An affirming approach to caring for transgender and gender-diverse youth.

Increasing numbers of youth identify as transgender or gender-diverse (TGD). Many paediatricians and primary care providers (PCPs) will encounter this population in their practice, either for gender-related care or general health needs. This statement is intended as a resource to guide paediatricians and PCPs in implementing an affirming approach to routine health care provision for all youth. Furthermore, it presents information to assist providers in responding to requests for counselling from TGD youth and their families around potential options for medical transition, and in making referrals to specialized services, if desired and relevant. Finally, as demand for gender-affirming care is anticipated to continue to increase, some health care providers (HCPs) may wish to develop the knowledge and skills required to initiate adolescents on hormone-blocking agents and gender-affirming hormones. This document is not intended to be a clinical practice guideline, but will provide foundational information regarding these potential components of gender-affirming care, recognizing that the needs and goals of individual adolescents may or may not include such interventions. Additional resources relevant to developing the expertise required to provide gender-affirming interventions will also be identified.

Une approche d'affirmation pour les soins aux jeunes transgenres et de diverses identités de genre.

Un nombre croissant de jeunes s'identifient comme transgenres ou de diverses identités de genre. De nombreux pédiatres et dispensateurs de soins de première ligne accueilleront cette population dans leur pratique, dans le cadre de soins liés au genre ou de soins de santé généraux. Le présent document de principes se veut une ressource pour orienter les pédiatres et les dispensateurs de soins de première ligne à adopter une approche d'affirmation pour la prestation des soins réguliers à tous les jeunes. De plus, il contient de l'information visant à aider les dispensateurs à répondre aux demandes de conseils des jeunes transgenres et de diverses identités de genre et de leur famille au sujet des possibilités de transition médicale et d'orientation vers des services spécialisés s'ils le désirent et le jugent pertinent. Enfin, on anticipe que la demande de soins d'affirmation de genre continue d'augmenter, et certains dispensateurs de soins peuvent souhaiter acquérir les connaissances et les habiletés nécessaires pour amorcer les inhibiteurs d'hormones et les hormones d'affirmation de genre chez les adolescents. Le présent document ne contient pas de directives cliniques, mais de l'information fondamentale au sujet des divers éléments possibles des soins d'affirmation de genre, tout en reconnaissant que les besoins et les objectifs d'adolescents particuliers n'incluent pas automatiquement de telles interventions. D'autres ressources permettant d'acquérir les compétences nécessaires pour offrir des interventions d'affirmation de genre sont également proposées.

Measuring severe obesity in pediatrics using body mass index-derived metrics from the Centers for Disease Control and Prevention and World Health Organization: a secondary analysis of CANadian Pediatric Weight management Registry (CANPWR) data.

To examine the (i) relationships between various body mass index (BMI)-derived metrics for measuring severe obesity (SO) over time based the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) references and (ii) ability of these metrics to discriminate children and adolescents based on the presence of cardiometabolic risk factors. In this cohort study completed from 2013 to 2021, we examined data from 3- to 18-year-olds enrolled in the CANadian Pediatric Weight management Registry. Anthropometric data were used to create nine BMI-derived metrics based on the CDC and WHO references. Cardiometabolic risk factors were examined, including dysglycemia, dyslipidemia, and elevated blood pressure. Analyses included Pearson correlations, intraclass correlation coefficients (ICC), and receiver operator characteristic area-under-the-curve (ROC AUC). Our sample included 1,288 participants (n = 666 [52%] girls; n = 874 [68%] white). The prevalence of SO varied from 60-67%, depending on the definition. Most BMI-derived metrics were positively and significantly related to one another (r = 0.45-1.00); ICCs revealed high tracking (0.90-0.94). ROC AUC analyses showed CDC and WHO metrics had a modest ability to discriminate the presence of cardiometabolic risk factors, which improved slightly with increasing numbers of risk factors. Overall, most BMI-derived metrics rated poorly in identifying presence of cardiometabolic risk factors.    Conclusion: CDC BMI percent of the 95th percentile and WHO BMIz performed similarly as measures of SO, although neither showed particularly impressive discrimination. They appear to be interchangeable in clinical care and research in pediatrics, but there is a need for a universal standard. WHO BMIz may be useful for clinicians and researchers from countries that recommend using the WHO growth reference. What is Known: • Severe obesity in pediatrics is a global health issue. • Few reports have evaluated body mass index (BMI)-derived metrics based on the World Health Organization growth reference. What is New: • Our analyses showed that the Centers for Disease Control and Prevention BMI percent of the 95th percentile and World Health Organization (WHO) BMI z-score (BMIz) performed similarly as measures of severe obesity in pediatrics. • WHO BMIz should be a useful metric to measure severe obesity for clinicians and researchers from countries that recommend using the WHO growth reference.

Do Clinical Data from Transgender Adolescents Support the Phenomenon of "Rapid Onset Gender Dysphoria"?

Although emergence of gender dysphoria at puberty is long established, a distinct pathway of rapid onset gender dysphoria was recently hypothesized based on parental data. Using adolescent clinical data, we tested a series of associations that would be consistent with this pathway, however, our results did not support the rapid onset gender dysphoria hypothesis.

Transgender Youth Referred to Clinics for Gender-Affirming Medical Care in Canada.

BACKGROUND AND OBJECTIVES: Referrals of transgender and gender-diverse (trans) youth to medical clinics for gender-affirming care have increased. We described characteristics of trans youth in Canada at first referral visit. METHODS: Baseline clinical and survey data (2017-2019) were collected for Trans Youth CAN!, a 10-clinic prospective cohort of n = 174 pubertal and postpubertal youth <16 years with gender dysphoria, referred for hormonal suppression or hormone therapy, and 160 linked parent-participants. Measures assessed health, demographics, and visit outcome. RESULTS: Of youth, 137 were transmasculine (assigned female) and 37 transfeminine (assigned male); 69.0% were aged 14 to 15, 18.8% Indigenous, 6.6% visible minorities, 25.7% from immigrant families, and 27.1% low income. Most (66.0%) were gender-aware before age 12. Only 58.1% of transfeminine youth lived in their gender full-time versus 90.1% of transmasculine (P < .001). Although transmasculine youth were more likely than transfeminine youth to report depressive symptoms (21.2% vs 10.8%; P = .03) and anxiety (66.1% vs 33.3%; P < .001), suicidality was similarly high overall (past-year ideation: 34.5%, attempts: 16.8%). All were in school; 62.0% reported strong parental gender support, with parents the most common support persons (91.9%). Two-thirds of families reported external gender-related stressors. Youth had met with a range of providers (68.5% with a family physician). At clinic visit, 62.4% were prescribed hormonal suppression or hormone therapy, most commonly depot leuprolide acetate. CONCLUSIONS: Trans youth in Canada attending clinics for hormonal suppression or gender-affirming hormones were generally healthy but with depression, anxiety, and support needs.

Prevalence of high blood pressure among Canadian Children: 2017 American Academy of Pediatrics guidelines with the Canadian Health Measures Survey.

BACKGROUND: We assess the impact of the 2017 American Academy of Pediatrics (AAP) guidelines on the prevalence of high blood pressure (BP) in generally healthy Canadian children and identify risk factors associated with high BP (elevated, stage 1, or stage 2 at a single visit). METHODS: A cohort of 7,387 children aged 6 to 18 years in the Canadian Health Measures Survey (CHMS, 2007 to 2015) had BPTru oscillometry with centiles and stages assigned using both the 2017 AAP guidelines and the 2004 Fourth Report from the National Institute of Health/National Heart Lung and Blood Institute (NIH/NHLBI). RESULTS: Although both shifted upwards significantly, mean population systolic BP and diastolic BP percentiles are now 24.2 (95% confidence interval: 23.3 to 25.2) and 46.4 (45.3 to 47.6). As a result, the population prevalence of high BP increased from 4.5% (3.9 to 5.2, NIH/NHLBI) to 5.8% (5.0 to 6.6, AAP), less than in US children measured by auscultation (14.2%, 13.4 to 15.0). Children with high BP were more likely to be overweight/obese, to be exposed to prenatal/household smoking, and to have hypertriglyceridemia, without differences in dietary salt, infant breastfeeding, neonatal hospitalizations, or exercise frequency. CONCLUSION: The 2017 AAP guidelines increase the prevalence of high BP in Canadian children; Canadian prevalence appears lower than in the USA. This may reflect differences in measurement methods or in the prevalence of childhood overweight/obesity between countries, that is, 31.1% (28.9 to 33.3) versus 40.6% (39.5 to 42.0), respectively. Those with high BP were more likely to have other cardiac risk factors, including overweight/obesity, prenatal/household smoking exposure, and hypertriglyceridemia.

Are there alternatives to over-the-counter diabetes-care glucose-gels for transitional neonatal hypoglycemia?

Transitional neonatal hypoglycemia is common in at-risk well newborns, requires immediate attention, interferes with breastfeeding, and frequently results in separation of mothers from their babies. Breastfeeding shortly after birth and screening at-risk newborns at 2 hours of age is standard practice in Canada. In the Sugar Babies Trial, a custom-made 40% glucose-gel massaged to the buccal mucosa in at-risk infants decreased intravenous glucose treatment, but not neonatal intensive care unit admission. It increased the rate of full breastfeeding after discharge but experts suggest that additional evidence is needed. Further, commercially available neonatal glucose-gels do not exist, so practitioners around the world have started using diabetes-care products, which do not meet standards for use in newborns. Here, we provide a condensed summary of the topic and of management alternatives.

Isolated diastolic high blood pressure: a distinct clinical phenotype in US children.

BACKGROUND: Screening studies have shown that 0.7-4.5% of generally healthy children have isolated diastolic high BP. We therefore studied the characteristics of children with diastolic BP in the elevated and hypertensive ranges according to current guidelines in US children from the National Health and Nutrition Examination Survey (NHANES, 1999-2016). METHODS: We studied 17,362 children (8-18 years) with BP measured by sphygmomanometry. High BP was categorized as isolated systolic (iSH), isolated diastolic (iDH), or Mixed. RESULTS: Overall, 86.0% (95% CI = 85.0-87.0) of the population had normal BP, 8.7% (8.0-9.3) elevated BP, 4.9% (4.4-5.5) Stage 1, and 0.4% (0.4-0.6) Stage 2. Moreover, 11.1% (10.3-12.0) had iSH, 1.9% (1.5-2.2) iDH, and 1.0% (0.8-1.2) Mixed. Children with iDH were more likely to be female, younger, white, and leaner than those with iSH, with lower rates of overweight/obesity. iDH was generally between normals and iSH. Resting heart rate was significantly higher in iDH even after adjustment for known covariates. CONCLUSIONS: Children with iDH may have a distinct clinical picture. A leaner habitus and higher resting heart rate may reflect differences in underlying pathophysiology. Longitudinal follow-up studies are needed to better define the pathogenesis, progression, and long-term prognosis in iDH. IMPACT: Using gold-standard auscultation and 2017 guidelines, isolated diastolic high BP (iDH) is found in 1.9% (95% CI 1.5-2.2) of American children; these children are younger, leaner, more female, and have fewer cardiometabolic risks. Resting heart rate is significantly higher in iDH compared to both normals and iSH even after adjustments for known covariates. Autonomic hyperactivity in iDH may speak to both etiology and therapeutic approaches. iDH appears to be a distinct clinical phenotype characterized by differences in anthropometric measures, sex, age, and resting heart rate. Follow-up studies are clearly needed to clarify its pathogenesis, progression, and prognosis.

Fluid management in children with diabetic ketoacidosis.

QUESTION: Previous research has indicated that rapid rehydration in children with type 1 diabetes who present with diabetic ketoacidosis could result in cerebral edema. I have been treating patients with diabetic ketoacidosis with gradual fluid replacement. With the risk of cerebral injury in these patients, should I continue management with slow fluid rehydration? ANSWER: Recent research has shown that neither fluid infusion rate nor sodium chloride concentration increases risk of cerebral injury. However, it is possible for subtle brain injury to occur during treatment, regardless of the fluid administration strategy. The 2018 International Society for Pediatric and Adolescent Diabetes guidelines have been updated in light of this research.

WHO height charts can be safely substituted when calculating BP Z-scores in a North American clinic setting.

OBJECTIVES: The Public Health Agency of Canada has officially adopted growth charts from the World Health Organization (WHO); nevertheless, North American blood pressure (BP) Z-scores and percentiles still depend on height Z-scores based on growth charts from the US Centers for Disease Control (CDC), which may differ significantly, particularly in toddlers. Since many practitioners simply replace CDC height scores with WHO equivalents for diagnosing hypertension, we explore the impact of this substitution on BP Z-scores in real-world BPs measured on more than 22,000 children aged 2 to 18 years. METHODS: We report agreement between two different measures of the same quantity as Bland-Altman limits of agreement (LOA). RESULTS: In toddlers aged 2 to 5 years, WHO height Z-scores are systematically lower with a bias (mean error) of -0.30 SD, and the 95% LOA range from -0.51 to -0.10 SD. Despite this difference, systolic BP Z-scores were nearly identical (bias = 0.06, LOA = 0.02 to 0.10). For older children and diastolic BP Z-scores, the errors were smaller still, and agreement was equally good for hypotensive, normotensive and hypertensive measurements. CONCLUSIONS: Clinicians may safely use WHO height charts when calculating BP Z-scores or percentiles against the National Institute of Health's National Heart, Lung, and Blood Institute reference data.

Prevalence and Severity of High Blood Pressure Among Children Based on the 2017 American Academy of Pediatrics Guidelines.

Importance: Based on the new 2017 blood pressure guidelines, the prevalence of high blood pressure (BP) among adults has increased from 32% to 46%. Based on new norms and diagnostic thresholds that better align with adult definitions, new clinical practice guidelines were also published for children. The American Academy of Pediatrics clinical practice guidelines for the management of elevated BP in children replace the 2004 fourth report from the National Heart, Lung, and Blood Institute. Objectives: To assess the consequences of the American Academy of Pediatrics clinical practice guidelines for the management of elevated BP in children on the prevalence and severity of elevated BP among children and to characterize risk factors for children with new-onset hypertension or a worsening in clinical stage ("reclassified upward"). Design, Setting, and Participants: This study applied both sets of guidelines to classify BP in 15 647 generally healthy, low-risk children aged 5 to 18 years from National Health and Nutrition Examination Surveys (from January 1, 1999, to December 31, 2014). In the case-control portion of the study, children whose BP was reclassified upward (cases) were matched for sex, age, and height with controls with normal BP. Anthropometric and laboratory risk factors were compared, and age- and sex-specific z scores for weight, waist circumference, and body mass index were calculated. Blood pressure was measured by auscultation by trained personnel. After the child rested quietly for 5 minutes, 3 to 4 consecutive BP readings were recorded. Main Outcomes and Measures: Blood pressure percentiles and clinical classification based on either the 2017 American Academy of Pediatrics guidelines or the 2004 National Heart, Lung, and Blood Institute report. Results: Among the 15 647 children in the study (7799 girls and 7848 boys; mean [SD] age, 13.4 [2.8] years), based on the American Academy of Pediatrics guidelines, the estimated (weighted) population prevalence of elevated BP increased from 11.8% (95% CI, 11.1%-13.0%) to 14.2% (95% CI, 13.4%-15.0%). Overall, 905 of 15 584 children (5.8%) had newly diagnosed hypertension (n = 381) or a worsening in clinical stage (n = 524), which represents a substantial increase in disease burden for the health care system. Children whose BP was reclassified upward were more likely to be overweight or obese, with higher z scores for weight, waist circumference, and body mass index. The prevalence of abnormal laboratory test results was also increased, with adverse lipid profiles and increased hemoglobin A1c levels (prediabetes). Conclusions and Relevance: Clustering of cardiovascular risk factors in otherwise healthy US children suggests that those whose BP was reclassified represent a high-risk population whose cardiovascular risk may previously have been underestimated.

Glucose control and autonomic response during acute stress in youth with type 1 diabetes: A pilot study.

BACKGROUND: Type 1 diabetes (T1D) is a chronic source of metabolic and neuropsychological stress, which may eventually lead to autonomic neuropathy and other complications related to micro- and macro-vasculopathies. We aimed to investigate the relationship between T1D chronic stress and autonomic response to acute stress testing that was expected being affected by chronic stress. METHODS: Twenty youths with confirmed diagnosis of T1D were assessed. Chronic stress assessment included hemoglobin A1c (HbA1c) ≥7.5%, psychological stress assessed by perceived stress scale (PSS), hypoglycemic events, and proinflammatory cytokines. The acute stress testing used standardized stress video games. Autonomic response to acute stress was assessed by the amplitude and direction of changes in heart rate variability. Analyses determined correlations between changes in parasympathetic nervous system during stress testing and chronic diabetes stressors. RESULTS: A strong correlation was found between the amplitude of high frequency (HF) changes and HbA1c values (ρ = 0.74, P < .001). Youths with HbA1c ≥7.5% showed a larger amplitude of HF changes during acute stress (49% vs 16%, P < .001) and a higher PSS score (22.5 vs 19.0, P = .003), compared to those with HbA1c <7.5%. Additionally, among youths with HbA1c ≥7.5%, those with positive changes in HF had a lower level of IL-8 than those with negative changes (5.40 vs 7.85 pg/mL, P = .009). CONCLUSIONS: Study findings support the need for better understanding the health effects of stress-related autonomic dysfunction in youth with T1D.

Adherence to a pediatric diabetic ketoacidosis protocol in children presenting to a tertiary care hospital.

OBJECTIVE: To review adherence to a provincial diabetic ketoacidosis (DKA) protocol and to assess factors associated with intravenous fluid administration and the length time on an insulin infusion. METHODS: A retrospective chart review was conducted of all DKA admissions to British Columbia Children's Hospital (BCCH) during September 2008 to December 2013. Data collection included diabetes history, estimation of dehydration, insulin and fluid infusion rates, and frequency of laboratory investigations. Markers of adherence included appropriate use of a fluid bolus, normal saline and insulin infusion time, fluid intake and outputs, and the frequency of blood work during the insulin infusion. A log-linear regression model was fitted to assess the factors associated with insulin infusion duration. RESULTS: Of 157 children (median [interquartile range] age: 10.6 years [5.0, 13.8]) hospitalized for DKA, 45% (n = 70) were male, 55% (n = 86) were transferred from other hospitals, and 26% (n = 40) were admitted to intensive care unit. Thirty-five percent of subjects estimated to have mild or moderate dehydration received fluid boluses. In the adjusted analysis, the average duration on DKA protocol was 39% (95% confidence interval [CI]: 12%, 67%) longer for children admitted with severe dehydration (compared to those with mild dehydration). CONCLUSIONS: Health care providers' adherence to the BCCH DKA protocol is poor. More severe dehydration at presentation is associated with longer duration of insulin infusion. Further knowledge translation initiatives focused on accurate estimation of volume depletion to ensure appropriate initial fluid resuscitation-as well as careful monitoring during DKA hospitalization-are important, especially in community centers.

Hypogonadotropic Hypogonadism in Males with Glycogen Storage Disease Type 1.

BACKGROUND: Glycogen storage disease type 1 is an autosomal recessive disorder with an incidence of 1 in 100,000. Long-term complications include chronic blood glucose lability, lactic academia, short stature, osteoporosis, delayed puberty, gout, progressive renal insufficiency, systemic or pulmonary hypertension, hepatic adenomas at risk for malignant transformation, anemia, vitamin D deficiency, hyperuricemic nephrocalcinosis, inflammatory bowel syndrome (type 1b), hypertriglyceridemia, and irregular menstrual cycles. We describe hypogonadotropic hypogonadism as a novel complication in glycogen storage disease (GSD) type 1. Case Studies and Methods: Four unrelated patients with GSD 1a (N = 1) and 1b (N = 3) were found to have hypogonadotropic hypogonadism diagnosed at different ages. Institutional Research Ethics Board approval was obtained as appropriate. Participant consent was obtained. A retrospective chart review was performed and clinical symptoms and results of investigations summarized as a case series. RESULTS: All patients were confirmed biochemically to have low luteinizing hormone (LH) and follicular stimulating hormone (FSH), and correspondingly low total testosterone. Clinical symptoms of hypogonadism varied widely. Investigations for other causes of hypogonadotropic hypogonadism were unremarkable. In addition, all patients were found to have disproportionately low bone mineral density at the lumbar spine compared to the hip. Common to all patients was erratic metabolic control, including recurrent hypoglycemia and elevated lactate levels. DISCUSSION: Recurrent elevations in cortisol in response to hypoglycemia may be the underlying pathology leading to suppression of gonadotropin-releasing hormone (GnRH) release. Incorporating clinical and/or biochemical screening of the hypothalamic-pituitary-gonadal axis may be important in the management of this disease. Testosterone therapy however needs to be carefully considered because of the risk of hepatic adenomas.

LMS tables for waist-circumference and waist-height ratio Z-scores in children aged 5-19 y in NHANES III: association with cardio-metabolic risks.

BACKGROUND: In adults, anthropometric measures of central adiposity, such as waist-height ratio (WHtR) and waist circumference (WC), are more strongly associated with cardio-metabolic risks than BMI. METHODS: To provide similar quantitative tools for North American children, we created smoothed centile charts and LMS tables for WHtR and WC based on data from the US National Health and Nutrition Survey, cycle III (NHANES III, N = 11,930 aged 2-24 y 1988-1994). RESULTS: Applying these reference charts to subsequent NHANES survey cycles, 1999-2012) demonstrated a significant mean increase in both Z-scores of approximately 0.30 SD. In measuring the strength of the association between anthropometric measures and cardio-metabolic risk factors, a unit change in Z-scores for WHtR, WC, and BMI significantly increased the odds of an adverse outcome in all cases (1.18-2.03, P < 0.0001). Z-scores for both measures of central adiposity were significantly more strongly associated with cardio-metabolic comorbidities than BMI-Z. CONCLUSION: Since Z-scores permit standardized comparisons across ages and genders, they are useful measures of central adiposity in both clinical or research settings. By providing LMS tables for children and adolescents based on North American reference data, we hope to provide quantitative tools for the study of obesity and its complications.

Managing type 1 diabetes in school: Recommendations for policy and practice.

Diabetes requiring insulin is increasingly common and likely to impact students in most, if not all, schools. Diabetes and its complications have major personal, social and economic impact, and improved diabetes control reduces the risk of both short- and long-term complications. Evidence shows that more intensive management of diabetes - through frequent blood glucose monitoring, insulin administration with injections and/or insulin pumps, and careful attention to diet and exercise - leads to better control. Since children spend 30 to 35 hours per week at school, effectively managing their diabetes while there is integral to their short- and long-term health. The Canadian Paediatric Society and the Canadian Pediatric Endocrine Group recommend that minimum standards for supervision and care be established across Canada to support children and youth with type 1 diabetes in schools. These recommendations are derived from evidence-based clinical practice guidelines, with input from diabetes care providers from across Canada, and are consistent with the Canadian Diabetes Association's Guidelines for the Care of Students Living with Diabetes at School.

Chez les enfants, la présence d'un diabète nécessitant l'insuline pour traitement est de plus en plus fréquente. De fait, il est fort probable que la majorité des écoles canadiennes ait au moins un élève touché par cette maladie. Le diabète et ses complications ont des répercussions personnelles, sociales et économiques majeures. Cependant, une meilleure maîtrise du diabète réduit les risques de complications à court et long terme. Il a été démontré qu'une prise en charge plus intensive du diabète ­ par une surveillance régulière de la glycémie, l'administration d'insuline par injection ou pompe à insuline et une attention particulière à l'alimentation et à l'activité physique ­ en facilite la maîtrise. Comme les enfants passent de 30 à 35 heures par semaine à l'école, il est essentiel pour leur santé que la prise en charge de leur diabète y soit efficace. La Société canadienne de pédiatrie et le Groupe canadien d'endocrinologie pédiatrique recommandent d'établir des normes minimales pancanadiennes de supervision et de soins pour aider les enfants et les adolescents atteints de diabète de type 1 dans les écoles. Ces recommandations ont été inspirées de lignes directrices de pratique clinique fondées sur des données probantes et de la contribution des cliniciens du domaine des soins en diabète pédiatrique de tout le Canada. Elles respectent les Guidelines for the Care of Students Living with Diabetes at School [lignes directrices pour les soins aux élèves diabétiques à l'école] de l'Association canadienne du diabète.

Autosomal dominant hypoparathyroidism caused by germline mutation in GNA11: phenotypic and molecular characterization.

CONTEXT: Most cases of autosomal dominant hypoparathyroidism (ADH) are caused by gain-of-function mutations in CASR or dominant inhibitor mutations in GCM2 or PTH. OBJECTIVE: Our objectives were to identify the genetic basis for ADH in a multigenerational family and define the underlying disease mechanism. SUBJECTS: Here we evaluated a multigenerational family with ADH in which affected subjects had normal sequences in these genes and were shorter than unaffected family members. METHODS: We collected clinical and biochemical data from 6 of 11 affected subjects and performed whole-exome sequence analysis on DNA from two affected sisters and their affected father. Functional studies were performed after expression of wild-type and mutant Gα11 proteins in human embryonic kidney-293-CaR cells that stably express calcium-sensing receptors. RESULTS: Whole-exome-sequencing followed by Sanger sequencing revealed a heterozygous mutation, c.179G>T; p.R60L, in GNA11, which encodes the α-subunit of G11, the principal heterotrimeric G protein that couples calcium-sensing receptors to signal activation in parathyroid cells. Functional studies of Gα11 R60L showed increased accumulation of intracellular concentration of free calcium in response to extracellular concentration of free calcium with a significantly decreased EC50 compared with wild-type Gα11. By contrast, R60L was significantly less effective than the oncogenic Q209L form of Gα11 as an activator of the MAPK pathway. Compared to subjects with CASR mutations, patients with GNA11 mutations lacked hypercalciuria and had normal serum magnesium levels. CONCLUSIONS: Our findings indicate that the germline gain-of-function mutation of GNA11 is a cause of ADH and implicate a novel role for GNA11 in skeletal growth.

Provincial disparities of growth hormone coverage for young adult survivors of paediatric brain tumours across Canada.

BACKGROUND: Young adult survivors of paediatric brain tumours (PBTs) who have been treated with radiation therapy will likely be severely growth hormone-deficient when retested at the achievement of final height. Growth hormone replacement therapy (GHRT) is administered to treat growth hormone deficiency (GHD). Public drug coverage for GHRT falls under the responsibility of provincial governments across Canada. This study sought to determine the extent of public drug coverage and cost in each Canadian province for GHRT to treat GHD during adulthood for young adult survivors of PBTs. METHODS: Data were collected from provincial government resources and drug formularies from 2012-2013 on the extent of coverage for GHRT based on a clinical case scenario representative of a young adult survivor of a PBT with childhood-onset radiation-induced GHD, the ingredient cost for GHRT and the applicable provincial public drug plan cost-sharing policies. A model was then created to simulate out-of-pocket costs incurred by a young adult male and a young adult female survivor of a PBT for one year of GHRT in each province with applicable cost-sharing arrangements and levels of low annual individual total income that best represent the majority of young adult survivors of PBTs. Out-of-pocket costs were expressed as a percentage of annual income. Comparisons were made between provinces descriptively, and variation among provinces was summarized statistically. RESULTS: Alberta, Manitoba, Ontario, Quebec, New Brunswick, and Newfoundland and Labrador provide coverage for GHD during adulthood on a case-by-case basis, while British Columbia, Saskatchewan, Nova Scotia and Prince Edward Island provide no coverage. The percentage of annual income to fund GHRT across the provinces without public coverage ranged from 14.4% to 25.5% for males and 21.5% to 38.3% for females, and with public coverage was 0.0% to 4.1% for males and 0.0% to 5.0% for females. INTERPRETATION: There are considerable out-of-pocket costs and variation in coverage provided by provincial public drug plans to fund GHRT for young adult survivors of PBTs with GHD. The implementation of a national drug formulary could potentially prevent undue financial hardship and remove disparities resulting from variations in provincial drug plans.