Consensus guidelines on the use of bisphosphonate therapy in children and adolescents.

Bisphosphonate therapy is the mainstay of pharmacological intervention in young people with skeletal fragility. The evidence of its use in a variety of conditions remains limited despite over three decades of clinical experience. On behalf of the Australasian Paediatric Endocrine Group, this evidence-based consensus guideline presents recommendations and discusses the graded evidence (using the GRADE system) for these recommendations. Primary bone fragility disorders such as osteogenesis imperfecta are considered separately from osteoporosis secondary to other clinical conditions (such as cerebral palsy, Duchenne muscular dystrophy). The use of bisphosphonates in non-fragility conditions, such as fibrous dysplasia, avascular necrosis, bone cysts and hypercalcaemia, is also discussed. While these guidelines provide an evidence-based approach where possible, further research is required in all clinical applications in order to strengthen the recommendations made.

A short report on current fertility preservation strategies for boys.

BACKGROUND: Advances in cancer treatment have led to improved long-term survival after childhood cancer, but often at a price of impaired future fertility. Fertility preservation (FP) in male children and early adolescents poses unique challenges as efficacy is unproven. OBJECTIVES: To describe characteristics of testicular tissue cryopreservation (TTCP) specimens taken from paediatric and adolescent patients, stratified by age, and prior chemotherapy, if any, and to demonstrate evidence for germ cells. MATERIALS AND METHODS: Retrospective review of gonadal biopsies and clinical records of patients consented into the Royal Children's Hospital FP programme between 1987 and 2015. Tissue was sliced into blocks, with one section sent for histopathology prior to cryopreservation. In boys ≥12 years where spermatogenesis could be expected, a portion of tissue was disaggregated completely to look for mature sperm and if found, additional tissue was dissected and the resulting suspension frozen. RESULTS: Testicular tissue cryopreservation specimens in 44 males (0.3-16.8 years) provided an average of 7.8 slices per patient. All the specimens were taken at the same time as another necessary surgical procedure, under one general anaesthesic. There was only one complication of scrotal wound dehiscence. Seven of the forty-four (15.9%) patients had chemotherapy prior to testicular biopsy, while the rest were chemotherapy naïve. Five of these were prepubertal, and two were pubertal patients. Eleven subjects had tissue dissected with mature sperm found in eight. Of these eight patients where sperm were found, all were pubertal with testicular size of more than 10 mL and showing histological evidence of spermatogenesis. No histologic specimen demonstrated any malignant cells. CONCLUSIONS: Testicular tissue cryopreservation can be performed in young patients without delay, preferably prior to cancer treatment. As testicular tissue contains germ cells from which haploid spermatozoa are ultimately derived, future technologies may allow their utilization for fertility in humans. This may be the only hope for biological offspring in some patients undergoing fertility compromising treatment. Retrieval of mature sperm from some pubertal patients, however, offers realistic hope to these patients of future fertility.

Thyroid carcinoma in children, adolescents and adults, both spontaneous and after childhood radiation exposure.

UNLABELLED: Thyroid carcinoma is the most common second malignancy for childhood cancer survivors. Radiation exposure is linked to risk. Thyroid nodules in children have a high risk for malignancy, whether spontaneous or after radiation. Due to the extremely limited available paediatric data, we sought to review a series of patients with thyroid carcinoma, seen over 25 years. Forty-six patients were identified. Thirty-nine (84.8 %) had papillary thyroid carcinoma, five (10.9 %) follicular carcinoma and 2 (4.3 %) medullary thyroid carcinoma (MEN2B). Thirty-three (71.7 %) had childhood radiation exposure (17 females) with thyroid malignancy occurring 6-37 years later. The smallest nodule size found on surveillance to have thyroid malignancy was 4 mm. Thyroid cancer in patients 16 years and under was seen in 22 patients (47.8 %). All had total thyroidectomy, with initial central node clearance from 2005. Diagnostic rTSH stimulated I(123) scan was followed by ablative I(131) if any uptake was seen. Sixteen (32.6 %) had metastases. Twenty-four (52.2 %) had I(131), four requiring multiple courses. Forty-two remain alive and well. CONCLUSION: Ultrasound screening is required for early diagnosis as small nodule size is not predictive of benign histology or absence of metastases. Central node clearance provides better outcome. Despite metastatic disease at presentation for some, prognosis is favourable. WHAT IS KNOWN: • Incidence of thyroid cancer has been increasing and radiation exposure in childhood cancer survivors is clearly linked to risk. • Published guidelines in many places can only provide very low level evidence due to extremely limited available paediatric data. What is New: • Paper provides good evidence to confirm existing views with the largest cohort of thyroid cancer reported to date in the paediatric age group in Australia, and the largest cohort in Australia where there have been specific high risks of radiation exposure. The only other reported larger studies have come from the Children's Oncology Group and Childhood Cancer Survivor Study [24]. • Using diagnostic rTSH stimulated I(123) scan 6 weeks after surgery helps to determine if radioactive iodine ablation is necessary and limits unnecessary bone marrow exposure for young patients in whom future leukaemia is of greater concern.

Establishment of hormone reference intervals for infants born < 30 weeks' gestation.

OBJECTIVE: Preterm infants, especially those born very preterm (<32 weeks' gestation), suffer a number of morbidities. Immaturity of the endocrine system and its potential impact on morbidity is the subject of numerous studies. Hormone concentrations are sometimes measured in very preterm infants, however there are little normative data available to be able to interpret the results. The aim of this study was to describe age appropriate hormone reference intervals for babies born less than 30 weeks' gestation. STUDY DESIGN: Samples were collected at 1, 4, 7, 14, 21, 28 and 42 days after birth from babies born 23-29 weeks' gestation. The serum was analyzed for seven hormones by automated chemiluminescent immunoassay (Siemens Immulite 2000). Results from the 107 infants who survived beyond 40 weeks' corrected gestational age were included in the data analysis. RESULTS: Cortisol, dehydroepiandrosterone sulfate, growth hormone and progesterone levels were highest during the first seven days with levels up to 10,801nmol/L; 26.6µmol/L; 343mU/L; and >63.6nmol/L respectively. Free thyroxine levels were as low as <2.6pmol/L for the first 28 days with the nadir at 7days. Estradiol levels ranged from <73 to 1626pmol/L over the six weeks. Reference intervals for IGF-1 could not be established as the levels were below the analyzer's sensitivity. There were no differences in reference intervals between male and female infants. CONCLUSIONS: We describe gestation appropriate reference intervals for six hormones measured in babies born <30 weeks' gestation. Utilization of these reference intervals permits the correct and timely interpretation of results to the clinician.

Successful treatment of a sacral aneurysmal bone cyst with zoledronic acid.

BACKGROUND: Aneurysmal bone cysts (ABCs) in the sacrum pose a management challenge as their location usually means that surgical excision is not possible. Strategies such as embolization have been used previously but have the potential for significant side effects. We report the successful use of bisphosphonate treatment (zoledronic acid) in an 8-year-old boy who presented with an ABC that did not respond to embolization. METHODS: The patient presented with pain and progressive limp. After radiologic and histologic confirmation of the diagnosis, embolization therapy was trialed, which was unsuccessful. At this point, he had severe pain and extremely limited mobility, requiring the use of a wheelchair. His ability to lie flat or sit erect was limited by the pain. Zoledronic acid therapy was subsequently commenced at 0.04 mg/kg per dose by intravenous infusion, at 4 monthly intervals, for a total of 2 years (7 doses). RESULTS: The infusions were well tolerated, with rapid reduction in pain and resolution of previously severe immobility, from being bed and chair bound at baseline to normal independent ambulation over several months. This was associated with marked radiologic improvement. We postulate that the effect of treatment is a combination of the anti-inflammatory effect of zoledronic acid and the antiresorptive effect of osteoclast inhibition. CONCLUSIONS: We conclude that bisphosphonates should be considered as possible second-line agents for ABCs. Further, study of a larger cohort would help to establish their efficacy in this setting. LEVEL OF EVIDENCE: Level IV (case report, no comparator/control arm).

Puberty, contraception, and hormonal management for young people with disabilities.

Assessment and management of a young person with a severe disability is multifaceted and complex. Variations of puberty can cause major concerns for parents and carers, with fears of imminent menstruation, peer and personal differences, concern for height outcome, as well as grief for a loss of childhood. Addressing physical, emotional, and social issues assists in optimizing outcomes. This article outlines specific evaluation and detailed management strategies for female and male pubertal problems in the context of disability, including treatments for extreme pubertal delay or acceleration, menstrual management at different ages, contraceptive issues, and sexual function and choices for both sexes.

Isolated intestinal ganglioneuromatosis with a new mutation of RET proto-oncogene.

A 13-year-old boy with a history of juvenile polyps of the colon was subsequently found to have isolated intestinal ganglioneuromatosis without any other features characteristic of multiple endocrine neoplasia (MEN) 2B. Screening for MEN 2B revealed a polymorphism of the RET proto-oncogene at codon 691 with a glycine to serine conversion. This mutation has not been described before in association with ganglioneuromatosis and MEN 2B. The phenotype and presentation are compared with those of previous case reports.

Pamidronate treatment of steroid associated osteonecrosis in young patients treated for acute lymphoblastic leukaemia--two-year outcomes.

AIMS: To assess outcomes of young patients with osteonecrosis (ON) treated with pamidronate in terms of relief of pain, prevention of progress and bony collapse of involved area. PATIENTS AND METHODS: A non-randomised interventional study in six patients with a history of acute lymphoblastic leukaemia (ALL) for which treatment protocols included long-term, high dose use of glucocorticoids. Subsequent development of ON was treated with a bisphosphonate (pamidronate) for 2 years. Mobility and pain control were assessed regularly with MRI and X-ray of affected areas at 0, 12 and 24 months. RESULTS: Reduction in pain was reported in four of six patients in the first year with increased mobility. Two patients who had radiological evidence of joint destruction prior to treatment and when continued on corticosteroids reported no improvement in pain or mobility. In the second year, patients who started treatment in the first few months after diagnosis were stable while patients who had treatment initiated later deteriorated but had less pain than prior to treatment with pamidronate. MRIs of affected areas were completely unchanged over 2 years. X-rays revealed no new bony collapse in four of six patients after 12 months of treatment. However, three of six patients continued to undergo extensive collapse of femoral heads (one at 12 months, two at 24 months) and all these required urgent hip replacement. CONCLUSION: Pamidronate treatment has a palliative effect in control of pain and may delay the natural history of bony collapse in the acute phase of ON, especially in early treated patients, but does not prevent late bone collapse and joint destruction in corticosteroid treated patients with ALL. Larger studies are needed to provide evidence as to whether bisphosphonate is indicated for treatment of ON for patients using corticosteroids.

K40E: a novel succinate dehydrogenase (SDH)B mutation causing familial phaeochromocytoma and paraganglioma.

OBJECTIVE: Germline mutations in succinate dehydrogenase (SDH)B, SDHC and SDHD, encoding three of the four subunits of mitochondrial complex II, have been implicated in the tumourigenesis of familial paragangliomas and phaeochromocytomas. Twenty-three SDHB mutations have been identified to date. PATIENTS: We present a novel missense SDHB exon 2 mutation (c.118 A > G; K40E) identified in an Australian family. The proband was diagnosed with phaeochromocytoma at an early age following an unexpected hypertensive crisis and was found to be SDHB mutation-positive. Subsequent genetic screening of 26 family members has identified 17 mutation-positive relatives. In addition to the proband, four mutation positive relatives were found to have clinical symptoms or a lesion and/or catecholamine excess after the identification of the mutation led to further evaluation. Both the proband and an uncle have required surgical removal of a tumour. CONCLUSIONS: This family indicates the importance of germline screening of first-degree relatives when a patient presents with an apparently sporadic extra adrenal phaeochromocytoma at a young age or whenever a patient with a nonsecretory paraganglioma is found.

IMAGe syndrome: a complex disorder affecting growth, adrenal and gonadal function, and skeletal development.

IMAGe syndrome (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, genital abnormalities; MIM 300290) is a multisystem disorder with a broad phenotype, which, if unrecognized, may result in major and possibly life-threatening complications. Initial clinical features overlap with those of Russell-Silver syndrome (RSS) and isolated growth hormone (GH) deficiency, conditions from which it must be distinguished. We report an Australian male with adrenal hypoplasia congenita (AHC) in association with IMAGe syndrome. The patient had intrauterine growth restriction (IUGR) and dysmorphic features comprising small, low-set ears, micrognathia, bilateral cryptorchidism, micropenis, and skeletal abnormalities. Signs of adrenal insufficiency occurred at aged 4.6 years. Our patient differs from those previously described by the late onset of adrenal insufficiency and the presence of GH deficiency. IMAGe is a complex syndrome involving dysmorphic features; disorders of growth, gonadal, and adrenal function; and skeletal abnormalities.

Megestrol acetate in pediatric oncology patients may lead to severe, symptomatic adrenal suppression.

BACKGROUND: Despite the widespread use of megestrol acetate (MA) among a growing number of pediatric oncology departments, there is only one published study on the use of MA in children with malignant disease. The objectives of the current study were to examine the effect of MA in improving the nutritional status of children with malignant disease and to describe and consider the implications of MA-associated adrenal suppression that was found consistently. METHODS: Medical records of 19 children with malignant disease who were treated with MA were reviewed. During MA therapy, clinical assessments every 4 weeks included anthropometrics, caloric intake, quality-of-life scores, and appetite scores. Serum cortisol levels, lipid profiles (including cholesterol levels) random blood glucose levels, and coagulation screening were measured at 4-6-week intervals. RESULTS: MA use was associated with significant increases in weight, weight z score, middle-upper arm circumference, triceps skin-fold thickness, appetite, and caloric intake. MA was extremely useful in aiding the efficient tapering of nasogastric feeds. However, a significant and potentially dangerous decrease in cortisol was seen in 10 of 11 patients tested, with 1 patient who manifested clinical hypoadrenalism with hemodynamic collapse, requiring inotropic support. This is the first report of MA-associated clinical adrenal suppression in a child with malignant disease. CONCLUSIONS: Although the results of this study support the ability of MA to improve nutritional status, its use was complicated by severe adrenal suppression in almost all patients tested, with a serious clinical adverse event occurring in one patient. Routine hydrocortisone supplementation throughout MA treatment should be considered as well as larger doses for patients with acute illness and patients who undergo surgery.

Ectopic posterior pituitary lobe and periventricular heterotopia: cerebral malformations with the same underlying mechanism?

BACKGROUND AND PURPOSE: Ectopic posterior pituitary lobe often occurs in children with growth hormone deficiency and is part of the spectrum associated with septo-optic dysplasia. Some cases of septo-optic dysplasia are caused by homozygous mutations in the homeobox gene HESX1, whereas heterozygous mutations are associated with milder phenotypes. To date, HESX1 is the only gene associated with ectopic posterior pituitary lobe. We describe an association between ectopic posterior pituitary lobe and periventricular heterotopia in four children without classic features of septo-optic dysplasia and suggest possible mechanisms on the basis of a review of pituitary embryology and recent molecular genetic advances. METHODS: Among 20 children with ectopic posterior pituitary lobe, four had associated periventricular heterotopia. We herein review the clinical and MR imaging findings of these four children. Mutation screening of HESX1 was performed in two. RESULTS: All four children had growth hormone deficiency. None had visual or neurologic disturbances. MR images showed a range of pituitary appearances, with scattered discrete periventricular heterotopia in each case. Other abnormalities were limited to small suprasellar lipomas and callosal dysgenesis. A heterozygous HESX1 mutation was present in one case. CONCLUSION: The coexistence of ectopic posterior pituitary lobe and periventricular heterotopia suggests they have a common underlying genetic basis that is due to gene expression at different locations and stages of development. The presence of a heterozygous HESX1 mutation in one case suggests this gene is important in the development of both ectopic posterior pituitary lobe and periventricular heterotopia and supports their place in the spectrum of septo-optic dysplasia. Further analysis of HESX1 and other genes in related developmental pathways will elucidate their roles in the development of both malformations.