Clinical features, diagnosis, treatment and molecular studies in paediatric Cushing's syndrome due to primary nodular adrenocortical hyperplasia.

BACKGROUND: Primary nodular adrenocortical hyperplasia (PNAH) is a well recognized, but infrequently studied cause of paediatric Cushing's syndrome (CS). OBJECTIVE: To assess presentation, diagnosis, radiological imaging, treatment and molecular analysis of patients with childhood-onset CS due to PNAH. PATIENTS: Four males and two females (median age 12.9 years, range 10.9-16.9 years) were studied. RESULTS: All had growth failure (mean height SDS -1.2; range -2.5-0.0), weight gain [mean body mass index (BMI) SDS 3.5; range 2.5-4.6] and clinical virilization, while five had hypertension [mean systolic blood pressure (SBP) 130 mmHg, diastolic blood pressure (DBP) 83 mmHg]. One patient had generalized lentigines, one had a tibial chondromyxomatous cyst and two had facial freckling. One patient had a family history of primary nodular adrenocortical disease. The diagnosis of CS was based on elevation of sleeping midnight serum cortisol and urinary free cortisol excretion, and impaired suppression of cortisol on both low- and high-dose dexamethasone suppression tests (DST). All patients had undetectable plasma ACTH with absent responses of both plasma ACTH and serum cortisol to an intravenous (i.v.) corticotrophin-releasing hormone (CRH) test. Computed tomography or magnetic resonance imaging showed normal or small adrenals, with nodules in two patients. All patients underwent bilateral adrenalectomy, performed by open (n = 2) or laparoscopic surgery (n = 4) at a mean of 0.4 years (range 0.2-0.8 years) from diagnosis. Hypercortisolaemia was treated preoperatively by metyrapone alone 0.50-0.75 g/day (n = 4), metyrapone 0.75-1.50 g/day + o'p'DDD/mitotane 1-2 g/day (n = 1), or ketoconazole (n = 1). Adrenal histology showed nodular cortical hyperplasia with shrinkage of intervening cortical tissue and pigmentation, present in four patients. Molecular analysis of the type 1-alpha regulatory subunit of protein kinase A (PRKAR1A) gene revealed a novel germline mutation in one patient. Postadrenalectomy, three patients, had catch-up growth with height velocities increasing from 3.0, 3.9 and 2.5-8.9, 8.3 and 9.0 cm/years, respectively. All six are well at a follow-up (mean 4.0 years; range 0.5-10.8 years). CONCLUSIONS: PNAH was associated with cushingoid features, virilization and hypertension with a lack of cortisol suppression on high DST, undetectable plasma ACTH and absent cortisol and ACTH responses to CRH. Adrenals were normal or small on imaging. PRKAR1A gene analysis may be helpful in the assessment of these patients.

An assessment of pancreatic endocrine function and insulin sensitivity in patients with transient neonatal diabetes in remission.

AIMS: To examine derived indices of beta cell function, peripheral insulin sensitivity, and the pancreatic response to intravenous glucose loading in children with a previous history of transient neonatal diabetes currently in remission, repeated after a period of two or more years. METHODS: The standard intravenous glucose tolerance test (IVGTT) was used to measure the first phase insulin response (FPIR) cumulatively at one and three minutes. In addition, fasting insulin and glucose values were used to estimate insulinogenic indices (beta cell function) and QUICKI (insulin sensitivity). PATIENTS: Six patients with known previous transient neonatal diabetes currently in remission with no exogenous insulin requirement were tested. Control data from 15 children of a similar age were available for derived fasting indices of beta cell functional capacity and insulin sensitivity. RESULTS: One child had a subnormal insulin secretory response to intravenous glucose that remained abnormal two and four years later. The other children had relatively normal or entirely normal responses over two years. Measures of beta cell function and insulin sensitivity in the fasting state showed comparable results to those obtained from normal controls. CONCLUSIONS: Most children with transient neonatal diabetes in remission have no evidence of beta cell dysfunction or insulin resistance in the fasting state, although they might have been expected to show subtle defects given the tendency to relapse in adolescence. Measures of insulin response to intravenous glucose loading are often normal but suggest future recurrence if profoundly abnormal.

Diabetes care in childhood and adolescence.

The presentation of diabetes in young people has changed significantly over recent years. Not only has there been a rising incidence of Type 1 diabetes, especially in young children, but also there is an increasing recognition of Type 2 diabetes. Young people are also increasingly being diagnosed with genetic defects of B-cell function and with diabetes in association with cystic fibrosis and other chronic diseases. There have also been significant changes in the pattern of paediatric diabetes care. This is increasingly being provided by a specialized paediatric multidisciplinary team in each health district working to agreed national standards. Despite improvements, diabetes control is still suboptimal with a high incidence of complications being reported in young adults. The challenge over the next few years is the provision of a uniform, equitable and first class paediatric service throughout the UK together with the introduction of new approaches to care, aiming to improve individual diabetic control and reduce long-term complications. Increased collaboration with adult colleagues is needed to enable the transition of care in adolescence to a service that young adults perceive to meet their needs, encourage their attendance and improve their diabetes control and quality of life. A national paediatric diabetes register together with regular audit will encourage these objectives.

Type 2 diabetes in obese white children.

We report four white adolescents aged 13 to 15 years (three females, one male) from the south and west region of England who presented with type 2 diabetes mellitus associated with significant obesity (body mass index more than +3SDS) in the past two years. Although these are the first reported obese, white cases from the UK to present with diabetes, we believe this clinical scenario will become more prevalent given the epidemic of childhood obesity in this country.

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.

Hormones and handedness.

BACKGROUND: The Wessex Growth Study has monitored the growth and psychological development of short normal (SN) and average height control subjects since they entered school in 1985/1986. During psychometric testing, we found that 25% SN compared to 9% control subjects wrote with their left hand. The short group also attained significantly lower scores on measures of IQ and attainment and displayed less internalisation of control. Laterality, however, is thought to be influenced by the intrauterine environment and has been associated with pubertal delay. At recruitment, short children had a relatively low birth weight, delayed bone age and were more likely than controls to be short for family. OBJECTIVES: To determine if birth conditions were associated with lateral preference and whether laterality could account for the differences found during the psychometric assessment or predict pubertal timing of SN children. METHODS: Subjects were classified as right- (RH) or left-handed (LH) according to the writing hand and the data were investigated examining the effect of handedness and stature. RESULTS: RH and LH SN children were no more likely to suffer birth complications than those of average height. Psychometric testing did not reveal any significant differences between RH and LH SN children and their patterns of growth appeared to be similar. However, both RH and LH SN children scored less well on tests of cognitive ability and analyses of covariance revealed significant gender/handedness effects for both the timing of puberty and final height. CONCLUSIONS: The increase in left-handedness among SN children did not appear to be related to adverse birth conditions, but it may be that the hormones responsible for growth and development also play some part in brain laterality and cognitive development.

An assessment of paediatric diabetes care in three centres in Russia and in Southampton, UK. The Paediatric Teams in Moscow, Tula, Tambov, Southampton.

AIMS: Young people in Russia with diabetes have an increased morbidity and a 10-fold increase in mortality compared with many European countries. This joint international study was set up to compare of care and outcomes against published guidelines in three Russian centres and one UK centre. METHODS: An assessment of the diabetic care of 368 children, based on the principles of the St Vincent Declaration, was undertaken in each centre. Data on prevalence, management, control and complications were collected in young people with diabetes < 16 years of age in each of the four centres over a 4-week period. RESULTS: The prevalence of diabetes was greater in Southampton (1:702 vs. 1:1378). At diagnosis Russian children had a higher incidence of ketoacidosis (69 vs. 29%) and stayed in hospital longer (30 vs. 3 days). In management Russian children received more injections per day (5 vs. 2). There was no significant difference in insulin dose for those under 10 years between countries (Southampton 0.69 U/kg vs. Russian 0.73 U/kg, P=NS). Older Russian children did not increase their insulin dosage, while children over 10 years in Southampton received significantly more insulin than the Russian children (Southampton 1.0 U/kg vs. Russian 0.77 U/kg, P< or =0.001). Twenty-nine per cent of the Russian children reported that they had insufficient insulin and 14% had to buy extra. HbA1c was higher in the Russian children (9.8% vs. 8.3%), increasing significantly with age. The Russian children showed a height deficit which correlated with HbA1c and diabetes duration. The Southampton children were heavier and with a higher body-mass index and their HbA1c did not rise similarly as in Russia. Severe hypoglycaemia was more common in the Southampton children (32 vs. 12%). Retinopathy was reported in 12% of the Russian children (Southampton 0%) and systolic blood pressure > 95th centile in 21% (Southampton 8%). CONCLUSIONS: This study demonstrates a significant difference in diabetic control and complications between the two countries which could be partially explained by a decreased availability and prescribing of insulin and blood glucose monitoring in Russia. Southampton has an education and management policy based on ambulatory care resulting in reduced hospital stay.

A decade of growth hormone treatment in girls with Turner syndrome in the UK. UK KIGS Executive Group.

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.

Pubertal growth of the short normal girl.

OBJECTIVES: To determine the timing, magnitude and duration of the pubertal spurt for short normal and average height girls, to compare these with Tanner's standard and to investigate predictors of pubertal growth. METHODS: The growth of 46 short normal and 55 control girls, identified at school entry, was monitored throughout puberty. Height and weight were measured at 6-month intervals from which body mass index (BMI) was derived. Annual velocities were calculated and used to estimate the age and magnitude of peak height velocity (PHV). Age of menarche was recorded to the nearest month. Parents provided information on the child's medical and social history. RESULTS: The mean age at PHV, the magnitude of PHV and age at menarche were similar for both groups and close to Tanner's 50th centile values. Pre-pubertal BMI predicted age at menarche for short and control girls, accounting for 17% of the variance. There was a tendency for early maturing girls of average stature to have greater PHV. However, this relationship was not observed in short girls, nor did any other variable, genetic or environmental, predict the timing or magnitude of their pubertal spurt. CONCLUSIONS: Delayed puberty in short normal girls is unlikely and their growth during puberty is comparable to girls of average height. The pubertal variables measured remain close to Tanner's original standards for both groups, suggesting the lack of a secular trend towards earlier puberty in girls. The onset of menstruation is influenced by pre-pubertal BMI. However, the clinician should be aware that short normal girls have normal pubertal growth and that no genetic or environmental variable can predict the timing or magnitude of their growth spurt.

Randomised trial of growth hormone in short normal girls.

BACKGROUND: There are few data on the long-term outcome of growth-hormone treatment in short normal children. We assessed the impact of growth-hormone treatment on pubertal development and near-final height in girls. METHODS: In a randomised controlled trial, we studied ten girls, with a mean age of 8.07 years and height 2 SDs or more below the mean for their age, and eight short untreated controls matched for age, and 20 short untreated girls who did not give consent for randomisation. The girls received either 30 IU/m2 somatropin per week as daily subcutaneous injections or no treatment. We assessed pubertal staging and height gain every 6 months. FINDINGS: Eight treated girls completed a mean of 6.2 years' therapy. By a mean age of 16.4 years, their mean height SD score had changed significantly from -2.42 to -1.14 (p=0.008) and they were, on average, 7.5 cm taller than the girls in the control group (height SD scores did not change significantly from -2.55) and 6.0 cm taller than the non-consent group. The timing of each pubertal stage, and the age and amplitude of peak height velocity were similar for all groups. INTERPRETATION: Growth-hormone therapy effectively increased height SD score among short normal girls started on treatment in early to mid childhood, with no untoward effect on pubertal progression.

Short stature at school entry--an index of social deprivation? (The Wessex Growth Study).

This study was carried out to examine the biological and environmental variables associated with non-organic short stature. We observed an unselected population of very short normal children (SN) and their age- and sex-matched controls (C) within the community. All 14,346 children in two health districts entering school during 2 consecutive years were screened for short stature, and those whose height lay below the 3rd centile, according to Tanner and Whitehouse standards (n = 180) were identified. Excluding 32 with pathology, five from ethnic minorities and three who refused to take part, the remaining SN children (mean height SDS-2.26) were matched with 140 age- and sex-matched controls (C) of average height (mean height SDs 0.14). Birth weight, target height and predicted adult height (based on parental height and bone age respectively), medical and social background (obtained from parental interviews), and school performance (assessed by class teachers) were the main outcome measures. Mean birth weight of the SN children was significantly lower than C (SN = 2845 g, C = 3337 g, P < 0.001). Mean mid-parental target height was also very different (SN = 162.0 cm, C = 170.9 cm, P < 0.001). Thirty-five per cent of SN children (C = 6%) had height SD scores below parental target range, though only 10% had predicted heights below target range (mean delay in bone age 0.68 years). There was a significant difference between SN children and C in the number of children in the household (SN = 2.8, C = 2.4 (P = 0.007) and in socio-economic status (P < 0.002). Many more SN children were in social classes IV and V (SN = 31%, C = 13%, P < 0.002), and had an unemployed father (SN = 22%, C = 10%, P < 0.010), highlighting the importance of environmental influences on growth. One in four SN children was judged to have serious psychosocial problems. However, the lower the socio-economic class, the less likely the SN children were to be inappropriately short for parents. Significantly more SN children were reported to have asthma (SN = 18%, C = 7%, P < 0.007) and eczema (SN = 19%, C = 5%, P < 0.001), though only the latter was significantly associated with stature below target height for both SN and C groups. Biological variables are often insufficient to explain short stature. No child, whatever the parental height, should be dismissed as normal without careful evaluation, as poor growth in the early years may be an important pointer to an adverse but potentially remediable environment.

Growth monitoring: testing the new guidelines.

OBJECTIVE: To assess the impact of recent guidelines from the UK joint working party of child health surveillance recommending that all children be measured at age 5 and again between 7 and 9 years of age to determine how many normal school age children are likely to be referred for specialist assessment. METHODS: The longitudinal data of 486 children measured by school nurses in a community setting were examined and compared with measurements made in a research setting by a single, skilled observer. MAIN OUTCOME MEASURES: Number of children identified as having abnormal stature (< 0.4th or > 99.6th centile) and abnormal growth rate height standard deviation score (HSDS) change > 0.67). RESULTS: The community survey identified seven (1.4%) children as having abnormal stature (four short, three tall), 11 (2.3%) were identified as "slow growing", and nine (1.9%) increased their HSDS by more than 0.67. These results were comparable to data collected in ideal research conditions. CONCLUSIONS: Following the recommendations would not result in an excess number of inappropriate referrals. However, this study highlights several unresolved issues such as interobserver variability and time interval between measurements. A large scale prospective study should be considered to establish realistic and cost-effective criteria before implementation of a national screening programme.

Are short normal children at a disadvantage? The Wessex growth study.

OBJECTIVE: To examine whether short stature through childhood represents a disadvantage at around 12 years. DESIGN: Longitudinal non-intervention study of the physical and psychological development of children recruited from the community in 1986-7 after entry into primary school at age 5-6 years; this is the second psychometric assessment made in 1994-5 after entry into secondary school at age 11-13 years. SETTING: Southampton and Winchester health districts. SUBJECTS: 106 short normal children (< 3rd centile for height when recruited) and 119 controls of average stature (10th-90th centile). MAIN OUTCOME MEASURES: Psychometric measures of cognitive development, self concept development, behaviour, and locus of control. RESULTS: The short children did not differ significantly from the control children on measures of self esteem (19.4 v 20.2), self perception (104.2 v 102.4), parents' perception (46.9 v 47.0), or behaviour (6.8 v 5.3). The short children achieved significantly lower scores on measures of intelligence quotient (IQ) (102.6 v 108.6; P < 0.005), reading attainment (44.3 v 47.9; P < 0.002), and basic number skills (40.2 v 43.5; P < 0.003) and displayed less internalisation of control (16.6 v 14.3; P < 0.001) and less satisfaction with their height (P < 0.0001). More short than control children, however, came from working class homes (P < 0.05). Social class was a better predictor than height of all measures except that of body satisfaction. Attainment scores were predicted by class and IQ together rather than by height. Height accounted for some of the variance in IQ and locus of control scores. CONCLUSIONS: These results provide only limited support for the hypothesis that short children are disadvantaged, at least up until 11-13 years old. Social class seems to have more influence than height on children's psychological development.

Psychological response to growth hormone treatment in short normal children.

This study provides a controlled assessment of the psychological (and physical) effects of growth hormone treatment. Fifteen short 'normal' children (height SD score < -2) have been treated with growth hormone since the age of 7/8 years. They, together with untreated short controls and average controls (10th-90th centiles), were assessed at recruitment, after three years, and after five years. Only the treated group showed a significant height increase (SD score -2.44 to -1.21 over five years). No significant differences were found at recruitment, three years, or five years in IQ, attainment, behaviour, or self esteem. Also at five years, there were no significant differences in locus of control, self perception, or parental perceptions of competence. Both short groups displayed less satisfaction with their height than the controls (p < 0.01), though all groups were optimistic of being tall adults. The treated children were no more unrealistic over final height than the untreated children. To date, no psychological benefits of treatment have been demonstrated; but nor have there been any discernible ill effects for either the treated or the untreated children.

Reliability of infant length measurement.

The reliability of length measurement was determined in 38 infants less than 1 year of age. The SD of a single length measurement was 0.28 cm at birth and 0.42 cm both at 6 weeks and at 8 months of age, comparable with the SD of a single height measurement in previously reported older children. There is no technical reason to prevent reliable measurement of young infants.

Cardiac effects of growth hormone in short normal children: results after four years of treatment.

Growth hormone excess is known to have adverse effects on the heart. The long term cardiac effects of growth hormone given to short normal children as part of a prospective randomised controlled trial of growth hormone treatment (Genotropin 30 IU/m2/week v no treatment) were therefore investigated. Echocardiographic findings are presented for 28 children who have been followed up for a minimum of four years. At the outset, the treated (n = 15) and untreated groups (n = 13) did not differ for any anthropometric or echocardiographic parameter. Their mean (SD) age at onset was 7.8 (0.5) years. After four years of treatment mean height SD score increased from -2.4 to -1.2 compared with no change (-2.5) in the untreated group. Left ventricular posterior wall and septal thickness and left ventricular shortening fraction did not differ between the groups, but a tendency towards increased left ventricular mass was seen in the treatment group (93 v 73 g). No such differential was observed after indexing left ventricular mass for body surface area (79 v 71 g/m2) or lean body mass (3.15 v 3.05 g/kg). It is concluded that prolonged growth hormone treatment does not cause important changes to the heart. A tendency towards increased left ventricular mass simply reflects the increase in lean body mass during treatment.

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.