Peter Betts

Poor growth in school entrants as an index of organic disease: the Wessex growth study.

OBJECTIVE--To establish whether poor height or height velocity, assessed during the year of school entry, might identify children with previously undiagnosed organic disease. DESIGN--Observation of a total population and their case controls. SETTING--Community base. SUBJECTS--All 14,346 children in two health districts entering school during two consecutive years were screened for height by school nurses, and those whose height lay below the 3rd centile according to Tanner and Whitehouse standards (n = 180) were identified. After excluding 32 with known organic disease, five from ethnic minorities, and three who refused to take part, the remaining 140 short normal children were matched with 140 age and sex matched controls of average height (10th-90th centile) and their height velocities over 12 months measured. MAIN OUTCOME MEASURES--Height, height velocity, previously diagnosed organic disease, and organic disease diagnosed as a result of blood tests and specialist examination. RESULTS--Twenty five of the 180 short children (14%) were already known to have chronic organic disease which could explain their poor growth. Blood tests and specialist examination revealed a further seven with organic disease, which was acquired rather than congenital in three, and a second cause of short stature in one with known organic disease. These eight conditions had been missed at the school entry medical examination. The shorter the child, the more likely an underlying organic disorder, with seven of the 12 children whose heights were more than 3 standard deviations below the mean having some organic disease. Height velocity measured over 12 months, however, did not distinguish short normal children from those with disease or from their matched controls. CONCLUSIONS--Height, but not height velocity, is a useful index for identifying unrecognised organic disease at school entry. The shorter the stature the greater the prevalence of organic disease. The frequency of newly diagnosed remediable disease in this study (1 in 3-4000) is similar to that of neonatal hypothyroidism, which is routinely screened for. Routine investigation of all very short school entrants is recommended.

Short stature in Noonan syndrome: response to growth hormone therapy

BACKGROUND Growth hormone (GH) has been used to promote growth in both the short and long term in a number of dysmorphic syndromes, including Turner syndrome. As this condition shares many clinical features with Noonan syndrome, it would seem logical to treat the latter group with GH. AIMS To assess the short and long term response to GH therapy in patients with Noonan syndrome. METHODS Analysis of patients with Noonan syndrome in the Pharmacia & Upjohn International Growth Study (this post-marketing database contains data on the majority of patients currently treated with GH in the UK). A questionnaire was also sent to participating clinicians. RESULTS Data on 66 patients (54 males) were available for study. At the start of GH therapy children were short, compared with both normal and Noonan children. During the first year of GH therapy height velocity increased from a mean of 4.9 to 7.2 cm per year. For patients treated long term with GH, mean height SDS increased from −2.9 pretreatment to −2.6 after one year and −2.3 after five years. Of the 10 patients at near final height, only one had a height above the 3rd centile for normal adults and above the mean for untreated Noonan patients. The mean increment in final height was 3.1 cm (range −1.1 to 6.5 cm). CONCLUSIONS GH therapy in patients with Noonan syndrome will improve height velocity in the short term. Longer-term therapy results in a waning of effect; initial indications are that final height is not improved substantially in most patients.

Personality functioning: the influence of stature

Background: The Wessex Growth Study has monitored the psychological development of a large cohort of short normal and average height control participants since school entry. Aims: To examine the effect of stature on their personality functioning now that they are aged 18–20 years. Methods: This report contains data from 48 short normal and 66 control participants. Mean height SD score at recruitment was: short normals −2.62 SD, controls −0.22 SD. Final height SD score was: short normals −1.86, controls 0.07. The Adolescent to Adult Personality Functioning Assessment (ADAPFA) measures functioning in six domains: education and employment, love relationships, friendships, coping, social contacts, and negotiations. Results: No significant effect of recruitment height or final height was found on total ADAPFA score or on any of the domain scores. Socioeconomic status significantly affected total score, employment and education, and coping domain scores. Gender had a significant effect on total score, love relationships, coping, and social contacts domain scores. Salient aspects of daily living for this sample were identified from the interviews (prevalence%): consuming alcohol (94%), further education (63%), love relationships (55%), current drug use (29%), experience of violence (28%), parenthood (11%), and unemployment (9%). Stature was not significantly related to behaviour in any of these areas. Conclusions: Despite previously reported links between short stature and poorer psychosocial adaptation, no evidence was found that stature per se significantly affected the functioning of the participants in these areas as young adults.

Effect of oxandrolone and timing of pubertal induction on final height in Turner’s syndrome: randomised, double blind, placebo controlled trial

Objective To examine the effect of oxandrolone and the timing of pubertal induction on final height in girls with Turner’s syndrome receiving a standard dose of growth hormone. Design Randomised, double blind, placebo controlled trial. Setting 36 paediatric endocrinology departments in UK hospitals. Participants Girls with Turner’s syndrome aged 7-13 years at recruitment, receiving recombinant growth hormone therapy (10 mg/m2/week). Interventions Participants were randomised to oxandrolone (0.05 mg/kg/day, maximum 2.5 mg/day) or placebo from 9 years of age. Those with evidence of ovarian failure at 12 years were further randomised to oral ethinylestradiol (year 1, 2 µg daily; year 2, 4 μg daily; year 3, 4 months each of 6, 8, and 10 μg daily) or placebo; participants who received placebo and those recruited after the age of 12.25 years started ethinylestradiol at age 14. Main outcome measure Final height. Results 106 participants were recruited, of whom 14 withdrew and 82/92 reached final height. Both oxandrolone and late pubertal induction increased final height: by 4.6 (95% confidence interval 1.9 to 7.2) cm (P=0.001, n=82) for oxandrolone and 3.8 (0.0 to 7.5) cm (P=0.05, n=48) for late pubertal induction with ethinylestradiol. In the 48 children who were randomised twice, the effects on final height (compared with placebo and early induction of puberty) of oxandrolone alone, late induction alone, and oxandrolone plus late induction were similar, averaging 7.1 (3.4 to 10.8) cm (P<0.001). No cases of virilisation were reported. Conclusion Oxandrolone had a positive effect on final height in girls with Turner’s syndrome treated with growth hormone, as did late pubertal induction with ethinylestradiol at age 14 years. However, these effects were not additive, so using both had no advantage. Oxandrolone could, therefore, be offered as an alternative to late pubertal induction for increasing final height in Turner’s syndrome. Trial registration Current Controlled Trials ISRCTN50343149.

A decade of growth hormone treatment in girls with Turner syndrome in the UK

Fifteen per cent of children treated with growth hormone (GH) are receiving treatment for Turner syndrome, but few results are available on final height in the UK. In this study, data were obtained from the UK KIGS database for 485 girls with Turner syndrome who were treated from 1986, allowing an audit of practice and outcome over 10 years. Over the decade, the mean age of starting growth hormone treatment fell from 10.4 to 8.5 years and the starting dose increased from 0.55 to 0.95 IU/kg/week. The frequency of injections increased from three to six or seven/week. Some girls received suboptimal doses, which also differed depending on whether they were based on weight or surface area. To assess what height gain might be expected at final height, all 52 girls who were prepubertal at the start of treatment, which continued for four years or more, and who had reached final height or had a growth velocity < 2 cm/year were selected. Their mean gain in final height was 5.2 cm and the GH dose was 0.78 IU/kg/week over 5.8 years. Final height gain correlated significantly with duration of treatment, total dose received, and first year response, which itself related to starting dose. This audit shows a changing pattern of treatment over the past decade, which in many instances has been inadequate. When treatment starts before puberty and continues through to final height, with a dose of 30 IU/m2/week in six or seven injections, a mean increase in final height of 5 cm or more would be expected.

A multicentre trial of recombinant growth hormone and low dose oestrogen in Turner syndrome: near final height analysis

BACKGROUND Turner syndrome accounts for 15–20% of childhood usage of growth hormone (GH) in the UK but final height benefit remains uncertain. The most effective strategy for oestrogen replacement is also unclear. METHODS Fifty eight girls who, at start of treatment, were of mean age 9.1 years and projected final height 142.2 cm were randomised to receive in year 1, either low dose ethinyloestradiol 50–75 ng/kg/day, GH 28 IU/m2 surface area/week as a daily injection, or a combination of ethinyloestradiol and GH. After the first year, the ethinyloestradiol treated girls received combination treatment. After two years, girls aged over 12 years were given escalating ethinyloestradiol to promote pubertal development. RESULTS Near final height was available for 49 girls at age 16.5 years, 146.8 cm, representing a gain of 4.6 cm, range −7.9 to +11.7 cm. Twelve of the 49 girls gaining 7.5 cm or more were less than 13 years at the start and had received GH for at least four years. Height gain was correlated with greater initial height deficit. Fifteen girls (31%) reached 150 cm or more compared to a predicted 10%. Early supplementation with ethinyloestradiol provided no final height advantage. CONCLUSIONS Final height gain was modest at 4.6 cm. Younger, shorter girls gained greatest height advantage from GH. Low dosage ethinyloestradiol before planned induction of puberty was not beneficial.

BLOODSPOT 17α-HYDROXYPROGESTERONE RADIOIMMUNOASSAY FOR DIAGNOSIS OF CONGENITAL ADRENAL HYPERPLASIA AND HOME MONITORING OF CORTICOSTEROID REPLACEMENT THERAPY

A convenient and inexpensive radioimmunoassay for bloodspot 17 alpha-hydroxyprogesterone (17-OHP) has been evaluated in the screening of newborn infants for congenital adrenal hyperplasia (CAH) and for home monitoring of CAH patients on steroid replacement therapy. In the screening study, analysis of 491 bloodspots taken for routine screening programmes for phenylketonuria and hypothyroidism established the upper limit of normal for infants aged 5-10 days as 64 nmol 17-OHP/l blood (99.9 centile). Home monitoring of patients by examination of fingerprick bloodspot 17-OHP profiles taken by parents over Saturday and Sunday on consecutive weekends showed that changes in control occurred as a result of transition from inpatient to outpatient treatment or following adjustment of steroid replacement regimens. The method was found to be valuable in the diagnosis and management of children with CAH.

Growth and metabolic consequences of growth hormone treatment in prepubertal short normal children.

Growth and the metabolic effects of growth hormone were monitored in a randomised, controlled group of 41 short, normal, prepubertal children. The treated group received daily injections of growth hormone as Genotropin (Kabi Pharmacia) 30 IU/m2/week. Fifteen children in the treated group (21 children) have completed three years of treatment, have grown significantly more than 14 (of 20) untreated children, and have a significantly greater adult height prediction. They do, however, remain leaner (body fat 13.5% in the treated group, 18% in the untreated group) and relatively hyperinsulinaemic (insulin 66.7 pmol/l in the treated group, 44.5 in the untreated group) after three years compared with untreated children. Although growth hormone appears to improve the height potential of prepubertal short normal children, the long term outcome is still uncertain.

Management of children and adolescents with diabetes requiring surgery

Department of Pediatrics, Uddevalla Hospital, Uddevalla,SwedenCorresponding author:Ragnar Hanas, MD, PhDDepartment of Pediatrics,Uddevalla Hospital,S-451 80 Uddevalla,Sweden.Tel: 146 522 92000;fax: 146 522 93149;e-mail: ragnar.hanas@vgregion.seConflicts of interest: SB is the owner of the New EnglandDiabetes and Endocrinology Center (NEDEC) and Presidentof New England Diabetes and Endocrinology ResearchFund, Incorporated (NEDERF, Inc.). He is a member of theadvisory panel, standing committee or board of directors:for American Diabetes Association (ADA), Juvenile DiabetesResearch Foundation (JDRF), International Diabetes Federation(IDF),International SocietyforPediatric andAdolescentDiabetes(ISPAD),AmericanAcademyofPediatrics(AAP),LawsonWilkinsPediatric Endocrine Society (LWPES); has received honorariaor speaker’s fees from Eli Lilly, Novo-Nordisk, Minimed,LifeScan, Genentech, Serono, Teva Pharmaceuticals; and hasreceived grants from Eli Lilly, Novo-Nordisk, NIH, SelfCare,InvernessMedical,MedicalFoods,Abbott-Medisense,LifeScan,Genentech, Pharmacia, Bristol-Squibb Myers, Pfizer, Serono,Johnson and Johnson. The remaining authors have declared noconflicts of interest.Editors of the ISPAD Clinical Practice Consensus Guidelines2009 comperdium: Ragnar Hanas, Kim Donaghue, GeorgeannaKlingensmith, Peter GF Swift.This article is a chapter in the

Biosynthetic human growth hormone treatment in the UK: an audit of current practice. Kabi Pharmacia International Growth Study.

Biosynthetic human growth hormone was licensed for use in the UK in 1985, shortly after the withdrawal of human pituitary derived growth hormone because of the risk of Creutzfelt-Jakob disease.1 The primary indication remains the treatment of short stature due to growth hormone deficiency; the short stature of Turners syndrome was a later approved indication. The release of biosynthetic growth hormone was paralleled by the cessation of the Health Service Human Growth Hormone Committee that had succeeded the Medical Research Council in supervising the selection of children for treatment. These bodies supported by a national network of growth centres had maintained a structured information base with the capacity for regular clinical audit.24 This mechanism became impractical with the dispersal of prescribing recommendations to many additional clinics. The premature demise of this mechanism has meant that, in relation to a costly health resource, we are unaware of the number of children treated with growth hormone, whether there are selection differences between major centres, whether children are treated early enough and with appropriate doses and frequency of injections, and whether they respond adequately. The Kabi Pharmacia International Growth Study (KIGS), an international postmarketing safety and efficacy study, provides growth hormone prescribing centres with the opportunity to review their own practice by comparison with national and international standards. The current KIGS database holds anonymised data on over 10 000 children of whom more than 1300 have been enrolled in the UK since 1988. Thus 30-40% of all children receiving growth hormone in the UK are entered into KIGS. In this paper the KIGS database has been used to compare practice in the UK with that in other European countries, to compare clinics within the UK, and to identify criteria that could be used in audit.