The Australian New Zealand Consortium in Children, Adolescents, and Young Adults Oncofertility action plan.

International and national oncofertility networks, including the US-led Oncofertility Consortium, FertiProtekt, and the Danish Network, have played pivotal roles in advancing the discipline of oncofertility over the last decade. Many other countries lack a shared approach to pediatric oncofertility health service delivery. This study aims to describe baseline oncofertility practices at Australian New Zealand Children's Haematology/Oncology Group centers in 2019-2021, describe binational priorities for care, and propose a 5-year action plan for best practice to be implemented by the newly formed Australian New Zealand Consortium in Children, Adolescents, and Young Adults (CAYA) Oncofertility (ANZCO).

Endocrine features of Langerhans cell histiocytosis in paediatric patients: A 30-year review.

Langerhans cell histiocytosis (LCH) is a rare proliferative disorder characterised as an inflammatory myeloid neoplasia. Endocrine manifestations of LCH, particularly central diabetes insipidus (CDI), have been described from the 1940s, through case studies and small cohort analyses. There are limited Australian paediatric data described in recent literature. AIM: To document the incidence of endocrine features in paediatric patients with LCH, treated at a tertiary paediatric centre in Victoria, Australia. METHODS: Retrospective chart review of electronic medical records and oncology database of patients with LCH managed at a tertiary paediatric centre. Patients were excluded if a biopsy did not suggest LCH or if records were incomplete. RESULTS: One hundred seventy-one patients were identified and 141 records of patients diagnosed with LCH over the last 30 years were assessed for endocrinopathies, from diagnosis to last documented follow-up. Mean age at diagnosis was 5 years 8 months. Of these, 15% (n = 21) had CDI, 7% had growth hormone deficiency (GHD) (n = 10) and 8% (n = 11) had more than one endocrinopathy noted during follow-up. Forty percent (n = 57) were pre-pubertal at the time of audit or upon discharge from tertiary services. CONCLUSIONS: Ongoing pituitary assessment, in addition to CDI, is required to detect evolving deficiencies of GHD and gonadotropins as these can be subtle, late or missed. Close follow-up of growth and progression through puberty, even if discharged from tertiary care, is essential.

Fertility outcomes in male adults with congenital hypogonadotropic hypogonadism treated during puberty with human chorionic gonadotropin and recombinant follicle stimulating hormone.

AIM: Hormone replacement therapy with testosterone for pubertal induction in boys with congenital hypogonadotropic hypogonadism (CHH) achieves virilization but not spermatogenesis. By contrast, human chorionic gonadotropin (hCG) and recombinant follicle stimulating hormone (rFSH) provides both virilization and spermatogenesis. Fertility outcomes of boys treated with recombinant therapy during adolescence have been infrequently described. We report fertility induction and pregnancy outcomes in CHH patients treated with recombinant gonadotropins during puberty. METHODS: Data of six subjects with CHH (n = 3 Kallmann syndrome & n = 3 Isolated hypogonadotropic hypogonadism) treated with hCG and FSH for pubertal induction were reviewed. Of these, five underwent subsequent fertility induction while one desired fertility at the end of pubertal induction. RESULTS: Partners of all subjects achieved pregnancies using hCG and rFSH, all with full term live births. All infants were clinically normal. CONCLUSION: This study provides early evidence of proof of concept of use of gonadotropin induction of puberty being beneficial in subsequent fertility outcome.

Fracture risk and impact in boys with Duchenne muscular dystrophy: A retrospective cohort study.

INTRODUCTION/AIMS: Boys with Duchenne muscular dystrophy (DMD) are at increased risk of fracture. This study investigated the incidence of fractures, factors contributing to risk of first fracture with emphasis on body mass index (BMI), and the impact of fractures on functional capacity in an Australian cohort of boys with DMD. METHODS: A retrospective cohort study included boys with DMD who attended a pediatric neuromuscular clinic from 2011 to 2018. Information regarding fractures, anthropometry measurements, body composition and functional assessment was collected. Factors associated with first fracture risk were analyzed with Cox-proportional hazards. Longitudinal analysis of function post-fracture was also conducted. RESULTS: This study included 155 boys with DMD. At least one fracture occurred in 71 (45%) boys; overall incidence of fractures was 399-per-10,000 persons-years. The first fracture was vertebral in 55%; 41% had non-vertebral fractures and 4% had both. Vertebral fractures occurred in significantly older (12.28 vs 9.28 y) boys with longer exposure to glucocorticoids (5.45 vs 2.50 y) compared to non-vertebral fractures. Boys with a history of fracture(s) had a steeper rate of functional decline (measured by Northstar Ambulatory Assessment score) than those with no recorded fractures. DISCUSSION: A high fracture burden was observed in a large Australian cohort of boys with DMD. Further investigation is required to understand preventative strategies and modifiable risk factors to reduce the incidence of fractures in DMD. The impact on fractures on ambulatory capacity should be closely monitored.

Metastatic neuroblastoma in fertility preservation biopsy of clinically normal testis: a case report.

RESEARCH QUESTION: Is there potential for the detection of neuroblastoma malignancy in testicular tissue extracted for fertility preservation for prepubertal boys at the time of tissue freezing? DESIGN: This is a case report. RESULTS: A boy was diagnosed with primary localized left adrenal neuroblastoma, with complete resection of the tumour. During 6 months' surveillance, he developed a relapse in the left para-renal region with progression of molecular and chromosomal features into undifferentiated neuroblastoma. Before highly gonadotoxic treatment, testicular biopsy for fertility preservation was taken, from a clinically normal testis. Histopathological examination of the testicular biopsy revealed metastatic neuroblastoma. CONCLUSIONS: Metastatic neuroblastoma detected histologically in a clinically normal testis highlights the importance of routine histological examination at the time of testicular cryopreservation. The histological evaluation of gonadal tissue for potential malignant contamination before freezing should be mandatory, regardless of the malignancy diagnosis. Advances in sensitive molecular detection and in-vitro maturation are critically required to decrease future risk of disease recurrence in both solid and haematological malignancies.

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.

DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency.

During genome replication, polymerase epsilon (Pol ε) acts as the major leading-strand DNA polymerase. Here we report the identification of biallelic mutations in POLE, encoding the Pol ε catalytic subunit POLE1, in 15 individuals from 12 families. Phenotypically, these individuals had clinical features closely resembling IMAGe syndrome (intrauterine growth restriction [IUGR], metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies in males), a disorder previously associated with gain-of-function mutations in CDKN1C. POLE1-deficient individuals also exhibited distinctive facial features and variable immune dysfunction with evidence of lymphocyte deficiency. All subjects shared the same intronic variant (c.1686+32C>G) as part of a common haplotype, in combination with different loss-of-function variants in trans. The intronic variant alters splicing, and together the biallelic mutations lead to cellular deficiency of Pol ε and delayed S-phase progression. In summary, we establish POLE as a second gene in which mutations cause IMAGe syndrome. These findings add to a growing list of disorders due to mutations in DNA replication genes that manifest growth restriction alongside adrenal dysfunction and/or immunodeficiency, consolidating these as replisome phenotypes and highlighting a need for future studies to understand the tissue-specific development roles of the encoded proteins.

Reducing adverse events associated with the glucagon stimulation test for the assessment of growth hormone deficiency in adults with a high prevalence of pituitary hormone deficiencies.

DESIGN: A retrospective review of the adverse events (AEs) in 78 patients during the glucagon stimulation test (GST) for the assessment of growth hormone deficiency (GHD) before and after protocol amendments which aimed to reduce AEs in a group of patients with a high prevalence of pituitary hormone deficiencies. PATIENTS: Based on our observations of frequent AEs during the standard GST protocol in an initial 25 patients (cohort 1), a modified protocol was introduced to include the routine administration of 20 mg of hydrocortisone pre-GST in a subsequent 53 patients (cohort 2). Post hoc analysis of the effect of glucocorticoid dosing pre-GST on AEs was examined in those receiving <20 mg hydrocortisone (group A, n = 19) vs ≥20 mg hydrocortisone (group B, n = 59). MEASUREMENTS: AEs including hypotension, hypoglycaemia and nausea/vomiting. RESULTS: Of the 78 patients undergoing the GST, 79% had ≥2 hormone deficiencies. Rates of AEs were 41% vs 30% for hypotension, 60% vs 28% for hypoglycaemia (p < .05) and 20% vs 13% for nausea/vomiting in cohort 1 compared with cohort 2, respectively. Post hoc analysis revealed lower rates of AEs in those receiving ≥20 mg hydrocortisone (group B) compared to those receiving <20 mg due to a reduction in hypoglycaemic events (82% vs 26%, p < .001) and hypotension (50% vs 27%, p = .05). Similar numbers of patients in group A and group B met criteria for GHD. CONCLUSIONS: In patients with a high prevalence of pituitary deficiencies, a modified GST protocol of additional stress dose glucocorticoid attenuated the frequency of AEs without appearing to compromise the performance of the GST.

Prior testosterone replacement therapy may impact spermatogenic response to combined gonadotropin therapy in severe congenital hypogonadotropic hypogonadism.

OBJECTIVE: To study the effect of prior testosterone replacement therapy (TRT) on the spermatogenic response to combined gonadotropin therapy (CGT) in severe and partial phenotype congenital hypogonadotropic hypogonadism (CHH) patients. DESIGN: Retrospective cohort study. SETTING: Tertiary care center. PATIENTS: Patients of CHH without (n = 17) and with prior TRT (n = 18) were subdivided into severe and partial groups, based on mean testicular volume ≤ 3 cc and > 3 cc respectively. INTERVENTION: Participants were treated with hMG at a dose of 75-150 U 3/week and gradually escalating doses of hCG until maximum dose (2000 U 3/week or 5000 U 2/week) or serum total testosterone of ≥ 3.5 ng/ml was reached. MAIN OUTCOME MEASURES: Final mean TV, trough serum testosterone (T), sperm concentration RESULTS: Thirty-five patients (20 severe, baseline mean TV of 3.6 ± 2.7 ml) were started on CGT at 24.8 ± 6.1 years. The median duration of prior TRT was 38 (IQR 10-63.75) months in the exposed group. After 33 ± 12 months, final mean TV was 8.9 ± 5.5 ml, 86% achieved serum testosterone > 3.5 ng/ml and 70% achieved spermatogenesis [median 5 (0-12.6) million/ml]. Patients without prior TRT had significantly higher peak sperm count than those with prior- TRT (median 9 vs 0.05 million/ml, p = 0.004). This effect of prior TRT was more pronounced in severe phenotype patients (median 7 vs 0 million/ml, p = 0.01). CONCLUSION: Prior-TRT may interfere with spermatogenic response to CGT in CHH patients, especially in those with a severe phenotype.

Growth hormone and targeted oncological agents: Are we stopping children with brain tumours from reaching their true height potential?

Children with low-grade gliomas have excellent long-term survival outcomes. The development of therapies targeted to the driver mutations along the Mitogen Activated Protein (MAP) kinase signalling pathway are providing long-term stability for many patients with these tumours. Given the frequency of these tumours residing within or near the suprasellar region, our patients commonly suffer from hormone deficiencies. In Australia, the Pharmaceutical Benefits Scheme currently restricts growth hormone therapy to patients who are not being actively treated for cancer, including those receiving targeted therapies. This viewpoint hopes to facilitate an important discussion amongst our colleagues as to whether this should be changed to allow growth hormone to become available to children on chronic tumour suppressive therapy.

The Enigma of the Adrenarche: Identifying the Early Life Mechanisms and Possible Role in Postnatal Brain Development.

Dehydroepiandrosterone (DHEA) and its sulfated metabolite (DHEAS) are dynamically regulated before birth and the onset of puberty. Yet, the origins and purpose of increasing DHEA[S] in postnatal development remain elusive. Here, we draw attention to this pre-pubertal surge from the adrenal gland-the adrenarche-and discuss whether this is the result of intra-adrenal gene expression specifically affecting the zona reticularis (ZR), if the ZR is influenced by the hypothalamic-pituitary axis, and the possible role of spino-sympathetic innervation in prompting increased ZR activity. We also discuss whether neural DHEA[S] synthesis is coordinately regulated with the developing adrenal gland. We propose that DHEA[S] is crucial in the brain maturation of humans prior to and during puberty, and suggest that the function of the adrenarche is to modulate, adapt and rewire the pre-adolescent brain for new and ever-changing social challenges. The etiology of DHEA[S] synthesis, neurodevelopment and recently described 11-keto and 11-oxygenated androgens are difficult to investigate in humans owing to: (i) ethical restrictions on mechanistic studies, (ii) the inability to predict which individuals will develop specific mental characteristics, and (iii) the difficulty of conducting retrospective studies based on perinatal complications. We discuss new opportunities for animal studies to overcome these important issues.

Spontaneous pregnancies in female survivors of childhood allogeneic haemopoietic stem cell transplant for haematological malignancies.

OBJECTIVE: Spontaneous pregnancies and live births are rarely reported after haematopoietic stem cell transplant (HSCT). We report spontaneous pregnancy outcomes of sexually active female survivors of childhood allogeneic HSCT, to provide more data for future counselling. DESIGN, PATIENTS AND MEASUREMENTS: Retrospective review of all female survivors of childhood haematological malignancies who had allogeneic HSCT at the Royal Children Hospital between 1985 and 2011. Data were retrieved from medical records, updated from treating haematologist or endocrinologist, and were cross-referenced with self-reported questionnaires. Female survivors who were sexually inactive were excluded from analysis. RESULTS: Six of 37 (16.2%) female survivors reported spontaneous pregnancies resulting in 8 live births. Amongst 22 women who received total body irradiation (n = 21) ± cranial irradiation or isolated cranial irradiation (n = 1), and high-dose cyclophosphamide, three reported pregnancy resulting in live births (14%), whilst three of 15 women who received chemotherapy alone had pregnancy with live births (20%). CONCLUSIONS: Our current finding, albeit a small sample size, reinforces the importance of counselling female survivors of HSCT about the possibility of spontaneous pregnancy occurring despite documented ovarian failure and for need of contraception to avoid unplanned pregnancy.

Disorders of Puberty: Pharmacotherapeutic Strategies for Management.

During puberty, with activation of the hypothalamic pituitary axis that has been quiescent since the neonatal period, linear growth accelerates, secondary sexual characteristics develop, and adult fertility potential and bone mass are achieved, together with psychosocial and emotional maturation.Disordered pubertal onset and progress, either early or late, presents frequently for endocrine care. Where a disorder is found, due either to a central hypothalamic pituitary cause or to primary gonadal failure, pharmacotherapeutic interventions are required to alter the trajectory of disturbed pubertal onset or progress and for maintenance of adolescent and adult sex hormone status. This paper describes pharmacologic interventions used for pubertal disorders but is not intended to address the diagnostic cascade in detail.

Global consensus on nutritional rickets: Implications for Australia.

In 2016, a global consensus on the prevention, diagnosis and management of nutritional rickets was published. The bone and mineral working group of the Australasian Paediatric Endocrine Group provides a summary and highlights differences to previous Australian and New Zealand (ANZ) guidelines on vitamin D deficiency and their implications for clinicians. Key points are: (i) The International Consensus document is focused on nutritional rickets, whereas the ANZ guidelines were focused on vitamin D deficiency. (ii) Definitions for the interpretation of 25-hydroxy vitamin D (25OHD) levels do not differ between statements. (iii) The global consensus recommends that routine 25OHD screening should not be performed in healthy children and recommendations for vitamin D supplementation are not based solely on 25OHD levels. The Australasian Paediatric Endocrine Group bone and mineral working group supports that screening for vitamin D deficiency should be restricted to populations at risk. (iv) Recommendations from the global consensus for vitamin D dosages for the therapy of nutritional rickets (diagnosed based on history, physical examination, biochemical testing and a confirmation by X-rays) are higher than in ANZ publications. (v) The global consensus recommends the implementation of public health strategies such as universal supplementation with vitamin D from birth to 1 year of age and food fortification. We conclude that updated global recommendations for therapy of nutritional rickets complement previously published position statements for Australia and New Zealand. Screening, management and the implementation of public health strategies need to be further explored for Australia.

Satisfaction, disappointment and regret surrounding fertility preservation decisions in the paediatric and adolescent cancer population.

PURPOSE: With over 80% of paediatric and adolescent cancer patients surviving into adulthood, quality-of-life issues such as future fertility are increasingly important. However, little is known about regret around decisions to pursue or forgo fertility preservation (FP). We investigated the risk of decision regret in families involved in making a FP decision and explored contributive factors. METHODS: Parents and patients ≥ 15 years were invited to participate. Participants completed a 10-item survey, including a validated Decision Regret Scale. Scores ≥ 30 indicated high regret. Free-text response items allowed participants to provide reasons for satisfaction or regret. RESULTS: A total of 108 parents and 30 patients participated. Most (81.4%) reported low regret (mean score 13.7). On multivariate analysis, predictors of low regret included having a FP procedure and a fertility discussion pre-treatment. Most participants believed that FP offers hope for future fertility. Some reported dissatisfaction with the process of decision-making. CONCLUSION: Overall levels of regret in the study population were low, with factors associated with quality, timely discussion and belief in the success of FP technology being predictors of low regret. However, dissatisfaction with the decision-making process itself revealed that refinements to the programme are required to meet families' needs.

Growth hormone-Insulin-like growth factor 1 axis hyperactivity on bone fibrous dysplasia in McCune-Albright Syndrome.

CONTEXT: In fibrous dysplasia (BFD), normal bone and bone marrow are replaced by fibro-osseous tissue, leading to fracture, deformity and pain. BFD may be isolated, or in association with cutaneous hyperpigmentation and/or hyperfunctioning endocrinopathies, termed McCune-Albright syndrome (MAS). GH hypersecretion has been described in 10%-20% of MAS-BFD patients. Aim of the study was to determine the impact of GH-insulin like growth factor 1 (IGF1) axis hyperactivity on MAS-BFD morbidities and the efficacy of GH excess therapy. DESIGN AND PATIENTS: A multicentric cross-sectional analysis was conducted on three different MAS cohorts. From 195 MAS patients, 37 subjects (19%) with GH excess were identified and compared with 34 MAS controls without GH hypersecretion. RESULTS: Mean head circumference SDS was significantly higher in GH excess: 4.025 SDS vs 0.683 SDS (P < .0001). The risk of optic neuropathy (Odds ratio 4.231; P = .039), hearing deficit (Odds ratio 2.961; P = .0481), facial asymmetry (Odds ratio 6.563; P = .0192), malignancies (Odds ratio 15.24; P = .0173) were higher in GH excess group. Overall, pharmacotherapy (octreotide alone 10-30 mg/mo or with pegvisomant 10-20 mg/d) was effective in IGF1 normalization (IGF1 Z-score between -2 and +2 SDS) in 21/29 patients (72.4%) with good compliance to the regimen. Late diagnosis and GH excess treatment after 16 years old of age was associated with an increased risk of optic neuropathy (Odds ratio 4.500; P = .0491) and growth of pituitary adenomas (Odds ratio 7.846; P = .050). CONCLUSIONS: GH-IGF1 hyperactivity increases risk of morbidities in MAS. Medical therapy is effective in normalizing IGF1 in most patients, and early treatment during paediatric age is associated with a decreased risk of optic neuropathy and GH-secreting adenomas growth.

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.