorelide acetate depots of 3.75 mg subcutaneously, every 4 weeks. RESULTS: At baseline, mean GH levels were comparable with those of controls, whereas IGF-I and IGFBP-3 standard deviation scores (SDS) were significantly lower than zero SDS. After 3 months of GnRHa treatment, all boys showed clinical arrest of puberty. The area under the curve above zero, mean and maximum LH and FSH had significantly decreased to prepubertal levels. Peak LH during the GnRH agonist test, however, indicated insufficient pubertal suppression in 43% of boys. Overnight GH profile characteristics and IGF-I and IGFBP-3 levels did not significantly change. CONCLUSIONS: Puberty was sufficiently suppressed by GnRHa treatment, as shown by the prepubertal LH and FSH profiles. After 3 months of GnRHa treatment, overnight GH profile characteristics had not significantly changed, reflecting that GH levels are comparable for prepubertal and early pubertal boys.

Youth With Type 1 Diabetes Taking Responsibility for Self-Management: The Importance of Executive Functioning in Achieving Glycemic Control: Results From the Longitudinal DINO Study.

OBJECTIVE: Successful self-management of type 1 diabetes requires cognitive skills such as executive functioning (EF). In the transition to adolescence, youth take over responsibility for diabetes management. We set out to test: 1) the association between EF and glycemic control over time and 2) whether this association was moderated by: a) youth, shared, or parent responsibility for diabetes management and b) youth's age. RESEARCH DESIGN AND METHODS: Within the Diabetes IN DevelOpment study (DINO), parents of youth with type 1 diabetes (8-15 years at baseline; N = 174) completed a yearly assessment over 4 years. Glycemic control (HbA1c) was derived from hospital charts. Youth's EF was measured using the Behavior Rating Inventory of Executive Functioning (BRIEF)-parent report. The Diabetes Family Responsibility Questionnaire (DFRQ)-parent report was used to assess diabetes responsibility (youth, shared, and parent). Linear generalized estimating equations were used to analyze data including youth's sex, age, and age of diabetes onset as covariates. RESULTS: Relatively more EF problems are significantly associated with higher HbA1c over time (ß = 0.190; P = 0.002). More EF problems in combination with less youth responsibility (ß = 0.501; P = 0.048) or more parental responsibility (ß = -0.767; P = 0.006) are significantly associated with better glycemic control over time. Only age significantly moderates the relationship among EF problems, shared responsibility, and glycemic control (ß = -0.024; P = 0.019). CONCLUSIONS: Poorer EF is associated with worse glycemic control over time, and this association is moderated by responsibility for diabetes management tasks. This points to the importance of EF when youth take over responsibility for diabetes management in order to achieve glycemic control.

Long-term follow-up after bilateral percutaneous epiphysiodesis around the knee to reduce excessive predicted final height.

CONTEXT: Percutaneous epiphysiodesis (PE) around the knee to reduce predicted excessive final height. Studies until now included small numbers of patients and short follow-up periods. OBJECTIVE AND DESIGN: This Dutch multicentre, long-term, retrospective, follow-up study aimed to assess adult height (AH), complications, knee function and patient satisfaction after PE. The primary hypothesis was that PE around the knee in constitutionally tall boys and girls is an effective treatment for reducing final height with low complication rates and a high level of patient satisfaction. PARTICIPANTS: 77 treated adolescents and 60 comparisons. INTERVENTION: Percutaneous epiphysiodesis. OUTCOME: AH, complications, knee function, satisfaction. RESULTS: In the PE-treated group, final height was 7.0 cm (±6.3 cm) lower than predicted in boys and 5.9 cm (±3.7 cm) lower than predicted in girls. Short-term complications in file search were seen in 5.1% (three infections, one temporary nerve injury), one requiring reoperation. Long-term complications in file search were seen in 2.6% (axis deformity 1.3%, prominent head of fibula 1.3%). No significant difference in knee function was found between treated cases and comparisons. Satisfaction was high in both the comparison and PE groups; most patients in the PE group recommended PE as the treatment for close relatives with tall stature. CONCLUSION: PE is safe and effective in children with predicted excessive AH. There was no difference in patient satisfaction between the PE and comparison group. Careful and detailed counselling is needed before embarking on treatment.

ACAN Gene Mutations in Short Children Born SGA and Response to Growth Hormone Treatment.

Background: Some children born small for gestational age (SGA) show advanced bone age (BA) maturation during growth hormone (GH) treatment. ACAN gene mutations have been described in children with short stature and advanced BA. Objective: To determine the presence of ACAN gene mutations in short SGA children with advanced BA and assess the response to GH treatment. Methods: BA assessment in 290 GH-treated SGA children. ACAN sequencing in 29 children with advanced BA ≥0.5 years compared with calendar age. Results: Four of 29 SGA children with advanced BA had an ACAN gene mutation (13.8%). Mutations were related to additional characteristics: midface hypoplasia (P = 0.003), joint problems (P = 0.010), and broad great toes (P = 0.003). Children with one or fewer additional characteristic had no mutation. Of children with two additional characteristics, 50% had a mutation. Of children with three additional characteristics, 100% had a mutation. All GH-treated children with a mutation received gonadotropin-releasing hormone analog (GnRHa) treatment for 2 years from onset of puberty. At adult height, one girl was 5 cm taller than her mother and one boy was 8 cm taller than his father with the same ACAN gene mutation. Conclusion: This study expands the differential diagnosis of genetic variants in children born SGA and proposes a clinical scoring system for identifying subjects most likely to have an ACAN gene mutation. ACAN sequencing should be considered in children born SGA with persistent short stature, advanced BA, and midface hypoplasia, joint problems, or broad great toes. Our findings suggest that children with an ACAN gene mutation benefit from GH treatment with 2 years of GnRHa.

Parental Diabetes Behaviors and Distress Are Related to Glycemic Control in Youth with Type 1 Diabetes: Longitudinal Data from the DINO Study.

OBJECTIVE: To evaluate (1) the longitudinal relationship between parental well-being and glycemic control in youth with type 1 diabetes and (2) if youth's problem behavior, diabetes parenting behavior, and parental diabetes-distress influence this relationship. RESEARCH DESIGN AND METHODS: Parents of youth 8-15 yrs (at baseline) (N = 174) participating in the DINO study completed questionnaires at three time waves (1 yr interval). Using generalized estimating equations, the relationship between parental well-being (WHO-5) and youth's HbA1c was examined. Second, relationships between WHO-5, Strength and Difficulties Questionnaire (SDQ), Diabetes Family Behavior Checklist (DFBC), Problem Areas In Diabetes-Parent Revised (PAID-Pr) scores, and HbA1c were analyzed. RESULTS: Low well-being was reported by 32% of parents. No relationship was found between parents' WHO-5 scores and youth's HbA1c (ß = -0.052, p = 0.650). WHO-5 related to SDQ (ß = -0.219, p < 0.01), DFBC unsupportive scale (ß = -0.174, p < 0.01), and PAID-Pr (ß = -0.666, p < 0.01). Both DFBC scales (supportive ß = -0.259, p = 0.01; unsupportive ß = 0.383, p = 0.017), PAID-Pr (ß = 0.276, p < 0.01), and SDQ (ß = 0.424, p < 0.01) related to HbA1c. CONCLUSIONS: Over time, reduced parental well-being relates to increased problem behavior in youth, unsupportive parenting, and parental distress, which negatively associate with HbA1c. More unsupportive diabetes parenting and distress relate to youth's problem behavior.

A novel homozygous insertion and review of published mutations in the NNT gene causing familial glucocorticoid deficiency (FGD).

Familial glucocorticoid deficiency (FGD) is an autosomal recessive disorder characterized by low levels of cortisol despite high adrenocorticotropin (ACTH) levels, due to the reduced ability of the adrenal cortex to produce cortisol in response to stimulation by ACTH. FGD is a heterogeneous disorder for which causal mutations have been identified in MC2R, MRAP, MCM4 and TXNRD2. Also mutations in STAR and CYP11A1 can sometimes present with a phenotype resembling FGD. Recently, it has been indicated that FGD can also be caused by mutations in NNT (nicotinamide nucleotide transhydrogenase). We identified a 6.67 Mb homozygous region harboring the NNT gene by SNP haplotyping in a 1-year old Dutch boy presenting with FGD, but without mutations in MC2R and MRAP. Exome-sequencing revealed a novel homozygous mutation (NM_012343.3: c.1259dupG) in NNT that was predicted to be disease-causing. The mutation is located in exon 9 and creates a frameshift leading to a premature stop-codon (p.His421Serfs*4) that is known to result in FGD. Both parents were shown to be heterozygous carriers. We reviewed the literature for all the reported NNT mutations and their clinical presentation. The median age of disease onset in 23 reported patients, including the present patient, was 12 months (range 3 days-39 months). There was no difference in age of disease onset between truncating and non-truncating NNT mutations. Based on recent literature, we advise to monitor patients with FGD due to NNT mutations for possible combined mineralocorticoid insufficiency and extra-adrenal manifestations.

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.

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.

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

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.

[Congenital hyperinsulinism in the north-east Netherlands. Clinical features and DNA diagnostics in 22 children]. / Congenitaal hyperinsulinisme in Noordoost-Nederland. Klinische kenmerken en DNA-diagnostiek bij 22 kinderen.

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.

Long-term effects of growth hormone (GH) treatment on body composition and bone mineral density in short children born small-for-gestational-age: six-year follow-up of a randomized controlled GH trial.

UNLABELLED: Context Alterations in the GH-IGF-I axis in short small-for-gestational-age (SGA) children might be associated with abnormalities in bone mineral density (BMD) and body composition. In addition, birth weight has been inversely associated with diabetes and cardiovascular disease in adult life. Data on detailed body composition in short SGA children and long-term effects of GH treatment are very scarce. OBJECTIVE: To investigate effects of long-term GH treatment on body composition and BMD by dual energy X-ray absorptiometry (DXA) in short SGA children. DESIGN: Longitudinal 6-year GH study with a randomized controlled part for 3 years. RESULTS: At baseline, fat percentage standard deviation score (SDS) and lumbar spine BMD SDS corrected for height (BMAD(LS) SDS) were significantly lower than zero. Lean body mass (LBM) SDS adjusted for age was also reduced, but LBM adjusted for height (LBM SDS(height)) was not decreased. GH treatment induced a decrease in fat percentage SDS and an increase in BMAD(LS) SDS. LBM SDS(height) remained similar in GH-treated children, but deteriorated in untreated controls. When these untreated controls subsequently started GH treatment, their LBM SDS(height) rapidly normalized to values comparable with zero. CONCLUSION: During long-term GH treatment in short SGA children, fat percentage SDS decreased and BMAD(LS) SDS increased. These effects of GH treatment were most prominent in children who started treatment at a younger age and in those with greater height gain during GH treatment. LBM SDS(height )remained around 0 SDS in GH-treated children, but declined to low normal values in untreated controls.