Shoshana Rath

Multinodular Goiter in children: an important pointer to a germline DICER1 mutation.

Department of Endocrinology and Diabetes (S.R.R., T.J., C.S.Y.C.), Princess Margaret Hospital for Children; School of Pediatrics and Child Health (S.R.R., G.B., T.J., C.S.Y.C.), University of Western Australia; Departments of Pathology (A.C.), and Diagnostic Imaging (A.B., N.P.), Princess Margaret Hospital for Children; Genetic Services of Western Australia (G.B.), Princess Margaret and King Edward Memorial Hospitals; Institute for Immunology and Infectious Diseases (G.B.), Murdoch University; Telethon Institute for Child Health Research (T.J.), Perth, WA 6008, Australia; (J.R.P.), Minneapolis, Minnesota; and Program in Cancer Genetics, Department of Oncology and Human Genetics (W.D.F.), McGill University, Montreal, QC H3T 1E2, Canada

Childhood craniopharyngioma: 20-year institutional experience in Western Australia

A retrospective audit was undertaken to evaluate modes of presentation and treatment outcomes for craniopharyngioma in a single paediatric institution over a 20‐year period.

Octreotide in children with hypoglycaemia due to sulfonylurea ingestion

Abstract:  Sulfonylureas are commonly prescribed for type 2 diabetes mellitus; however, overdose or accidental ingestion may result in profound and prolonged hypoglycaemia with permanent neurological sequelae and death. We describe two cases of children with hypoglycaemia due to presumed accidental ingestion of sulfonylureas, where traditional methods of raising blood sugar levels were unsatisfactory. Two studies describe Octreotide for adults with hypoglycaemia, but there are no studies examining the use of Octreotide in children for this indication. Given that Octreotide has been shown to be safe in children when used for other indications, we used Octreotide to safely restore euglycaemia.

Parental pre-pregnancy BMI is a dominant early-life risk factor influencing BMI of offspring in adulthood.

We examined parental and early‐life variables in order to identify risk factors for adulthood overweight and obesity in offspring. We report here on the longitudinal prevalence of overweight and obesity in Australian children born between 1989 and 1991 and followed from birth to age 22.

NNT Pseudoexon Activation as a Novel Mechanism for Disease in Two Siblings With Familial Glucocorticoid Deficiency

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.

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

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.

Early cessation and non-response are important and possibly related problems in growth hormone therapy: An OZGROW analysis

OBJECTIVE To investigate growth hormone (GH) treatment and treatment cessation with respect to efficacy and efficiency. To identify factors that best classify or predict cessation type: completed treatment (CT), early cessation (EC), or non-response (NR). DESIGN Observational study (1990-2013) of the Australian GH Program comparing CT, EC, and NR groups with respect to demographic, clinical, and response criteria. All patients treated for GH deficiency (GHD; 909), short stature and slow growth (SSSG; 2144), and Turner Syndrome (TS; 626) were included. Information was retrieved from the OZGROW database. RESULTS 51.9% of patients were EC, 40.7% CT and 7.4% NR.Median treatment durations for NR patients were often longer than patients who completed treatment. EC and NR groups were both associated with poor growth response with males overrepresented.Socioeconomic status differentiated NR (higher) and EC (lower) groups. CONCLUSIONS EC was observed at very high rates and appears, generally, to be a little-recognised but frequent problem in GH therapy.EC and delayed recognition of NR may be interrelated being differentiated by the decision to cease or continue treatment following poor response.Poor treatment compliance is likely a major causal factor in EC.Strategies to address poor response and compliance have been developed, however, given the scale of these problems, it may be that long acting GH formulations or individualized treatment need consideration.

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

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.

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

Abstract 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.

Autosomal dominant Kenny-Caffey syndrome with congenital hypoparathyroidism, short stature and normal intellect: a case report.

Kenny-Caffey syndrome (KCS) is characterized by proportionate short stature, cortical thickening and medullary stenosis of tubular bones, delayed closure of anterior fontanelle, eye abnormalities, and hypoparathyroidism. The autosomal dominant form (KCS Type 2) caused by mutations in FAM111A is distinguished from the autosomal recessive form (KCS Type1), caused by mutations in TBCE gene, by the absence of mental retardation. Our proband presented on day 8 of life with hypocalcaemic seizures secondary to hypoparathyroidism. Normocalcaemia was achieved with IV calcium gluconate and maintained by oral calcium carbonate 100mg BD and calcitriol 0.1mcg BD for the first 2 years of life while serum PTH remained low at <0.3pmol/L. There has been no evidence of nephrocalcinosis on follow up. The dose of supplemental calcium and calcitriol is being gradually reduced. She also has persistent mild microcytic anaemia with normal iron stores. Her phenotype included small hands and feet, triangular hypoplastic and dystrophic nails, hypoplastic mid-face, macrocrania and large persistent fontanelles. Karotype and FISH for 22q11 deletion were normal. Initial investigations included a normal ECHO, renal ultrasound and MRI brain. Her neurodevelopment is normal but her growth is compromised. At 1 year, her length was 65.5cms (SDS -2.9) and at 3 years, her height was 80cms (SDS -3.8). There is no family history of short stature or hypoparathyroidism. She is growth hormone sufficient on pharmacological testing; however she has been commenced on growth hormone treatment based on her poor growth velocity and short stature. It is currently too early to determine response. A skeletal survey performed at 2 years of age was suggestive of KCS. Genetic testing revealed a heterozygous mutation c.1622C>A (p.Ser541Tyr) in FAM111A. However, the unusual nails, the reducing calcium requirement and the unexplained microcytic anaemia are unique to our patient. Written informed Consent for this patient has been taken including results of the genetic analyses and images according to the Institutional Ethics Committee procedures of our health service.