Biochemical tests in the diagnosis of childhood growth hormone deficiency.

GH stimulation tests are widely used in the diagnosis of GH deficiency (GHD), although they are associated with a high false positive rate. We have examined, therefore, the performance of other tests of the GH axis [urinary GH excretion, serum insulin-like growth factor I(IGF-I), and IGF-binding protein-3 (IGFBP-3) levels] compared with GH stimulation tests in identifying children defined clinically as GH deficient. Group I comprised 60 children (mean age, 10.3 +/- 4.8 yr) whose diagnosis of GHD was based on a medical history indicative of pituitary dysfunction (n = 43) or on the typical phenotypic features and appropriate auxological characteristics of isolated GHD (n = 17). Group II comprised 110 short children (mean age, 9.8 +/- 4 yr) in whom GHD was not suspected, but needed exclusion. The best sensitivity for a single GH test was 85% at a peak GH cut-off level of 10 ng/mL, whereas the best specificity was 92% at 5 ng/mL. The sensitivities of IGF-I, IGFBP-3, and urinary GH, using a cut-off of -2 SD score were poor at 34%, 22%, and 25%, respectively, with specificities of 72%, 92%, and 76% respectively. Only 2 of 21 pubertal children in group I and none of the 27 subjects with radiation-induced GHD had an IGFBP-3 SD score less than -1.5. We devised a scoring system based on the positive predictive value of each test, incorporating data from the GH test and the IGF-I and IGFBP-3 levels. A specificity of 94% could be achieved with a score of 10 or more (maximum 17) (sensitivity 34%). The latter could not be improved above 81% with a score of 5 points or more (specificity, 69%). A high score was, therefore, highly indicative of GHD, but was achieved by few patients. A normal IGFBP-3 level, however, did not exclude GHD, particularly in patients with radiation-induced GHD and those in puberty. A GH test with a peak level more than 10 ng/mL was the most useful single investigation to exclude a diagnosis of GHD.

The relationship between lean body mass and bone mineral content in paediatric health and disease.

INTRODUCTION: The correct interpretation of DXA data is critical to the diagnosis and management of children with suspected bone disease. This study examines the various influences on bone mineral content (BMC), as measured by dual-energy X-ray absorptiometry (DXA). MATERIALS AND METHODS: Six hundred and forty-six healthy school children and forty-three children with chronic diseases, aged 5-18 years, had their lumbar spine and whole body measured using a Lunar DPX-L DXA scanner. RESULTS: Stepwise linear regression identified lean body mass (LBM) as the strongest single predictor of BMC in the lumbar spine and the total body. A significant gender difference was observed in the relationship between BMC and LBM with girls having significantly more bone per unit LBM from 9 years of age in the spine and 13 years of age in the total body. To investigate the relationship between LBM and BMC in children with chronic disease, a two-stage algorithm based upon calculation of Z scores from the normative data was applied. Stage 1 assessed LBM for height and stage 2 assessed BMC for LBM. Ten children with spinal muscular atrophy had a mean LBM for height Z score of -1.8(1.4) but a mean BMC for LBM Z score of 1.2(1.3) indicating their primary abnormality was reduced muscle mass (sarcopenia) with no evidence of osteopenia. In contrast, 21 children with osteogenesis imperfecta had a mean LBM for height Z score of 0.4(1.7) but a mean BMC for LBM Z score of -2.5(1.8) indicating normal LBM for size but significantly reduced BMC for LBM (i.e. osteopenia) confirming a primary bone abnormality. A third group consisting of 12 children with low trauma fractures demonstrated little evidence of sarcopenia [mean LBM for height Z score -1.1(2.1)] but significant osteopenia [mean BMC for LBM Z score -1.9(1.5)]. CONCLUSION: The results from this study demonstrate how the relationship between height and lean body mass, and lean body mass and bone mineral content can be a useful method of diagnosing osteoporosis in children and how the relationships can be used to identify if the primary abnormality is in muscle or bone.

Apolipoprotein E1-Hammersmith (Lys146-->Asn;Arg147-->Trp), due to a dinucleotide substitution, is associated with early manifestation of dominant type III hyperlipoproteinaemia.

Apolipoprotein E (apoE) is one of the major protein constituents of chylomicron and very low density lipoprotein (VLDL) remnants and plays a central role as a ligand in the receptor-mediated uptake of these particles by the liver. Here we describe a new variant of apoE, apoE1-Hammersmith, which is associated with dominantly expressed type III hyperlipidaemia. The propositus, aged 26, developed tubero-eruptive xanthomas at the age of 3, her daughter developed similar lesions at age 7 but her son, aged 3, shows no clinical abnormality so far. All three cases had an apoE3E1 phenotype and a broad beta band on lipoprotein electrophoresis. Cysteamine modification resulted in a shift of apoE1 to the apoE2 isoform position, indicating that the mutation leading to apoE1-Hammersmith occurred on an apoE3 background. ApoE genotyping confirmed these results. Sequence analysis of DNA of the propositus was performed for exons 3 and 4 and revealed a dinucleotide substitution causing two amino acid changes at adjacent positions (Lys146-->Asn) and (Arg147-->Trp).

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.

Prevalence of maternal dietary iodine insufficiency in the north east of England: implications for the fetus.

BACKGROUND: Maternal subclinical hypothyroidism is a cause of poor neurodevelopment outcome in the offspring. Although iodine deficiency is the most common cause of hypothyroidism world wide, there are no screening programmes for it in the United Kingdom where the population is assumed to be iodine replete. OBJECTIVE: To determine the prevalence of reduced iodine intake by measuring urinary iodide concentrations in pregnant and non-pregnant women from the north east of England. METHODS: Urinary iodide excretion (UIE) rate was estimated using inductively coupled mass spectrometry in 227 women at 15 weeks gestation and in 227 non-pregnant age matched controls. A reduced intake of iodine is indicated by a concentration in urine of less than 50 microg/l or less than 0.05 microg iodine/mmol creatinine. RESULTS: Eight (3.5%) pregnant women and 13 (5.7%) controls had a reduced iodine/creatinine ratio. These values were higher when UIE was expressed as iodine concentration: 16 (7%) and 20 (8.8%) respectively. Ninety (40%) of the pregnant women had a UIE of 0.05-0.10, which is consistent with borderline deficiency. CONCLUSION: In this study, 3.5% of pregnant women had evidence of iodine deficiency, and 40% may be borderline deficient. Larger scale studies are required to estimate the true prevalence of iodine deficiency in the United Kingdom.

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.

Bone density at the os calcis: reference values, reproducibility, and effects of fracture history and physical activity.

AIMS: To establish reference values for bone mineral density (BMD) measured at the os calcis (OC) in healthy UK Caucasian children. Secondary objectives were to assess the reproducibility of the measurement and the effects of fracture history and habitual physical activity. METHODS: A total of 403 children aged 5-18 were studied. Main outcome measures were: BMDoc measured by peripheral DXA, total BMD measured by whole body axial scanner, age, anthropometry, pubertal status, self-reported fracture history, and physical activity (PA) expressed as a three point score. RESULTS: Complete data were available on 171 girls and 123 boys free of a history of fracture. BMDoc was related positively to age, body size, and total BMD, and could be predicted using a proportional model based on height alone (R2: 65% girls, 77% boys). Mean BMDoc appears to plateau in girls at 15 years and attain a value that concurs with the mean peak value in adult women. The 95% limits of agreement in repeated measures were -0.029 to 0.029 g/cm2 (n = 53). Compared with sedentary children, those doing regular sports or PA for more than five hours a week had an increased BMDoc (by about 0.03 g/cm2 or about 7% of the overall mean). A history of fracture (n = 81) was associated with a reduced BMDoc in boys but not in girls, though our study may have been underpowered for a subgroup analysis. CONCLUSIONS: BMDoc can be measured easily and quickly in children older than 5 years and provides an objective measure of areal bone density for clinical and research studies using a reference range derived from its relation to height.

Patterns of admissions for children with special needs to the paediatric assessment unit.

BACKGROUND: Children with special needs present a challenge to those involved in their care. AIMS: To determine the role of the acute assessment unit for these children. METHODS: Case notes and other records were reviewed for information on referrals, admissions, readmission within 7 and 28 days, length of stay, and management of 86 children registered for special needs. The study covered five years between January 1997 and December 2001. RESULTS: Of the 86 children, 48 (58%) were boys; 62 children had cerebral palsy and 52 learning disability. There were 914 episodes, with 44% of these being self referrals and 35% from general practitioners; 35.5% of the episodes were managed in the assessment unit. The average length of stay in hospital was 5 days, ranging from <24 hours to 63 days; 37.5% of those admitted to the ward stayed for less than 24 hours. Respiratory tract infections and seizures were the main reasons for referral and admission. CONCLUSION: Children with special needs tend to have a predictable pattern of conditions requiring inpatient care. One third of the inpatients episodes did not need a prolonged stay in hospital. This latter group of children could be managed at home with support of community nurses. Integrated care pathways need to be developed to minimise disruption to their lives. Appropriate resources should be made available to achieve these goals.

Unscheduled return visits within 72 hours to an assessment unit.

Unscheduled return visits were looked at to determine the quality of care and safety of patients in a paediatric assessment unit. The reasons for unscheduled return visits were also investigated. Two per cent of patients discharged from the unit returned, the main reason being parental perception of illness. There were only two patients re-referred by their family doctor. These findings have implications for clinical care and education.

A seven year experience of medical emergencies in the assessment unit.

AIMS: To analyse retrospectively all referrals to the assessment unit during a seven year period, to determine their sources and destination. METHODS: All referrals over the seven year period were analysed. Parental satisfaction was determined using a questionnaire in some of the patients. The disease pattern and the investigations performed were determined. The community nurses' working hours and type of work done were analysed. RESULTS AND CONCLUSIONS: A total of 43 496 children were seen in the unit. Over 65% of the patients were referred by the general practitioners; 13 517 (34.2%) of those referred to the unit were discharged directly from the unit. Respiratory disorders and gastrointestinal problems were commonly seen. The children discharged from the unit did not have significantly more tests done on them. Most of the parents whose children were discharged from the unit were happy to be managed at home. The community nurses attended many children who needed intravenous therapy and advice on fluid rehydration. Community nurses reduce admission to the wards by working with other members in the assessment unit. This in turn provides a single point of entry and bridges the gap between primary and secondary care. We suggest recommendations on setting up such a unit.

Indicators of malnutrition in leukaemic children.

In 24 children with acute leukaemia a low serum albumin concentration (31 g/l or less) and a median weight:height ratio of less than 0.95 on admission were indicators of severe weight loss.

Prevention of cisplatin-induced hypomagnesemia.

Twenty-eight children were treated for various cancers with protocols that included dichlorodiamine platinum (cisplatin). Sixteen children were given intravenous magnesium after the administration of cisplatin, and 12 were given intravenous magnesium before and after administration of cisplatin. Serum magnesium concentration levels were monitored before, during, and after the full course of treatment and found to be lower in the first group of patients than in the second group. We recommend that magnesium supplements be given to patients receiving cisplatin during the precisplatin hydration period to prevent hypomagnesemia.

A review of astrocytoma in childhood.

Between 1954 and 1984, 282 children with astrocytoma were included in the Manchester Children's Tumour Registry (MCTR), giving an overall incidence of 9.3 per million person-years. There were 110 children with adult astrocytoma and 172 children with juvenile astrocytoma. The five-year survival for adult astrocytoma was 15% and 75% for juvenile astrocytoma. There were no significant improvements in survival with time. There were 21 children with neurofibromatosis (NF) and 4 children had tuberous sclerosis. Some children had other recognized syndromes and others had major or minor abnormalities. Nine children had second tumors, mainly associated with NF, and seven siblings had malignant tumors. A number of mothers of these children were found to have breast cancer. Some of these families may represent examples of the Li-Fraumeni cancer family syndrome. We conclude that astrocytomas is an important problem in childhood and that a proportion of cases may have a genetic origin.

Nutrition, infection, and morbidity in leukemia.

Seven of the 25 children with acute leukemia were malnourished on admission. Of the 11 children who presented with fever, 6 had protein energy malnutrition and a bacterial infection was confirmed. They had a lower total leucocyte count. Out of 18 well-nourished children, 5 presented with a fever and the causative organism was isolated in 1 patient. There were more patients with a palpable liver in the malnourished group, and they had a high morbidity due to infections during remission induction.

Plasma growth hormone (GH) responses to growth hormone releasing factor (hp GRF 1-44) in familial GH deficiency.

In four children with familial GH deficiency peak and integrated GH responses to an acute intravenous bolus of hp GRF 1-44 were lower than in 18 children with non-familial idiopathic GH deficiency and in 5 children with structural hypothalamic abnormalities. It is possible that the familial forms of GH deficiency described may be due to absence or biological inactivity of endogenous GRF or possibly GRF receptor or post receptor abnormalities.