Publications by authors named "Catherine S Choong"

50 Publications

Using a trauma informed practice framework to enhance understanding of and identify support strategies for behavioural difficulties in young people with Prader-Willi syndrome.

Res Dev Disabil 2021 Mar 20;110:103839. Epub 2021 Jan 20.

Telethon Kids Institute, University of Western Australia, PO Box 855, West Perth, Western Australia, 6872, Australia; School of Physiotherapy and Exercise Science, Curtin University, Perth, Western Australia, Australia. Electronic address:

Background: Behavioural support for young people with Prader-Willi syndrome (PWS) is necessary in home and school environments. The Trauma Informed Practice (TIP) framework has been used to support young people with complex behavioural needs in school settings.

Aims: To identify parent and professional perspectives on behavioural challenges experienced by young people with PWS and strategies for supports, to inform understanding of how they are aligned with the TIP framework.

Method: Semi-structured interviews were conducted with eight families with a 12-21 year old child with PWS, four clinicians and two teachers to investigate the contexts and mechanisms associated with challenging, calm and productive behaviours. Data were analysed using directed content analysis, using TIP principles as a framework.

Results: Strategies to support young people with PWS aligned with the four overarching TIP Principles:Empowerment, voice and choice; Creating safe environments; Creating a collaborative environment; and Trustworthiness and transparency. Additional Novel domains included: Behavioural underpinnings, Modifying environments and Supporting family capacity.

Conclusion: These novel domains can be used to supplement the TIP framework for guidance on how to support young people with PWS.

Health Implications: Development and implementation of strategies to reduce behavioural difficulties in young people with PWS through positive support mechanisms could improve function and social engagement within their families and communities.
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http://dx.doi.org/10.1016/j.ridd.2020.103839DOI Listing
March 2021

Early markers of cardiovascular injury in childhood leukaemia survivors treated with anthracycline chemotherapy.

Cardiooncology 2019 14;5:11. Epub 2019 Aug 14.

1School of Human Sciences: Exercise and Sport Science, The University of Western Australia, 35 Stirling Highway, Perth, WA 6009 Australia.

Background: Cardiovascular disease (CVD) is the leading non-malignant cause of death in childhood cancer survivors. Heightened risk of CVD is often attributable to treatment with anthracycline chemotherapy. Anthracycline-mediated cardiac injury may lie latent for years following cessation of treatment and is therefore often not detected until disease is advanced and aggressive therapy is required. Symptomatic CVD may be preceded by subclinical cardiac and vascular dysfunction. This study aimed to determine whether such dysfunction could be detected in healthy, anthracycline-treated survivors of childhood leukaemia.

Methods: Cardiac magnetic resonance imaging (cMRI) with late gadolinium enhancement and endothelial function were used to characterise pre-clinical stages of CVD. Twenty-two long-term (>5 years survival; age 21 ± 3 years) childhood leukaemia survivors were assessed. All survivors were asymptomatic and had normal resting echocardiography. To exclude potential confounding effects of radiotherapy, no survivors had received this treatment. Twenty-two similarly aged (25 ± 3 years) gender-matched controls were recruited for comparison.

Results: Left ventricular ejection fraction was lower in the survivors (55.0 ± 4.6%) compared to the controls (59.4 ± 6.2%;  = 0.010). Further, five survivors (23%) had clinically reduced (<50%) left ventricular ejection fraction. Normalised left ventricular end systolic volume was augmented in survivors (40.0 ± 9.1 mL·m vs. 34.5 ± 7.5 mL·m;  = 0.038). Cardiac MRI did not show any late gadolinium enhancement. High resolution, ultrasound-derived flow mediated dilation was impaired in survivors (6.7 ± 2.1% vs. 8.60 ± 1.91%,  = 0.005).

Conclusions: We detected subclinical changes in cardiovascular structure and function indicative of early disease in anthracycline-treated childhood leukaemia survivors with normal echocardiography. Early detection and characterisation of underlying disease allows for timely intervention and improved outcomes in this at-risk population.
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http://dx.doi.org/10.1186/s40959-019-0047-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048057PMC
August 2019

Variable persistence of serum testosterone in infants and children exposed to topical testosterone.

J Paediatr Child Health 2020 Sep 26;56(9):1464-1467. Epub 2020 Feb 26.

Department of Endocrinology and Diabetes, Perth Children's Hospital, Perth, Western Australia, Australia.

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http://dx.doi.org/10.1111/jpc.14795DOI Listing
September 2020

Cardiovascular Testing Detects Underlying Dysfunction in Childhood Leukemia Survivors.

Med Sci Sports Exerc 2020 03;52(3):525-534

School of Human Sciences: Exercise and Sport Science, The University of Western Australia, Perth, Western Australia, AUSTRALIA.

Purpose: Childhood leukemia survivors commonly develop late-onset cardiovascular disease after treatment with anthracyclines. Resting echocardiogram is the standard procedure for monitoring cardiac health but this method may not be sensitive enough to detect subclinical injury. Exercise echocardiography may provide a viable alternative.

Methods: Nineteen (9 males; age, 19 ± 3 yr) anthracycline-treated survivors of childhood leukemia and 17 (8 males) healthy individuals of similar age (22 ± 2 yr) were recruited. All survivors had normal resting echocardiography upon recruitment. Exercise echocardiography was performed using contemporary imaging techniques. Flow-mediated dilation (FMD), body composition, and cardiorespiratory fitness (V˙O2peak) were assessed to determine predisposition to additional disease.

Results: Mitral valve peak flow velocity in late diastole (interaction, P = 0.007) increased from rest in survivors (P = 0.023) and controls (P = 0.020) immediately postexercise but did not recover again in the survivors (exercise-recovery, P = 0.784) after recuperation. Consequently, E/A ratio (interaction, P < 0.001) was lower in the survivors at recovery (P < 0.001). Survivors had reduced FMD (7.88 ± 1.70 vs 9.65 ± 2.83; P = 0.030), maximal and recovery HR (P = 0.001; P < 0.001), minute ventilation (P < 0.001), and V˙O2peak (absolute, 2.64 ± 0.62 vs 3.14 ± 0.74 L·min, P = 0.034; relative, 36.78 ± 11.49 vs 45.14 ± 6.80 mL·kg·min; P = 0.013) compared with controls. They also had higher total body fat (percentage, P = 0.034; mass, P = 0.024) and fat mass in the central (P = 0.050), peripheral (P = 0.039) and visceral (P < 0.001) regions. Survivors matched controls with regard to height (173.0 ± 7.8 cm vs 173.8 ± 9.1 cm; P = 0.796), body mass (76.16 ± 19.05 kg vs 70.07 ± 13.96 kg; P = 0.287) and body mass index (25.2 ± 5.1 vs 22.9 ± 2.7; P = 0.109).

Conclusions: Exercise echocardiography unmasked subclinical diastolic dysfunction that may indicate late anthracycline toxicity in apparently healthy survivors of childhood leukemia. Presence of secondary risk factors indicates increased predisposition to comorbidities and highlights the importance of assessing cardiovascular health during follow-up.
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http://dx.doi.org/10.1249/MSS.0000000000002168DOI Listing
March 2020

Requirements for improving health and well-being of children with Prader-Willi syndrome and their families.

J Paediatr Child Health 2019 Sep 30;55(9):1029-1037. Epub 2019 Jun 30.

Telethon Kids Institute, Centre for Child Health Research, University of Western Australia, Perth, Western Australia, Australia.

Prader-Willi syndrome (PWS) is a rare genetic condition with multi-system involvement. The literature was reviewed to describe neurodevelopment and the behavioural phenotype, endocrine and metabolic disorders and respiratory and sleep functioning. Implications for child and family quality of life were explored. Challenging behaviours contribute to poorer well-being and quality of life for both the child and caregiver. Recent evidence indicates healthy outcomes of weight and height can be achieved with growth hormone therapy and dietary restriction and should be the current target for all individuals with PWS. Gaps in the literature included therapies to manage challenging behaviours, as well as understanding the effects of growth hormone on respiratory and sleep function. New knowledge regarding the transition of children and families from schooling and paediatric health services to employment, accommodation and adult health services is also needed. Developing a national population-based registry could address these knowledge gaps and inform advocacy for support services that improve the well-being of individuals with PWS and their families.
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http://dx.doi.org/10.1111/jpc.14546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852695PMC
September 2019

Completeness of protocols for clinical trials in children submitted to ethics committees.

J Paediatr Child Health 2019 Mar 30;55(3):291-298. Epub 2018 Aug 30.

Centre for Kidney Research, Children's Hospital at Westmead, Sydney, New South Wales, Australia.

Aim: Studies of published clinical trials involving children have shown frequent omissions in key aspects of design and conduct, but these problems may be artefactual and due to editorial processes and space limitations. To determine actual design and conduct, we analysed the completeness of key domains in trial protocols involving children submitted to Human Research Ethics Committees.

Methods: The ethics committees of all eight children's hospitals in Australia were invited to participate. De-identified trial protocols submitted for review in 2012 were evaluated using a checklist derived from Consolidated Standards of Reporting Trials, the Cochrane Risk of Bias Tool and Good Clinical Practice guidelines.

Results: Four ethics committees agreed to participate, and 69 protocols were analysed. The domains almost always reported were clustered around the background and trial plan (planned interventions for each group (99%), specific objectives (97%) and scientific background (96%)). Risk-of-bias domains such as random sequence generation and blinding of participants were often reported (75-90%). Domains least reported were clustered around the statistical analysis plan (66%), specified intention-to-treat analysis (54%), the justification for the proposed trial based upon a systematic review (48%) and age-specific outcomes (48%).

Conclusions: Protocols of trials involving children assessed by ethics committees generally include details on background and basic design, but many key domains in trial design and conduct are not covered. Despite widespread recognition of how problems in the design and conduct of trials may lead to unreliable results, investigators still appear to be omitting key elements in trial protocols.
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http://dx.doi.org/10.1111/jpc.14189DOI Listing
March 2019

Exercise training improves vascular function and secondary health measures in survivors of pediatric oncology related cerebral insult.

PLoS One 2018 9;13(8):e0201449. Epub 2018 Aug 9.

School of Human Sciences, Exercise and Sport Science, The University of Western Australia, Perth, Western Australia, Australia.

Adolescent and young adult (AYA) survivors of pediatric oncology related cerebral insult are vulnerable to numerous treatment-induced deficits that significantly enhance cardiovascular disease risk. Regular exercise improves endothelial function, fitness, body composition and musculoskeletal function which may reduce predisposition for cardiovascular disease. Here we assessed the feasibility and effectiveness of a 24-week exercise intervention on cardiovascular, physical and metabolic outcomes in this population. Thirteen survivors (6 male, 7 female; median age 19 y (range 16-23 y) were recruited to participate in a 48-week study consisting of a 24-week control period (regular care) followed by a 24-week exercise intervention. Outcome measures were collected at entry (week 0) and following regular care (24-week) and exercise (48-week). Assessed variables included endothelial function (flow mediated dilation, FMD), blood pressure, heart rate (HR), aerobic capacity, anthropometry, body composition, muscular strength (3 repetition maximum testing), muscular endurance (repetitions/min) and physical activity levels (accelerometry). Compared to baseline, delta diameter (p = 0.008) and FMD (p = 0.029) of the brachial artery increased following exercise. Bicep-curl strength also increased following exercise compared to baseline (p = 0.019), while submaximal (6 min mark) measures of ventilation (p = 0.012), rating of perceived exertion (p = 0.012), HR (p = 0.001), absolute (p = 0.000) and relative (p = 0.000) aerobic capacity decreased. Breaks in sedentary time increased (p = 0.043) following exercise compared to regular care. Although the sample was small and heterogeneous, this study demonstrates that exercise is achievable and has positive effects on vascular function, submaximal fitness, local strength and physical activity in a population of AYA survivors of pediatric oncology related cerebral insult.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201449PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6084859PMC
January 2019

A Case Report of Syndromic Multinodular Goitre in Adolescence: Exploring the Phenotype Overlap between Cowden and DICER1 Syndromes.

Eur Thyroid J 2018 Jan 21;7(1):44-50. Epub 2017 Nov 21.

Department of Endocrinology and Diabetes, Princess Margaret Hospital for Children, Subiaco, Washington, Australia.

Background: Hereditary tumour predisposition syndromes may increase the risk for development of thyroid nodules at a young age. We present the case of an adolescent female with Cowden syndrome who had some atypical phenotypic features which overlapped with the DICER1 syndrome.

Material And Methods: A 17-year-old female presented with a 3-month history of progressive right neck swelling. Fine needle cytology of the thyroid revealed a follicular neoplasm with features suggestive of follicular variant of papillary thyroid carcinoma and she underwent a hemithyroidectomy. Enlarging nodules in the remaining thyroid led to a completion thyroidectomy at 19 years of age. The patient's past medical history included an ovarian mixed malignant germ cell tumour, pulmonary nodules and cysts, renal cysts, mucocutaneous lesions, an arachnoid cyst, and a fibrous breast lesion. Macrocephaly was noted on physical examination.

Results: Based on the patient's complex phenotype and young age, a hereditary predisposition syndrome was suspected and genetic testing of and was undertaken. A heterozygous truncating germ-line mutation was identified, which combined with clinical findings, met criteria for the diagnosis of Cowden syndrome. Additional loss of heterozygosity of the wild-type allele was detected in the right thyroid lesion and ovarian tumour. No mutations were identified.

Conclusions: Genetic testing was crucial in elucidating this patient's predisposition to the early development of neoplastic and non-neoplastic conditions. Our report also highlights the phenotypic overlap between the Cowden and DICER1 syndromes and illustrates the importance of recognising the variable phenotypic features of hereditary syndromes in order to enable timely implementation of appropriate care.
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http://dx.doi.org/10.1159/000481620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836238PMC
January 2018

Metabolic and Psychological Impact of a Pragmatic Exercise Intervention Program in Adolescent and Young Adult Survivors of Pediatric Cancer-Related Cerebral Insult.

J Adolesc Young Adult Oncol 2018 06 22;7(3):349-357. Epub 2018 Mar 22.

1 Department of Diabetes and Endocrinology, Princess Margaret Hospital , Perth, Australia .

Purpose: To assess metabolic function among adolescent and young adult (AYA) survivors of childhood cancer-related brain surgery or cranial irradiation (CRT) and to determine feasibility, safety, and metabolic as well as psychological impact of a 6-month exercise program in this cohort.

Methods: Twenty AYAs aged 15-23 years were recruited. All had completed cancer treatment by age 15.5 and were more than 1 year after end of treatment. Metabolic function was assessed at baseline (T1), after a 6-month non-intervention period (T2), and after the 6-month intervention (T3). Psychological assessments were performed at T1 and T3. Eight to 12 months after the program (T4), its lasting impact was assessed by questionnaire. The 6-month intervention consisted of small group-based, tailored, supervised exercise sessions combining resistance and aerobic exercise. Sessions were offered up to thrice per week and adherence defined as participation in ≥24 sessions. Flexibility was built into the design with an alternative home-based program offered to those who could not attend the gymnasium.

Results: Thirteen of the 20 recruited participants were adherent to the program. There was one fall during exercise, but no injury was sustained. Higher rates of metabolic impairment than would be expected in a healthy cohort were found at baseline both among brain tumor survivors and survivors of total body irradiation. Central adiposity reduced post-intervention (p = 0.014) and improvements in adaptive function were seen. Participants enjoyed the program, but work and study commitments limited attendance.

Conclusion: AYA survivors of childhood brain tumors and CRT should be screened for metabolic and psychological well-being. Small group-based exercise is safe, feasible, and enjoyable for this cohort and may benefit them both metabolically and psychologically.

Trial Registration: ACTRN12614000796684. Retrospectively registered July 28, 2014.
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http://dx.doi.org/10.1089/jayao.2017.0105DOI Listing
June 2018

A novel, homozygous mutation in () in a 46, XY patient with dysgenetic testes presenting with primary amenorrhoea: a case report.

Int J Pediatr Endocrinol 2018 2;2018. Epub 2018 Mar 2.

1Department of Endocrinology and Diabetes, Princess Margaret Hospital, Subiaco, WA Australia.

Background: () mutations have been described in only a limited number of individuals with 46, XY disorders of sex development (DSD) presenting as either partial or complete gonadal dysgenesis. Gonadal tumours and peripheral neuropathy have been associated with mutations. Herein we report a novel, homozygous mutation of identified through a targeted, massively parallel sequencing (MPS) DSD panel, in a patient presenting with partial gonadal dysgenesis. This novel mutation is two amino acids away from a previously described mutation in a patient who presented with complete gonadal dysgenesis. Adding to the complexity of work-up, our patient also expressed gender identity concern.

Case Presentation: A 14-year-old, phenotypic female presented with primary amenorrhoea and absent secondary sex characteristics. Investigations revealed elevated gonadotrophins with low oestradiol, testosterone of 0.6 nmol/L and a 46, XY karyotype. Müllerian structures were not seen on pelvic ultrasound or laparoscopically and gonadal biopsies demonstrated dysgenetic testes without neoplasia (partial gonadal dysgenesis). The patient expressed gender identity confusion upon initial notification of investigation findings. Formal psychiatric evaluation excluded gender dysphoria. Genetic analysis was performed using a targeted, MPS DSD panel of 64 diagnostic and 927 research candidate genes. This identified a novel, homozygous mutation in exon 2 of (DHH:NM_021044:exon2:c.G491C:p.R164P). With this finding our patient was screened for the possibility of peripheral neuropathy which was not evident clinically nor on investigation. She was commenced on oestrogen for pubertal induction.

Conclusion: The evaluation of patients with DSD is associated with considerable psychological distress. Targeted MPS enables an affordable and efficient method for diagnosis of 46, XY DSD cases. Identifying a genetic diagnosis may inform clinical management and in this case directed screening for peripheral neuropathy. In addition to the structural location of the mutation other interacting factors may influence phenotypic expression in homozygous mutations.
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http://dx.doi.org/10.1186/s13633-018-0056-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834851PMC
March 2018

Growth Hormone Research Society perspective on biomarkers of GH action in children and adults.

Endocr Connect 2018 Mar 26;7(3):R126-R134. Epub 2018 Feb 26.

Aarhus University HospitalAarhus, Denmark

Objective: The Growth Hormone Research Society (GRS) convened a Workshop in 2017 to evaluate clinical endpoints, surrogate endpoints and biomarkers during GH treatment of children and adults and in patients with acromegaly.

Participants: GRS invited 34 international experts including clinicians, basic scientists, a regulatory scientist and physicians from the pharmaceutical industry.

Evidence: Current literature was reviewed and expert opinion was utilized to establish the state of the art and identify current gaps and unmet needs.

Consensus Process: Following plenary presentations, breakout groups discussed questions framed by the planning committee. The attendees re-convened after each breakout session to share the group reports. A writing team compiled the breakout session reports into a document that was subsequently discussed and revised by participants. This was edited further and circulated for final review after the meeting. Participants from pharmaceutical companies were not part of the writing process.

Conclusions: The clinical endpoint in paediatric GH treatment is adult height with height velocity as a surrogate endpoint. Increased life expectancy is the ideal but unfeasible clinical endpoint of GH treatment in adult GH-deficient patients (GHDA) and in patients with acromegaly. The pragmatic clinical endpoints in GHDA include normalization of body composition and quality of life, whereas symptom relief and reversal of comorbidities are used in acromegaly. Serum IGF-I is widely used as a biomarker, even though it correlates weakly with clinical endpoints in GH treatment, whereas in acromegaly, normalization of IGF-I may be related to improvement in mortality. There is an unmet need for novel biomarkers that capture the pleiotropic actions of GH in relation to GH treatment and in patients with acromegaly.
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http://dx.doi.org/10.1530/EC-18-0047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868631PMC
March 2018

Fitness, body composition and vascular health in adolescent and young adult survivors of paediatric brain cancer and cranial radiotherapy.

Int J Adolesc Med Health 2017 Sep 20;31(5). Epub 2017 Sep 20.

The University of Western Australia, School of Human Sciences, Exercise and Sport Science, Perth, Australia.

Background Survivors of paediatric brain cancer and/or cranial radiotherapy (CRT) are at an increased risk of developing serious comorbidities. Established risk factors for chronic disease include central obesity, endothelial abnormalities and diminished fitness. Objectives Here we characterised anthropometry, body composition, bone mineral density (BMD), heart rate (HR), blood pressure (BP), endothelial function, muscular strength and endurance and aerobic fitness in adolescent and young adult (AYA) survivors. Methods Twenty survivors (10 male, 10 female; 20 ± 2 years) were compared with 19 matched controls. Muscular strength was assessed using three repetition maximum tests, while muscular endurance was determined as number of repetitions performed per minute. Peak oxygen uptake (VO2 peak) was assessed on a treadmill using a modified chronotropic protocol. Anthropometric measurements, HR and BP were taken using standard clinical protocols, while body composition and BMD were determined using dual X-ray absorptiometry (DXA). Endothelial function was measured using the flow mediated dilation technique. Results Survivors demonstrated deficits in muscular strength (latissimus dorsi pull-down, p = 0.020; bicep curl, p = 0.009), muscular endurance (squats, p = 0.012; sit-ups, p = 0.030; push-ups, p = 0.013), minute ventilation at peak exericse (p = 0.002) and VO2peak (L/min, p = 0.002; mL/kg/min, p = 0.008; mL/kg LBM/min, p = 0.010). Additionally, survivors had greater waist-to-hip ratios (p = 0.032), resting HR (p = 0.048) and higher percentage of total body (p = 0.017), central (p = 0.009) and peripheral (p = 0.032) fat. Lean body mass (p = 0.004) and BMD (p = 0.005) were lower in the survivor group. Conclusion AYA survivors of paediatric brain cancer and/or CRT exhibit altered body composition, increased resting HR and reduced BMD, muscular strength, muscular endurance and cardiorespiratory fitness compared to controls.
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http://dx.doi.org/10.1515/ijamh-2017-0082DOI Listing
September 2017

Sequencing of DICER1 in sarcomas identifies biallelic somatic DICER1 mutations in an adult-onset embryonal rhabdomyosarcoma.

Br J Cancer 2017 Jun 18;116(12):1621-1626. Epub 2017 May 18.

Department of Human Genetics, McGill University, 1205 Dr. Penfield Avenue, Stewart Biology Building, Room N5/13, Montréal, QC H3A 1B1, Canada.

Background: Sarcomas are rare and heterogeneous cancers. We assessed the contribution of DICER1 mutations to sarcoma development.

Methods: The coding region of DICER1 was sequenced in 67 sarcomas using a custom Fluidigm Access Array. The RNase III domains were Sanger sequenced in six additional sarcomas to identify hotspot DICER1 variants.

Results: The median age of sarcoma diagnosis was 45.7 years (range: 3 months to 87.4 years). A recurrent embryonal rhabdomyosarcoma (ERMS) of the broad ligament, first diagnosed at age 23 years, harboured biallelic pathogenic somatic DICER1 variants (1 truncating and 1 RNase IIIb missense). We identified nine other DICER1 variants. One somatic variant (p.L1070V) identified in a pleomorphic sarcoma and one germline variant (c.2257-7A>G) may be pathogenic, but the others are considered to be benign.

Conclusions: We show that deleterious DICER1 mutations underlie the genetic basis of only a small fraction of sarcomas, in particular ERMS of the urogenital tract.
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http://dx.doi.org/10.1038/bjc.2017.147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518865PMC
June 2017

Low dose growth hormone treatment in infants and toddlers with Prader-Willi syndrome is comparable to higher dosage regimens.

Growth Horm IGF Res 2017 06 24;34:1-7. Epub 2017 Mar 24.

Child Health Research Centre, The University of Queensland, Brisbane, Australia.

Objective: Evaluate benefit and risk of low dose growth hormone treatment (GHT, 4.5mg/m/week) in very young children with Prader-Willi Syndrome (PWS).

Design: Prospective longitudinal clinical intervention.

Methods: We evaluated 31 infants (aged 2-12months) and 42 toddlers (13-24months) from the PWS-OZGROW database for height, weight and BMI using the World Health Organization standard deviation scores (SDS) and PWS specific BMI (SDS), bone age, insulin-like growth factor 1 (IGF-I) levels and adverse events over 3years of GHT.

Results: At commencement of GHT infants had a lower BMI SDS (-0.88 vs 0.40) than toddlers, while toddlers had a lower height SDS (-1.44 vs -2.09) (both P<0.05). All increased height SDS (2year delta height infants +1.26 SDS, toddlers+1.21 SDS), but infants normalised height sooner, achieving a height SDS of -0.56 within 1year, while toddlers achieved a height SDS of -0.88 in two years. BMI SDS increased, while BMI SDS decreased (both P<0.0001) and remained negative. The GHT response did not differ with gestation (preterm 23%) or genetic subtype (deletion vs maternal uniparental disomy). Bone age advancement paralleled chronological age. All children had low serum IGF-I at baseline which increased, but remained within the age-based reference range during GHT (for 81% in first year). Four children had spinal curvature at baseline; two improved, two progressed to a brace and two developed an abnormal curve over the observation period. Mild to severe central and/or obstructive sleep apnoea were observed in 40% of children prior to GHT initiation; 11% commenced GHT on positive airway pressure (PAP), oxygen or both. Eight children ceased GHT due to onset or worsening of sleep apnoea: 2 infants in the first few months and 6 children after 6-24months. Seven resumed GHT usually after adjusting PAP but five had adenotonsillectomy. One child ceased GHT temporarily due to respiratory illness. No other adverse events were reported. Two children substantially improved their breathing shortly after GHT initiation.

Conclusion: Initiation of GHT in infants with 4.5mg/m/week was beneficial and comparable in terms of auxological response to a dose of 7mg/m/week. Regular monitoring pre and post GH initiation assisted in early detection of adverse events. IGF-I levels increased with the lower dose but not excessively, which may lower potential long-term risks.
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http://dx.doi.org/10.1016/j.ghir.2017.03.001DOI Listing
June 2017

Transient pseudohypoaldosteronism in infancy secondary to urinary tract infection.

J Paediatr Child Health 2017 May 24;53(5):458-463. Epub 2017 Feb 24.

Department of Endocrinology and Diabetes, The University of Western Australia, Perth, Western Australia, Australia.

Aim: Hyponatraemia with hyperkalaemia in infancy is a typical presentation of congenital adrenal hyperplasia. In the presence of pyelonephritis, the same biochemical picture can occur with transient type 1 pseudohypoaldosteronism (PHA-1) also termed type 4 renal tubular acidosis. Recognition of PHA-1 enables appropriate management thus avoiding unnecessary investigations and treatment. To improve awareness of this condition, we present a case series to highlight the clinical and biochemical features of PHA-1.

Methods: A retrospective chart review of patients diagnosed with transient PHA-1 at a tertiary children's hospital in Western Australia was conducted.

Results: Five male infants (32 days to 6 months) with transient PHA-1 were identified. Failure to thrive was the most common symptom with hyponatraemia on presentation. Two infants had antenatally diagnosed bilateral hydronephrosis and urinary tract infection (UTI) on admission. Two infants were treated for congenital adrenal hyperplasia and received hydrocortisone. All infants had UTI and required parenteral antibiotics. The condition was transient and hyponatraemia corrected by day 4 in all infants. There was no correlation between plasma sodium and aldosterone levels. The severity of PHA-1 was independent of the underlying renal anomaly. Four infants had hydronephrosis and vesicoureteric reflux. Surgical intervention was required in two infants.

Conclusions: PHA-1 may be precipitated by UTI or urinary tract anomalies in early infancy. Urine analysis should be performed in infants with hyponatraemia. Diagnosis of PHA-1 facilitates appropriate renal investigations to reduce long-term morbidity.
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http://dx.doi.org/10.1111/jpc.13481DOI Listing
May 2017

Short stature and hypoparathyroidism in a child with Kenny-Caffey syndrome type 2 due to a novel mutation in gene.

Int J Pediatr Endocrinol 2017 25;2017. Epub 2017 Jan 25.

Department of Endocrinology, Princess Margaret Hospital, Perth, Australia.

Background: Hypoparathyroidism in children is a heterogeneous group with diverse genetic etiologies. To aid clinicians in the investigation and management of children with hypoparathyroidism, we describe the phenotype of a 6-year-old child with hypoparathyroidism and short stature diagnosed with Kenny-Caffey syndrome (KCS) Type 2 and the subsequent response to growth hormone (GH) treatment.

Case Presentation: The proband presented in the neonatal period with hypocalcemic seizures secondary to hypoparathyroidism. Her phenotype included small hands and feet, hypoplastic and dystrophic nails, hypoplastic mid-face and macrocrania. Postnatal growth was delayed but neurodevelopment was normal. A skeletal survey at 2 years of age was suggestive of KCS Type 2 and genetic testing revealed a novel heterozygous mutation c.1622C > A (p.Ser541Tyr) in . At 3 years and 2 months, her height was 80cms (SDS -3.86). She had normal overnight GH levels. GH therapy was commenced at a dose of 4.9 mg/m/week for her short stature and low height velocity of 5cms/year. At the end of the first and second years of GH treatment, height velocity was 6.5cms/year and 7.2cms/year, respectively with maximal dose of 7.24 mg/m/week.

Conclusion: This case highlights the phenotype and the limited response to GH in a child with genetically proven KCS type 2. Long-term registries monitoring growth outcomes following GH therapy in patients with rare genetic conditions may help guide clinical decisions regarding the use and doses of GH in these conditions.
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http://dx.doi.org/10.1186/s13633-016-0041-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5264330PMC
January 2017

Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort.

Genome Biol 2016 11 29;17(1):243. Epub 2016 Nov 29.

Department of Medical Genetics, Sydney Children's Hospital, Randwick, NSW, Australia.

Background: Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients receive an accurate clinical genetic diagnosis. To address this we have developed a massively parallel sequencing targeted DSD gene panel which allows us to sequence all 64 known diagnostic DSD genes and candidate genes simultaneously.

Results: We analyzed DNA from the largest reported international cohort of patients with DSD (278 patients with 46,XY DSD and 48 with 46,XX DSD). Our targeted gene panel compares favorably with other sequencing platforms. We found a total of 28 diagnostic genes that are implicated in DSD, highlighting the genetic spectrum of this disorder. Sequencing revealed 93 previously unreported DSD gene variants. Overall, we identified a likely genetic diagnosis in 43% of patients with 46,XY DSD. In patients with 46,XY disorders of androgen synthesis and action the genetic diagnosis rate reached 60%. Surprisingly, little difference in diagnostic rate was observed between singletons and trios. In many cases our findings are informative as to the likely cause of the DSD, which will facilitate clinical management.

Conclusions: Our massively parallel sequencing targeted DSD gene panel represents an economical means of improving the genetic diagnostic capability for patients affected by DSD. Implementation of this panel in a large cohort of patients has expanded our understanding of the underlying genetic etiology of DSD. The inclusion of research candidate genes also provides an invaluable resource for future identification of novel genes.
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http://dx.doi.org/10.1186/s13059-016-1105-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126855PMC
November 2016

Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study.

Acta Neuropathol Commun 2016 06 1;4(1):56. Epub 2016 Jun 1.

Department of Pathology, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, 69500, France.

Non-syndromic pituitary gigantism can result from AIP mutations or the recently identified Xq26.3 microduplication causing X-linked acrogigantism (XLAG). Within Xq26.3, GPR101 is believed to be the causative gene, and the c.924G > C (p.E308D) variant in this orphan G protein-coupled receptor has been suggested to play a role in the pathogenesis of acromegaly.We studied 153 patients (58 females and 95 males) with pituitary gigantism. AIP mutation-negative cases were screened for GPR101 duplication through copy number variation droplet digital PCR and high-density aCGH. The genetic, clinical and histopathological features of XLAG patients were studied in detail. 395 peripheral blood and 193 pituitary tumor DNA samples from acromegaly patients were tested for GPR101 variants.We identified 12 patients (10 females and 2 males; 7.8 %) with XLAG. In one subject, the duplicated region only contained GPR101, but not the other three genes in found to be duplicated in the previously reported patients, defining a new smallest region of overlap of duplications. While females presented with germline mutations, the two male patients harbored the mutation in a mosaic state. Nine patients had pituitary adenomas, while three had hyperplasia. The comparison of the features of XLAG, AIP-positive and GPR101&AIP-negative patients revealed significant differences in sex distribution, age at onset, height, prolactin co-secretion and histological features. The pathological features of XLAG-related adenomas were remarkably similar. These tumors had a sinusoidal and lobular architecture. Sparsely and densely granulated somatotrophs were admixed with lactotrophs; follicle-like structures and calcifications were commonly observed. Patients with sporadic of familial acromegaly did not have an increased prevalence of the c.924G > C (p.E308D) GPR101 variant compared to public databases.In conclusion, XLAG can result from germline or somatic duplication of GPR101. Duplication of GPR101 alone is sufficient for the development of XLAG, implicating it as the causative gene within the Xq26.3 region. The pathological features of XLAG-associated pituitary adenomas are typical and, together with the clinical phenotype, should prompt genetic testing.
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http://dx.doi.org/10.1186/s40478-016-0328-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4888203PMC
June 2016

Growth Hormone Research Society perspective on the development of long-acting growth hormone preparations.

Eur J Endocrinol 2016 Jun 23;174(6):C1-8. Epub 2016 Mar 23.

Cedars-Sinai Medical Center Los Angeles, California, USA.

Objective: The Growth Hormone (GH) Research Society (GRS) convened a workshop to address important issues regarding trial design, efficacy, and safety of long-acting growth hormone preparations (LAGH).

Participants: A closed meeting of 55 international scientists with expertise in GH, including pediatric and adult endocrinologists, basic scientists, regulatory scientists, and participants from the pharmaceutical industry.

Evidence: Current literature was reviewed for gaps in knowledge. Expert opinion was used to suggest studies required to address potential safety and efficacy issues.

Consensus Process: Following plenary presentations summarizing the literature, breakout groups discussed questions framed by the planning committee. Attendees reconvened after each breakout session to share group reports. A writing team compiled the breakout session reports into a draft document that was discussed and revised in an open forum on the concluding day. This was edited further and then circulated to attendees from academic institutions for review after the meeting. Participants from pharmaceutical companies did not participate in the planning, writing, or in the discussions and text revision on the final day of the workshop. Scientists from industry and regulatory agencies reviewed the manuscript to identify any factual errors.

Conclusions: LAGH compounds may represent an advance over daily GH injections because of increased convenience and differing phamacodynamic properties, providing the potential for improved adherence and outcomes. Better methods to assess adherence must be developed and validated. Long-term surveillance registries that include assessment of efficacy, cost-benefit, disease burden, quality of life, and safety are essential for understanding the impact of sustained exposure to LAGH preparations.
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http://dx.doi.org/10.1530/EJE-16-0111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081743PMC
June 2016

Efficacy and safety of sirolimus in a neonate with persistent hypoglycaemia following near-total pancreatectomy for hyperinsulinaemic hypoglycaemia.

J Pediatr Endocrinol Metab 2015 Nov;28(11-12):1391-8

Hyperinsulinaemic hypoglycaemia (HH) is characterised by inappropriate insulin secretion and is the most common cause for persistent neonatal hypoglycaemia. The only treatment available for medically unresponsive hypoglycaemia is a near-total pancreatectomy. A neonate with severe HH, due to a homozygous ABCC8 mutation, was not responsive to treatment with maximal doses of diazoxide and subcutaneous daily octreotide, and underwent a near-total pancreatectomy; however, hypoglycaemia persisted. Introduction of sirolimus, an mTOR (mammalian target of rapamycin) inhibitor, obviated the requirement for glucose infusion. Euglycaemia was achieved with no significant adverse events from the drug. Sirolimus therapy was ceased at 13 months of age. No episodes of persistent hypoglycaemia were observed after cessation of sirolimus. This report demonstrates the successful use of sirolimus for persistent hypoglycaemia in the critically ill infant post pancreatectomy. Sirolimus could be considered in patients with severe HH not responsive to conventional medical and surgical therapy. However, the long-term efficacy and safety with this immunosuppressive drug in very young patients are not assured.
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http://dx.doi.org/10.1515/jpem-2015-0094DOI Listing
November 2015

Clinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients.

Endocr Relat Cancer 2015 Oct 17;22(5):745-57. Epub 2015 Jul 17.

Departments of Endocrinology and Human GeneticsCentre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumClinical Center of Endocrinology and GerontologyMedical University, Sofia, BulgariaDepartment of EndocrinologyKing Edward Memorial Hospital, Mumbai, IndiaAssistance Publique-Hôpitaux de ParisHôpitaux Universitaires Paris-Sud, Service d'Endocrinologie et des Maladies de la Reproduction et Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Le Kremlin-Bicêtre F-94275, FranceUMR S1185Univ Paris-Sud, F-94276 Le Kremlin-Bicêtre, FranceINSERM U1185Faculté de Médecine Paris-Sud, F-94276 Le Kremlin-Bicêtre, FranceServicio de Endocrinología y NutriciónHospital Universitario La Paz, Madrid, SpainSection on Endocrinology and GeneticsProgram on Developmental Endocrinology & Genetics & Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health (NIH), Bethesda, Maryland 20892, USADivision of EndocrinologyDepartment of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USADepartment of EndocrinologyGreenlane Clinical Centre, Auckland, New ZealandSection of EndocrinologyDepartment of Internal Medicine, Erasmus Medical Centre, Rotterdam, The NetherlandsSection of Endocrinology and Internal MedicineDepartment of Medical Sciences, University of Ferrara, Via Savonarola 9, 44121 Ferrara, ItalyServicio de EndocrinologíaHospital Universitario Puerta De Hierro, Majadahonda, Madrid, SpainService d'endocrinologie-diabétologieCentre Hospitalier Lucien Hussel, Montée du Docteur Chapuis BP127, 38 209 Vienne cedex, FranceMurdoch Children's Research InstituteRoyal Children's Hospital, University of Melbourne, Parkville, Victoria, AustraliaDepartments of Internal Medicine and PediatricsOulu University Hospital, University of Oulu, Oulu, FinlandDepartments of Neuroen

Despite being a classical growth disorder, pituitary gigantism has not been studied previously in a standardized way. We performed a retrospective, multicenter, international study to characterize a large series of pituitary gigantism patients. We included 208 patients (163 males; 78.4%) with growth hormone excess and a current/previous abnormal growth velocity for age or final height >2 s.d. above country normal means. The median onset of rapid growth was 13 years and occurred significantly earlier in females than in males; pituitary adenomas were diagnosed earlier in females than males (15.8 vs 21.5 years respectively). Adenomas were ≥10 mm (i.e., macroadenomas) in 84%, of which extrasellar extension occurred in 77% and invasion in 54%. GH/IGF1 control was achieved in 39% during long-term follow-up. Final height was greater in younger onset patients, with larger tumors and higher GH levels. Later disease control was associated with a greater difference from mid-parental height (r=0.23, P=0.02). AIP mutations occurred in 29%; microduplication at Xq26.3 - X-linked acrogigantism (X-LAG) - occurred in two familial isolated pituitary adenoma kindreds and in ten sporadic patients. Tumor size was not different in X-LAG, AIP mutated and genetically negative patient groups. AIP-mutated and X-LAG patients were significantly younger at onset and diagnosis, but disease control was worse in genetically negative cases. Pituitary gigantism patients are characterized by male predominance and large tumors that are difficult to control. Treatment delay increases final height and symptom burden. AIP mutations and X-LAG explain many cases, but no genetic etiology is seen in >50% of cases.
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http://dx.doi.org/10.1530/ERC-15-0320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533620PMC
October 2015

Increased Body Mass Index during Therapy for Childhood Acute Lymphoblastic Leukemia: A Significant and Underestimated Complication.

Int J Pediatr 2015 25;2015:386413. Epub 2015 May 25.

School of Paediatrics and Child Health, The University of Western Australia, Perth, WA 6009, Australia ; Department of Endocrinology, Princess Margaret Hospital, Perth, WA 6008, Australia.

Objective & Design. We undertook a retrospective review of children diagnosed with acute lymphoblastic leukemia (ALL) and treated with modern COG protocols (n = 80) to determine longitudinal changes in body mass index (BMI) and the prevalence of obesity compared with a healthy reference population. Results. At diagnosis, the majority of patients (77.5%) were in the healthy weight category. During treatment, increases in BMI z-scores were greater for females than males; the prevalence of obesity increased from 10.3% to 44.8% (P < 0.004) for females but remained relatively unchanged for males (9.8% to 13.7%, P = 0.7). Longitudinal analysis using linear mixed-effects identified associations between BMI z-scores and time-dependent interactions with sex (P = 0.0005), disease risk (P < 0.0001), age (P = 0.0001), and BMI z-score (P < 0.0001) at diagnosis and total dose of steroid during maintenance (P = 0.01). Predicted mean BMI z-scores at the end of therapy were greater for females with standard risk ALL irrespective of age at diagnosis and for males younger than 4 years of age at diagnosis with standard risk ALL. Conclusion. Females treated on standard risk protocols and younger males may be at greatest risk of becoming obese during treatment for ALL. These subgroups may benefit from intervention strategies to manage BMI during treatment for ALL.
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http://dx.doi.org/10.1155/2015/386413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4458559PMC
June 2015

Ovarian sex cord-stromal tumors in patients with probable or confirmed germline DICER1 mutations.

Int J Gynecol Pathol 2015 May;34(3):266-74

Departments of Histopathology (E.E.O., H.S.), SJOG Pathology King Edward Memorial Hospital (C.J.R.S.) Schools for Paediatrics and Child Health (A.C., C.S.C.) School for Women's and Infants' Health (Y.L., S.S., J.T., C.J.R.S.), University of Western Australia Department of Medical Genetics (S.T.), King Edward Memorial Hospital, Perth, WA Program in Cancer Genetics (L.W., W.D.F.), Departments of Oncology and Human Genetics, McGill University Department of Medical Genetics (L.W., W.D.F.), Segal Cancer Centre and Lady Davis Institute, McGill University Health Centre, Montreal, QC, Canada.

The DICER1 gene encodes an endoribonuclease involved in the production of mature microRNAs which regulates gene expression through several mechanisms. Recent studies have demonstrated somatic mutations in DICER1 in approximately 60% of ovarian Sertoli-Leydig cell tumors. Furthermore, patients with germline mutations in DICER1 are predisposed to developing a range of rare neoplasms including ovarian sex cord-stromal tumors most of which have been classified as Sertoli-Leydig cell tumor. However, the histologic features of these tumors have not been reported in detail. We describe the morphologic and immunophenotypic findings of 4 sex cord-stromal tumors arising in patients with proven or likely germline DICER1 mutations including 3 individuals from 1 family. Three tumors showed similar appearances characterized by marked architectural and cytologic heterogeneity including sertoliform, juvenile granulosa cell tumor-like, and unclassifiable elements. The remaining case mainly showed heterologous mucinous epithelial and neuroendocrine differentiation with only a minor intermediate-grade Sertoli cell component. This tumor and one of the 3 former cases arose in related patients with identical germline DICER1 mutations indicating that additional factors influence tumor morphology. All tumors were positive for steroidogenic factor-1 and FOXL2 on immunohistochemical analysis, whereas there was more variable expression of inhibin, calretinin, CD56, CD99, and hormone receptors. The present small series suggests that some ovarian Sertoli-Leydig cell tumor associated with germline DICER1 mutations may show distinctive histologic features in particular admixed Sertoli cell and juvenile granulosa cell tumor-like features. Larger studies are required to establish whether heterologous elements are also a more common feature of these tumors.
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http://dx.doi.org/10.1097/PGP.0000000000000150DOI Listing
May 2015

X-linked acrogigantism syndrome: clinical profile and therapeutic responses.

Endocr Relat Cancer 2015 Jun 24;22(3):353-67. Epub 2015 Feb 24.

Department of EndocrinologyCentre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, BelgiumProgram on Developmental Endocrinology and GeneticsSection on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892-1862, USAHelmholtz Zentrum MünchenInstitute of Pathology, Neuherberg, GermanyDepartment of Molecular and Human GeneticsBaylor College of Medicine, Houston, Texas, USADepartment of Pediatric Endocrinology and DiabetesPrincess Margaret Hospital for Children, Subiaco, Western Australia, AustraliaDepartment of Clinical GeneticsCentre Hospitalier Universitaire de Liège, University of Liège, Liège, BelgiumEndocrinology and Diabetology UnitFondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Clinical Sciences and Community Health, University of Milan, Milan, ItalyDepartment of EndocrinologyUniversity of Brasilia, Brasilia, BrazilDepartment of Paediatric EndocrinologyRoyal Victoria Infirmary, Newcastle University, Newcastle upon Tyne, UKINSERM U 693GHU Paris-Sud - Hôpital de Bicêtre, 78 rue du Général Leclerc, 94270 Le Kremlin-Bicêtre, FrancePediatric Endocrinology UnitUniversité Catholique de Louvain, Bruxelles, BelgiumMater Medical Research InstituteUniversity of Queensland, Brisbane, Queensland, AustraliaDepartment of EndocrinologyKEM Hospital, Mumbai, IndiaEndocrinology and Diabetes UnitBC Children's Hospital, Vancouver, British Columbia, CanadaSection of EndocrinologyDepartment of Medical Sciences, University of Ferrara, Ferrara, ItalyService d'Anatomie et Cytologie PathologiquesHopital Foch, Suresnes, FranceINSERM Unité 1016Institut Cochin, Hopital Cochin, Université Paris Descartes, Paris, FranceInstitute of Pediatric EndocrinologyEndocrinological Research Centre, Moscow

X-linked acrogigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, which is highly upregulated in pituitary tumors. We conducted this study to explore the clinical, radiological, and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X-LAG and microduplication of chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in two families was dominant, with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2-3 months of age (median 12 months). At diagnosis (median delay 27 months), patients had a median height and weight standard deviation scores (SDS) of >+3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF1 and usually prolactin, due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection, but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despite moderate to high levels of expression of somatostatin receptor subtype-2 in tumor tissue. Postoperative use of adjuvant pegvisomant resulted in control of IGF1 in all five cases where it was employed. X-LAG is a new infant-onset gigantism syndrome that has a severe clinical phenotype leading to challenging disease management.
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http://dx.doi.org/10.1530/ERC-15-0038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433400PMC
June 2015

Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation.

N Engl J Med 2014 Dec 3;371(25):2363-74. Epub 2014 Dec 3.

The authors' affiliations are listed in the Appendix.

Background: Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood.

Methods: We performed clinical and genetic studies of samples obtained from 43 patients with gigantism and then sequenced an implicated gene in samples from 248 patients with acromegaly.

Results: We observed microduplication on chromosome Xq26.3 in samples from 13 patients with gigantism; of these samples, 4 were obtained from members of two unrelated kindreds, and 9 were from patients with sporadic cases. All the patients had disease onset during early childhood. Of the patients with gigantism who did not carry an Xq26.3 microduplication, none presented before the age of 5 years. Genomic characterization of the Xq26.3 region suggests that the microduplications are generated during chromosome replication and that they contain four protein-coding genes. Only one of these genes, GPR101, which encodes a G-protein-coupled receptor, was overexpressed in patients' pituitary lesions. We identified a recurrent GPR101 mutation (p.E308D) in 11 of 248 patients with acromegaly, with the mutation found mostly in tumors. When the mutation was transfected into rat GH3 cells, it led to increased release of growth hormone and proliferation of growth hormone-producing cells.

Conclusions: We describe a pediatric disorder (which we have termed X-linked acrogigantism [X-LAG]) that is caused by an Xq26.3 genomic duplication and is characterized by early-onset gigantism resulting from an excess of growth hormone. Duplication of GPR101 probably causes X-LAG. We also found a recurrent mutation in GPR101 in some adults with acromegaly. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.).
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http://dx.doi.org/10.1056/NEJMoa1408028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4291174PMC
December 2014

NNT pseudoexon activation as a novel mechanism for disease in two siblings with familial glucocorticoid deficiency.

J Clin Endocrinol Metab 2015 Feb 2;100(2):E350-4. Epub 2014 Dec 2.

Centre for Endocrinology (T.V.N., L.F.C., L.A.M.), William Harvey Research Institute, John Vane Science Centre, Queen Mary, University of London, London, EC1M 6BQ, United Kingdom; Department of Endocrinology (S.R.R., G.P., C.S.C.), Princess Margaret Hospital, Child and Adolescent Services, Subiaco, Perth, Western Australia 6008; Department of Diagnostic Genomics (K.C.), PathWest Laboratory Medicine, Nedlands, Western Australia 6009; Genetic Services of Western Australia (N.P.), King Edward Memorial Hospital, Subiaco, Western Australia 6008; and School of Pediatrics and Child Health (S.R.R., N.P., C.S.C.), and School of Women's and Infants' Health (J.E.D.), University of Western Australia, Perth, Australia 6009.

Context: Intronic DNA frequently encodes potential exonic sequences called pseudoexons. In recent years, mutations resulting in aberrant pseudoexon inclusion have been increasingly recognized to cause disease.

Objectives: To find the genetic cause of familial glucocorticoid deficiency (FGD) in two siblings.

Patients: The proband and his affected sibling, from nonconsanguineous parents of East Asian and South African origin, were diagnosed with FGD at the ages of 21 and 8 months, respectively.

Design: Whole exome sequencing was performed on genomic DNA (gDNA) of the siblings. Variants in genes known to cause FGD were assessed for causality. Further analysis of gDNA and cDNA was performed by PCR/RT-PCR followed by automated Sanger sequencing.

Results: Whole exome sequencing identified a single, novel heterozygous variant (p.Arg71*) in nicotinamide nucleotide transhydrogenase (NNT) in both affected individuals. Follow-up cDNA analysis in the proband identified a 69-bp pseudoexon inclusion event, and Sanger sequencing of his gDNA identified a 4-bp duplication responsible for its activation. The variants segregated with the disease: p.Arg71* was inherited from the mother, the pseudoexon change was inherited from the father, and an unaffected sibling had inherited only the p.Arg71* variant.

Conclusions: FGD in these siblings is caused by compound heterozygous mutations in NNT; one causing pseudoexon inclusion in combination with another leading to Arg71*. Discovery of this pseudoexon activation mutation highlights the importance of identifying sequence changes in introns by cDNA analysis. The clinical implications of these findings include: facilitation of antenatal genetic diagnosis, early institution of potentially lifesaving therapy, and the possibility of preventative or curative intervention.
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http://dx.doi.org/10.1210/jc.2014-3641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4318891PMC
February 2015

Report and review of described associations of Mayer-Rokitansky-Küster-Hauser syndrome and Silver-Russell syndrome.

J Paediatr Child Health 2015 May 23;51(5):555-560. Epub 2014 Nov 23.

Department of Endocrinology and Diabetes, Princess Margaret Hospital for Children, Perth, Western Australia, Australia.

Silver-Russell syndrome (SRS) and Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome are described in isolation. However, their co-occurrence has only been rarely reported. Here, we present a case report of an adolescent with SRS who was diagnosed with MRKH during the evaluation of primary amenorrhoea. Multiplex ligation-dependent probe amplification analysis showed a normal methylation pattern and normal dosage at 11p15.5. A PubMed search for all peer-reviewed publications (original articles and reviews) using the key words Silver-Russell syndrome, Mayer-Rokitansky-Küster-Hauser syndrome, genetics, hypomethylation and reproductive anomalies identified three cases of SRS with MRKH, two of which were associated with significant hypomethylation of the H19 imprinting control region of the 11p15.5 locus. This report highlights the association between SRS and MRKH. The absence of hypomethylation and normal dosage at 11p15.5 suggests these two rare entities share alternative aetiopathogenic mechanisms.
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http://dx.doi.org/10.1111/jpc.12778DOI Listing
May 2015

Germ-line and somatic DICER1 mutations in pineoblastoma.

Acta Neuropathol 2014 Oct 15;128(4):583-95. Epub 2014 Jul 15.

Department of Human Genetics, McGill University, Montreal, QC, Canada.

Germ-line RB-1 mutations predispose to pineoblastoma (PinB), but other predisposing genetic factors are not well established. We recently identified a germ-line DICER1 mutation in a child with a PinB. This was accompanied by loss of heterozygosity (LOH) of the wild-type allele within the tumour. We set out to establish the prevalence of DICER1 mutations in an opportunistically ascertained series of PinBs. Twenty-one PinB cases were studied: Eighteen cases had not undergone previous testing for DICER1 mutations; three patients were known carriers of germ-line DICER1 mutations. The eighteen PinBs were sequenced by Sanger and/or Fluidigm-based next-generation sequencing to identify DICER1 mutations in blood gDNA and/or tumour gDNA. Testing for somatic DICER1 mutations was also conducted on one case with a known germ-line DICER1 mutation. From the eighteen PinBs, we identified four deleterious DICER1 mutations, three of which were germ line in origin, and one for which a germ line versus somatic origin could not be determined; in all four, the second allele was also inactivated leading to complete loss of DICER1 protein. No somatic DICER1 RNase IIIb mutations were identified. One PinB arising in a germ-line DICER1 mutation carrier was found to have LOH. This study suggests that germ-line DICER1 mutations make a clinically significant contribution to PinB, establishing DICER1 as an important susceptibility gene for PinB and demonstrates PinB to be a manifestation of a germ-line DICER1 mutation. The means by which the second allele is inactivated may differ from other DICER1-related tumours.
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http://dx.doi.org/10.1007/s00401-014-1318-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4381868PMC
October 2014

Efficacy of Hydrochlorothiazide and low renal solute feed in Neonatal Central Diabetes Insipidus with transition to Oral Desmopressin in early infancy.

Int J Pediatr Endocrinol 2014 20;2014(1):11. Epub 2014 Jun 20.

Department of Endocrinology and Diabetes, Princess Margaret Hospital, Perth, Australia ; School of Paediatrics and Child Health, The University of Western Australia, Perth, Australia.

Background: The treatment of central diabetes insipidus (DI) with desmopressin in the neonatal period is challenging because of the significant risk of hyponatremia with this agent. The fixed anti-diuresis action of desmopressin and the obligate high fluid intake with milk feeds lead to considerable risk of water intoxication and hyponatremia. To reduce this risk, thiazide diuretics, part of the treatment of nephrogenic DI, were used in conjunction with low renal solute feed and were effective in a single case series of neonatal central DI.

Aim: We evaluated the efficacy of early treatment of neonatal central DI with hydrochlorothiazide with low solute feed and investigated the clinical indicators for transition to desmopressin during infancy.

Methods: A retrospective chart review was conducted at Princess Margaret Hospital, Perth of neonates diagnosed with central DI and treated with hydrochlorothiazide, between 2007 and 2013. Four newborns were identified. Mean sNa and mean change in sNa with desmopressin and hydrochlorothiazide treatment were recorded along with episodes of hyponatremia and hypernatremia. Length and weight trajectories during the first 12 months were assessed.

Results: The mean change in sNa per day with hydrochlorothiazide and low renal solute feed was 2.5 - 3 mmol/L; on desmopressin treatment, the mean change in sNa was 6.8-7.9 mmol/L. There was one episode of symptomatic hyponatremia with intranasal desmopressin with no episodes of hyponatremia or hypernatremia during treatment with hydrochlorothiazide or following transition to oral desmopressin. Transition to oral desmopressin between 3 to 12 months of age was associated with good control of DI. Following introduction of solids, sNa remained stable but weight gain was slow. This improved following transition to desmopressin in one infant.

Conclusions: Hydrochlorothiazide with low renal solute feed is a safe and effective treatment option in neonatal central DI. However, transition to desmopressin should be considered early in infancy following initiation of solids to facilitate growth.
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http://dx.doi.org/10.1186/1687-9856-2014-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4084573PMC
July 2014

Comparison of Centers for Disease Control and Prevention and World Health Organization references/standards for height in contemporary Australian children: analyses of the Raine Study and Australian National Children's Nutrition and Physical Activity cohorts.

J Paediatr Child Health 2014 Nov 22;50(11):895-901. Epub 2014 Jun 22.

OZGROW, Mater Research, The University of Queensland, Brisbane, Queensland, Australia.

Aim: (i) To compare the Centers for Disease Control and Prevention (CDC) reference and World Health Organization (WHO) standard/reference for height, particularly with respect to short stature and eligibility for growth hormone (GH) treatment by applying them to contemporary Australian children; (ii) To examine the implications for identifying short stature and eligibility for GH treatment.

Methods: Children from the longitudinal Raine Study were serially measured for height from 1991 to 2005 (2-15-year-old girls (660) and boys (702) from Western Australia). In the cross-sectional Australian National Children's Nutrition and Physical Activity survey (2-16-year-old boys (2415) and girls (2379) from all states), height was measured in 2007. Heights were converted to standard deviation scores (SDSs) based on CDC and WHO.

Results: Means and standard deviations of height-SDS varied between CDC and WHO definitions and with age and gender within each definition. However, both identified similar frequencies of short stature (<1st centile for GH eligibility), although these were very significantly less than the anticipated 1% (0.1-0.7%) of the Australian cohorts. Mean heights in the Australian cohorts were greater than both the WHO and CDC means.

Conclusions: Neither CDC nor WHO height standardisations accurately reflect the contemporary Australian child population. Australian children are taller than the CDC or WHO height means, and significantly less than 1% of Australian children are defined as being short using either CDC or WHO. This study suggests there may be a case for an Australian-specific standard/reference for height.
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http://dx.doi.org/10.1111/jpc.12672DOI Listing
November 2014