Adrenal suppression following intralesional corticosteroids for periocular haemangiomas.

BACKGROUND/AIMS: Treatment with intralesional triamcinolone/betamethasone is recommended for infantile sight-threatening periocular haemangiomas. This study investigates the endocrine and weight changes in 15 infants undergoing therapy over 12 years. METHODS: 15 infants, median age 19 weeks (range 10-56) receiving intra/perilesional triamcinolone/betamethasone underwent serial measurement of weight, early morning serum cortisol and adrenocorticotropic hormone (ACTH) before and after injection. RESULTS: Cortisol fell from a median (range) of 383 (112-594) to 28 (<10-506) nmol/l (p=0.005) and ACTH from 26 (14-134) to 9 (5-20) ng/l (p=0.05) from before injection to 4 weeks after treatment. Prolonged adrenal suppression occurred in 13 out of 15 cases with time to recovery being 19.5 (4-65) weeks. Failure to gain weight appropriately was observed in 14 infants but recovered once normal adrenal function was re-established. CONCLUSION: Prolonged adrenal suppression following triamcinolone/betamethasone injection for periocular haemangiomas is common and associated with faltering weight gain.

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.

Perception of effort at low and moderate intensity exercise in survivors of childhood acute lymphoblastic leukaemia.

OBJECTIVE: The study examined the degree to which male and female survivors of acute lymphoblastic leukaemia (ALL) perceive effort at low and moderate intensity exercise in association with related physiological variables. MATERIALS AND METHODS: Participants were 67 children. Thirty-five (14 boys and 21 girls) were long-time survivors of ALL and 32 (18 boys and 14 girls) were control subjects. The Children's Effort Rating Table (CERT) was used to measure whole-body perceived exertion at low and moderate intensity exercise. Peak oxygen uptake was measured using a motorized treadmill. CERT and physiological data were analysed using 2 x 2 mixed analyses of variance, appropriate t-tests and coefficients of correlation. RESULTS: In absolute terms, boys treated for ALL found perception of effort to be more strenuous at both low (3.9 vs. 3.5 units) and moderate (6.1 vs. 5.3 units) intensity exercise than control subjects, although differences were not significant (p > 0.05); girls treated for ALL found perception of effort to be the same as controls at low intensity exercise (3.1 vs. 3.1 units) but slightly higher than controls at moderate intensity exercise (5.6 vs. 5.2 units); neither of these differences were significant (p > 0.05). When CERT values were adjusted for (.-)VO(2) peak (%) and heart rate (HR) peak (%) differences remained non-significant. There were no significant interactions (Intensity x Group) in males, but the interaction for (.-)VO(2) peak (%) was significant in females (p < 0.05). The main effect for Intensity (low and moderate) was significant for all variables in boys and girls (p < 0.0001). The main effect for Group (ALL and controls) identified significantly greater absolute (b.p.m.) and relative (%) HR values in ALL boys at low and moderate intensity exercise. In female ALL and control subjects the interaction (Intensity x Group) distinguished between (.-)VO(2) peak (%) at moderate intensity exercise and HR peak (%) at low and moderate intensity exercise. Coefficients of correlation between perceived effort and (.-)VO(2) peak (%) in boys and girls were low to high (0.28-0.76), and between absolute and relative HR were also low to high (0.33-0.73). There were low correlations between time 'off therapy' and perceived effort, (.-)VO(2) peak (%) and HR peak (%) (-0.003 to -0.49). CONCLUSION: It was concluded that perception of effort in survivors of ALL at low and moderate intensity exercise was the same as that of control subjects. Correlations between perceived effort and physiological variables at moderate exercise were low to high, while those between perceived effort and time from treatment were generally weak.

Craniopharyngiomas in children and adults: systematic analysis of 121 cases with long-term follow-up.

BACKGROUND: Craniopharyngiomas account for 2-5% of all primary intracranial tumours. Despite their benign histological appearance, they are often associated with an unfavourable prognosis and their optimal treatment remains controversial. AIM: To analyse the natural history and treatment outcome of children and adults presenting to the Departments of Paediatrics and Endocrinology with craniopharyngioma between 1964 and 2003. PATIENTS AND METHODS: The records of 121 patients (age range 2.5-83 years, 42 aged < 16 and 79 aged > or = 16) were identified. The mean follow-up period since presentation was 103 months (8.6 years) (range 0.3-468 months). Sixteen patients underwent gross total removal (A), 3 gross total removal + radiotherapy (B), 51 partial removal (C), 33 partial removal + radiotherapy (D), 6 cyst evacuation alone (E) and 3 cyst evacuation + radiotherapy (F). The clinical, imaging and endocrinological data at presentation and during follow-up were analysed. RESULTS: Headache and visual field defects were the most common presenting clinical features (64% and 55%, respectively). Ninety-four per cent of the tumours had an extrasellar component and 23% of them were associated with hydrocephalus. There was a significant difference in the recurrence-free survival rates between groups A-D [at 10 years: 100% (A), 100% (B), 38% (C) and 77% (D), P < 0.01], which persisted even when analysing patients operated after 1980. The median time of first recurrence was 2.5 years (range 0.5-36). The peri-operative mortality of the patients who had any type of neurosurgical intervention due to recurrence was higher than that observed after primary surgery (24%vs. 1.8%) (P < 0.01). The rate of re-accumulation of the cyst fluid was 58% during the first year in patients of group E, whereas none of the subjects of group F experienced such an event during their follow-up period. There was no reversal of pre-existing pituitary hormone deficits after any surgical intervention. The probabilities of GH, FSH/LH, ACTH, TSH deficiency and diabetes insipidus at the 10-year follow-up were 88%, 90%, 86%, 80% and 65%, respectively. After excluding the non-tumour-related deaths, the 10-year survival rate following presentation was 90%. Patients with recurrence had a significantly lower probability for survival compared with those without it (at 10 years: 70%vs. 99%, P < 0.01). At the 10-year follow-up the probability of the presence of major visual field defects was 48%, hyperphagia/obesity 39%, epilepsy 12% and hemi-/monoparesis 11%. In this large series no substantial differences in the outcome of tumours diagnosed during childhood or adult life were found. CONCLUSIONS: Craniopharyngiomas remain tumours associated with significant morbidity. Gross total removal provides favourable results in terms of recurrences. If this cannot be achieved safely, adjuvant radiotherapy is beneficial in preventing tumour re-growth. Childhood- and adult-onset lesions generally behave similarly.

Pitfalls in the assessment of body composition in survivors of acute lymphoblastic leukaemia.

BACKGROUND: Body fat mass (FM) and fat free mass (FFM) in childhood are often estimated by conversion of a measured variable into compartmental body composition using constants or regression equations that have been previously derived in healthy individuals. Application of such constants or equations to children with disease states may lead to inappropriate conclusions since the "normal" relationships may become altered. AIMS AND METHODS: To test this hypothesis by taking measurements of body composition using dual energy x ray absorptiometry (DEXA) as a "gold standard" method and calculating hydration and body potassium constants using isotopic water dilution and whole body potassium counting. Measurements of bioelectrical impedance (BIA) by two different analysers (RJL and Holtain) were also performed to allow comparison with body water measurements. RESULTS: Measurements were performed in 35 children treated for acute lymphoblastic leukaemia (ALL) and compared to those in 21 children treated for a variety of other malignancies and 32 healthy sibling controls. The mean hydration and potassium content of FFM was significantly reduced in the ALL group compared to both other malignancies and controls. Application of equations derived from controls for the measurement of FFM derived from bioelectrical impedance led to an underestimation of 1.15 kg when compared to that derived from DEXA in children treated for ALL but not in other malignancies. For all groups combined, BIA was significantly different in the two analysers. CONCLUSION: Care needs to be taken in the application of equations derived from the normal population to body composition measurement in children treated for ALL.

Relative osteopenia after treatment for acute lymphoblastic leukemia.

Osteoporosis in adult life is associated with a significant morbidity and may be predisposed to by osteopenia and failure to reach peak bone mass in childhood. Children treated for acute lymphoblastic leukemia (ALL) may be at risk of osteopenia as a result of previous therapy or as a consequence of the disease process itself. Dual energy x-ray absorptiometry measurements of bone mineral content (BMC) for the whole body and at the lumbar spine and hip were taken in 35 (14 male) long-term survivors of ALL and compared with results in 20 (10 male) survivors of other malignancies and 31 (17 male) healthy sibling controls. The measured BMC was expressed as a percentage of a predicted value derived from the control group and based on the variables that had influence upon it. BMC (%) was reduced at the spine in the ALL group compared with controls [92.4 (8.0)% versus 100.4 (9.7)%, respectively; p < 0.005] and at the hip compared with both other malignancies and controls [89.0 (11.5)% versus 96.1 (11.7)% and 100.4 (9.2)%, respectively; p < 0.0005]. Increasing length of time off therapy was associated with a significant increase in %BMC at both the spine and the hip. For the spine, this association was significantly different between the ALL group and other malignancies, suggesting that any gain in %BMC after therapy was slower in children treated for ALL. Both exercise capacity and levels of physical activity were correlated with %BMC at the hip (r = 0.44, p < 0.001 and r = 0.29, p < 0.01, respectively). Previous exposure to methotrexate, ifosfamide, and bleomycin was associated with a reduction in %BMC at the spine. Exposure to 6-mercaptopurine and cisplatin was associated with a reduction at the hip. In conclusion, children treated for ALL are osteopenic. The mechanism is probably multifactorial but is partially related to previous chemotherapy, limited exercise capacity, and relative physical inactivity.

Daily energy expenditure and physical activity in survivors of childhood malignancy.

Changes in body composition, in particular the onset of obesity, may result from reductions in total daily energy expenditure (TDEE) as a consequence of relative physical inactivity. Children previously treated for acute lymphoblastic leukemia (ALL) become obese, yet the mechanism remains undefined. TDEE and physical activity levels [PAL = TDEE/basal metabolic rate (BMR)] were measured in 34 long-term survivors of ALL and compared with results from 21 survivors of other malignancies and 32 healthy sibling control subjects using the flex-heart rate technique. Body composition was measured by dual energy x-ray absorptiometry. The median TDEE was reduced in the ALL group (150 kJ x kg d(-1)) compared with other malignancies and controls (207 and 185 kJ x kg d(-1), respectively, p < 0.01). This reduction was accounted for mainly by a relative decrease in the PAL of the ALL group (1.24) compared with both other malignancies and controls (1.58 and 1.47, respectively, p < 0.01). TDEE and PAL were correlated with percentage body fat (r = -0.39, p < 0.001 and r = -0.24, p < 0.05, respectively). Obesity in survivors of ALL may, in part, be explained by a reduction in TDEE as a consequence of reduced PAL. The cause of such reduction is uncertain.

Measured and predicted bone mineral content in healthy boys and girls aged 6-18 years: adjustment for body size and puberty.

Dual-energy X-ray absorptiometry (DEXA) is a rapid and precise technique for the assessment of bone mineralization in children. Interpretation of the results in growing children is complex as results are influenced by age, body size (height and weight) and puberty. Conventionally, bone mineral data derived from DEXA have been presented as an areal density [BMD; bone mineral content (BMC, g)/projected bone area (BA, cm2)], yet this fails to account for changes in BMC that result from changes in age, body size or pubertal development. Measurement of BMC and BA of the whole body, lumbar spine and left hip were made in 58 healthy boys and girls using DEXA. The relationship between BMC and BA was curvilinear, with the best fit being that of a power model (BMD = BMC/BAlambda, where lambda is the exponent to which BA is raised in order to remove its influence on BMC). The value of lambda changed when measures of body size and puberty were taken into account (e.g. for lumbar spine from 1.66 to 1.49). Predictive formulae for BMC were produced using regression analysis and based on the variables of age, body size and pubertal development. This provides a method for interpreting the measured BMC which is independent of such variables and a constant reference range for children aged 6-18 y.

The validity of body mass index for the assessment of adiposity in children with disease states.

Recently published standards for body mass index (BMI) based on population studies of height and weight in healthy British children allow an easy but indirect assessment of adiposity in healthy children. However, assessment of adiposity based on standards derived from reference populations may not be appropriate for use in subjects with disease states associated with abnormalities of growth and body composition. This hypothesis was tested by comparison between BMI standard deviation scores (SDS) and more direct measures of body fat derived from dual-energy X-ray absorptiometry (DEXA) and skinfold thickness in groups of children, receiving growth hormone, with inflammatory bowel disease, previously treated for malignancy, and healthy controls. Excess adiposity was defined as a body fat greater than the 85th percentile and was compared to a BMI SDS of +1.0. Overall the sensitivity and specificity for a BMI SDS of +1.0 to correctly identify individuals as having excess adiposity was 66% and 94%, respectively, when body fat was measured by DEXA, and 50% and 100% when estimated from skinfold measurements, respectively. There were no significant differences in these statistics whether applied to the individual disease groups or to healthy controls. These findings suggest that BMI under-predicts the prevalence of excess adiposity in children with disease states but surprisingly to no greater degree than that seen in healthy subjects.

Relationship between cardiopulmonary response to exercise and adiposity in survivors of childhood malignancy.

Many long term sequelae result from previous treatment for malignancy in childhood. However, little information exists on cardiopulmonary response and energy expenditure during exercise and their possible associations with excess body fat. Measurements of body composition and exercise capacity both at low intensity and maximal aerobic capacity were made on 56 long term survivors of childhood malignancy (35 survivors of acute lymphoblastic leukaemia (ALL) and 21 survivors of other malignancies) and 32 siblings acting as controls. Female survivors of ALL had significantly greater mean (SD) body fat than survivors of other malignancies and siblings (32.5 (6.4)% v 24.3 (4.4)% and 26.3 (8.5)% respectively, p < 0.005). Energy expenditure at low intensity exercise was reduced in survivors of ALL, and negatively correlated with body fat after controlling for weight (partial r range -0.21 to -0.47, p < 0.05). Stroke volume, measured indirectly, was reduced and heart rate raised in ALL survivors at sub-maximal exercise levels. Peak oxygen consumption was significantly reduced in girls and boys treated for ALL compared with siblings (30.5 v 41.3 ml/kg/min for girls, p < 0.05 and 39.9 v 47.6 ml/kg/min for boys, p < 0.05 respectively). Reduced exercise capacity may account in part for the excess adiposity observed in long term survivors of ALL.

Inflammatory bowel disease and predisposition to osteopenia.

The prevalence of osteopenia in children with inflammatory bowel disease (IBD) is unknown. The effect of nutritional state, disease activity, and steroid therapy on bone mineral content (BMC) of whole body, lumbar spine, and left femoral neck measured by dual energy x ray absorptiometry in 32 children with IBD was assessed by comparison with 58 healthy local school children. Using the control data, a predicted BMC was calculated taking into account bone area, age, height, weight, and pubertal stage. The measured BMC in children with IBD was expressed as a percentage of this predicted value (% BMC). Mean (SD) % BMC was significantly reduced for the whole body and left femoral neck in the children with IBD (97.0 (4.5)% and 93.1 (12.0)% respectively, p < 0.05). Of the children with IBD, 41% had a % BMC less than 1 SD below the mean for the whole body and 47% at the femoral neck. Reduction in % BMC was associated with steroid usage but not with the magnitude of steroid dose, disease activity, or biochemical markers of bone metabolism. In conclusion, osteopenia is relatively common in childhood IBD and may be partly related to the previous use of steroids.