Pubertal abnormalities in adolescents with chronic disease.

Pubertal disorders in the context of chronic disease especially in those with chronic inflammatory disorders or those requiring prolonged periods of treatment with glucocorticoid are common reasons for referral to the paediatric endocrine clinic. Disorders of puberty are also common in adolescents with disability requiring management by paediatric endocrinologists. In these adolescents, impaired skeletal development is also observed and this can be associated with fragility fractures. Chronic inflammation, glucocorticoid and sub-optimal nutrition all impact on the hypothalamic-pituitary gonadal axis, and can also impact on skeletal development locally by their effects on the growth plate and bone. Addressing pubertal disorders is important to ensure adolescents with chronic disease are matched with their peers, promote adequate bone mass accrual and linear growth. Careful discussion with primary clinicians, the young person and the family is needed when instituting endocrine therapies to address puberty and manage bone health.

Gender differences in doxorubicin pharmacology for subjects with chemosensitive cancers of young adulthood.

PURPOSE: For many cancers, adolescents and young adults (AYA) have worse outcomes than for children and adults. Many factors may contribute to the AYA survival gap, including differences in biology, therapeutic intent, and adherence to therapy. It has been observed that male AYAs have poorer outcomes than females. The purpose of this work was to test the proposition that gender-related pharmacologic factors may account for a component of the AYA survival gap. PATIENTS AND METHODS: A prospective, multi-institutional pharmacologic study of 79 patients in total with chemosensitive cancers (Ewing sarcoma, osteosarcoma and Hodgkin lymphoma) was conducted, with conventional doxorubicin treatment. Pharmacokinetic data of 13 children, 40 AYAs and 13 adults were valid for analysis. Population pharmacokinetics models were developed for doxorubicin and its metabolite doxorubicinol based on the data created in this study. Consequently, model-based analysis was conducted to investigate the relevant topics. RESULTS: The clearance of doxorubicinol (normalized to body surface area), the main active metabolite of doxorubicin, appears faster in male AYAs than female (p = 0.04, 95% CI 0.1-3.9 L/h). The exposure of doxorubicinol (normalized to dose) is lower in male AYA than female (p = 0.03, 95% CI - 0.005 to - 0.0002 h/L). These might be correlated to the observed difference on nadir neutrophil count between male AYA and female (p = 0.027, 95% CI 0.09-1.4). CONCLUSION: Gender-related differences in doxorubicin pharmacology may account for worse outcomes for male AYAs with chemosensitive cancers compared to females. These findings may reduce the AYA survival gap compared to other age groups.

Growth hormone effects on cortical bone dimensions in young adults with childhood-onset growth hormone deficiency.

UNLABELLED: Growth hormone (GH) treatment in young adults with childhood-onset GH deficiency has beneficial effects on bone mass. The present study shows that cortical bone dimensions also benefit from GH treatment, with endosteal expansion and increased cortical thickness leading to improved bone strength. INTRODUCTION: In young adults with childhood-onset growth hormone deficiency (CO GHD), GH treatment after final height is reached has been shown to have beneficial effects on spine and hip bone mineral density. The objective of the study was to evaluate the influence of GH on cortical bone dimensions. METHODS: Patients (n = 160; mean age, 21.2 years; 63% males) with CO GHD were randomised 2:1 to GH or no treatment for 24 months. Cortical bone dimensions were evaluated by digital x-ray radiogrammetry of the metacarpal bones every 6 months. RESULTS: After 24 months, cortical thickness was increased compared with the controls (6.43%, CI 3.34 to 9.61%; p = 0.0001) and metacarpal index (MCI) (6.14%, CI 3.95 to 8.38%; p < 0.0001), while the endosteal diameter decreased (-4.64%, CI -7.15 to -2.05; p < 0.001). Total bone width did not change significantly (0.68%, CI -1.17 to 2.57%; not significant (NS)). A gender effect was seen on bone width (p < 0.0001), endosteal diameter (p < 0.01) and cortical thickness (p < 0.01), but not with MCI (NS). CONCLUSIONS: Cortical bone reacts promptly to reinstitution of GH beyond the attainment of final height by increasing the cortical thickness through endosteal bone growth. This leads to a higher peak bone mass and may reduce the risk of cortical bone fragility later in life.

Pregnancy in a woman with proportionate (primordial) dwarfism: a case report and literature review.

Primordial dwarfism is a rare form of severe proportionate dwarfism which poses significant challenges in pregnancy. A 27-year-old with primordial dwarfism (height 97 cm, weight 22 kg) and coexisting morbidities of familial hypercholesterolaemia and hypertension presented to our unit. Early pregnancy was complicated by difficult blood pressure control, sinus tachycardia, biochemical hyperthyroidism and insulin-requiring gestational diabetes. Delivery was indicated at 24 weeks with uncontrollable hypertension, progressive renal impairment and intrauterine growth restriction. A caesarean section was performed under general anaesthesia, resulting in the delivery of a 486 g male infant. This case highlights the difficulties of managing pregnancy in a woman with primordial dwarfism. Her limited capacity to respond to the physiological demands of pregnancy created a life-threatening situation, culminating in profound preterm birth.

Disorders of ovarian function in childhood and adolescence: evolving needs of the growing child. An endocrine perspective.

Over the past 15 years there have been changes in the care of children and adolescents paralleling increased longevity of those with chronic illnesses and increased survival after childhood cancer and organ transplantation. A broad understanding of holistic management and long-term risks is required. Optimisation of pubertal progress and normalisation of bone and hormonal health by the end of puberty will reduce the impact of later adult bone loss in chronic disease conditions. Psychosocial issues related to both precocious and delayed puberty can have profound effects on family function.

Safety and efficacy of intravenous zoledronic acid in paediatric osteoporosis.

AIM: To study the safety and efficacy of zoledronic acid treatment in children with osteoporotic bone disorders. STUDY DESIGN: Observational study in 22 patients with osteogenesis imperfecta and related conditions who were treated at our institution with zoledronic acid. These patients had initial treatment with pamidronate. Lumbar spine z-scores, annual change in areal bone mineral density, bone mineral adjusted density, fracture number and linear growth before and after zoledronic acid treatment was commenced were compared. RESULTS: Patients were treated for a mean of 3.4 years with zoledronic acid after a mean of 3.75 years of pamidronate therapy. There was no difference in areal bone mineral density accrual in the first year of zoledronic acid treatment compared to the preceding year of pamidronate treatment. Lumbar spine z-scores and bone mineral adjusted density continued to increase with zoledronic acid. Number of fractures during treatment was significantly reduced compared to baseline with either bisphosphonate, with no difference between treatments. Linear growth was not affected. CONCLUSIONS: Zoledronic acid is at least as effective as pamidronate as treatment for paediatric osteoporosis, and has a similar safety profile.

Treatment for 24 months with recombinant human GH has a beneficial effect on bone mineral density in young adults with childhood-onset GH deficiency.

OBJECTIVE: Discontinuation of growth hormone (GH) therapy on completion of linear growth may adversely affect bone mineral density (BMD) in young adults with childhood-onset GH-deficiency (GHD). In the present study, we analyzed the impact of GH treatment on bone in young adults with GHD. METHODS: BMD at the lumbar spine (L2-L4), total hip, and total body was measured at baseline and after 24 months in a cohort of young adults (18-25 years; n=160) with severe GHD treated with GH during childhood who were randomized to GH (n=109) or no treatment (n=51) in a multicenter, multinational, open-label study. GH starting doses (0.2 mg/day (males), 0.4 mg/day (females)) were increased after 1 month to 0.6 mg/day (males) and 0.9 mg/day (females) and then to 1.0 mg/day (males) and 1.4 mg/day (females) at 3 months for the remainder of the study. RESULTS: After 24 months, lumbar spine BMD had increased significantly more in GH-treated patients than in controls (6 vs 2%; estimated treatment difference; 3.5% (95% confidence interval, 1.52-5.51) P<0.001). GH also had a significant positive effect on total hip BMD (P=0.015). Total body BMD was unchanged from baseline (P=0.315). CONCLUSIONS: In young adults treated for childhood-onset GHD, there is a beneficial effect of continued GH treatment on BMD in adult life. Twenty-four months of GH treatment in these young adults was associated with an estimated 3.5% greater increase in BMD of the lumbar spine compared with controls.

Current concepts in bone and reproductive health in adolescents with anorexia nervosa.

Anorexia nervosa (AN) initiates an adaptive response at the level of the hypothalamus, which results in a complex interplay involving most elements of the neuroendocrine axis. Consequences of onset of disease in adolescence include amenorrhoea, pubertal arrest with potential loss of target height, and osteoporosis with reduced capacity for future attainment of peak bone mass. With recovery, delay in restoration of menses is common. Hormonal therapies for restoration of bone mineral density (BMD) in adolescents have shown limited efficacy. This review will discuss the reproductive endocrine effects of AN in adolescence, and discuss new investigative tools for monitoring restoration of reproductive function and BMD in this population.

Bisphosphonate-associated osteonecrosis of the jaw: does it occur in children?

BACKGROUND: Bisphosphonate use in adult patients has been linked to osteonecrosis of the jaw (ONJ). This complication has not been systematically assessed in a paediatric population receiving bisphosphonates. OBJECTIVE: To assess our cohort of paediatric patients treated with intravenous bisphosphonate for occurrence of ONJ. DESIGN: Observational study at a tertiary children's hospital. PATIENTS: A total of 42 paediatric patients with osteoporosis who received bisphosphonate infusions for a mean of 6.5 years (SD 2.7 years) were assessed clinically and radiographically for possible ONJ. Among 42, 37 patients had received disodium pamidronate 1 mg/kg/dose at a mean cumulative dose of 19.8 mg/kg and zoledronic acid (ZA) 0.05 mg/kg/dose at a mean cumulative dose of 0.49 mg/kg; four had received ZA and one received pamidronate alone. Invasive dental treatment during bisphosphonate treatment, a known risk factor for osteonecrosis, was specifically assessed. RESULTS: In all patients assessed, including 11 who had invasive dental treatment, there were no cases of osteonecrosis. CONCLUSION: ONJ has so far not been demonstrated in this patient group.

Pituitary function in paediatric survivors of severe traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI)-mediated hypopituitarism is an increasingly recognised problem. Paediatric survivors of TBI may be vulnerable to the possible effects of pituitary deficits as pituitary hormones control normal growth and development. Research concerning pituitary dysfunction following childhood TBI is limited. AIM: To identify pituitary dysfunction in paediatric survivors of severe TBI. METHODS: Of 1020 children who sustained a TBI and were admitted to the Royal Children's Hospital, Melbourne, Australia over 10 years, 117 were identified as survivors of severe TBI. 54 patients (31 males) were enrolled and administered questionnaires regarding quality of life and possible endocrine dysfunction. Where indicated, hormone testing was performed. RESULTS: 29 of the 54 patients underwent hormonal investigations, while 21 who had satisfactory questionnaires did not (four patients had already been diagnosed with pituitary deficiencies). In those 29 patients, TBI occurred at ages ranging from 0.25 to 16.80 years (median 9.7 years). Time from TBI to study ranged from 0.9 to 8.5 years (median 4.5 years). Of the 54 patients, nine had pituitary dysfunction, of whom four had multiple pituitary hormone deficiencies. CONCLUSIONS: Our study that confirms that paediatric survivors of severe TBI may develop pituitary dysfunction. Pituitary function should therefore be determined in these patients.

Management of paediatric thyroid carcinoma: recent experience with recombinant human thyroid stimulating hormone in preparation for radioiodine therapy.

BACKGROUND: Thyroid carcinoma in children is rare and raises unique management issues. Although metastatic disease is more common in this age group, prognosis remains good with appropriate treatment. The aim of the study was to report recent experience in the management of differentiated thyroid carcinoma in children, especially in the use of radioiodine after recombinant human thyroid stimulating hormone (rhTSH) stimulation. METHODS: Eight patients, aged 5-17 years (five were boys) presented following total thyroidectomy for thyroid carcinoma between May 2003 and June 2005. Seven had papillary carcinoma and one had follicular carcinoma. Five had known lymph node metastases and one had pulmonary metastases at presentation. Four patients had previously received therapeutic irradiation for malignancy. All eight underwent diagnostic iodine scans, seven with rhTSH stimulation. Seven went on to receive radioiodine treatment as hospital inpatients, comanaged by the paediatric and nuclear medicine units. The dosage of 131I ranged from 1.5 to 3.7 x 10(9) Bq. All except one were prepared by rhTSH stimulation. RESULTS: Seven of eight patients had significant uptake in the neck on diagnostic scan and two had pulmonary abnormalities. Six of seven evaluable patients achieved complete thyroid ablation. Both patients with pulmonary abnormalities had scan resolution, although one of them only after a second radioiodine treatment. All patients had thyroxine replacement in doses to suppress TSH and all remain alive and well at time of carrying out this study. CONCLUSION: Optimal management of paediatric thyroid carcinoma necessitates a multidisciplinary approach. Radioiodine therapy under rhTSH is an effective and safe adjuvant treatment in this special subgroup.

The psychosocial impact of Klinefelter syndrome--a 10 year review.

OBJECTIVE: To describe psychosocial morbidity in a cohort of young males with hypogonadism due to Klinefelter syndrome, to document the effect of androgen replacement on behaviour, to underline issues confronting clinicians involved in treatment of this condition and to demonstrate a need for a structured program for prospective intervention for this group. We also compare this group to young men with hypogonadotrophic hypogonadism. DESIGN: A retrospective audit of patients with Klinefelter and Kallmann syndromes, presenting for medical assessment from 1994-2004. PATIENTS: Postpubertal males with Klinefelter syndrome (n = 32) and Kallmann syndrome (n = 19) were audited by chart review for psychosocial comorbidities, pubertal management, and the need for exogenous testosterone. RESULTS: Seventeen of 32 postpubertal patients with Klinefelter syndrome required testosterone therapy while 11 were documented to have serum testosterone in the normal adult range. All patients with Kallmann syndrome required long term testosterone treatment. Significant psychosocial and behavioural problems were present in 22/32 of patients with Klinefelter syndrome, including seven who were testosterone replete, with an identifiable pattern of disorder, including marked lack of insight, poor judgement and impaired ability to learn from adverse experience. Use of long term replacement testosterone treatment reduced episodes of behavioural indiscretion. Of those patients with Kallmann syndrome, 5/19 reported mild depressive symptoms only, all resolving with testosterone replacement. CONCLUSION: Inadequately treated hypogonadism in Klinefelter syndrome increases recognized psychosocial morbidity. There is a need for prospectively planned and timed support for young men with Klinefelter syndrome, to ameliorate current poor psychosocial outcomes.

Dexamphetamine use for management of obesity and hypersomnolence following hypothalamic injury.

UNLABELLED: Unrelenting weight gain, morbid obesity and disturbance of the sleep-wake cycle are well-recognized sequelae of hypothalamic injury. These health problems and their risk of significant associated co-morbidity drive the search for potential treatment modalities. OBJECTIVE: To report effects on weight change and wakefulness in a cohort of 12 patients with structural hypothalamic lesions treated with low-dose dexamphetamine. METHOD: Retrospective review of case notes. RESULTS: Twelve patients received dexamphetamine 5 mg twice daily (median duration 13 months in males, 15 months in females). Ten of 12 patients experienced either stabilisation of weight or weight loss on treatment (median loss -0.7 SDS in males, -0.44 SDS in females). Eleven patients reported improvement in daytime wakefulness and/or concentration and exercise tolerance. CONCLUSION: Low-dose dexamphetamine therapy has a positive impact on inexorable weight gain and daytime somnolence following hypothalamic injury.

Health related quality of life and psychological outcome in patients treated for craniopharyngioma in childhood.

UNLABELLED: Patients with craniopharyngioma are at risk for many adverse effects related to the tumour's invasive behaviour and its proximity to many vital structures. Profound psychosocial problems, memory impairment, pituitary and hypothalamic dysfunction in addition to the physical handicap of visual loss are frequently recognized sequelae of craniopharyngioma treatment. OBJECTIVES: To examine health related quality of life (QoL) and psychological outcomes of patients treated for craniopharyngioma at the Royal Children's Hospital, Melbourne, between January 1980 and September 2003. PATIENTS: Seven (17.4%) of 46 (26 male) had died. Thirty-nine remained, of whom 30 were contactable. Eighteen of 30 (8 male), mean age 21.2 +/- 6.7 years, agreed to evaluation, of whom 16/18 (88.9%) had three or more pituitary hormone deficiencies, 11/18 had visual impairment and 9/18 obesity. MEASUREMENTS: The Adult GH-Deficient Assessment (AGHDA) and Psychological General Well-Being (PGWB) questionnaires were employed to assess quality of life in patients and age- and sex-matched healthy controls. Additional psychological assessment, including intellectual and academic skills, emotional function, and adaptive behaviour, had been undertaken in 12 patients at a previous time. RESULTS: High levels of physical morbidity and psychological disability were described. The General Health score of patients was significantly worse than for controls on PGWB (p = 0.025), anxiety was higher in those who had surgery alone (p = 0.008) and subjective QoL associated with GHD using AGHDA was lower (p = 0.006). Few craniopharyngioma survivors (18/30) were available for evaluation, demonstrating difficulties in attempts to assess this complex group. The discrepancy between results of objective and subjective measures of QoL is discussed in terms of adaptation to illness, disabilities and changed perception of life fulfilment. CONCLUSIONS: Craniopharyngioma and its treatment result in significant, complex medical, social, psychological and emotional difficulties. The degree of global disability is not reflected in subjective QoL reports for this group, highlighting the need for careful selection of assessment instruments.

Health-care problems of Turner syndrome in the adult woman: a cross sectional study of a Victorian cohort and a case for transition.

The aim of this study was to assess current care and to survey comorbidity in a cohort of 39 adult women with Turner syndrome in Victoria. Patients with Turner syndrome (TS) drift away from medical care as they achieve adulthood, despite the need for regular surveillance and management of associated conditions, which would reduce morbidity and prevent complications. Clinical assessment was undertaken for 39 women with TS, mean age 30.1 (+/-11.7) years and information was gathered through personal communication regarding past growth hormone use, oestrogen treatment, hearing loss and health problems. Twenty-four (63.2%) had regular follow-up, but only 17 (43.6%) had adequate recommended surveillance for comorbidities. Forty-three percent had two or more cardiovascular risk factors. Thirty-four (87.2%) were identified with one or more associated disorders. Uterine size was of normal adult dimensions in patients who had received oestrogen before age of 15 years. Adult care for adults with TS is suboptimal and assessment of comorbidities remains sporadic. Adequate transition guidelines and patient education are needed for long-term management of women with TS, to impact on quality of life and longevity.