Longitudinal study of thyroid function in Down's syndrome in the first two decades.

AIMS AND METHODS: Thyroid function tests were initially carried out on 122 children with Down's syndrome aged 6-14 years and then repeated four to six years later in 103 adolescents (85% of the group of 122) when they were aged 10-20 years (median 14.4 years). At the second test two were hypothyroid and two with isolated raised thyroid stimulating hormone (IR-TSH) were receiving thyroxine. RESULTS: At the first test there were 98 (80%) euthyroid children: 83 were retested and four (5%) had IR-TSH. At the first test 24 had IR-TSH: 20 were retested and 14 (70%) had become normal. Seventeen with IR-TSH on initial testing had a thyrotrophin releasing hormone test within three months; TSH had become normal in eight (47%) of these children. There was no association between reported clinical symptoms and IR-TSH, but there were clear symptoms in one of the two with definite hypothyroidism. CONCLUSIONS: The likelihood ratio for a positive result on second testing when raised TSH and positive antibody status on first testing are combined is 20. This suggests initial testing results could be used as a basis to select a subgroup for further testing at say five yearly intervals unless new symptoms emerge in the interim. It also suggests that yearly screening (as recommended by the American Academy of Pediatrics, 2001) is probably not justified in the first 20 years of life.

Does adjustment of GFR to extracellular fluid volume improve the clinical utility of cystatin C?

BACKGROUND: Cystatin C measurement has been proposed as a replacement for creatinine as a serum measure of glomerular filtration rate (GFR). It has also been suggested that GFR itself should be adjusted to the extracellular fluid volume (ECV) of a child rather than the body surface area (BSA). AIMS: To assess the potential of cystatin C compared to serum creatinine in assessing GFR and to establish whether adjustment of GFR to ECV rather than BSA affects the potential usefulness of cystatin C. METHODS: Cystatin C and plasma creatinine were measured in 64 paediatric patients undergoing 77 (51)Cr-EDTA GFR measurements over a six month period. RESULTS: 1/cystatin C concentrations were more closely related to GFR (median 98 ml/min/1.73 m(2), range 8-172) after adjustment for patient BSA (r = 0.81 versus r = 0.44). 1/Creatinine concentrations appeared to be an inferior estimate of BSA adjusted GFR (r = 0.41), even following the use of the Schwartz formula (r = 0.37). Bland Altman statistics showed cystatin C could still only predict 95% of GFR values to within +/-41 ml/min/1.73 m(2) of the (51)Cr-EDTA method. The relation between GFR and 1/cystatin C was not improved by adjusting (51)Cr-EDTA GFR to ECV rather than BSA (r = 0.76 versus r = 0.81). CONCLUSIONS: Cystatin C appears superior to serum creatinine in paediatric subjects although its performance is unlikely to supplant (51)Cr-EDTA GFR measurement. This performance is not being underestimated because of adjusting GFR to BSA rather than ECV.

Prenatal origin of acute lymphoblastic leukaemia in children.

BACKGROUND: There is little current insight into the natural history of childhood leukaemia or the timing of relevant mutational events. TEL-AML1 gene fusion due to chromosomal translocation is frequently seen in the common form of childhood acute lymphoblastic leukaemia. We investigated whether this abnormality arises prenatally. METHODS: We identified, by reverse-transcriptase PCR screening of blood or bone marrow, TEL-AML1 fusion in 12 children, plus a pair of identical twins, aged 2-5 years from Italy and the UK, who had newly diagnosed acute lymphoblastic leukaemia. We amplified and sequenced the genomic TEL-AML1 fusion gene with a long-distance inverse PCR method. Primers were designed that could be used in short-range PCR to screen for patient-specific, leukaemia clone-specific TEL-AML1 genomic fusion sequences in neonatal blood spots from each child. FINDINGS: We initially identified TEL-AML1 fusion sequences in blood spots from the identical twins, diagnosed with concordant acute lymphoblastic leukaemia at age 4 years, who shared a single or clonotypic TEL-AML1 sequence that suggested prenatal origin in one twin. Three children were excluded because control genes could not be amplified. Of the other nine patients, six had positive blood spots. Blood spots that were classified as negative were uninformative. INTERPRETATION: Our findings showed that childhood acute lymphoblastic leukaemia is frequently initiated by a chromosome translocation event in utero. Studies in identical twins show however that such an event is insufficient for clinical leukaemia and that a postnatal promotional event is also required.

Plasma 1,5-anhydroglucitol concentrations are influenced by variations in the renal threshold for glucose.

AIMS: Measurement of serum 1,5-anhydroglucitol (1,5AG) concentrations has been proposed as an alternative to HbA1c as both a marker of diabetic glycaemic control and as a screening test for diabetes. The sugar competes with glucose for renal tubular reabsorption, so hyperglycaemia leads to reduced serum 1,5AG concentrations through increased urinary loss. This study has sought to establish whether plasma 1,5AG can be influenced by not only hyperglycaemia, but by variations in renal threshold for glucose. METHODS: Thirty-eight pregnant women (median age 30 years, range 20-43) found to be normoglycaemic after a 75-g carbohydrate load had plasma 1,5AG and urine glucose measured. RESULTS: Using multivariate analysis, the presence and degree of detectable glycosuria at 2 h post glucose load was strongly predictive of a low plasma 1,5AG concentration (P=0.0012) independently of fasting plasma glucose (P=0.96), 2 h glucose (P=0.029), subject age (P=0.97) and gestation (P=0.36). Thus, when matched for plasma glucose areas under the glucose load curve, 16 glycosuric subjects had significantly lower 1,5AG concentrations compared to 16 nonglycosuric ones (median 1,5AG 46 micromol/l (IQR 30-56) vs. 72 micromol/l (IQR 55-79, P=0.017). CONCLUSIONS: People with the same glucose tolerance may demonstrate variable plasma 1,5AG concentrations depending on their renal threshold for glucose. This inherent characteristic is likely to limit the usefulness of the test when monitoring or screening for diabetes.

Secondary analysis of economic data: a review of cost-benefit studies of neonatal screening for phenylketonuria.

STUDY OBJECTIVE: To estimate the net financial benefit of neonatal screening for phenylketonuria (PKU): by a simple pooling of cost data from the literature; and by a more complex modelling approach. DESIGN: A systematic literature review was conducted to identify papers containing data on the monetary costs and benefits of neonatal screening for PKU. The methodological quality of the studies was appraised, and data were extracted on resource use and expenditure. Monetary data were converted to common currency units, and standardised to UK incidence rates. Net benefits were calculated for median, best case and worst case scenarios, and the effect of excluding poor quality studies and data was tested. The net benefit was also estimated from a model based on data from the literature and assumptions appropriate for the current UK situation. Extensive sensitivity analysis was conducted. MAIN RESULTS: The direct net benefit of screening based on the median costs and benefits from the 13 studies identified was 143,400 Pounds per case detected and treated (39,000 Pounds and 241,800 Pounds for worst case and best case scenarios respectively). The direct net benefit obtained by the modelling approach was lower at 93,400 Pounds per case detected and treated. Screening remained cost saving under sensitivity analysis, except with low residential care costs (less than 12,300 Pounds per annum), or very low incidence rates (less than 1 in 27,000). CONCLUSIONS: The economic literature on PKU screening is of variable quality. The two methods of secondary analysis lead to the same conclusion: that neonatal PKU screening is worthwhile in financial terms alone in the UK, and that it justifies the infrastructure for collecting and testing neonatal blood samples. This result cannot necessarily be extrapolated to other countries.

Linear growth in prepubertal children with atopic dermatitis.

OBJECTIVE: To define the evolution of prepubertal growth in atopic dermatitis and the factors influencing that growth pattern. METHODS: Height and height velocity over two years, weight, triceps and subscapular skin fold thickness, and bone age were assessed in 80 prepubertal patients with atopic dermatitis and a control group of 71 healthy prepubertal school children. RESULTS: Height standard deviation scores (SDS) and height velocity SDS did not differ between patients and controls, and were not influenced by body surface area affected by atopic dermatitis, topical glucocorticoid potency, or coexisting asthma. However, height SDS (r = -0.37) and height velocity SDS (r = -0.31) correlated inversely to age in patients but not in controls. A greater proportion (z = 2.84) of patients than controls had year 2 height velocity SDS less than -1.96. Patients had a mean delay in bone age of 0.22 years and 0.41 years at the beginning of year 1 and year 2 of the study, respectively. The delay in bone age correlated positively with age (r = 0.39) and duration of atopic dermatitis (r = 0.39), and negatively with height SDS (r = -0.51) and height velocity SDS (r = -0.38). CONCLUSIONS: Prepubertal children with atopic dermatitis are not short compared with controls. However, as they approach the teenage years their height velocity decreases, the proportion of children with extremely low height velocity increases, and the delay in bone age increases. These features are consistent with the pattern of growth seen in people with constitutional growth delay.

A systematic review of evidence for the appropriateness of neonatal screening programmes for inborn errors of metabolism.

BACKGROUND: Developments in screening technology and increased understanding of the natural history and treatment of inborn errors of metabolism (IEMs) have produced pressure to extend neonatal screening programmes. This review aims to assess the evidence for the appropriateness of such programmes. METHODS: A formal systematic literature review was conducted. Exclusion and inclusion criteria were used to select papers for critical appraisal by pairs of reviewers. Standard criteria were used to assess the appropriateness of neonatal screening for various IEMs. Site visits were conducted to assess new technologies for newborn screening. RESULTS: A total of 1866 papers were identified and 407 systematically selected for full critical appraisal. Published evidence confirmed that universal newborn screening for phenylketonuria (PKU) meets all of the screening criteria and justifies the expense and infrastructure necessary for the collection and testing of neonatal blood spots. There was insufficient evidence in the literature to assess the cost-effectiveness of screening for any other IEMs. There was reasonable evidence to support inclusion in extended neonatal screening of four other IEMs: biotinidase deficiency, congenital adrenal hyperplasia (CAH), medium-chain acyl CoA dehydrogenase (MCAD) deficiency and glutaric aciduria type 1 (GA1). CONCLUSIONS: Large-scale trials of screening for biotinidase, CAH, MCAD and GA1 should be conducted, with careful evaluation to establish their clinical effectiveness and cost-effectiveness in practice. Screening for the latter two disorders would be dependent upon the use of tandem mass spectrometry (tandem MS). The application of tandem MS to newborn screening requires further evaluation. The extension of neonatal screening programmes to other IEMs is not currently justified.

Urinary IGF and IGF binding protein-3 in children with disordered growth. The North West Paediatric Endocrine Group.

OBJECTIVE: Both IGF-I and IGFBP-3 reflect spontaneous GH secretion in healthy individuals. We have evaluated the clinical usefulness of urinary IGF-I and IGFBP-3 measurements in the diagnosis of children with disordered growth. DESIGN: Serum IGF-I and IGFBP-3 radioimmunoassays (RIA) were developed, and modified for quantitation in urine. The relationship between serum and urine levels, and the performance of these tests in the diagnosis of GH deficiency (GHD) were examined. PATIENTS: Sixty-nine children (age 9.5 +/- 3.6 years; 37 boys, 32 girls) provided a timed overnight urine collection and a serum sample collected on the same morning. Subjects were defined as GHD (n = 22) or short normal (SN; n = 47) on the basis of medical history, clinical examination, auxology and peak response to a GH stimulation test (< 20 mU/L in GHD patients). MEASUREMENTS: IGF-I and IGFBP-3 in serum and urine were measured by RIA, urinary GH (uGH) by immunoradiometric assay (IRMA) after dialysis and urinary creatinine by the alkaline picrate method. Urine results were expressed as total amount excreted (tulGFBP-3 (microgram), tulGF-1 (ng), tuGH (ng), tuCrt (mmol). RESULTS: Urine IGF-I and IGFBP-3 excretion correlated significantly to serum levels of IGF-I and IGFBP-3 and also to tuGH excretion. There was a strong positive relationship between both urinary peptides and tuCrt, which suggested that renal filtration was the source of these peptides in urine. In addition, there were significant correlations with age, bone age and height SD score, of similar magnitude to those for tuGH. In prepubertal children, serum IGF-I and IGFBP-3 were significantly lower in GHD compared with SN children, while in puberty only serum IGFBP-3 was significantly lower in GHD. There was no difference however, in tulGF-I or tulGFBP-3 between GHD and SN children either prepubertally or in puberty with near complete overlap of the values between groups. CONCLUSIONS: Measurements of tulGF-I and tulGFBP-3 have no place in the diagnosis of childhood GHD. Nonetheless, the significant correlations between serum and urinary IGF-I and IGFBP-3 levels and their correlation to uGH indicate that these peptides could be used as non-invasive physiological markers of the GH-IGF axis.

Newborn screening for inborn errors of metabolism: a systematic review.

OBJECTIVES. To establish a database of literature and other evidence on neonatal screening programmes and technologies for inborn errors of metabolism. To undertake a systematic review of the data as a basis for evaluation of newborn screening for inborn errors of metabolism. To prepare an objective summary of the evidence on the appropriateness and need for various existing and possible neonatal screening programmes for inborn errors of metabolism in relation to the natural history of these diseases. To identify gaps in existing knowledge and make recommendations for required primary research. To make recommendations for the future development and organisation of neonatal screening for inborn errors of metabolism in the UK. HOW THE RESEARCH WAS CONDUCTED. There were three parts to the research. A systematic review of the literature on inborn errors of metabolism, neonatal screening programmes, new technologies for screening and economic factors. Inclusion and exclusion criteria were applied, and a working database of relevant papers was established. All selected papers were read by two or three experts and were critically appraised using a standard format. Seven criteria for a screening programme, based on the principles formulated by Wilson and Jungner (WHO, 1968), were used to summarise the evidence. These were as follows. Clinically and biochemically well-defined disorder. Known incidence in populations relevant to the UK. Disorder associated with significant morbidity or mortality. Effective treatment available. Period before onset during which intervention improves outcome. Ethical, safe, simple and robust screening test. Cost-effectiveness of screening. A questionnaire which was sent to all newborn screening laboratories in the UK. Site visits to assess new methodologies for newborn screening. The classical definition of an inborn error of metabolism was used (i.e., a monogenic disease resulting in deficient activity in a single enzyme in a pathway of intermediary metabolism). RESEARCH FINDINGS. INBORN ERRORS OF METABOLISM. Phenylketonuria (PKU) (incidence 1:12,000) fulfilled all the screening criteria and could be used as the 'gold standard' against which to review other disorders despite significant variation in methodologies, sample collection and timing of screening and inadequacies in the infrastructure for notification and continued care of identified patients. Of the many disorders of organic acid and fatty acid metabolism, a case can only be made for the introduction of newborn screening for glutaric aciduria type 1 (GA1; estimated incidence 1:40,000) and medium-chain acyl CoA dehydrogenase (MCAD) deficiency (estimated incidence 1:8000-1:15,000). Therapeutic advances for GA1 offer prevention of neurological damage but further investigation is required into the costs and benefits of screening for this disorder. MCAD deficiency is simply and cheaply treatable, preventing possible early death and neurological handicap. Neonatal screening for these diseases is dependent upon the introduction of tandem mass spectrometry (tandem MS). This screening could however also simultaneously detect some other commonly-encountered disorders of organic acid metabolism with a collective incidence of 1:15,000.(ABSTRACT TRUNCATED)

Changes in the urinary excretion of creatinine, albumin and N-acetyl-beta-D-glucosaminidase with increasing age and maturity in healthy schoolchildren.

UNLABELLED: Raised urinary levels of albumin and N-acetyl-beta-D-glucosaminidase (NAG) are predictive of abnormal renal function and excretion of these substances is often expressed as a creatinine ratio. However, it is important to establish normal reference limits of albumin and NAG excretion for comparison of values from patients. For this reason, overnight excretion rates of creatinine, albumin and NAG were determined in timed overnight urine samples from 528 healthy schoolchildren (260 boys, 268 girls; 4-16 years) of normal size. There was a significant correlation with age and puberty for all substances in both sexes (P < 0.01). Peak creatinine excretion occurred at 16 years in boys, at 15 years in girls and at pubertal stage 5 in both sexes. Maximum albumin excretion was seen at 15 years and genital stage 5 in boys and at 16 years and breast stage 4 in girls. Peak NAG excretion occurred earlier, at 14 years and genital stage 4 in boys and at 13 years and breast stage 3 in girls. Boys excreted significantly more creatinine compared with girls before and during puberty (reflecting greater muscle mass) (P < 0.001) while excretion rates for albumin and NAG were similar in both sexes. Height and weight combined accounted for 58% and 29% of the variation in creatinine and NAG excretion respectively, while height alone predicted 20% of variation in albumin excretion. CONCLUSION: Age and puberty influence the urinary excretion of albumin and NAG while sex has an additional effect on creatinine excretion. The urinary excretion of albumin and NAG in children with renal disorders should be compared with age-related normal ranges while creatinine excretion could be used as a marker of muscle growth.

Acute biochemical effects of growth hormone treatment compared with conventional treatment in familial hypophosphataemic rickets.

OBJECTIVE: Conventional treatment of familial hypophosphaiaemic rickets with oral phosphate and 1 alpha-hydroxycholecalciferol (1 alpha HCC) does not satisfactorily correct the metabolic or physical defects of the disease and can have adverse effects, such as nephrocalcinosis. Hyperoxaluria from increased oral phosphate intake may contribute to nephrocalcinosis. Growth hormone enhances renal tubular phosphate reabsorption and 1,25-dihydroxy-cholecalciferol production in normal and in GH deficient individuals, and may thus be of benefit to patients with familial hypophosphataemic rickets. PATIENTS: We have assessed the acute effects of GH on phosphate and calcium metabolism in 6 children (age 4-14 years) with familial hypophosphataemic rickets. DESIGN: Each patient served as his/her own control and received the following in a sequential non-randomized design: conventional treatment with oral phosphate 1.0-3.4 mmol/kg/day in 3-6 divided doses and 1 alpha HCC 18-31 ng/kg/day-no treatment-GH 0.05 mg/kg daily-GH and 1 alpha HCC-and GH with phosphate and 1 alpha HCC. Each treatment was given for 7 days with 7 day periods of no treatment in between. MEASUREMENTS AND RESULTS: Glomerular filtration rate, tubular maximum rate of phosphate reabsorption per litre of glomerular filtrate (TmP/GFR) and serum 1,25-dihydroxycholecalciferol increased with GH. Mean 24-hour plasma phosphate concentrations did not increase with GH but were higher in the treatment phases which included phosphate and 1 alpha HCC (P = 0.002). Serum PTH was higher when GH was given in combination with phosphate and 1 alpha HCC compared to other phases. Urine oxalate excretion did not differ between the treatment phases. CONCLUSIONS: GH seemed to partially correct the defects in renal tubular phosphate transport and 1 alpha-hydroxylation of 25-hydroxycholecalciferol. We speculate that the net effect of GH treatment was an increase in body phosphate, although this was not reflected in a change in plasma phosphate. Therefore, GH in combination with 1 alpha HCC may act as a phosphate sparing agent, permitting treatment with lower and less frequent doses of oral phosphate and reducing adverse effects such as nephrocalcinosis.

Insulin-like growth factor binding protein-3 generation: an index of growth hormone insensitivity.

GH insensitivity may be an inherited condition or may arise as a consequence of disease of malnutrition. Laron syndrome is the most severe form of GH insensitivity, arising from an absent or defective GH receptor. Less severe forms of GH insensitivity, however, may exist, resulting in short stature but in few other features of Laron syndrome. We have identified a heterogeneous group of children with short stature and either high basal (> 10 mU/L) or high peak GH levels (> 40 mU/L) on GH provocation testing, to examine biochemical markers of GH sensitivity. These children received 4 d of GH (0.1 U/kg) and the increment in IGF-I, IGF binding protein (BP)-3, and GHBP was determined. Eight GHD children, commencing GH therapy, were recruited as positive controls. The two groups could not be differentiated by age, height SDS (SD score), height velocity SDS, or body mass index. IGF-I and IGFBP-3 generation were correlated in all children (delta SDS IGF-I versus delta SDS IGFBP-3, r = 0.49, p = 0.03). Neither basal GHBP levels or the increment in GHBP were predictive of the IGF-I or IGFBP-3 response to GH. The GHI group had a significantly reduced IGFBP-3 response to stimulation with 4 d of GH (median percent increment in IGFBP-3, 26%, versus 72% in the GHD group, P = 0.03); their IGF-I response to GH was also reduced (median % increment in IGF-I 75% versus 144% in the GH deficient group), but this did not achieve significance, p = 0.06. In all children, the percentage rise or delta SDS in both IGF-I and IGFBP-3 inversely correlated with the GH peak obtained on provocation testing, the latter being the most significant determinant of GH peak. We propose that the "IGF generation test", in particular IGFBP-3 generation, can be used in the investigation of partial GH insensitivity. Further work, however, is required to establish diagnostic criteria for partial GH insensitivity.

Infradian rhythms in urinary growth hormone excretion.

All studies of urinary GH excretion in normal and disordered growth have revealed marked day to day (infradian) variation. We used serial overnight urinary GH estimations as an indirect measure of endogenous GH secretion in eight normal prepubertal children (aged 3.6-7.3 yr) over 90-365 days to determine whether longer term rhythms in GH output could exist. This study constitutes a first step in examining the potential relationship between GH excretion and growth. Urinary GH was measured by immunoradiometric assay after dialysis, expressed as the total amount excreted (nanograms per night) or as the GH/creatinine ratio (nanograms per mmol), and assessed by pulse counting techniques and time-series analysis. Variability in urinary GH excretion (median coefficient of variation, 46%) was significantly greater than creatinine (median coefficient of variation, 25%; P = 0.003). Additionally, there was marked month by month variation in baseline urinary GH in all children. High frequency pulses of urinary GH were defined in all children, with periods between 3-5 days. In the two children followed for 7 months or more, time-series analysis was also undertaken on urinary GH data divided into weekly series. This revealed significant rhythms present at 2.6 and 4.1 weeks. There were, therefore, three components to urinary GH excretion: long term basal fluctuation (over months), short term pulses (over days), and intermediate rhythms (over weeks). Further work is required to establish the relationship between these patterns of GH excretion and short term growth.

Adrenal function following topical steroid treatment in children with atopic dermatitis.

Adrenal suppression is a potential complication of topical corticosteroid treatment in atopic dermatitis. We used a low-dose adrenocorticotrophic hormone (ACTH) test (500 ng/1.73 m2) to detect subtle changes in adrenal glucocorticoid function in 14 prepubertal children with moderate or severe atopic dermatitis affecting 16-90% (median 58%) of the body surface area. All had received regular treatment with mild potency BNF (British National Formulary) classification topical corticosteroid ointments (hydrocortisone 48.7-223.2 mg/m2 body surface area/day; median 134.2) for 3-10 years (median 6.5 years). Nine children had also intermittently used moderate potency preparations. However, none had been treated with corticosteroids by any other route in the preceding 6 months. Fourteen prepubertal children with constitutional short stature, without atopic disease, served as controls. The basal, peak, increment and area-under-curve in plasma cortisol concentrations in children with atopic dermatitis were not significantly different from controls, indicating normal adrenal sensitivity to low-dose ACTH. However, the peak in plasma cortisol occurred earlier in children with atopic dermatitis (median 17.5 min) than in controls (median 25 min) (P = 0.02). In addition, there was a significant inverse relationship between time to peak and extent of atopic dermatitis (rs = -0.52; P < 0.05), but not topical steroid treatment dose or score in children with atopic dermatitis. These findings indicate accelerated adrenal responsiveness to ACTH in children with atopic dermatitis, which is independent of treatment. Mild to moderately potent topical corticosteroid ointments in these doses did not suppress adrenal glucocorticoid function in this sample of children with atopic dermatitis.

Nocturnal urinary growth hormone excretion in growth hormone-deficient children on and off growth hormone treatment.

Non-compliance has been reported as a major issue in growth hormone (GH) therapy. We explored the use of urinary GH (uGH) measurements to monitor the GH treatment of 18 children (aged 5-16 years) diagnosed as GH deficient on the basis of history, phenotype, auxology and peak GH concentration during 2 provocation tests of < 15 mU/l. Each child collected 5 consecutive overnight urine samples while on GH replacement schedules, then discontinued treatment for 2 days and collected a further 5 urine samples. The mean mass of uGH excreted on treatment (8.6 ng, range 3.6-13.0 ng) was significantly greater than that off treatment (1.2 ng, range 0.6-2.7 np; p < 0.01). All uGH values on treatment exceeded the mean nocturnal uGH excretion of normal age- and sex-matched children. The clear distinction between uGH levels on and off GH treatment indicates that uGH measurement would determine whether two or more GH injections had been missed. A series of uGH estimates over a 2-week period may provide a realistic perspective on injection frequency.