Obesity in children with congenital adrenal hyperplasia in the Minnesota cohort: importance of adjusting body mass index for height-age.

OBJECTIVES: To evaluate obesity and overweight in children with congenital adrenal hyperplasia (CAH) and associations with glucocorticoids, fludrocortisone and disease control. Adjusting body mass index-for-height-age (BMIHA ) percentile is proposed to correct misclassification of obese/overweight status in CAH children with advanced bone age and tall-for-age stature. DESIGN: Longitudinal. PATIENTS: One hundred and ninety-four children with CAH seen from 1970 to 2013: 124 salt wasting (SW); 70 simple virilizing (SV); 102 females. MEASUREMENTS: Body mass index (BMI) end-points were overweight (85-94 percentile) and obese (≥95 percentile). RESULTS: Approximately 50% of the children had at least one BMI measurement ≥95 percentile and about 70% had at least one ≥85 percentile. Using BMIHA percentiles, obesity incidence decreased slightly in SW children (47-43%) and markedly in SV children (50-33%); however, overweight status was not reduced. Only 6% of SW and 1% of SV children were persistently obese (≥3 clinic visits) when BMIHA was applied, whereas overweight status persisted in 35% of SW and 33% of SV children. Most obesity or overweight when using BMIHA occurred before age 10 and there was no association with hydrocortisone (HC) or fludrocortisone dosing. Adiposity rebound for SW children occurred by 3·3 years and in SV females by age 3·8 years, over a year earlier than the adiposity rebound for healthy children. CONCLUSION: Children with CAH are at higher risk for early onset obesity and overweight with or without using BMIHA but rates of persistent obesity were lower than previously reported. Careful HC dosing during early childhood is needed to prevent increased weight gain and an early adiposity rebound.

Home Use of an Artificial Beta Cell in Type 1 Diabetes.

BACKGROUND: The feasibility, safety, and efficacy of prolonged use of an artificial beta cell (closed-loop insulin-delivery system) in the home setting have not been established. METHODS: In two multicenter, crossover, randomized, controlled studies conducted under free-living home conditions, we compared closed-loop insulin delivery with sensor-augmented pump therapy in 58 patients with type 1 diabetes. The closed-loop system was used day and night by 33 adults and overnight by 25 children and adolescents. Participants used the closed-loop system for a 12-week period and sensor-augmented pump therapy (control) for a similar period. The primary end point was the proportion of time that the glucose level was between 70 mg and 180 mg per deciliter for adults and between 70 mg and 145 mg per deciliter for children and adolescents. RESULTS: Among adults, the proportion of time that the glucose level was in the target range was 11.0 percentage points (95% confidence interval [CI], 8.1 to 13.8) greater with the use of the closed-loop system day and night than with control therapy (P<0.001). The mean glucose level was lower during the closed-loop phase than during the control phase (difference, -11 mg per deciliter; 95% CI, -17 to -6; P<0.001), as were the area under the curve for the period when the glucose level was less than 63 mg per deciliter (39% lower; 95% CI, 24 to 51; P<0.001) and the mean glycated hemoglobin level (difference, -0.3%; 95% CI, -0.5 to -0.1; P=0.002). Among children and adolescents, the proportion of time with the nighttime glucose level in the target range was higher during the closed-loop phase than during the control phase (by 24.7 percentage points; 95% CI, 20.6 to 28.7; P<0.001), and the mean nighttime glucose level was lower (difference, -29 mg per deciliter; 95% CI, -39 to -20; P<0.001). The area under the curve for the period in which the day-and-night glucose levels were less than 63 mg per deciliter was lower by 42% (95% CI, 4 to 65; P=0.03). Three severe hypoglycemic episodes occurred during the closed-loop phase when the closed-loop system was not in use. CONCLUSIONS: Among patients with type 1 diabetes, 12-week use of a closed-loop system, as compared with sensor-augmented pump therapy, improved glucose control, reduced hypoglycemia, and, in adults, resulted in a lower glycated hemoglobin level. (Funded by the JDRF and others; AP@home04 and APCam08 ClinicalTrials.gov numbers, NCT01961622 and NCT01778348.).

Growth and hormone profiling in children with congenital melanocytic naevi.

BACKGROUND: Multiple congenital melanocytic naevi (CMN) is a rare mosaic RASopathy, caused by postzygotic activating mutations in NRAS. Growth and hormonal disturbances are described in germline RASopathies, but growth and hormone status have not previously been investigated in individuals with CMN. OBJECTIVES: To explore premature thelarche, undescended testes, and a clinically abnormal fat distribution with CMN through prospective endocrinological assessment of a cohort of subjects with CMN, and a retrospective review of longitudinal growth of a larger group of patients with CMN from outpatient clinics (which included all subjects in the endocrinological assessment group). PATIENTS AND METHODS: Longitudinal growth in a cohort of 202 patients with single or multiple CMN was compared with the U.K. National Child Measurement Programme 2010. Forty-seven children had hormonal profiling including measurement of circulating luteinizing hormone, follicle-stimulating hormone, thyroid stimulating hormone, adrenocorticotrophic hormone, growth hormone, prolactin, pro-opiomelanocortin, estradiol, testosterone, cortisol, thyroxine, insulin-like growth factor-1 and leptin; 10 had oral glucose tolerance testing 25 had dual-energy X-ray absorptiometry scans for body composition. RESULTS: Body mass index increased markedly with age (coefficient 0·119, SE 0·016 standard deviation scores per year), at twice the rate of the U.K. population, due to increased adiposity. Three per cent of girls had premature thelarche variant and 6% of boys had persistent undescended testes. Both fat and muscle mass were reduced in areas underlying large naevi, resulting in limb asymmetry and abnormal truncal fat distribution. Anterior pituitary hormone profiling revealed subtle and variable abnormalities. Oral glucose tolerance tests revealed moderate-severe insulin insensitivity in five of 10, and impaired glucose tolerance in one. CONCLUSIONS: Interpersonal variation may reflect the mosaic nature of this disease and patients should be considered individually. Postnatal weight gain is potentially related to the underlying genetic defect; however, environmental reasons cannot be excluded. Naevus-related reduction of fat and muscle mass suggests local hormonal or metabolic effects on development or growth of adjacent tissues, or mosaic involvement of these tissues at the genetic level. Premature thelarche and undescended testes should be looked for, and investigated, as for any child.

The relationship between Insulin-like Growth Factor 1, sex steroids and timing of the pubertal growth spurt.

OBJECTIVE: Progress through puberty involves a complex hormonal cascade, but the individual contributions of hormones, particularly IGF-1, are unknown. We reanalysed Chard growth study data to explore the tempo of puberty based on changes in both height and hormone levels, using a novel method of growth curve analysis. DESIGN AND SUBJECTS: Schoolboys (n = 54) and girls (n = 70) from Chard, Somerset, England, recruited in 1981 at age 8/9 and followed to age 16. MEASUREMENTS: Every 6 months, height and Tanner stages (genitalia, breast, pubic hair) were recorded, and in a subsample (24 boys, 27 girls), blood samples were taken. Serum IGF-1, testosterone (boys) and oestradiol (girls) were measured by radioimmunoassay. Individual growth curves for each outcome were analysed using variants of the super-imposition by translation and rotation (SITAR) method, which estimates a mean curve and subject-specific random effects corresponding to size, and age and magnitude of peak velocity. RESULTS: The SITAR models fitted the data well, explaining 99%, 65%, 86% and 47% of variance for height, IGF-1, testosterone and oestradiol, respectively, and 69-88% for the Tanner stages. During puberty, the variables all increased steeply in value in individuals, the ages at peak velocity for the different variables being highly correlated, particularly for IGF-1 vs height (r = 0·74 for girls, 0·92 for boys). CONCLUSIONS: IGF-1, like height, the sex steroids and Tanner stages, rises steeply in individuals during puberty, with the timings of the rises tightly synchronized within individuals. This suggests that IGF-1 may play an important role in determining the timing of puberty.

Surgical treatment of children with hyperparathyroidism: single centre experience.

BACKGROUND: Hyperparathyroidism (HPT) in children is rare and surgical management is supported only by limited evidence. METHODS: Retrospective case series of all children under the age of 16 years who underwent parathyroidectomy (PTx) between 1978 and 2012. RESULTS: We identified 29 children who had surgery for HPT. Six were neonates with neonatal severe hyperparathyroidism (NSHPT) and 23 older children (age range 7-16 years) with sporadic (16) or familial (7) HPT and 93% were symptomatic. Accuracy of ultrasound and MIbi in localising solitary parathyroid adenomas was 96%, but less helpful in hyperplasia and neonates. Children with NSHPT underwent 5 curative total and 1 subtotal PTx (no reoperations). Children with familial HPT underwent 3 total and 4 subtotal PTx. One child with subtotal PTx required a reoperation. Children with sporadic HPT underwent subtotal PTx prior to 1980 (2), exploration and removal of enlarged glands 1980-2002 (5) and minimally invasive PTx since 2002 (9) and all cured by the first operation. CONCLUSIONS: Our study documents that HPT in children is predominantly symptomatic on presentation and genetically determined in 46% of cases. Imaging is accurate in localising parathyroid adenomas, but not hyperplasias. Total PTx for familial HPT was curative and minimally invasive PTx is the operation of choice for older children with sporadic HPT.

Paediatric estimated average glucose in children with Type 1 diabetes.

AIM: Estimated average glucose has been used to transform HbA1c into a glucose measure that might better inform patients of their glycaemic control. The data set used to obtain the estimated average glucose equation was derived in adults with Type 1 and Type 2 diabetes, along with normal healthy control subjects, and requires testing in children. METHODS: This was a cross-sectional study of 234 children and young people (106 male) with Type 1 diabetes aged 4.0-23.5 years who underwent continuous glucose monitoring over a 5-day period along with a measure of HbA1c . Regression analysis was used to determine estimated average glucose and agreement was assessed with the average glucose estimated from the Nathan equation: Nathan average glucose equation = 1.59 (HbA1c% ) - 2.59. RESULTS: Mean HbA1c was 76 mmol/mol (25.1) [9.1 (2.3)%] and mean continuous glucose monitoring tissue glucose was 10.4 (2.6) mmol/l. The relationship between continuous glucose monitoring tissue glucose and HbA1c was described by the paediatric equation: paediatric estimated average glucose = 0.49 (HbA1c %) + 5.95 (r = 0.45; P < 0.001). The mean paediatric estimated average glucose was 10.4 (1.1) mmol/l compared with that from the Nathan average glucose equation of 11.9 (3.7) mmol/l (P < 0.001). Overall, the paediatric estimated average glucose was 2.7 mmol/l lower than the Nathan estimated average glucose, with a 95% limit of agreement of ± 0.5 mmol/l. The agreement was very close with HbA1c values below 80 mmol/mol (9.5%). CONCLUSION: These data suggest that the Nathan estimated average glucose could be used in children and young people with Type 1 diabetes. Caution should still be exercised in the estimates derived for average glucose as the data set is skewed in both Nathan and paediatric average glucose estimates in opposite directions because of the differences in average HbA1c .

Deprivation and ethnicity impact on diabetes control and use of treatment regimen.

AIMS: Deprivation and/or ethnicity impact on care delivery. We have assessed how these factors influence diabetes care in a paediatric clinic. METHODS: We related access to care [type of insulin treatment regimen-twice daily, multiple daily injections and insulin pump therapy (continuous subcutaneous insulin infusion)], measures of care process (HbA(1c)) and an approximate measure of satisfaction with the service (clinic attendance rate) in 325 (170 male) children and young people with Type 1 diabetes (mean age 10.6 years, mean duration of diabetes of 4.5 years), with indices of deprivation and ethnicity. RESULTS: Of the 325 children and young people, 2.7% received twice-daily insulin, 48.4% multiple daily injections and 48.9% continuous subcutaneous insulin infusion. Median clinic HbA(1c) was 62 mmol/mol (7.8%) and those receiving the insulin pump therapy had the lowest HbA(1c). Four ethnic groups were represented; White British 81.6%, Asian non-Indian 6.5%, African 8.1% and Asian Indian 3.8%. Mean deprivation score was 21.06. White British and Asian Indian groups were more likely to receive insulin pump therapy (χ(2) = 50.3; P < 0.001). Attendance rates were 94.1% and did not differ across ethnic groups. Deprivation was related to ethnicity and HbA(1c) (R(2) = 0.02; P = 0.02). There was no relationship between clinic attendance and deprivation. Insulin regimen and ethnicity were associated with HbA(1c) (R(2) = 0.096; P < 0.001). Similar findings were obtained when analysis was confined to the White British population. CONCLUSIONS: These data suggest that deprivation and ethnicity influence diabetes control and how intensive insulin therapy is utilized. A better consideration of the needs of different ethnic groups is required to ensure equitable care delivery in paediatric diabetes.

The relationship between body mass index and mid-arm circumference in a pregnant population.

Our objective was to correlate body mass index (BMI) with mid-arm circumference (MAC) and also to ascertain whether maternal BMI could be calculated from MAC at booking. We approached all Caucasian women who met the inclusion criteria attending the University College Hospital, London between 1 April 1996 and 30 June 1997 and the Rotunda Hospital, Dublin, Ireland between 15 April 2003 and 19 May 2004. A total of 2,912 women agreed to participate in the research. The participants' maternal height and weight were measured. Their BMI was calculated using the formula: BMI = weight (kg) ÷ height (m(2)). The MAC was measured in cm. Statistical analysis was performed using SPSS for Windows version 11 with p < 0.05 as significant. We found that BMI is directly correlated with MAC (r = 0.836) and estimates of BMI may be calculated from the simple equation BMI = MAC ± 2. Alternatively, a MAC of ≥ 27 cm allowed for a detection rate for overweight patients of 75%, with a false positive rate of 15%.

Does plasma IGF-BP3 measurement contribute to the diagnosis of growth hormone deficiency in children?

OBJECTIVE: To audit the contribution of plasma IGF-PB3 measurement to the diagnosis of growth hormone deficiency (GHD) in children. POPULATION AND METHODS: Retrospective case study including boys and girls aged 0 to 18 years who attended our paediatric endocrinology clinic for short stature and/or post-irradiation follow-up, and had at least one GH provocative testing. Children with hypothyroidism, Laron or Kowarski syndromes, severe malnutrition, chronic renal failure and liver failure were excluded. RESULTS: Fifty-eight children were enrolled and grouped as GHD [+] (19 cases) and GDH [-] (39 cases). IGF-I and IGF-BP3 assay was carried out in 88% and 62% cases respectively, both groups were comparable for age, sex, BMI, target height, pubertal stage and bone age. There was a significant difference in peak GH between GDH [-] and GHD [+] groups (41.8 mUI/L ± 21.7 versus 11.5 ± 5.9 mUI/L, P<0.00001, respectively). No difference was found between groups with regards to IGF-I Z-scores and IGF-BP3 Z-scores. There was, however, a positive correlation between IGF-I Z-scores and IGF-BP3 Z-scores (r=0.50; P<0.0016). IGF-BP3 measurement could not differentiate between GHD [+] and GHD [-] groups. CONCLUSIONS: Measurement of plasma IGF-BP3 level contributes poorly to the diagnosis of GHD. We do not recommend it in routine use.

Use of intravenous etomidate to control acute psychosis induced by the hypercortisolaemia in severe paediatric Cushing's disease.

BACKGROUND: Psychosis secondary to paediatric Cushing's disease (CD) is extremely rare and presents a significant management challenge. METHOD: We report a 14.7-year-old CD patient with acute psychosis and self-inflicted injuries following failed transsphenoidal pituitary surgery. Her mental state rapidly deteriorated precluding medical therapy. RESULTS: Emergency intravenous low-dose etomidate infusion (3-3.5 mg/h) with dose titration according to the serum cortisol combined with a hydrocortisone infusion, in an intensive care setting, was effective in controlling the hypercortisolaemia. Her mental state improved with normalisation of her cortisol levels enabling oral administration of ketoconazole and bilateral adrenalectomy to be performed. CONCLUSION: This case illustrates the safe and effective use of a low-dose etomidate infusion in an unusual case of paediatric CD.

Founder effect in the Horn of Africa for an insulin receptor mutation that may impair receptor recycling.

AIMS/HYPOTHESIS: Genetic insulin receptoropathies are a rare cause of severe insulin resistance. We identified the Ile119Met missense mutation in the insulin receptor INSR gene, previously reported in a Yemeni kindred, in four unrelated patients with Somali ancestry. We aimed to investigate a possible genetic founder effect, and to study the mechanism of loss of function of the mutant receptor. METHODS: Biochemical profiling and DNA haplotype analysis of affected patients were performed. Insulin receptor expression in lymphoblastoid cells from a homozygous p.Ile119Met INSR patient, and in cells heterologously expressing the mutant receptor, was examined. Insulin binding, insulin-stimulated receptor autophosphorylation, and cooperativity and pH dependency of insulin dissociation were also assessed. RESULTS: All patients had biochemical profiles pathognomonic of insulin receptoropathy, while haplotype analysis revealed the putative shared region around the INSR mutant to be no larger than 28 kb. An increased insulin proreceptor to ß subunit ratio was seen in patient-derived cells. Steady state insulin binding and insulin-stimulated autophosphorylation of the mutant receptor was normal; however it exhibited decreased insulin dissociation rates with preserved cooperativity, a difference accentuated at low pH. CONCLUSIONS/INTERPRETATION: The p.Ile119Met INSR appears to have arisen around the Horn of Africa, and should be sought first in severely insulin resistant patients with ancestry from this region. Despite collectively compelling genetic, clinical and biochemical evidence for its pathogenicity, loss of function in conventional in vitro assays is subtle, suggesting mildly impaired receptor recycling only.

Do centimetres matter? Self-reported versus estimated height measurements in parents.

AIM: An impressive discrepancy between reported and measured parental height is often observed. The aims of this study were: (a) to assess whether there is a significant difference between the reported and measured parental height; (b) to focus on the reported and, thereafter, measured height of the partner; (c) to analyse its impact on the calculated target height range. METHODS/RESULTS: A total of 1542 individual parents were enrolled. The parents were subdivided into three groups: normal height (3-97th Centile), short (<3%) and tall (>97%) stature. Overall, compared with men, women were far better in estimating their own height (p < 0.001). Where both partners were of normal, short or tall stature, the estimated heights of their partner were quite accurate. Women of normal stature underestimated the short partner and overestimated the tall partner, whereas male partners of normal stature overestimated both their short as well as tall partners. Women of tall stature estimated the heights of their short partners correctly, whereas heights of normal statured men were underestimated. On the other hand, tall men overestimated the heights of their female partners who are of normal and short stature. Furthermore, women of short stature estimated the partners of normal stature adequately, and the heights of their tall partners were overestimated. Interestingly, the short men significantly underestimated the normal, but overestimated tall female partners. CONCLUSION: Only measured heights should be used to perform accurate evaluations of height, particularly when diagnostic tests or treatment interventions are contemplated. For clinical trails, we suggest that only quality measured parental heights are acceptable, as the errors incurred in estimates may enhance/conceal true treatment effects.

Glycaemic risk assessment in children and young people with Type 1 diabetes mellitus.

AIM: To ascertain if those with diabetes (and their carers) ascribe a similar level of risk to blood glucose control as healthcare professionals. METHODS: We used a structured questionnaire to ask fifty healthcare professionals how 'dangerous' a given blood glucose value was. Their answers were modelled to produce an algorithm of assessed risk. To examine if patients (and their carers) would apportion a similar level of risk to that of healthcare professionals, the same questionnaire was issued to fifty children and adolescents with Type 1 diabetes. For patients under 8 years old the carers completed the questionnaires (n = 23). Both patient and carers together completed the questionnaire for those aged 8-11 years (n = 15) and patients over the age of 11 years completed the questionnaire themselves (n = 12). The median results and interquartile range of the assessed level of risk, as determined by the two groups, were compared using a generalized linear model. RESULTS: A significant difference (P < 0.0001) was identified between the median risk assessments of the two groups. The zero level of assessed risk was upward shifted in the patient group by 0.8 mmol/l and indicated the patients' view of risk increased. CONCLUSIONS: Patients with Type 1 diabetes (and their carers) evaluate the risk from blood glucose values differently from healthcare professionals. The euglycaemic state (zero ascribed risk) that patients chose was 0.8 mmol/l greater than that of healthcare professionals, indicating, perhaps, hypoglycaemia avoidance, a more pragmatic approach or less exposure to current trends in glycaemic control.

High prevalence of Mycobacterium tuberculosis infection and disease in children and adolescents with type 1 diabetes mellitus.

SETTING: Western Cape Province, South Africa. OBJECTIVES: To describe the prevalence of tuberculosis (TB) infection and disease in children with type 1 diabetes and to investigate the association between glycaemic control and prevalence of TB infection and disease. DESIGN: Cross-sectional hospital-based study conducted at two public referral hospitals. All children and adolescents (aged <21 years) with type 1 diabetes underwent a Mantoux tuberculin skin test (>or=10 mm classified as Mycobacterium tuberculosis infection), measurement of glycosylated haemoglobin and a chest radiograph. Patients with symptoms suggestive of TB were investigated using mycobacterial culture. Radiologically and/or bacteriologically confirmed disease was classified as TB disease. RESULTS: Of 291 eligible patients, 258 (88.7%) were included (58% female). The prevalence of M. tuberculosis infection was 29.8% (95%CI 24.2-35.4); nine patients were diagnosed with prevalent TB disease (point prevalence disease 3488 per 100,000 population). Poor glycaemic control (hazard ratio 1.39, 95%CI 1.18-1.63 per unit increase in glycated haemoglobin [HbA1c]) and contact with a TB source case (P = 0.0011) was associated with prevalent TB disease. CONCLUSIONS: There is a high prevalence of TB disease in diabetic children and adolescents in this setting. Routine TB screening of children with type 1 diabetes may be indicated in settings highly endemic for TB. Preventive treatment should be considered for diabetic children with proof of TB exposure and/or infection.

Establishing glycaemic control with continuous subcutaneous insulin infusion in children and adolescents with type 1 diabetes: experience of the PedPump Study in 17 countries.

AIMS/HYPOTHESIS: To assess the use of paediatric continuous subcutaneous infusion (CSII) under real-life conditions by analysing data recorded for up to 90 days and relating them to outcome. METHODS: Pump programming data from patients aged 0-18 years treated with CSII in 30 centres from 16 European countries and Israel were recorded during routine clinical visits. HbA(1c) was measured centrally. RESULTS: A total of 1,041 patients (age: 11.8 +/- 4.2 years; diabetes duration: 6.0 +/- 3.6 years; average CSII duration: 2.0 +/- 1.3 years; HbA(1c): 8.0 +/- 1.3% [means +/- SD]) participated. Glycaemic control was better in preschool (n = 142; 7.5 +/- 0.9%) and pre-adolescent (6-11 years, n = 321; 7.7 +/- 1.0%) children than in adolescent patients (12-18 years, n = 578; 8.3 +/- 1.4%). There was a significant negative correlation between HbA(1c) and daily bolus number, but not between HbA(1c) and total daily insulin dose. The use of <6.7 daily boluses was a significant predictor of an HbA(1c) level >7.5%. The incidence of severe hypoglycaemia and ketoacidosis was 6.63 and 6.26 events per 100 patient-years, respectively. CONCLUSIONS/INTERPRETATION: This large paediatric survey of CSII shows that glycaemic targets can be frequently achieved, particularly in young children, and the incidence of acute complications is low. Adequate substitution of basal and prandial insulin is associated with a better HbA(1c).

A randomised study of two doses of biosynthetic human growth hormone on final height of pubertal children with growth hormone deficiency.

AIMS: To determine the effectiveness of different doses of r-hGH therapy during puberty in children with growth hormone deficiency (GHD). METHODS: Randomized controlled trial of different doses of r-hGH therapy administered during puberty in 49 children with GHD. The patients were allocated randomly using a random number table to one of two groups: group 1 (15 IU/m(2)/week) or group 2 (30 IU/m(2)/week). Patients were included if they had received r-hGH daily at a dose of 15 IU/m(2)/week (0.7 mg/m(2)/day) for at least 1 year before randomization. RESULTS: Height increase standard deviation scores (SDS) were similar between the two groups (group 1: 1.1; group 2: 1.2; p = 0.81). CONCLUSION: A higher dose of r-hGH administered during puberty does not appear to have a significant effect on final height of children with GH deficiency. Altering pubertal tempo or intensifying prepubertal r-hGH therapy may be a more promising approach to improving final height in children with GH deficiency.

A randomised study of the effect of two doses of biosynthetic human growth hormone on final height of children with familial short stature.

BACKGROUND/AIMS: The effects of biosynthetic human growth hormone (r-hGH) in children with familial short stature (FSS) are varied. We determined whether responsivity to r-hGH in FSS is dose-dependent. METHOD: Randomised trial of two doses (20 or 40 IU/m(2) body surface area/week by daily subcutaneous injection) of r-hGH in 29 (24 male, 5 female) FSS children with assessment at adult height. RESULTS: Age range at presentation was 5.1-10.5 years, height less than 1.5 standard deviation scores (SDS) below the mean, height velocity SDS greater than -1.5 and peak growth hormone response to provocative testing over 13.5 mU/l. Adult height data (SDS) at 16.5 +/- 2.1 years for the low-dose group and 16.1 +/- 1.1 years for the high-dose group (p = 0.62) were similar [low dose -1.06 (SD 0.75), high dose -1.02 (SD 0.83); p = 0.88]. The incremental effect of both doses on stature was minimal [low-dose difference in height actual-predicted 0.79 (SD 0.94), high dose 1.27 (SD 0.88); p = 0.12]. CONCLUSION: Using this r-hGH dosing schedule there were little short- or long-term effects on height in children with FSS.

Childhood body mass index (BMI), breastfeeding and risk of Type 1 diabetes: findings from a longitudinal national birth cohort.

AIMS: To perform a longitudinal analysis of the association between childhood body mass index (BMI) and later risk of Type 1 diabetes, controlling for socio-economic status, birthweight, height in early and late childhood, breastfeeding history and pubertal status. METHODS: Analysis of the 1970 British Birth Cohort, followed up at age 5, 10 and 30 years (n = 11,261). Data were available on birthweight, breastfeeding; height, weight, pubertal status, socio-economic status at age 10 years; self-report data on history of diabetes (type, age at onset) at age 30 years. Cox proportional hazards models were used to examine relations of childhood growth, socio-economic status and breastfeeding history to the incidence of Type 1 diabetes between 10 and 30 years of age. RESULTS: Sixty-one subjects (0.5%) reported Type 1 diabetes at 30 years of age; 47 (77%) reported onset >or= age 10 years. Higher BMI z-score at 10 years predicted higher risk of subsequent Type 1 diabetes (hazard ratio 1.8, 95% confidence interval 1.2 to 2.8, P = 0.01) when adjusted for birthweight, pubertal status, breastfeeding history and socio-economic status. Repeating the model for childhood obesity, the hazard ratio was 3.1 (1.0, 9.3; P = 0.05). Birthweight, breastfeeding, height growth and pubertal timing were not associated with incidence of Type 1 diabetes. CONCLUSIONS: Higher BMI in childhood independently increased the risk of later Type 1 diabetes, supporting suggestions that obesity may provide a link between Type 1 and Type 2 diabetes. This supports observations of a rise in Type 1 diabetes prevalence. Reduction in childhood obesity may reduce the incidence of Type 1 as well as Type 2 diabetes.

Plasma aldosterone response to the low-dose adrenocorticotrophin (ACTH 1-24) stimulation test.

BACKGROUND: Endocrine tests for adrenal insufficiency use pharmacological doses of stimulant such as ACTH. More physiological tests have often used high-dose protocols for sampling frequency. AIMS: To evaluate the response of plasma aldosterone concentration to low doses (125, 250 and 500 ng/m(2) body surface area) of synthetic ACTH. DESIGN: A randomised trial in six normal adult males aged 18-27 years. MATERIALS AND METHODS: Aldosterone concentration was measured by radioimmunoassay in serum from blood samples taken at 10 min intervals for 90 min. RESULTS: All three doses produced a significant rise in plasma aldosterone concentration (125 ng/m(2), P = 0.003; 250 ng/m(2), P < 0.001; 500 ng/m(2), P < 0.001) but there was no effect of dose on either the peak or incremental plasma aldosterone concentration. Mean time to peak was similar between the doses and the two higher doses were associated with a longer secretory profile (125 ng/m(2) 56 (26 SD) mins, 250 ng/m(2) 74 (19) mins, 500 ng/m(2) 77 (21) mins; F = 3.39; P = 0.04). Peaks of 100% were detected within 30 min of drug administration and peak response was associated with the prestimulation plasma aldosterone concentration (r = 0.45; P = 0.003). The between- and within-individual coefficients of variation for prestimulation concentrations were 37.0% and 32.8%, and for the peak response were 27.2% and 27.2%, respectively. CONCLUSIONS: The response of plasma aldosterone concentrations to low-dose ACTH administration requires a blood sampling protocol of 0, 10, 20 and 30 min to capture concentrations near the peak response. The high-dose protocol would have missed the response. Over the dose range studied no dose-response was observed so the selection of dose should be based on the dose effective to release steroids in the glucocorticoid pathway if this study is to be used in conjunction with such evaluation.