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Objectives: Biallelic pathogenic variants in CYPA24A1 and SLC34A1 are causes of idiopathic infantile hypercalcemia. Pathogenic variants in both may also give rise to hypercalciuria with nephrocalcinosis or nephrolithiasis without previous hypercalcemia (renal group). Our objective was to examine the frequency of CYP24A1 or SLC34A1 variants in children with early hypercalcemia or late-onset hypercalciuria. Method: Forty-one children from 7 centers across Canada were recruited. Local investigations were undertaken. The serum was evaluated by liquid chromatography tandem-mass spectrometry for the ratio of 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3, (25-OH-D3:24,25-(OH)2D3), an elevation pathognomonic for the loss of function of the CYP24A1 enzyme. Mutational analyses were undertaken. Family cascade screening was performed if pathogenic variants were detected in probands. Results: Twenty-nine children had early-onset hypercalcemia; none had elevated 25-OH-D3:24,25-(OH)2D3 or variants. Interestingly, 2 of 12 in the renal group had elevated 25-OH-D3:24,25-(OH)2D3 and presented as preadolescents. In case 1, cascade testing revealed a sibling and parent with asymptomatic pathogenic variants in CYP24A1. Four CYP24A1 pathogenic variants were identified in these 2 probands: 3 have been described in European populations, and 1 is a rare variant in exon 7 (c931delC) that is likely pathogenic. No SLC34A1 pathogenic variants were detected. Conclusion: In Canada, pathogenic variants in CYP24A1 appear to manifest with late-onset hypercalciuria and its sequelae. The 25-OH-D3:24,25-(OH)2D3 ratio is an excellent tool for screening for biallelic pathogenic variants in CYP24A1. We confirm that cascade testing is important for these variants.

Objectives Evaluate the current state of postgraduate medical education on gender diversity in Canadian paediatric residency programs, exploring both resident and program director perceptions. Background Primary care providers are seeing more gender diverse children and youth in their offices, along with an exponential growth in referrals to Canadian specialty clinics and potential for significant mental health comorbidities. Gender-affirming support and management have been shown to improve overall outcomes. There is no mandatory curriculum on gender diversity for Canadian paediatric residency programs. Methods Cross-sectional online surveys in English and French distributed to program directors (PDs) and paediatric residents in the 17 Canadian paediatric residency programs. Data were analyzed by descriptive statistics with 95% confidence intervals. Results Response rate was 88.2% from PDs and 24.5% from paediatric residents. Among PDs, 14.3% (95% confidence interval [CI]: 6.3, 22.3) reported a formal curriculum for gender diversity teaching. Sixty-four per cent (53.3, 75.2) of PDs estimated their residents received ≤ 2 hours teaching on gender diversity. Residents reported comfort levels ≤ 50% on specific topics. Among residents, 73.8% (67.9, 79.6) reported that mandatory time in a gender diversity clinic would be the most effective teaching tool while PDs favoured an online module (66.7% [58.2, 75.1]). Barriers to more teaching included lack of time in a busy curriculum. Over 90% of resident indicated that more teaching on gender diversity is required. Conclusions Significant variability in education on gender diversity is seen amongst Canadian paediatric residency programs. Discussion regarding a formal paediatric curriculum on gender diversity is needed.

BACKGROUND AND OBJECTIVES Puberty onset and development contribute substantially to adolescents’ bone mass and body composition. Our objective with this study was to examine the effects of gonadotropin-releasing hormone agonists (GnRHa) on these puberty-induced changes among youth with gender dysphoria (GD). METHODS Medical records of the endocrine diversity clinic in an academic children’s hospital were reviewed for youth with GD seen from January 2006 to April 2017 with at least 1 baseline dual-energy radiograph absorptiometry measurement. RESULTS At baseline, transgender females had lower lumbar spine (LS) and left total hip (LTH) areal bone mineral density (aBMD) and LS bone mineral apparent density (BMAD) z scores. Only 44.7% of transgender youth were vitamin D sufficient. Baseline vitamin D status was associated with LS, LTH aBMD, and LS BMAD z scores. Post-GnRHa assessments revealed a significant drop in LS and LTH aBMD z scores (transgender males and transgender females) without fractures and LS BMAD (transgender males), an increase in gynoid (fat percentage), and android (fat percentage) (transgender males and transgender females), and no changes in BMI z score. CONCLUSIONS GnRHa monotherapy negatively affected bone mineral density of youth with GD without evidence of fractures or changes in BMI z score. Transgender youth body fat redistribution (android versus gynoid) were in keeping with their affirmed gender. The majority of transgender youth had vitamin D insufficiency or deficiency with baseline status associated with bone mineral density. Vitamin D supplementation should be considered for all youth with GD.

Biallelic pathogenic variants in CYPA24A1 and SLC34A1 are causes of idiopathic infantile hypercalcemia. Pathogenic variants in both may also give rise to hypercalciuria with nephrocalcinosis or nephrolithiasis without previous hypercalcemia (renal group). Our objective was to examine the frequency of CYP24A1 or SLC34A1 variants in children with early hypercalcemia or late-onset hypercalciuria.Forty-one children from 7 centers across Canada were recruited. Local investigations were undertaken. The serum was evaluated by liquid chromatography tandem-mass spectrometry for the ratio of 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3, (25-OH-D3:24,25-(OH)2D3), an elevation pathognomonic for the loss of function of the CYP24A1 enzyme. Mutational analyses were undertaken. Family cascade screening was performed if pathogenic variants were detected in probands.Twenty-nine children had early-onset hypercalcemia; none had elevated 25-OH-D3:24,25-(OH)2D3 or variants. Interestingly, 2 of 12 in the renal group had elevated 25-OH-D3:24,25-(OH)2D3 and presented as preadolescents. In case 1, cascade testing revealed a sibling and parent with asymptomatic pathogenic variants in CYP24A1. Four CYP24A1 pathogenic variants were identified in these 2 probands: 3 have been described in European populations, and 1 is a rare variant in exon 7 (c931delC) that is likely pathogenic. No SLC34A1 pathogenic variants were detected.In Canada, pathogenic variants in CYP24A1 appear to manifest with late-onset hypercalciuria and its sequelae. The 25-OH-D3:24,25-(OH)2D3 ratio is an excellent tool for screening for biallelic pathogenic variants in CYP24A1. We confirm that cascade testing is important for these variants.

Objectives There are few studies exploring why adherence to clinical practice guidelines for the treatment of childhood type 1 diabetes is suboptimal. Our objective was to describe healthcare providers' perspectives on the facilitators of and barriers to adhering to pediatric diabetes treatment guidelines. Methods We fielded an electronic survey to 260 pediatric diabetes healthcare providers (physicians, nurses, dietitians) in British Columbia, Canada, followed by qualitative interviews with a purposeful sample (N=15) of physicians and allied healthcare providers. Descriptive statistics and directed content analysis were used. Results We received 95 of 260 survey responses(37%). Of the 260 healthcare providers who received the survey, 116 were known to be working in a pediatric diabetes centre, and 71 of 116 (61%) responded. Almost all providers were aware of (92%) and familiar with (77%) the Canadian Diabetes Association clinical practice guidelines, and most were in agreement with the recommendations. Patient-level factors, such as poor adherence and patient/family preferences for higher glycemic targets, as well as inadequate resources (i.e. funding, mental health support), were identified as significant barriers. Qualitative interviews identified 3 key themes: 1) working collectively provincially; 2) supporting emotional and mental health and 3) frequent interactions with patients. A provincial health delivery and communication model, as well as mental health support integrated into routine patient care, were recommended. Conclusions The results of this study can guide resource allocation toward key priorities, such as increased investment in mental health support for children with diabetes. The next steps include collecting patient and family perspectives on improving guideline adherence.

We present the investigation and management of a premature, hypotensive neonate born after a pregnancy complicated by anhydramnios to highlight the impact of early and informed management for rare kidney disease. Vasopressin was used to successfully treat refractory hypotension and anuria in the neonate born at 27 weeks of gestation. Next generation sequencing of a targeted panel of genes was then performed in the neonate and parents. Subsequently, two compound heterozygous deletions leading to frameshift mutations were identified in the angiotensin 1-converting enzyme gene ACE; exon 5:c.820_821delAG (p.Arg274Glyfs*117) and exon24: c.3521delG (p.Gly1174Alafs*12), consistent with a diagnosis of renal tubular dysgenesis. In light of the molecular diagnosis, identification, and treatment of associated low aldosterone level resulted in further improvement in renal function and only mild residual chronic renal failure is present at 14 months of age. Truncating alterations in ACE most often result in fetal demise during gestation or in the first days of life and typically as a result of the Potter sequence. The premature delivery, and serendipitous early treatment with vasopressin, and then later fludrocortisone, resulted in an optimal outcome in an otherwise lethal condition.

Rat bite fever (RBF), a systemic infection of Streptobacillus moniliformis or Spirillum minus characterized by fever, arthralgias and petechial-purpuric rash on the extremities, carries a mortality rate of 7% to 10% if untreated. In Canada, one adult and two paediatric cases of RBF have been reported since 2000. In recent years, pet rats have become quite popular among children, placing them at an increased risk for RBF. Thus, paediatricians need to be more wary of the potential for RBF in their patients. In the present report, a culture-confirmed case of RBF and two additional cases of suspected infection are described.

Huntingtin interacting protein 1 (HIP1) is an endocytic adaptor protein with clathrin assembly activity that binds to cytoplasmic proteins, such as F-actin, tubulin, and huntingtin (htt). To gain insight into diverse functions of HIP1, we characterized the male reproductive defect of HIP1 � /� mice from 7 to 30 weeks of age. High levels of HIP1 protein were expressed in the testis of wild-type mice as seen by Western blots and as a reaction over Sertoli cells and elongating spermatids as visualized by immunocyto- chemistry. Accordingly, major structural abnormalities were evident in HIP1 � /� mice with vacuolation of seminiferous tubules caused by an apparent loss of postmeiotic spermatids and a significant reduction in mean profile area. Remaining spermatids revealed deformations of their heads, flagella, and/or acro- somes. In some Sertoli cells, ectoplasmic specializa- tions (ES) were absent or altered in appearance accounting for the presence of spherical germ cells in the epididymal lumen. Quantitative analyses of sperm counts from the cauda epididymidis demonstrated a significant decrease in HIP1 � /� mice compared to wild-type littermates. In addition, computer-assisted sperm analyses indicated that velocities, amplitude of lateral head displacements (ALH), and numbers and percentages of sperm in the motile, rapid, and progressive categories were all significantly reduced in HIP1 � /� mice, while the numbers and percentages of sperm in the static category were greatly increased. Taken together, these various abnormalities corrobo- rate reduced fertility levels in HIP1 � /� mice and suggest a role for HIP1 in stabilizing actin and microtubules, which are important cytoskeletal ele- ments enabling normal spermatid and Sertoli cell morphology and function. Mol. Reprod. Dev. 74: 341-359, 2007. 2006 Wiley-Liss, Inc.

A five-year-four-month-old Caucasian boy of nonconsanguineous parents presented with a one-year history of papules over the cheeks, glabella and ears. His mother noted that he experienced several episodes of body odour that resolved spontaneously. He also experiences occasional headaches. He had no history of salt-craving, axillary or pubic hair, or change in phallus size. Rapid growth was noted by the mother in the past six months. His medical history was unremarkable, and the family history only revealed that the paternal grandmother’s first child died shortly after birth. No autopsy results were available. On examination, the patient was in no distress. His blood pressure was 94/53 mmHg, and his pulse was 87 beats/min. His height was 120.7 cm and his weight was 21.3 kg, at the 97th and 80th percentiles, respectively. He had no body odour, his penile length was 7 cm (>2 SD) and his testes were descended and 3 mL in volume. His cutaneous examination revealed multiple keratotic papules on his cheeks, as well as open comedones around the inner and outer ears and nose. He exhibited no cutaneous hyperpigmentation. Partial initial laboratory results demonstrated a normal complete blood count, electrolyte levels, and normal tests of liver and renal function. Follicle-stimulating and luteinizing hormone levels were also within normal limits. His bone age was nine years. Additional investigations revealed the diagnosis.

To describe patient characteristics at presentation, treatment, and response to treatment in youth with gender dysphoria.A retrospective chart review of 84 youth with a diagnosis of gender dysphoria seen at BC Children's Hospital from 1998-2011.Of the 84 patients, 45 (54%) identified as female-to-male (FtM), 37 (44%) as male-to-female (MtF), and 2 (2%) as natal males who were undecided. Median age of presentation was 16.9 years (range 11.4-19.8 years) and 16.6 years (range 12.3-22.5 years) for FtM and MtF youth, respectively. Gonadotropin-releasing hormone analog treatment was prescribed in 27 (32%) patients. One FtM patient developed sterile abscesses with leuprolide acetate; he was switched to triptorelin and tolerated this well. Cross-sex hormones were prescribed in 63 of 84 patients (39 FtM vs 24 MtF, P.02). Median age at initiation of testosterone injections in FtM patients was 17.3 years (range 13.7-19.8 years); median age at initiation of estrogen therapy in MtF patients was 17.9 years (range 13.3-22.3 years). Three patients stopped cross-sex hormones temporarily due to psychiatric comorbidities (2 FtM) and distress over androgenic alopecia (1 FtM). No severe complications were noted in patients treated with testosterone or estrogen.Treatment with gonadotropin-releasing hormone analog and/or cross-sex hormones, in collaboration with transgender-competent mental health professionals, is an intervention that appears to be appropriate in carefully selected youth with gender dysphoria. Long-term follow-up studies are needed to determine the safety of these treatments in this age group.

Background/Aims: To evaluate factors contributing to the decision to initiate treatment with growth hormone (GH) in patients with Turner syndrome (TS). Methods: Data collected included ethnicity, parents’ education and work status, mid-parental height, age at diagnosis, karyotype, pubertal development, clinical severity score, bone age, height SDS and ages when GH was proposed and initiated. Results: GH was proposed to 59 of 72 patients >6 years (82%), and of these 46 (78%) accepted. Reasons for not proposing GH included late diagnosis, good growth and loss to follow-up. GH-treated and untreated girls differed by age at diagnosis (mean ± SD: 6.8 ± 4.7 vs. 4.3 ± 5.1 years; p = 0.04), TS-specific height SDS (0.08 ± 0.81 vs. 066 ± 0.87; p = 0.01) and spontaneous puberty (5/46 vs. 4/26, p = 0.024). Mean age at which it was suggested to begin GH was 9.2 ± 2.9 years. Reasons for parental refusal of GH were not related to reimbursement issues since GH treatment is covered fully by our insurance plan but included concern with other medical issues, mental health problems and fear of injections or unknown side effects. Conclusion: GH treatment was not acceptable to all patients with TS.