Intragastric balloon as an adjunct to lifestyle programme in severely obese adolescents: impact on biomedical outcomes and skeletal health.

Intragastric Balloons are a temporary, reversible and safer option compared to bariatric surgery to promote significant weight loss, leading to improved metabolic outcomes. However, due to subsequent weight regain, alternative procedures are now preferred in adults. In adolescents, more amenable to lifestyle change, balloons may be an alternative to less reversible procedures. Our aim was to assess the tolerability and efficacy of the intragastric balloon in severely obese adolescents and the impact of associated weight loss on biomedical outcomes (glucose metabolism, blood pressure, lipid profiles) and bone density. A 2-year cohort study of 12 adolescents (BMI >3.5 s.d., Tanner stage >4) following 6 months intragastric balloon placement was carried out. Subjects underwent anthropometry, oral glucose tolerance test, and DEXA scans at 0, 6 and 24 months. The results showed clinically relevant improvements in blood pressure, insulin: glucose metabolism, liver function and sleep apnoea at 6 months. Changes were not sustained at 2 years though some parameters (Diastolic BP, HBA1c, insulin AUC) demonstrated longer-term improvement despite weight regain. Despite weight loss, bone mass accrual showed age appropriate increases. In conclusion, the intragastric balloon was safe, well tolerated and effective in supporting short-term weight loss and clinically relevant improvement in obesity-related complications, which resolved in some individuals. Benefits were not sustained in the majority at 2 years.

Adult height of preterm infants: a longitudinal cohort study.

BACKGROUND: Many infants born prematurely experience growth failure following delivery, with subsequent catch-up growth. Traditionally catch-up was thought to be complete in the first few years of life. Most studies have focused on groups of infants defined by birth weight, for example <1500 g, resulting in disproportionate numbers of small for gestational age infants. This study aimed to determine whether appropriate weight for gestation (AGA) preterm born children reach their expected adult height when compared with term controls. METHODOLOGY: This UK based prospective longitudinal cohort study recruited 204 preterm children born at a tertiary neonatal unit during 1994 and 50 matched controls. Growth parameters have been assessed annually until the completion of growth. RESULTS: There was no significant difference in the final height SD score (SDS) of children born at term (n=30) and those born prematurely and AGA (n=70) (0.45 term vs 0.22 preterm). Catch-up growth however, continued throughout the whole of childhood. When the difference between final height SDS and mid-parental height SDS were compared, there were again no significant differences (0.13 term vs 0.03 preterm). CONCLUSIONS: Those born prematurely with an AGA achieve a comparable adult height to children born at term, however, catch-up growth continues for much longer than traditionally thought.

Intra-gastric balloon as an adjunct to lifestyle support in severely obese adolescents; impact on weight, physical activity, cardiorespiratory fitness and psychosocial well-being.

BACKGROUND: Severe adolescent obesity (body mass index (BMI) >99.6th centile) is a significant public health challenge. Current non-invasive treatments, including community-based lifestyle interventions, are often of limited effectiveness in this population, with NICE guidelines suggesting the use of bariatric surgery as the last line of treatment. Health professionals are understandably reluctant to commission bariatric surgery and as an alternative, the use of an intra-gastric balloon as an adjunct to a lifestyle programme might offer a reversible, potentially safer and less invasive option. OBJECTIVES: Explore the use of an intra-gastric balloon as an adjunct to a lifestyle support programme, to promote weight loss in severely obese adolescents. Outcomes included weight loss, waist and hip measurements, psychosocial outcomes including health-related quality of life (HRQoL) and physical self perceptions, physical activity and cardiorespiratory fitness. METHOD: Non-randomised pilot study. RESULTS: Twelve severely obese adolescents (5 males, 7 females; mean age 15 years; BMI >3.5 s.d.; puberty stage 4 or more) and their families were recruited. Mean weight loss at 12 months (n=9) was 3.05 kg±14.69; d=0.002, P=0.550, and a BMI Z-score (n=12) change of 0.2 s.d.; d=0.7, P=0.002 was observed at 6 months with a large effect, but was not sustained at 12 months (mean change 0.1 s.d.; d=0.3, P=0.146). At 24 months (n=10), there was a weight gain from baseline of +9.9 kg±1.21 (d=0.4; P=0.433). Adolescent and parent HRQoL scores exceeded the minimal clinical important difference between baseline and 12 months for all domains but showed some decline at 24 months. CONCLUSION: An intra-gastric balloon as an adjunct to a lifestyle support programme represents a safe and well-tolerated treatment approach in severely obese adolescents, with short-term effects on weight change. Improvements in psychosocial health, physical activity and cardiorespiratory fitness were maintained at 12 months, with varying results at 24 months.

Effectiveness of the Kids in Control of Food (KICk-OFF) structured education course for 11-16 year olds with Type 1 diabetes.

AIM: To assess the effect of a 5-day structured education course (Kids in Control of Food; KICk-OFF) on biomedical and psychological outcomes in young people with Type 1 diabetes. METHODS: This was a cluster-randomized trial involving 31 UK paediatric centres. Participants were recruited prior to stratified centre randomization. Intervention centres delivered KICk-OFF courses, whereas control centres delivered usual care. Participants were 11-16 years of age and had Type 1 diabetes for at least one year. The KICk-OFF course was delivered by trained educators to eight participants per course. Glycaemic control and quality of life were measured at baseline, 6, 12 and 24 months. Secondary outcomes were hypoglycaemia, ketoacidosis, fear of hypoglycaemia and diabetes self-efficacy. RESULTS: Three hundred and ninety-six participants provided baseline data (199 intervention and 197 control). At 6 and 12 months the intervention group showed significantly improved total generic quality of life scores compared with controls (baseline: 80 vs. 82; 6 months: 82 vs. 82; P = 0.04). Across the whole intervention group mean HbA1c levels were not significantly different from controls; baseline HbA1c mean (95% confidence interval), 78 mmol/mol (75-81) vs. 76 mmol/mol (74-79) [9.3% (9-9.6%) vs. 9.1% (8.9-9.4%); 24 months: 77 mmol/mol (74-79) vs. 78 mmol/mol (75-81) (9.2% (8.9-9.4%) vs. 9.3% (9-9.6%)], adjusted mean difference, -2.0 mmol/mol (6.5-2.5) [2.3% (-2.7% to 2.4%)], P = 0.38. CONCLUSIONS: Attending a KICk-OFF course was associated with significantly improved total quality of life scores within 6 months. Glycaemic control, as measured by HbA1c , was no different at 24 months. (Clinical Trial Registry No: ISRCTN3704268).

Expanding the Clinical Spectrum Associated With GLIS3 Mutations.

CONTEXT: GLIS3 (GLI-similar 3) is a member of the GLI-similar zinc finger protein family encoding for a nuclear protein with 5 C2H2-type zinc finger domains. The protein is expressed early in embryogenesis and plays a critical role as both a repressor and activator of transcription. Human GLIS3 mutations are extremely rare. OBJECTIVE: The purpose of this article was determine the phenotypic presentation of 12 patients with a variety of GLIS3 mutations. METHODS: GLIS3 gene mutations were sought by PCR amplification and sequence analysis of exons 1 to 11. Clinical information was provided by the referring clinicians and subsequently using a questionnaire circulated to gain further information. RESULTS: We report the first case of a patient with a compound heterozygous mutation in GLIS3 who did not present with congenital hypothyroidism. All patients presented with neonatal diabetes with a range of insulin sensitivities. Thyroid disease varied among patients. Hepatic and renal disease was common with liver dysfunction ranging from hepatitis to cirrhosis; cystic dysplasia was the most common renal manifestation. We describe new presenting features in patients with GLIS3 mutations, including craniosynostosis, hiatus hernia, atrial septal defect, splenic cyst, and choanal atresia and confirm further cases with sensorineural deafness and exocrine pancreatic insufficiency. CONCLUSION: We report new findings within the GLIS3 phenotype, further extending the spectrum of abnormalities associated with GLIS3 mutations and providing novel insights into the role of GLIS3 in human physiological development. All but 2 of the patients within our cohort are still alive, and we describe the first patient to live to adulthood with a GLIS3 mutation, suggesting that even patients with a severe GLIS3 phenotype may have a longer life expectancy than originally described.

Assessment of childhood obesity in secondary care: OSCA consensus statement.

This expert opinion provides detailed guidance on assessing obesity in secondary paediatric practice. This guidance builds on existing recommendations from National Institute of Health and Clinical Excellence in the UK, and is evidence based where possible. Guidance is provided on which obese children and young people are appropriate to be seen in secondary care and relevant history and investigations, and guidance on when further investigation of causes and obesity-related comorbidity is appropriate.

Very low birth weight survivors have reduced peak bone mass and reduced insulin sensitivity.

CONTEXT: Increasing numbers of very low birth weight (VLBW) infants are surviving into adulthood because of improvements in neonatal intensive care. Adverse events in early life can have long-term effects through reprogramming of metabolic systems. OBJECTIVE: To determine whether young adult VLBW survivors have abnormalities of skeletal development or endocrine function. DESIGN: Cross-sectional, observational, case-control study. PARTICIPANTS: Thirty-seven VLBW subjects and 27 healthy controls at peak bone mass (mean age 23). MEASUREMENTS: Differences between cases and controls in body size, body composition, bone mass and bone geometry [assessed by dual-energy X-ray absorptiometry (DXA), hip structure analysis and peripheral quantitative computed tomography (pQCT)], bone turnover [urine N-terminal telopeptide of type I collagen (NTX), serum C-terminal telopeptide of type I collagen (CTX)], aminoterminal propeptide of type I procollagen (PINP) and bone alkaline phosphatase), hormones (sex steroids, IGF-1, PTH and 25-OH vitamin D) and insulin sensitivity (HOMA-IR and oral glucose tolerance testing). RESULTS: VLBW subjects had lower bone density at the lumbar spine (5.7%) and femoral neck (8.6%), which persisted after correction for bone size by the estimation of volumetric density (bone mineral apparent density). Urine NTX was higher in VLBW subjects than in controls, but there were no significant differences in other bone turnover markers. VLBW survivors had lower insulin sensitivity (mean INS-30 controls = 57.0, VLBW subjects = 94.3, P < 0.01), but there were no differences in whole body fat mass or truncal fat mass between VLBW subjects and controls. CONCLUSIONS: Young adult VLBW survivors have reduced bone density for their bone size and reduced insulin sensitivity, which may have significant implications for their risk of fracture and diabetes in later life.

Novel GLIS3 mutations demonstrate an extended multisystem phenotype.

INTRODUCTION: Mutations in the GLI-similar 3 (GLIS3) gene encoding the transcription factor GLIS3 are a rare cause of neonatal diabetes and congenital hypothyroidism with six affected cases from three families reported to date. Additional features, described previously, include congenital glaucoma, hepatic fibrosis, polycystic kidneys, developmental delay and facial dysmorphism. SUBJECTS: We report two new cases from unrelated families with distinct novel homozygous partial GLIS3 deletions. Both patients presented with neonatal diabetes mellitus, severe resistant hypothyroidism in the presence of elevated thyroglobulin and normal thyroid anatomy, degenerative liver disease, cystic renal dysplasia, recurrent infections and facial dysmorphism. These novel mutations have also resulted in osteopenia, bilateral sensorineural deafness and pancreatic exocrine insufficiency, features that have not previously been associated with GLIS3 mutations. Gene dosage analysis showed that the parents were carriers of a deletion encompassing exons 1-2 (case 1) or exons 1-4 (case 2) of the 11 exon gene. Genome-wide SNP analysis did not reveal a common ancestral GLIS3 haplotype in patient 2. CONCLUSIONS: Our results confirm partial gene deletions as the most common type of GLIS3 mutations, accounting for four of five families identified to date. We propose that mutations in GLIS3 lead to a wider clinical phenotype than previously recognised. We also report the first case of a recessive GLIS3 mutation causing neonatal diabetes and congenital hypothyroidism in a child from a non-consanguineous pedigree, highlighting the importance of molecular genetic testing in any patient with this phenotype.

Adipokines, bone-derived factors and bone turnover in obese children; evidence for altered fat-bone signalling resulting in reduced bone mass.

UNLABELLED: Obese children, particularly those who have fractured, have reduced body size-adjusted total body and regional bone mass. We performed an observational cross-sectional cohort study to determine the relationship between adipokines (leptin and adiponectin), bone-derived cytokines and bone turnover in children which may explain this observation. Participants aged 5-16 years were recruited into obese (BMI SDS 3.3±0.6) and lean (BMI SDS 0.2±1.0) groups and further subdivided into groups by fracture history. Free leptin (leptin/leptin soluble receptor) and adiponectin; RANK-ligand (RANKL), osteoprotegerin (OPG); Dickkopf-1 (DKK1); and the bone turnover markers procollagen type I amino propeptide (P1NP) and carboxy-terminal telopeptide of type I collagen (CTx). Total body and truncal fat mass were measured by DXA. RESULTS: Free leptin (p>0.0001) and adiponectin (p=0.0002) were higher and lower in obese children respectively. OPG was lower in obese children (p=0.01), being inversely related to free leptin (p=0.009), total body and truncal fat mass (both p=0.01). RANKL was inversely related to free leptin in children with prior fracture (p=0.03). CTx was higher in obese children (p=0.003). Free leptin was positively associated with both CTx (p=0.03) and P1NP (p=0.02). DKK1 was inversely related to adiponectin (p=0.02). CONCLUSION: Bone formation relative to resorption was reduced in obese children; this difference was accentuated in those with prior fracture. Adipokines may regulate these changes. Osteoprotegerin may play a fundamental role in the failure of obese children to accrue bone mass appropriately.

Reliability of the low dose synacthen test in children undergoing pituitary function testing.

BACKGROUND: There are few data in the paediatric literature on the normal cortisol response to stimulation during the low dose synacthen test (LDST) (1 microg). AIM: To examine the cortisol responses in children, subsequently presumed to be normal, who had an LDST during anterior pituitary function tests (APFTs). METHODS: A retrospective review of results in children with short stature and normal growth hormone levels. RESULTS: Of 33 children tested, seven had suboptimal cortisol responses based on accepted criteria (peak <500 nmol/l)--a false positive rate of 21%. Only three of these children had a repeat LDST, which was normal in all cases. The peak cortisol response (median 633, range, 417-1052 nmol/l) was inversely correlated with age (r = -0.44, p < 0.05). CONCLUSION: One in five tests did not meet normal criteria. This false positive rate (21%) should be borne in mind when interpreting synacthen tests to prevent overdiagnosis of adrenal insufficiency.

Adrenal insufficiency in phytosterolaemia.

BACKGROUND: Phytosterolaemia (sitosterolaemia) is a rare autosomal recessive condition caused by mutations on the ABCG5 and ABCG8 gut transporter proteins. This leads to accumulation of plant-derived cholesterol-like molecules in blood and tissues. CASE: We describe a family of Bangladesh origin, where three siblings (two males and one female) have homozygous mutations for phytosterolaemia, and exhibit short stature and adrenal failure with the female having ovarian failure. FINDINGS: The index case (18-year-old female) and her sibling (16 years) have adrenal insufficiency with hyperpigmentation and raised levels of ACTH, at 367 and 690 ng/l respectively. The youngest child at 7 years has normal adrenal function. In addition, the index case has ovarian failure and sibling 2 has partial growth hormone deficiency. CONCLUSION: Although short stature is a recognised phenomenon, no previous association has been made between phytosterolaemia and other endocrine abnormalities. We postulate that the elevated plant sterol levels in phytosterolaemia may interfere with endocrine hormone synthesis; in particular, we present evidence that adrenal cholesterol metabolism may be preferentially affected, accounting for the adrenal insufficiency.

Growth and the premature baby.

There is considerable evidence to show that babies born prematurely have poor postnatal growth, and the more premature the baby, the greater the impairment is likely to be and the longer it will persist. Nutrition has been shown to play an important part in this, but adequate nutrition is difficult, if not impossible, to achieve in these infants. In the most immature infants, growth retardation may continue for many months and catch-up may be delayed and incomplete. Evidence from long-term studies suggests that preterm infants will be shorter and lighter than term controls and that reduced stature and head size may be linked with lower intelligence. Although there is evidence linking better growth to better neurodevelopmental outcome, with reports suggesting that this can be achieved with dietary manipulation, there are also data that suggest that there could be a link between increased postnatal growth and increased morbidity and mortality in later childhood and adult life. Here, we provide an overview of current understanding of growth impairment in infants born prematurely and the effects in later life.

Stomatocytic haemolysis and macrothrombocytopenia (Mediterranean stomatocytosis/macrothrombocytopenia) is the haematological presentation of phytosterolaemia.

Phytosterolaemia (sitosterolaemia) is a recessively inherited metabolic condition in which the absorption of both cholesterol and plant-derived cholesterol-like molecules at the gut is unselective and unrestricted. In haematology, Mediterranean stomatocytosis or Mediterranean macrothrombocytopenia is a poorly understood haematological condition that combines stomatocytic haemolysis with the presence of very large platelets. Five pedigrees showing this haematology were identified. Gas chromatography mass spectrometry (GC-MS) showed that all of the patients with this highly specific haematology had grossly elevated levels of phytosterols in the blood, diagnostic of phytosterolaemia. All showed mutations in the ABCG5 and ABCG8 previously linked to phytosterolaemia. Three pedigrees showed five new mutations, while two pedigrees showed the common W361X mutation in ABCG8. We draw the following four conclusions: (i) that Mediterranean stomatocytosis/macrothrombocytopenia is caused by an excess of phytosterols in the blood; (ii) that phytosterolaemia, which does not respond to standard statin treatment, can be diagnosed via the distinctive haematology described here, even when the cholesterol is normal; (iii) that phytosterolaemia should be considered in the differential diagnosis of all patients with large platelets; and (iv) that the platelet size should be noted in patients with hypercholesterolaemia.

An unusal case of hermaphroditism--a 46,XX/69,XXY chimera.

A diploid/triploid karyotype is an uncommon but important cause of true hermaphroditism and ambiguous genitalia. Individuals have a recognisable phenotype and characteristic hydatidiform placental changes. We report a 46,XX/69,XXY chimeric hermaphrodite. This case highlights the typical features (large placenta, intrauterine growth retardation, asymmetric growth, cranio-facial anomalies, syndactyly and pigmentary dysplasia). It illustrates the importance of obtaining skin and gonadal karyotypes in the case of genital ambiguity, as the venous lymphocytic karyotype is usually diploid.

IGF-I and IGF-binding protein-3 measurements on filter paper blood spots in children and adolescents on GH treatment: use in monitoring and as markers of growth performance.

BACKGROUND/AIM: In childhood an appropriate response to GH treatment is achieved by titration of growth response against dose administered, with careful observation for side-effects. In order to evaluate the potential use of IGF monitoring in children treated with GH, a cross-sectional study has been carried in 215 children and adolescents (134 with GH deficiency (GHD), 54 with Turner syndrome (TS) and 27 with non-GHD growth disorders) treated with GH for 0.2-13.7 years. METHODS: IGF-I and IGF-binding protein-3 (IGFBP-3) were measured in ELISAs, using dried capillary blood collected onto filter papers. Results were expressed as the mean S.D. range (SDS). Values of either analyte < -2 or > +2 SDS were considered abnormal. RESULTS: IGF-I and IGFBP-3 SDS were higher in the TS and non-GHD groups (mean +0.01 and +0.1 respectively) than in those with GHD (mean value -0.6). Nineteen per cent of the IGF-I values (13% low, 6% high) and 12% of IGFBP-3 values were abnormal (10% low, 2% high). Abnormalities, either low or high, were most common in the GHD group. There was a weak but significant relationship between change in height SDS over the Year up to the time of sampling in the whole group and IGF-I SDS. Satisfactory growth performance (+0.5>change in height SDS> -0.5) was found in those with high (7.2%), normal (60%) and low (9.3%) IGF-I levels. Overall, it was estimated that 26% of the tests would indicate that an adjustment to GH dose (up in 18% and down in 8%) could be considered. CONCLUSIONS: From this cross-sectional study of IGF monitoring across a broad range of diagnoses and ages, it can be concluded that the majority of children on GH have normal levels of IGF-I and IGFBP-3, but 26% of tests could suggest that a change of GH dose should be considered. Regular monitoring of IGF-I and IGFBP-3 should be considered in any child on GH treatment.

The incidence of hypoglycaemia in children with type 1 diabetes and treated asthma.

AIMS: To investigate whether treatment of coexisting asthma has any effect on the incidence of hypoglycaemia and on glycaemic control in children with type 1 diabetes. METHODS: An observational study of children attending the paediatric diabetes clinics of five hospitals in the North Trent Region. Information on the frequency of hypoglycaemia in the preceding three months, treatment for asthma, and the individual's latest HbA1c, was recorded when they attended for review. RESULTS: Data were collected on 226 children, of whom 27 (12%) had treated asthma. Only 11/27 children with asthma were taking their prescribed inhaled steroids. All used beta agonists at least once a week. There was a reduction of 20% in the incidence of hypoglycaemia in the diabetic children with treated asthma. Of the children with diabetes and treated asthma, 52% reported an episode of hypoglycaemia in the previous three months compared to 72% of those with only diabetes. There was no difference in the proportion of children experiencing nocturnal or severe hypoglycaemia. Although not significant, those with asthma and diabetes also had better overall control (HbA1c 8.8%) compared to those with diabetes alone (HbA1c 9.3%). CONCLUSIONS: Diabetic children with treated asthma have significantly fewer episodes of hypoglycaemia and better glycaemic control compared to children with diabetes alone. This observation needs further investigation but raises an interesting question. Do the drugs used to treat asthma, in particular beta agonists, have the therapeutic potential to reduce hypoglycaemia and facilitate an improvement in glycaemic control?

Serum leptin and leptin binding activity in children and adolescents with hypothalamic dysfunction.

Marked disturbance in eating behaviour and obesity are common sequelae of hypothalamic damage. To investigate whether these were associated with dysfunctional leptin central feedback, we evaluated serum leptin and leptin binding activity in 37 patients (age 3.5-21 yr) with tumour or trauma involving the hypothalamic-pituitary axis compared with 138 healthy children (age 5.0-18.2 yr). Patients were subdivided by BMI <2 SDS or > or = 2 SDS and healthy children and children with simple obesity of comparable age and pubertal status served as controls. Patients had higher BMI (mean 1.9 vs 0.2 SDS; p <0.001), a greater proportion had BMI > or = 2 SDS (54% vs 8%; p <0.001) and higher serum leptin (mean 2.1 vs 0.04 SDS; p <0.001) than healthy children. Serum leptin (mean 1.1 vs -0.1 SDS; p = 0.004) and values adjusted for BMI (median 0.42 vs 0.23 microg/l:kg/m2; p = 0.02) were higher in patients with BMI <2 SDS. However, serum leptin adjusted for BMI was similar in patients with BMI > or = 2 SDS compared to corresponding controls (1.08 vs 0.95; p = 0.6). Log serum leptin correlated with BMI SDS in all subject groups but the relationship in patients with BMI <2 SDS was of higher magnitude (r = 0.65, slope = 0.29, p =0.05 for difference between slopes) than in healthy controls (r = 0.42, slope = 0.19). Serum leptin binding activity (median 7.5 vs 9.3%; p = 0.02) and values adjusted for BMI (median 0.28 vs 0.48 % x m2/kg; p <0.001) were lower in patients than in healthy children. The markedly elevated leptin levels with increasing BMI in non-obese patients with hypothalamic-pituitary damage are suggestive of an unrestrained pattern of leptin secretion. This along with low leptin binding activity and hence higher free leptin levels would be consistent with central leptin insensitivity.

Proton magnetic resonance spectroscopy of brain lesions in children with neurofibromatosis type 1.

Two of the recognized cranial MRI findings in children with neurofibromatosis type 1 (NF1) are neurofibromatosis bright objects (NBO) and brain glioma. Their differential diagnosis can be problematic. This study aimed to determine the features of these abnormalities on short echo-time in-vivo proton magnetic resonance spectroscopy. Twenty children under the age of 16 with NF1 were studied. A single voxel, short echo-time technique (TE = 20 ms; TR = 5000 ms) was used to obtain proton spectra of typical NBO and any regions suggestive of atypical bright objects or tumor. Nine children without neurofibromatosis with no structural brain abnormality acted as aged-matched comparisons. A semi-quantitative analysis indicated significant increase in choline and myo-inisitol in tumors compared to typical NBO (p < 0.05) and compared to controls (p < 0.05); reduction in the levels of N-acetyl moieties in NBO compared to controls (p < 0.05); reduction in N-acetyl in tumors compared to controls (p < 0.001); and reduction in glutamate/glutamine in tumors compared to controls (p < 0.05). This cross-sectional data suggests that proton spectroscopy can aid differentiating between NBO and brain (non-optic/hypothalamic) glioma. Typical NBO have different short echo-time spectroscopic appearances compared to normal brain.