Klinefelter Syndrome: What should we tell prospective parents?

Klinefelter syndrome (KS) or 47,XXY is the most common sex chromosome aneuploidy (SCA), occurring at a prevalence of 1 in 600 male pregnancies. Historically, only 25% of individuals with KS came to medical attention, for a range of issues across the life course including under-virilisation at birth, developmental and social concerns in childhood, absence, delay or arrest of puberty in adolescence or infertility in adulthood. Our understanding of the phenotypic spectrum of KS has been largely influenced by this ascertainment bias. With increasing uptake of antenatal noninvasive prenatal testing (NIPT), a corresponding increase in identification of KS has been documented. Population-based longitudinal data from infancy to adulthood on these individuals is lacking, which impedes balanced antenatal genetic counselling and raises issues for prospective parents and clinicians alike.

A comparative study of quality of life, functional and bone outcomes in osteogenesis imperfecta with bisphosphonate therapy initiated in childhood or adulthood.

Bisphosphonates have been used for treatment of bone fragility disorders for over 25 years to increase bone mineral density (BMD). Anecdotally, bisphosphonate-treated Osteogenesis Imperfecta (OI) has a different trajectory to the natural history of untreated OI in terms of fracture incidence, quality of life and physical function, with minimal published evidence to support this clinical observation. This study describes functional outcomes of a cohort of adults with OI, stratified according to severity and treated with intravenous bisphosphonates as children. Reported outcomes included fracture incidence before and after puberty, mobility and BMD outcomes of this cohort. The cohort was compared to adults with OI who were never treated as children. All participants completed four questionnaires: a study specific questionnaire addressing fracture and treatment history, WHOQOL-BREF (quality of life), SF-36 (musculoskeletal function) and IPAQ (physical activity), and medical records were reviewed. Fifty-two adults with OI (80% response rate) completed the questionnaires; 33 of whom were treated with bisphosphonates in childhood. The childhood treated cohort had higher lumbar spine BMD than the adult treated cohort (z-score - 0.4 at mean age 21.3 years versus -2.1 at mean age 40.9 years; p = 0.003). Pre-pubertal fracture incidence was reduced for all severities of OI in the childhood treated cohort (less severe OI, p = 0.01; more severe OI, p < 0.001), but post-pubertal fracture incidence was higher for less severe OI (p < 0.001). In less severe OI, childhood treated individuals had higher levels of physical activity (p = 0.004) and physical functioning (p = 0.01) than adult treated individuals. Incidence of scoliosis was not different between cohorts. There were no differences in quality of life scores between the two cohorts. Improvements in BMD do not appear to influence the prevalence of scoliosis. Results suggest that treatment with bisphosphonates at an earlier age improves physical activity, particularly in less severe forms of OI but may not alter quality of life.

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.

Intravenous glucagon in a deliberate insulin overdose in an adolescent with type 1 diabetes mellitus.

Massive insulin overdose may be associated with unpredictable and prolonged hypoglycemia. Concerns surrounding the potential provocation of insulin release from beta cells have previously prevented the use of intravenous glucagon as an adjunct to infusion of dextrose in this situation. We describe the case of a 15-yr-old boy with type 1 diabetes mellitus (T1DM) who presented with profound hypoglycemia following an overdose of an unknown quantity of premixed insulin. Owing to an increasing dextrose requirement and a dependence on hourly intramuscular glucagon injections, a continuous intravenous infusion of glucagon was commenced which successfully avoided the requirement for central venous access or concentrated dextrose infusion. Nausea was managed with anti-emetics. Intramuscular and subcutaneous glucagon is effective in the management of refractory and severe hypoglycemia in youth with both T1DM and hyperinsulinism. Concerns regarding the precipitation of rebound hypoglycemia with the use of intravenous glucagon do not relate to those with T1DM. This treatment option may be a useful adjunct in the management of insulin overdose in youth with T1DM and may avoid the requirement for invasive central venous access placement.

Hormone modeling in preterm neonates: establishment of pituitary and steroid hormone reference intervals.

CONTEXT: Reports suggest significant differences in serum levels of hormones in extremely preterm compared with late preterm and full-term infants. OBJECTIVES: The purpose of this study was to develop reference intervals (RIs) for 3 pituitary hormones and 5 steroid hormones in serum of preterm infants. DESIGN: Blood samples were collected from 248 (128 male and 120 female) preterm neonates born between 24 and 32 weeks' gestation. SETTING: PARTICIPANTS were recruited from 3 neonatal intensive care wards in Melbourne, Australia. PARTICIPANTS: No infant in this cohort had ambiguous genitalia or other endocrine abnormalities. All infants included in the RI determination survived beyond the equivalent of term. INTERVENTIONS: Serum was analyzed for prolactin, FSH, and LH by automated electrochemiluminescence immunoassay (Roche Cobas 8000-e601). Liquid chromatography coupled with tandem mass spectrometry was used for analysis of 17-hydroxyprogesterone, androstenedione, cortisol, cortisone, and testosterone. MAIN OUTCOME MEASURES: The robust method was applied to define the central 95% RI, after each hormone measure was transformed using a Box-Cox transformation to correct for asymmetry. RESULTS: RIs were established for 8 hormones. Gender-specific intervals were developed for FSH, LH, and testosterone. Cortisone and 17- hydroxyprogesterone required division based on gestational age, with neonates born at <30 weeks' gestation demonstrating higher levels than their older counterparts. Androstenedione, cortisol, and prolactin did not require any division within this cohort for RI assignment. CONCLUSIONS: This report provides the first characterization of serum steroids measured by mass spectrometry in preterm neonates, with the additional characterization of 3 pituitary hormones in infants born at ≤32 weeks' gestation. Use of these data allows for correct interpretation of results for very preterm neonates and reduces the risk of incorrect diagnosis due to misinterpretation of data.

Bone density assessment in a tertiary paediatric centre over 13 years: Referral patterns and limitations.

AIM: This study aims to examine the referral practices for the Royal Children's Hospital (RCH) bone density service over the past 13 years and to demonstrate referral patterns and possible limitations to accessing paediatric bone densitometry. METHODS: All patients attending the RCH Healthy Bones Unit for bone densitometry from 1 July 1999 to 30 June 2012, aged under 18 years of age, were included. Densitometry results were downloaded directly from the Hologic scanner into an Excel document. However, the referring unit and indication for referral were collected manually from either the referral card or the hospital's scanned medical records system. RESULTS: A total of 5767 bone densitometry scans were performed over the study period on 3004 patients. The majority of referrals were made by the Endocrinology department, followed by Adolescent Medicine, Gastroenterology and Neurology. Relatively few referrals were made by general paediatrics. The most common indication for bone density test overall was eating disorders, followed by steroid use, osteogenesis imperfecta and other collagen disorders and inflammatory bowel disease. The lowest lumbar spine z-scores by indication were for cerebral palsy and other causes of immobility. CONCLUSIONS: Multiple childhood diseases predispose to low bone density; however, paediatric bone densitometry is still underutilised and not appropriately supported by subsidies.

A guide to understanding the steroid pathway: new insights and diagnostic implications.

Steroid analysis has always been complicated requiring a clear understanding of both the clinical and analytical aspects in order to accurately interpret results. The literature relating to this specialised area spans many decades and the intricacies of the steroid pathway have evolved with time. A number of key changes, including discovery of the alternative androgen pathway, have occurred in the last decade, potentially changing our understanding and approach to investigating disorders of sexual development. Such investigation usually occurs in specialised paediatric centres and although preterm infants represent only a small percentage of the patient population, consideration of the persistence of the foetal adrenal zone is an additional important consideration when undertaking steroid hormone investigations. The recent expanded role of mass spectrometry and molecular diagnostic methods provides significant improvements for accurate steroid quantification and identification of enzyme deficiencies. However analysis of steroids and interpretation of results remain complicated. This review aims to provide an insight into the complexities of steroid measurement in children and offers an updated guide to interpretation, of serum and urine steroids through the presentation of a refined steroid pathway.

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.

Fertility in Turner syndrome.

There is increasing interest in fertility and use of assisted reproductive technologies for women with Turner syndrome (TS). Current parenting options include adoption, surrogacy, and spontaneous and assisted reproduction. For women with TS, specific risks of pregnancy include higher than usual rates of spontaneous abortion, foetal anomaly, maternal morbidity and mortality. Heterologous fertility assistance using oocytes from related or unrelated donors is an established technique for women with TS. Homologous fertility preservation includes cryopreservation of the patient's own gametes prior to the progressive ovarian atresia known to occur: preserving either mature oocytes or ovarian tissue containing primordial follicles. Mature oocyte cryopreservation requires ovarian stimulation and can be performed only in postpubertal individuals, when few women with TS have viable oocytes. Ovarian tissue cryopreservation, however, can be performed in younger girls prior to ovarian atresia - over 30 pregnancies have resulted using this technique, however, none in women with TS. We recommend consideration of homologous fertility preservation techniques in children only within specialized centres, with informed consent using protocols approved by a research or clinical ethics board. It is essential that further research is performed to improve maternal and foetal outcomes for women with TS.

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).

Incidence of vitamin D deficiency rickets among Australian children: an Australian Paediatric Surveillance Unit study.

OBJECTIVE: To determine the incidence of and factors associated with vitamin D deficiency rickets in Australian children. DESIGN: 18-month questionnaire-based prospective observational study, using Australian Paediatric Surveillance Unit (APSU) data. SETTING: Australian paediatricians and child health workers, January 2006 - July 2007. PARTICIPANTS: Children aged ≤ 15 years with vitamin D deficiency rickets (25-hydroxyvitamin D [25OHD] ≤ 50 nmol/L, and elevated alkaline phosphatase levels [> 229 IU/L] and/or radiological rickets). MAIN OUTCOME MEASURES: Incidence of vitamin D deficiency rickets. Description of demographics, clinical presentation, identification and further analysis of overrepresented groups, and treatment regimens compared with best-practice guidelines. RESULTS: We identified 398 children with vitamin D deficiency (55% male; median age, 6.3 years [range, 0.2-15 years]). The overall incidence in children ≤ 15 years of age in Australia was 4.9/100 000/year. All had a low 25OHD level (median, 28 nmol/L [range, 5-50 nmol]) and an elevated alkaline phosphatase level (median, 407 IU/L [range, 229-5443 IU/L]), and 48 (12%) were hypocalcaemic. Ninety-five children had wrist x-rays, of whom 67 (71%) had rachitic changes. Most (98%) had dark or intermediate skin colour and 18% of girls were partially or completely veiled. Most children were born in Africa (252; 63%) and 75% of children were refugees. Duration of exclusive breastfeeding was inversely related to serum vitamin D levels in children < 3 years of age. Empirical vitamin D treatment was given to 4% of children before diagnosis. CONCLUSIONS: Vitamin D deficiency rickets is a significant problem in Australia among known high-risk groups. Public health campaigns to prevent, identify and tre@vitamin D deficiency, especially in high-risk groups, are essential.

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.

Foot problems and effectiveness of foot care education in children and adolescents with diabetes mellitus.

OBJECTIVES: To assess foot care in paediatric and adolescent patients with diabetes mellitus and to evaluate the effectiveness of foot care education given to participants. RESEARCH DESIGN AND METHODS: An 8-month prospective study of foot care in children and adolescents with type 1 and type 2 diabetes mellitus who attended diabetes clinics at the Royal Children's Hospital, Melbourne, where foot examination was performed at baseline and at follow-up. Patients and parents were given oral and written advice regarding foot care. RESULTS: Five hundred and fifty-seven patients were examined at baseline, and 312 patients were reviewed at follow-up 3-6 months later. The majority of foot problems found at first assessment were potentially modifiable disorders of skin and nails (68.8%). The remainder (31.2%) were structural musculoskeletal disorders requiring referral to a podiatrist/orthotist. A total of 532 foot problems were recorded at baseline in a cohort of 557 patients and 161 foot problems at follow-up of 312 patients. Significant reduction of modifiable foot problems was seen at follow-up, particularly in those with longer duration of diabetes and in those whose body mass index was higher. CONCLUSIONS: This study highlights the importance of foot examination and foot care advice for children and adolescents with diabetes. Larger prospective studies are required to establish prevalence and to optimize preventive interventions.

Bisphosphonate treatment in chronic recurrent multifocal osteomyelitis.

OBJECTIVE: To test the safety and efficacy of biphosphonates in chronic recurrent multifocal osteomyelitis (CRMO). STUDY DESIGN: Five patients with CRMO, all of whom had ongoing pain and loss of function despite conventional treatment with non-steroidal anti-inflammatory agents, were treated with pamidronate (1 mg/kg/dose with a dosing frequency of 2 to 4 monthly for a total treatment duration of 12 to 42 months). RESULTS: Pain decreased after the first infusion for 4 of 5 patients, with symptomatic improvement maintained with time. Significant improvement was seen in radiological lesions for these 4 patients. CONCLUSION: Bisphosphonates appear to be a useful and safe adjunctive treatment in CRMO when simple therapies such as anti-inflammatory agents fail to control symptoms or cases in which lesion expansion continues.