Publications by authors named "Margaret Zacharin"

129 Publications

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

J Paediatr Child Health 2021 Jun 11. Epub 2021 Jun 11.

Children's Cancer Centre, The Royal Children's Hospital Melbourne, Melbourne, Victoria, Australia.

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.
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http://dx.doi.org/10.1111/jpc.15607DOI Listing
June 2021

Randomized Controlled Trial Evaluating the Use of Zoledronic Acid in Duchenne Muscular Dystrophy.

J Clin Endocrinol Metab 2021 Jul;106(8):2328-2342

Department of Endocrinology, Children's Hospital at Westmead, Sydney, Australia.

Context: Patients with glucocorticoid-dependent Duchenne muscular dystrophy (DMD) have increased fracture risk and reduced bone mineral density (BMD), often precipitating mobility loss.

Objective: To investigate use of zoledronic acid (ZA) in DMD in improving BMD.

Methods: Two arm, parallel, randomized controlled trial, set in pediatric hospitals across Australia and New Zealand. Sixty-two (31 per arm) boys with glucocorticoid-dependent DMD between 6 and 16 years were included. Five ZA infusions (0.025 mg/kg at months 0, and 3, and 0.05 mg/kg at months 6, 12, and 18), plus calcium and vitamin D, were compared with calcium and vitamin D alone. The main outcome measures were change in lumbar spine (LS) BMD raw and Z-score by dual energy absorptiometry x-ray (DXA) at 12 and 24 months, secondary outcomes assessing mobility, fracture incidence, bone turnover, peripheral quantitative computerized (pQCT) and pain scores.

Results: At 12 and 24 months, mean difference in changes of LS BMD Z-score from baseline was 1.2 SD (95% CI 0.9-1.5), higher by 19.3% (14.6-24.0) and 1.4 SD (0.9-1.9), higher by 26.0% (17.4-34.5) in ZA than control arms respectively (both P < .001). Five controls developed Genant 3 vertebral fractures, 0 in the ZA arm. Mobility, pain, and bone turnover markers were similar between arms at 12 and 24 months. Trabecular BMC and vBMD pQCT at radius and tibia were greater at 12 months in the ZA cohort than control; the evidence for this difference remained at 24 months for radius but not tibia.

Conclusion: ZA improved BMD in glucocorticoid-dependent DMD boys. Although the small cohort precluded demonstrable fracture benefit, improved BMD might reduce incident vertebral fracture.
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http://dx.doi.org/10.1210/clinem/dgab302DOI Listing
July 2021

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

Int J Mol Sci 2021 Apr 21;22(9). Epub 2021 Apr 21.

School of Health & Biomedical Sciences, Bundoora Campus, RMIT University, Melbourne, VIC 3083, Australia.

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.
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http://dx.doi.org/10.3390/ijms22094296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122518PMC
April 2021

Behavioural changes in an adolescent boy: Not always as it seems.

J Paediatr Child Health 2021 Mar 17. Epub 2021 Mar 17.

Department of Pediatric Endocrinology, Royal Children's Hospital and Murdoch Children's Research Institute, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1111/jpc.15446DOI Listing
March 2021

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.

Clin Endocrinol (Oxf) 2021 Jul 28;95(1):125-133. Epub 2021 Mar 28.

Department of Endocrinology & Diabetes, St. Vincent's Hospital Melbourne, Fitzroy, Vic., Australia.

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.
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http://dx.doi.org/10.1111/cen.14464DOI Listing
July 2021

Debilitating limb pain and weakness as complications of long-term voriconazole therapy.

J Paediatr Child Health 2021 Mar 8. Epub 2021 Mar 8.

Department of Endocrinology, Royal Children's Hospital, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1111/jpc.15414DOI Listing
March 2021

Outcomes of Zoledronic Acid Use in Paediatric Conditions.

Horm Res Paediatr 2020 28;93(7-8):442-452. Epub 2021 Jan 28.

Hormone Research, Murdoch Children's Research Institute, Melbourne, Victoria, Australia,

Introduction: Limited evidence is available concerning experience with use of zoledronic acid (ZA) and treatment for conditions other than primary bone fragility.

Materials And Methods: A retrospective review of all Royal Children Hospital patients who had been administered at least 1 dose of intravenous ZA from 2002 to 2015 was undertaken.

Results: The audit included 309 children with 228 being treated for bone fragility conditions. Of the 228, 68 had height-adjusted lumbar spine bone mineral density Z-scores available over up to a 5-year period, and median increases were +2.0 SD (median absolute deviation = 0.9) (N = 36, p value for median increase of at least 0.5 in Z-score <0.001), for patients with osteogenesis imperfecta or other primary bone fragility disorders, +1.0 SD (0.9) (N = 14, p = 0.029), for immobility conditions, +0.5 SD (0.7) (N = 10, p = 0.399), and for glucocorticoid-induced secondary osteoporosis, +0.7 SD (0.6) (N = 8, p = 0.015). 81/309 children were treated for bone abnormality indications (e.g., avascular necrosis [AVN], fibrous dysplasia, and bone cysts). Of 39 with AVN, outcome data were available for 33, with joint integrity maintained for 24/33 from 6 to 24 months after last ZA, subjective reports (22/28) of reduced pain. Reduction in bone lesion size was seen in 2/4 patients with bone cysts within 12 months of ZA commencement.

Discussion/conclusion: This is the largest cohort of reported outcomes of ZA use in a paediatric population. Results demonstrate a good efficacy profile and associated improved bone density for osteoporotic conditions and stabilization of non-traumatic AVN with a low rate of joint collapse.
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http://dx.doi.org/10.1159/000512730DOI Listing
January 2021

Horse riding, energy drinks and cardiogenic shock: A clinical conundrum.

J Paediatr Child Health 2020 Dec 4. Epub 2020 Dec 4.

Department of Endocrinology, Royal Children's Hospital, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1111/jpc.15288DOI Listing
December 2020

Severe Fibrous Dysplasia in McCune-Albright Syndrome: A Need for Continuous Surveillance.

Horm Res Paediatr 2020 2;93(6):402-408. Epub 2020 Dec 2.

Department of Endocrinology, The Royal Children's Hospital, Parkville, Victoria, Australia,

Introduction: McCune-Albright syndrome (MAS) is a rare condition, in which GNAS mutations affect multiple organs. Fibrous dysplasia (FD), affecting only one or multiple skeletal territories, may severely affect craniofacial structures. Concomitant occurrence of acromegaly aggravates skull deformity, leading to eye, ear, and posterior cranial fossa compromise.

Case Presentation: A 30-year-old man diagnosed with MAS at the age of 3 developed almost all known complications of the syndrome. The craniofacial component of his polyostotic FD increased over time, aggravated by difficult to control acromegaly. Acute onset of severe headache and neurologic compromise, caused by subarachnoid haemorrhage, caused his demise. Post-mortem examination revealed a meningeal artery aneurysm caused by disruption of the intracranial vasculature by severe bone disease. Adrenal histology revealed nodular hyperplasia without clinical evidence of hypercortisolism.

Discussion: The post-mortem findings described aid understanding of the multiorgan involvement of MAS, providing new insights into possible pathogenetic mechanisms underlying the systemic effects of GNAS mutations, and highlight a need for systematic surveillance for cerebrovascular changes in craniofacial FD that may be amenable to intervention to avoid catastrophic outcome.
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http://dx.doi.org/10.1159/000511752DOI Listing
December 2020

Clinical Outcomes and Complications of Pituitary Blastoma.

J Clin Endocrinol Metab 2021 Jan;106(2):351-363

Minneapolis, Minnesota, USA.

Context: Pituitary blastoma is a rare, dysontogenetic hypophyseal tumor of infancy first described in 2008, strongly suggestive of DICER1 syndrome.

Objective: This work aims to describe genetic alterations, clinical courses, outcomes, and complications in all known pituitary blastoma cases.

Design And Setting: A multi-institutional case series is presented from tertiary pediatric oncology centers.

Patients: Patients included children with pituitary blastoma.

Interventions: Genetic testing, surgery, oncologic therapy, endocrine support are reported.

Outcome Measures: Outcome measures included survival, long-term morbidities, and germline and tumor DICER1 genotypes.

Results: Seventeen pituitary blastoma cases were studied (10 girls and 7 boys); median age at diagnosis was 11 months (range, 2-24 months). Cushing syndrome was the most frequent presentation (n = 10). Cushingoid stigmata were absent in 7 children (2 with increased adrenocorticotropin [ACTH]; 5 with normal/unmeasured ACTH). Ophthalmoplegia and increased intracranial pressure were also observed. Surgical procedures included gross/near-total resection (n = 7), subtotal resection (n = 9), and biopsy (n = 1). Six children received adjuvant therapy. At a median follow-up of 6.7 years, 9 patients were alive; 8 patients died of the following causes: early medical/surgical complications (n = 3), sepsis (n = 1), catheter-related complication (n = 1), aneurysmal bleeding (n = 1), second brain tumor (n = 1), and progression (n = 1). Surgery was the only intervention for 5 of 9 survivors. Extent of resection, but neither Ki67 labeling index nor adjuvant therapy, was significantly associated with survival. Chronic complications included neuroendocrine (n = 8), visual (n = 4), and neurodevelopmental (n = 3) deficits. Sixteen pituitary blastomas were attributed to DICER1 abnormalities.

Conclusions: Pituitary blastoma is a locally destructive tumor associated with high mortality. Surgical resection alone provides long-term disease control for some patients. Quality survival is possible with long-term neuroendocrine management.
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http://dx.doi.org/10.1210/clinem/dgaa857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823240PMC
January 2021

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

Pituitary 2021 Jun 23;24(3):326-333. Epub 2020 Nov 23.

Department of Endocrinology, Seth GS Medical College & KEM Hospital, 103, 1st floor, OPD Building, KEM Hospital Campus, Parel, Mumbai, Maharashtra, 40012, India.

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.
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http://dx.doi.org/10.1007/s11102-020-01111-6DOI Listing
June 2021

Multilingual Global E-Learning Pediatric Endocrinology and Diabetes Curriculum for Front Line Health Care Providers in Resource-Limited Countries: Development Study.

JMIR Form Res 2020 Nov 5;4(11):e18555. Epub 2020 Nov 5.

Division Endocrinology, Department of Pediatrics, Sophia Children's Hospital, Erasmus University Medical Center, Rotterdam, Netherlands.

Background: Electronic learning (e-learning) is a widely accessible, low-cost option for learning remotely in various settings that allows interaction between an instructor and a learner.

Objective: We describe the development of a free and globally accessible multilingual e-learning module that provides education material on topics in pediatric endocrinology and diabetes and that is intended for first-line physicians and health workers but also trainees or medical specialists in resource-limited countries.

Methods: As complements to concise chapters, interactive vignettes were constructed, exemplifying clinical issues and pitfalls, with specific attention to the 3 levels of medical health care in resource-limited countries. The module is part of a large e-learning portal, ESPE e-learning, which is based on ILIAS (Integriertes Lern-, Informations- und Arbeitskooperations-System), an open-source web-based learning management system. Following a review by global experts, the content was translated by native French, Spanish, Swahili, and Chinese-speaking colleagues into their respective languages using a commercial web-based translation tool (SDL Trados Studio).

Results: Preliminary data suggest that the module is well received, particularly in targeted parts of the world and that active promotion to inform target users is warranted.

Conclusions: The e-learning module is a free globally accessible multilingual up-to-date tool for use in resource-limited countries that has been utilized thus far with success. Widespread use will require dissemination of the tool on a global scale.
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http://dx.doi.org/10.2196/18555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677026PMC
November 2020

Letter to the Editor From Gabby Atlas et al: "Long-term Outcomes of Treatments for Central Precocious Puberty or Early and Fast Puberty in Chinese Girls".

J Clin Endocrinol Metab 2020 10;105(10)

Department of Endocrinology, Royal Children's Hospital, Parkville VIC, Australia.

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http://dx.doi.org/10.1210/clinem/dgaa504DOI Listing
October 2020

Effect of Testosterone Treatment for Delayed Puberty in Duchenne Muscular Dystrophy.

Horm Res Paediatr 2020 1;93(2):108-118. Epub 2020 Jul 1.

Hormone Research, Murdoch Children's Research Institute, Melbourne, Victoria, Australia,

Objective: To evaluate the impact of pubertal induction with testosterone on bone health, body composition, and motor function in boys with Duchenne muscular dystrophy (DMD) receiving long-term glucocorticoid.

Study Design: A retrospective, observational, pre-post study investigating the impact of testosterone therapy on bone mass accrual, vertebral fracture incidence, body composition, motor function, and quality of life in boys with DMD. All those boys aged ≥14 years, on chronic steroid therapy, who had delayed puberty, and were receiving oral testosterone or oral and then transitioned to intramuscular testosterone, to complete virilization, were included. Prior/concomitant zoledronic acid use was included. The primary outcome was lumbar spine areal bone mineral density (BMD LS).

Results: Puberty was induced, using oral testosterone undecanoate in 16 individuals, 10 of whom had transited to intramuscular testosterone at time of assessment. Median age at testosterone onset was 14.5 years (range 14-17.7). Median duration of testosterone therapy was 2.5 years (range 1.0-4.5). There was statistically significant increase in median BMD LS (0.523-0.700, p < 0.001) and median annualized percentage change of BMD LS (-1.34 to +10.08%, p < 0.001), with median Tanner stage 4 at evaluation (range 2-4). Ten of 14 assessed had no progression in vertebral fractures. Fat mass index (FMI) standard deviation score (SDS), lean body mass index (LBMI) SDS, and percentage change of FMI and LBMI were statistically unchanged. Cardiac function remained stable. Motor function in non-ambulatory individuals with Egen Klassifikation scores improved in 7 of 8.

Conclusion: Testosterone for delayed puberty acted as an adjunct to bisphosphonates to increase bone density and stabilize vertebral fracture in most boys with DMD.
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http://dx.doi.org/10.1159/000508290DOI Listing
July 2021

Global consensus on nutritional rickets: Implications for Australia.

J Paediatr Child Health 2020 06;56(6):841-846

Institute of Endocrinology and Diabetes, Children's Hospital Westmead, Sydney, New South Wales, 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.
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http://dx.doi.org/10.1111/jpc.14941DOI Listing
June 2020

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

Clin Endocrinol (Oxf) 2020 10 30;93(4):466-472. Epub 2020 Jun 30.

Hormone Research, Murdoch Children's Research Institute, Melbourne, Vic., Australia.

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.
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http://dx.doi.org/10.1111/cen.14266DOI Listing
October 2020

McCune Albright Syndrome: Gastrointestinal Polyps and Platelet Dysfunction over 12 Years.

Horm Res Paediatr 2020 8;93(1):40-45. Epub 2020 May 8.

Department of Endocrinology, The Royal Children's Hospital, Parkville, Victoria, Australia.

Background And Objective: Gastrointestinal (GI) polyps with unknown malignant potential and a platelet storage pool deficiency that increases the risk of severe intraoperative and other types of bleeding have been identified in McCune-Albright syndrome (MAS). The natural course of these disorders has not been well characterized. The aim of this study was to report the follow-up of GI polyps and platelet dysfunction (PD) in a cohort of 28 patients with MAS.

Methods: Twenty-eight patients with MAS (15 females) were included. Endoscopic screening for GI polyps was undertaken in 14 subjects and 19 were tested for PD.

Results: Six subjects (5 males) were diagnosed with GI polyps at a median age of 23 (range 15-43) years, and were monitored for a median period of 8 (range 4.5-11.5) years. At endoscopic follow-up, the 4 patients with hamartomatous polyps at first endoscopy had either normal findings (n = 2), or duodenal gastric metaplasia (n = 2). Two patients with caecal polyps were identified. Of 8 subjects with a platelet storage pool deficiency, 5 required transfusions during surgery, and subsequent platelet cover in 2 markedly reduced intraoperative blood loss.

Conclusions: New polyps with uncertain malignant potential are diagnosed after long term follow-up in MAS. Platelet cover reduces the need for red blood cell transfusion during orthopaedic surgery and may be useful to reduce non-operative bleeding events. We recommend regular upper and lower endoscopy and screening for PD in all MAS patients.
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http://dx.doi.org/10.1159/000507442DOI Listing
April 2021

Fertility Preservation in Children and Adolescents With Cancer: Pilot of a Decision Aid for Parents of Children and Adolescents With Cancer.

JMIR Pediatr Parent 2018 Nov 28;1(2):e10463. Epub 2018 Nov 28.

Department of Obstetrics & Gynaecology, The Royal Women's Hospital, University of Melbourne, Parkville, Australia.

Background: Future infertility is a significant concern for survivors of childhood and adolescent cancer. Children and adolescents may have the opportunity to undergo fertility preservation (FP) procedures (which preserve gonadal tissue or gametes for future use) prior to the cancer treatment. However, the decision is very complex, as it is often made by parents as proxy decision makers at the time of cancer diagnosis, and is time-sensitive (needing to occur before the cancer treatment begins). Furthermore, FP procedures in children and adolescents are experimental and cannot guarantee future fertility. An uninformed decision may result in future decision regret.

Objective: This study aimed to assess the acceptability, usability, and feasibility of a Web-based FP decision aid (DA) in parents of children and adolescents with cancer and clinicians. Fertility knowledge and decision regret were compared in families who reviewed the DA compared with those who did not.

Methods: The Web-based DA was developed according to the International Patient Decision Aid Standards. A cross-sectional study of parents of patients with cancer, who discussed fertility, and clinicians at a tertiary children's hospital was undertaken. The acceptability, usability, and feasibility of the DA were assessed using a pre-post survey design. Measures included the validated Decision Regret Scale, a purpose-designed fertility-related knowledge scale, questions regarding satisfaction with the DA, and open-ended responses for additional feedback. Furthermore, clinicians involved in FP were also invited to review the DA.

Results: We enrolled 34 parents and 11 clinicians in this study. Participants who reviewed the DA (15 parents and 11 clinicians) expressed satisfaction with its content and functionality. Parents reported an improved understanding of cancer treatments, infertility, and FP procedures and did not report greater decision regret after DA review. Most parents (13/15, 86%) would recommend the DA to other parents. All clinicians had a consensus that this was a valid and relevant information source for all involved in fertility care.

Conclusions: It is an international standard of care to discuss the impact of cancer treatment on fertility before cancer treatment. This is the first fertility DA for parents of children and adolescents with cancer and is found to be relevant and acceptable by parents and clinicians. This DA has the potential to help support parents to make informed fertility-related decisions for their children and adolescents. However, future research is needed to assess the impact of the DA on prospective decision making.
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http://dx.doi.org/10.2196/10463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715396PMC
November 2018

Puberty.

Best Pract Res Clin Endocrinol Metab 2019 06 31;33(3):101301. Epub 2019 Jul 31.

Royal Children's Hospital and Murdoch Children's Research Institute, Department of Endocrinology and Centre for Hormone Research, Flemington Rd., Parkville, Victoria, 3052, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.beem.2019.101301DOI Listing
June 2019

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

J Assist Reprod Genet 2019 Sep 9;36(9):1805-1822. Epub 2019 Aug 9.

Department of Paediatric & Adolescent Gynaecology, The Royal Children's Hospital, Parkville, Australia.

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.
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http://dx.doi.org/10.1007/s10815-019-01536-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6730729PMC
September 2019

Disorders of Puberty: Pharmacotherapeutic Strategies for Management.

Handb Exp Pharmacol 2020 ;261:507-538

Department of Endocrinology, Royal Children's Hospital, Parkville, VIC, Australia.

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.
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http://dx.doi.org/10.1007/164_2019_208DOI Listing
October 2020

Incidence of disorders of sexual development in neonates in Ghana: prospective study.

Arch Dis Child 2019 07 16;104(7):636-638. Epub 2019 May 16.

Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.

Objective: The incidence of disorders of sexual development (DSD) is unknown in sub-Saharan Africa. We describe the characteristics and incidence of DSD in a cohort of infants born in Ghana.

Design: Trained research assistants performed systematic genital examination at birth. All infants with suspected abnormal genitalia were further examined by a paediatric endocrinologist.

Setting: Komfo Anokye Teaching Hospital, Kumasi, Ghana.

Patients: Consecutive infants born in a single centre over a 1-year period (May 2014 to April 2015).

Main Outcome Measures: Incidence of DSD. Micropenis was defined as a stretched length <2.1 cm and clitoromegaly as a clitoral length >8.6 mm.

Results: We examined 9255 infants (93% of all live births) within 72 hours of birth. Twenty-six neonates had a DSD. Nineteen infants had DSD without genital ambiguity: isolated micropenis (n=2), hypospadias (n=7), cryptorchidism (n=4) and clitoromegaly (n=6). Seven infants had DSD with ambiguity: clitoromegaly with a uterus on ultrasound and elevated 17-hydoxyprogesterone, suggesting XX DSD due to congenital adrenal hyperplasia (CAH)(n=4) and micropenis, hypospadias and gonads in a bifid scrotum or in the inguinal region, consistent with XY DSD (n=3).

Conclusion: The incidence of atypical genitalia was 28/10,000 (95% CI 17/10 000 to 39/10 000) live births. The incidence of CAH was 4.3/10 000 (95% CI 1.2/10 000 to 11.1/10 000) and was strongly associated with consanguinity.
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http://dx.doi.org/10.1136/archdischild-2019-316986DOI Listing
July 2019

A tale of two steroids: The importance of the androgens DHEA and DHEAS for early neurodevelopment.

J Steroid Biochem Mol Biol 2019 04 15;188:77-85. Epub 2018 Dec 15.

School of Health & Biomedical Sciences, RMIT University - Bundoora Campus, Melbourne, 3083, Australia. Electronic address:

DHEA and DHEAS are neuroactive neurosteroids that interact with several major receptor systems in the brain, including sigma (σ), glutamate, and GABA-A receptors. It has been recognized as early as 1952, that the loss of DHEA/DHEAS in adult life is associated with neuropsychiatric disorders (eg schizophrenia, depression). However, the mechanistic role for DHEA/DHEAS in any of these domains remains speculative, not the least because the presence of these androgens in the adrenal gland and brain is largely confined to humans and only some non-human primates. DHEA and DHEAS are dynamically regulated from before birth and before the onset of puberty, and therefore an understanding of the synthesis, regulation, and functions of this important androgen pathway warrants attention. Here, we draw attention to the possible modulating influence of DHEA/DHEAS in early brain development from fetal life to the remarkable increase of these steroids in early childhood - the adrenarche. We propose that the pre-pubertal DHEA/DHEAS surge plays a key role in modulating early brain development, perhaps by prolonging brain plasticity during childhood to allow the pre-adolescent brain to adapt and re-wire in response to new, and ever-changing social challenges. Nonetheless, the aetiology of neurodevelopmental phenomena in relation to DHEA/DHEAS synthesis and action cannot be easily studied in humans due to the obvious ethical restrictions on mechanistic studies, the uncertainty of predicting the future mental characteristics of individuals, and the difficulty of conducting retrospective investigations based on pre-birth and/or neonatal complications. We discuss new opportunities for animal studies to resolve these important questions.
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http://dx.doi.org/10.1016/j.jsbmb.2018.12.007DOI Listing
April 2019

DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency.

Am J Hum Genet 2018 12 29;103(6):1038-1044. Epub 2018 Nov 29.

Sorbonne Université, INSERM, UMR_S 938, APHP, Hospital Trousseau, 75012 Paris, France.

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.
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http://dx.doi.org/10.1016/j.ajhg.2018.10.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288413PMC
December 2018

Extreme hypercalcaemia due to accidental vitamin D intoxication.

J Paediatr Child Health 2019 Jan 19;55(1):104-106. Epub 2018 Jul 19.

Department of General Medicine, Royal Children's Hospital Melbourne, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1111/jpc.14127DOI Listing
January 2019

Resistant Paediatric Somatotropinomas due to AIP Mutations: Role of Pegvisomant.

Horm Res Paediatr 2018 28;90(3):196-202. Epub 2018 Jun 28.

Murdoch Children's Research Institute, Parkville, Victoria,

Background: Somatotropinomas are rare in childhood and frequently associated with genetic mutations. AIP mutations are found in 20-25% cases and cause aggressive somatotropinomas, often resistant to somatostatin analogues.

Aims: To assess responses to multimodal therapy including pegvisomant in 2 children with sporadic somatotropinomas due to AIP mutations.

Case Description: We report 2 children, a boy aged 13 and a girl aged 10, with rapid growth, visual impairment, and growth hormone hypersecretion. Magnetic resonance imaging confirmed a pituitary macroadenoma with parasellar extension in both. Despite multiple surgical attempts to debulk tumour mass, residual tumour persisted. Genetic analysis showed two different AIP mutations (patient 1: c.562delC [p.Arg188Glyfs*8]; patient 2: c.140_ 163del24 [p.Gly47_Arg54del8]). They were initially treated with a long-acting somatostatin analogue (octreotide LAR 30 mg/month) and cabergoline as a dopamine agonist, with the later addition of pegvisomant titrated up to 20 mg/day and with radiotherapy for long-term control. Somatostatin analogue was ceased due to patient intolerance and lack of control. Patient 1 had normalization of insulin-like growth factor-1 (IGF-1) after 5 months of combined therapy with pegvisomant and cabergoline. For patient 2, normalization of IGF-1 was achieved after 2 months of cabergoline and pegvisomant.

Conclusion: AIP-associated tumours can be resistant to management with somatostatin analogues. Pegvisomant can safely be used, to normalize IGF-1 levels and help control disease.
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http://dx.doi.org/10.1159/000488856DOI Listing
February 2019

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

Bone 2018 08 19;113:137-143. Epub 2018 May 19.

Hormone Research, Murdoch Childrens Research Institute, Royal Children's Hospital, 50 Flemington Rd, Parkville, 3052, Victoria, Australia; Department of Paediatrics, University of Melbourne, Parkville 3052, Victoria, Australia; Department of Endocrinology, Royal Children's Hospital, 50 Flemington Rd, Parkville, 3052, Victoria, Australia. Electronic address:

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.
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http://dx.doi.org/10.1016/j.bone.2018.05.021DOI Listing
August 2018

A Clinical Decision Support System to Assist Pediatric Oncofertility: A Short Report.

J Adolesc Young Adult Oncol 2018 08 7;7(4):509-513. Epub 2018 May 7.

1 Department of Obstetrics & Gynaecology, Royal Women's Hospital, University of Melbourne , Victoria, Australia .

Purpose: Fertility preservation discussions with pediatric and adolescent cancer patients can be difficult for clinicians. This study describes the acceptability of a fertility clinician decision support system (CDSS).

Methods: A cross-sectional study of clinicians at The Royal Children's Hospital, Melbourne. Participants were trained on CDSS purpose, contents, and use. A survey captured the perceived benefits and weaknesses of the CDSS.

Results: Thirty-nine clinicians participated. Over 90% felt the CDSS aims and format were clear, and understood the components. Over 80% felt it would enable adherence to clinical pathways, policy, and standards of care.

Conclusions: The CDSS provided significant perceived benefits to oncofertility care.
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http://dx.doi.org/10.1089/jayao.2018.0006DOI Listing
August 2018

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

Clin Endocrinol (Oxf) 2018 07 17;89(1):56-64. Epub 2018 May 17.

Section on Skeletal Disorders and Mineral Homeostasis, NIDCR, NIH, Bethesda, MD, USA.

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.
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http://dx.doi.org/10.1111/cen.13722DOI Listing
July 2018

Protocol for a randomised control trial of bisphosphonate (zoledronic acid) treatment in childhood femoral head avascular necrosis due to Perthes disease.

BMJ Paediatr Open 2017 14;1(1):e000084. Epub 2017 Sep 14.

Discipline of Child and Adolescent Health, The Children's Hospital at Westmead Clinical School, University of Sydney, Sydney, New South Wales, Australia.

Introduction: Perthes disease (PD) is an idiopathic disorder presenting with avascular necrosis to the femoral head, which frequently results in flattening. Long-term function is directly related to the subsequent femoral head sphericity. Current treatment includes mechanical modalities and surgical procedures, which are therapeutic but are not uniformly able to prevent collapse. The use of the nitrogen-containing bisphosphonate zoledronic acid (ZA) to inhibit osteoclastic bone resorption is aimed at preserving femoral head strength, reducing collapse and thus maintaining shape. The proposed multicentre, prospective, randomised controlled trial intends to evaluate the efficacy of ZA treatment in PD.

Methods And Analysis: An open-label randomised control trial recruiting 100 children (50 each treatment arm) 5 to 16 years old with unilateral PD. Subjects are randomly assigned to either (a) ZA and standard care or (b) Standard care. The primary outcome measure is deformity index (DI), a radiographic parameter of femoral head roundness assessed at 24 months, following 12 months of ZA treatment (3-monthly doses of ZA 0.025 mg/kg at baseline, 3, 6, 9 and 12 months) plus 12 months observation (group A) or 24 months of observation (group B). Secondary outcome measures are femoral head subluxation, Faces Pain scale, Harris hip score and quality of life. Assessments are made at baseline, 3 monthly during the first year of follow-up and then 6 monthly, until the 24th month.

Ethics And Dissemination: The study commenced following the written approval from the Human Research Ethics Committee. Safety considerations regarding the effects of ZA are monitored which include the subject's symptomatology, mineral status, bone mass and turnover activity, and metaphyseal modelling. Data handling plan requires that all documents, clinical information, biological samples and investigation results will be held in strict confidence by study investigators to preserve its safety and confidentiality.

Trial Registration Number: Australian and New Zealand Clinical Trials ACTRN12610000407099, pre-results.
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http://dx.doi.org/10.1136/bmjpo-2017-000084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862235PMC
September 2017
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