Metabolomic associations of impaired awareness of hypoglycaemia in type 1 diabetes.

This study investigates impaired awareness of hypoglycaemia (IAH), a complication of insulin therapy affecting 20-40% of individuals with type 1 diabetes. The exact pathophysiology is unclear, therefore we sought to identify metabolic signatures in IAH to elucidate potential pathophysiological pathways. Plasma samples from 578 individuals of the Dutch type 1 diabetes biomarker cohort, 67 with IAH and 108 without IAH (NAH) were analysed using the targeted metabolomics Biocrates AbsoluteIDQ p180 assay. Eleven metabolites were significantly associated with IAH. Genome-wide association studies of these 11 metabolites identified significant single nucleotide polymorphisms (SNPs) in C22:1-OH and phosphatidylcholine diacyl C36:6. After adjusting for the SNPs, 11 sphingomyelins and phosphatidylcholines were significantly higher in the IAH group in comparison to NAH. These metabolites are important components of the cell membrane and have been implicated to play a role in cell signalling in diabetes. These findings demonstrate the potential role of phosphatidylcholine and sphingomyelins in IAH.

[Diabetes, not harmless in young adults]. / Diabetes, ook bij jongvolwassenen niet onschuldig.

A recent publication in JAMA again demonstrates that a significant proportion of young adults with type-1 or type-2 diabetes develop diabetes-related complications and comorbidities. These complications and comorbidities already occur after a relative short disease duration and is most frequently seen in young adults with type-2 diabetes. Future research should focus on medical, social and psychological factors that will improve diabetes care.

Bilateral renal agenesis, cerebral angiodysplasia and esophageal atresia.

The combination of bilateral renal agenesis, vascular abnormalities in the brain and esophageal atresia is exceptional. MR and ultrasound data of the brain findings are presented for the first time in such a case.

[A girl with breath-holding spells and anaemia, treated with iron supplementation]. / Een meisje met 'breath-holding spells' en anemie, behandeld door ijzersuppletie.

A girl aged 1.5 years was presented because of frequent breath-holding spells. Anaemia was also diagnosed. Iron supplementation reduced the frequency and severity of the spells until they fully disappeared. The pathophysiological relationship between breath-holding spells and anaemia has not been clarified, but iron supplementation appears to be effective in many patients.

A randomized controlled trial of three years growth hormone and gonadotropin-releasing hormone agonist treatment in children with idiopathic short stature and intrauterine growth retardation.

We assessed the effectiveness and safety of 3 yr combined GH and GnRH agonist (GnRHa) treatment in a randomized controlled study in children with idiopathic short stature (ISS) or intrauterine growth retardation (IUGR). Gonadal suppression, GH reserve, and adrenal development were assessed by hormone measurements in both treated children and controls during the study period. Thirty-six short children, 24 girls (16 ISS/8 IUGR) and 12 boys (8 ISS/4 IUGR), with a height SD score of -2 SD or less in early puberty (girls, B2-3; boys, G2-3), were randomly assigned to treatment (n = 18) with GH (genotropin 4 IU/m(2). day) and GnRHa (triptorelin, 3.75 mg/28 days) or no treatment (n = 18). At the start of the study mean (SD) age was 11.4 (0.56) or 12.2 (1.12) yr whereas bone age was 10.7 (0.87) or 10.9 (0.63) yrs in girls and boys, respectively. During 3 yr of study height SD score for chronological age did not change in both treated children and controls, whereas a decreased rate of bone maturation after treatment was observed [mean (SD) 0.55 (0.21) 'yr'/yr vs. 1.15 (0.37) 'yr'/yr in controls, P < 0.001, girls and boys together]. Height SD score for bone age and predicted adult height increased significantly after 3 yr of treatment; compared with controls the predicted adult height gain was 8.0 cm in girls and 10.4 cm in boys. Furthermore, the ratio between sitting height/height SD score decreased significantly in treated children, whereas body mass index was not influenced by treatment. Puberty was effectively arrested in the treated children, as was confirmed by physical examination and prepubertal testosterone and estradiol levels. GH-dependent hormones including serum insulin-like growth factor I and II, carboxy terminal propeptide of type I collagen, amino terminal propeptide of type III collagen, alkaline phosphatase, and osteocalcin were not different between treated children and controls during the study period. Thus, a GH dose of 4 IU/m(2) seems adequate for stabilization of the GH reserve and growth in these GnRHa-treated children. We conclude that 3 yr treatment with GnRHa was effective in suppressing pubertal development and skeletal maturation, whereas the addition of GH preserved growth velocity during treatment. This resulted in a considerable gain in predicted adult height, without demonstrable side effects. Final height results will provide the definite answer on the effectiveness of this combined treatment.

Early puberty in girls.

Early puberty is not well defined in paediatric endocrinology. This chapter reviews the current insights on definitions, patient groups and treatment modalities in girls with early puberty. It is concluded that there is no clear evidence for a beneficial effect of gonadotrophin releasing hormone agonist (GnRHa) treatment in auxological terms. A clinical approach is presented, including both auxological and psychological items. Further research is needed to answer the question of whether early puberty should be treated with GnRHa.

Bone mineral density and body composition and influencing factors in children with rheumatic diseases treated with corticosteroids.

In rheumatic diseases the use of corticosteroids (CS), immobility, or the disease itself, may cause osteoporosis and growth retardation. We evaluated bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA), growth and physical activity in 27 children with rheumatic disease, all treated with high dose CS for at least one year, in a cross-sectional design. BMD SDS was significantly lower than zero: -1.02 for total body and -1.49 for lumbar spine measurement. SDS for fat mass was higher than zero. In multiple regression analysis the Child Health Assessment Questionnaire score significantly correlated with BMD of the lumbar spine. There was no significant correlation with cumulative dose or duration of CS treatment. Height SDS decreased during treatment to -1.57 (p <0.001 compared to 0). In conclusion, BMD and body composition in children with rheumatic disease treated with CS are influenced by physical activity, as well as corticosteroid treatment and type of rheumatic disease.

Final height after gonadotrophin releasing hormone agonist treatment for central precocious puberty: the Dutch experience.

Final height (FH) data of 96 children (87 girls) treated with GnRH agonist for central precocious puberty were studied. In girls mean FH exceeded initial height prediction by 7.4 (5.7) cm (p < 0.001); FH was significantly lower than target height, but still in the genetic target range. When treatment started < 6 years of age, height gain was significantly higher than when started > 8 years of age. Bone age (BA) and chronological age (CA) at start of treatment, as well as BA advance at cessation of treatment, were the most important variables influencing height gain in multiple regression analysis. BA advance at start of treatment was most important in simple correlation. In girls, GnRHa treatment seems to restore FH into the target range. A younger age and advanced bone age at start of treatment are associated with more height gain from GnRHa treatment.

A mosaic de novo duplication of 17q21-25 is associated with GH insensitivity, disturbed in vitro CD28-mediated signaling, and decreased STAT5B, PI3K, and NF-κB activation.

OBJECTIVE: The established causes of GH insensitivity include defects of the GH receptor and STAT5B. The latter condition is also characterized by severe immunodeficiency. A recent case with short stature, GH resistance, and immunodeficiency due to an IκB mutation suggests that the NF-κB pathway may interact with STAT5B signaling. DESIGN: Here, we present a case of a short child with several congenital anomalies as well as GH insensitivity and mild immunodeficiency associated with a mosaic de novo duplication of chromosome 17q21-25, suggesting that overexpression of one of the duplicated genes may be implicated in GH resistance. METHODS AND RESULTS: In vitro studies on blood lymphocytes showed disturbed signaling of the CD28 pathway, involving NF-κB and related proteins. Functional studies on cultured skin fibroblasts revealed that NF-κB activation, PI3K activity, and STAT5 phosphorylation in response to GH were suppressed, while the sensitivity to GH in terms of MAPK phosphorylation was increased. An in silico analysis of the duplicated genes showed that MAP3K3 and PRKCA are associated with the NF-κB pathway. Baseline MAP3K3 expression in T-cell blasts (TCBs) was normal, but PRKCA expression in TCBs and fibroblasts was significantly higher than that in control cells. CONCLUSIONS: We conclude that the 17q21-25 duplication is associated with GH insensitivity and disturbed STAT5B, PI3K, and NF-κB signaling, possibly due to PRKCA mRNA overexpression.

A girl with type 1 diabetes and a yellowish appearance.

Type 1 diabetes mellitus in children has been associated with other autoimmune diseases, especially coeliac disease and autoimmune thyroiditis. This association may be the result of a common pathogenic background. We describe the case of a girl with type 1 diabetes mellitus who developed icterus due to autoimmune hepatitis, a disease rarely found in children. Thyroiditis-associated and diabetes-associated autoantibodies were also present. Human leucocyte antigen typing revealed DRB1*03 heterozygosity, which has been associated with the occurrence of both autoimmune hepatitis and type 1 diabetes. This finding implies that similar pathogenic pathways may be involved in different autoimmune diseases including type 1 diabetes and autoimmune hepatitis. The patient was successfully treated with prednisolone and azathioprine. Autoimmune hepatitis can be a serious co-occurring disease in patients with type 1 diabetes.

Should blood gas analysis be part of the diagnostic workup of short children? Auxological data and blood gas analysis in children with renal tubular acidosis.

BACKGROUND: Renal tubular acidosis (RTA) is a rare cause of growth failure, therefore it is uncertain whether routine screening with blood gas analysis of short infants and children is cost-effective. OBJECTIVE: To investigate the clinical, growth and laboratory parameters in children with RTA to estimate the possible value of laboratory screening for this disorder in infants and children referred for short stature according to a recent guideline. METHOD: Retrospective chart analysis of 30 children diagnosed between 1978 and 2005 in The Netherlands and 3 centers in Belgium. RESULTS: The current guideline for short stature detected 33% of children with RTA. Assuming a pre-test probability of RTA of 0.6 per 100,000 births, the likelihood ratio of poor growth was 58 and 17 below and above 3 years, respectively. Sensitivity was 17/30 and 12/24 for a -2.0 SDS cutoff for weight and body mass index, respectively. In infants and toddlers diagnosed before 3 years of age, the mean weight loss was 1.5 SD, and 0.8 SDS in older children. In short children >3 years RTA was extremely rare, always associated with clinical symptoms, and rarely detected by blood gas analysis. CONCLUSION: According to our data a decreasing weight SDS for age is a sufficient indication to perform blood gas analysis in children <3 years of age, particularly in the presence of additional clinical features, whereas it can be omitted in short children >3 years of age.

The use of GnRH agonists in precocious puberty.

In this review several aspects of gonadotrophin releasing hormone agonists (GnRHa) treatment in central precocious puberty (CPP) are highlighted. These include issues of the definition of precocity, assessment of CPP and thelarche variants. Indications for treatment with GnRH agonists are discussed, not only in CPP but also in children with other reasons to suppress central activation, e.g. adopted or developmental retardation. Finally, outcome data are summarized, both on growth and psychosocial parameters.

Growth hormone treatment in children with rheumatic disease, corticosteroid induced growth retardation, and osteopenia.

BACKGROUND: In children with severe rheumatic disease (RD), treatment with corticosteroids (CS) is frequently needed and growth retardation and osteopenia may develop. A beneficial effect of human growth hormone (hGH) has been reported but mostly in trials without a control group. AIMS: To study the effect of hGH on growth, bone mineral density (BMD), and body composition, taking the disease activity and CS use into account. METHODS: Randomised controlled trial on 17 prepubertal RD patients with growth retardation and/or decreased BMD. The hGH group (n = 10) received treatment with hGH 4 IU/m2/day (approximately 0.045 mg/kg/day) during two years. The controls (n = 7) received no GH treatment. RESULTS: During the two year study period the disease activity, and use of CS and methotrexate (MTX) did not differ between the groups. There was a significant mean increase in height standard deviation score (HSDS) in the hGH group (0.42+/-0.16 SDS) and a non-significant decrease in the controls (-0.18+/-0.11 SDS). Change in BMD did not differ significantly between the groups, although the increase in BMD for lumbar spine within the hGH group was significant. Lean body mass improved significantly in the hGH group compared to controls (0.64+/-0.19 SDS versus -0.20+/-0.17 SDS), while the decrease in percentage fat was not significant. CONCLUSIONS: There was a significant effect of hGH on growth and lean body mass, but a longer duration of treatment might be necessary to evaluate the effect of hGH on BMD.

Final height after treatment of early puberty in short adopted girls with gonadotrophin releasing hormone agonist with or without growth hormone.

OBJECTIVE: To compare final height data after treatment with gonadotrophin releasing hormone agonist (GnRHa) alone or in combination with growth hormone (GH) in short adopted girls with early puberty. DESIGN: A randomized controlled trial. PATIENTS AND METHODS: Twenty-six girls with onset of puberty before 10 years of age were treated for 3 years with either GnRHa alone (group A, n = 12) or with GnRHa and GH (group B, n = 14). Mean age at start of treatment was 9.6 years in both groups, bone age was 10.7 (SD 1.1) years in group A and 11.6 (0.8) years in group B. RESULTS: Initial height prediction with average Bayley & Pinneau tables was 149.8 (5.6) and 146.8 (4.8) cm, respectively. Bone age at discontinuation of treatment was 12.3 (0.9) and 13.0 (0.6) years in group A and B, respectively. Height gain defined as the difference between initial height prediction and attained final height, was significantly different between group A and B (5.2 (3.7) and 8.2 (3.4) cm, P < 0.05) using average tables for height prediction. With accelerated tables for prediction the numbers were -1.0 (3.6) and 3.3 (3.5) cm, respectively. At final height, there was no significant difference in height: group A: 155.0 (5.6) cm and group B: 155.0 (5.5) cm. CONCLUSIONS: After 3 years of GnRHa treatment in adopted girls with early puberty, FH is significantly higher than initial height prediction. The addition of GH resulted in a limited further increase in height gain. In the interpretation of the results methodological issues concerning height prediction have to be taken into account.

Growth hormone in short children: beyond medicine?

UNLABELLED: The indications for growth hormone (GH) treatment in non-GH-deficient short children are in debate, with some arguing that this treatment does not belong solely in the medical domain. We describe three different approaches to the issue, and argue that neither a disease-oriented nor client-oriented approach is sufficient. Both lead to withdrawal of medical interventions or to an undesirable application. CONCLUSION: An approach focusing on suffering as an indication for treatment of short stature is the most appropriate. The challenge is to develop proper tools by which to evaluate suffering and the efficacy of GH treatment in these children in order to relieve or prevent suffering.

Early puberty in adopted children.

Early puberty is frequently observed in adopted children. In various studies, early puberty has been associated with decreased final height. In Europe, studies were undertaken to treat early puberty in adopted children with GnRH agonist. This article reviews the current understanding of early puberty in adopted children, including prevalence, background and treatment options. Data from the European studies are briefly described. Besides auxological aspects, psychological items are addressed as well. Studies on the psychological effect of early puberty in adopted children are reported. Future issues include further study in the mechanism of early puberty in adopted children, evaluation of final height results of the growth studies and quality of life assessments in this specific group of children.