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.

CYP24A1 and SLC34A1 Pathogenic Variants Are Uncommon in a Canadian Cohort of Children with Hypercalcemia or Hypercalciuria.

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.

Central diabetes insipidus and pain medications - a risky combination.

BACKGROUND: Central Diabetes Insipidus (CDI) results from decreased production of antidiuretic hormone (ADH) leading to an inability to concentrate urine. CDI is treated with desmopressin (DDAVP). Rarely reported in the literature, opioids and non-steroidal anti-inflammatories (NSAIDs) can induce hyponatremia in individuals treated for CDI. CASE PRESENTATION: A 10-year-old boy with septo-optic dysplasia and CDI was treated with DDAVP 1.6 mg orally TID maintaining normal sodium levels. Post admission for a femur fracture, he was discharged on ibuprofen and hydromorphone. Sodium was 136 mmol/l two days before discharge. He returned to the ED after having a seizure at home. He was euvolemic and mildly lethargic. Sodium was low at 108 mmol/l. DDAVP and hydromorphone were held and he was fluid restricted, but the sodium remained low. Sodium began to rise when Ibuprofen was stopped. Intermittent small doses of DDAVP were given to facilitate gradual correction of hyponatremia. At discharge, sodium had normalized. CONCLUSION: Hyponatremia has occasionally been described as a side effect of opioids and rarely of NSAIDs in patients with CDI. Stimulation of the thirst centre may play a role with opioids while a decrease in urine output may be the mechanism with NSAIDs.

Adrenal suppression from glucocorticoids: preventing an iatrogenic cause of morbidity and mortality in children.

Adrenal suppression (AS) is an important side effect of glucocorticoids (GCs) including inhaled corticosteroids (ICS). AS can often be asymptomatic or associated with non-specific symptoms until a physiological stress such as an illness precipitates an adrenal crisis. Morbidity and death associated with adrenal crisis is preventable but continues to be reported in children. There is a lack of consensus about the management of children at risk of AS. However, healthcare professionals need to develop an awareness and approach to keep these children safe. In this article, current knowledge of the risk factors, diagnosis and management of AS are reviewed while drawing attention to knowledge gaps and areas of controversy. Possible strategies to reduce the morbidity associated with this iatrogenic condition are provided for healthcare professionals.

Symptomatic adrenal suppression among children in Canada.

BACKGROUND: Adrenal suppression (AS) is an under-recognised side effect of glucocorticoid (GC) use. AS may go undetected until a physiological stress precipitates an adrenal crisis. The incidence of AS has not been established. We sought to estimate the minimum national incidence and presenting features of paediatric symptomatic AS. METHODS: Through the established methodology of the Canadian Paediatric Surveillance Program, over 2500 paediatricians were surveyed monthly for 2 years (April 2010-March 2012) to report new cases of symptomatic AS. RESULTS: Forty-six cases of symptomatic AS were confirmed. The estimated annual incidence is 0.35/100 000 children aged 0-18 years (95% CI 0.26 to 0.47). The most common presentations were growth failure (35%), non-specific symptoms (28%) or both (13%). Adrenal crisis occurred in six cases (13%). Thirty-seven children (80%) had received inhaled corticosteroid (ICS) alone or in combination with other GC forms. Many children received high but commonly prescribed doses of ICS. CONCLUSIONS: AS is responsible for significant morbidity in children, including susceptibility to adrenal crisis. The minimal estimated incidence reported is for the entire paediatric population and would be much higher in the at-risk group (ie, children treated with GCs). Close monitoring of growth and possible symptoms of AS, which may be non-specific, are important in children on all forms of GC therapy including ICS. To reduce the risk of AS, physicians must be aware of the risk of AS, revisit GC doses frequently and use the lowest effective dose.

The role of morning basal serum cortisol in assessment of hypothalamic pituitary-adrenal axis.

PURPOSE: The use of morning basal serum cortisol levels as an alternative to dynamic testing for assessment of hypothalamic-pituitary-adrenal (HPA) axis has previously been reported. The purpose of this study was to determine the lower and upper cutoff values that would obviate subsequent HPA axis testing. METHODS: A single-centre, retrospective study from a tertiary care endocrinology clinic was conducted, analyzing data from 106 adult individuals referred for HPA axis testing who had undergone a 0800-0900 morning basal serum cortisol test followed by a standard dose (250 µg) adrenocorticotropin (ACTH) stimulation test. The ability of morning basal serum cortisol values to predict post-ACTH 30 or 60 minute peak cortisol value of >500 or >550 nmol/L was investigated. RESULTS: A morning basal cutoff of <128 nmol/L is sufficient for predicting a post-ACTH value<550 nmol/L, and morning basal cutoff levels of >243 nmol/L and >266 nmol/L predict peak post-ACTH values of >500 and >550 nmol/L respectively, obviating the need for dynamic testing. Regression analysis further demonstrated the log-linear relationship between morning basal and peak levels, while also finding a significant decrease in peak post-ACTH levels for patients diagnosed with secondary hypothyroidism (76 nmol/L lower, p=0.003) or secondary hypogonadism (61 nmol/L lower, p=0.02). These data suggest that the risk of cortisol deficiency is significantly higher in individuals with additional pituitary insufficiencies. The odds ratios for cortisol deficiency in patients with history of isolated secondary hypothyroidism was 3.41 (p=0.015), with isolated secondary hypogonadism was 4.77 (p=0.002) and with both was 7.45 (p=0.0002). CONCLUSION: Morning basal serum cortisol levels show promise as an effective screening test for HPA insufficiency for most patients. Clinicians should consider the high probability of HPA insufficiency in patients with one or more pituitary insufficiencies.

Occurrence of slipped capital femoral epiphysis in children undergoing gonadotropin-releasing hormone agonist therapy for the treatment of central precocious puberty.

BACKGROUND: Obesity, age and hormone imbalances including hypothyroidism and growth hormone deficiency and therapy, but not gonadotropin-releasing hormone agonist (GnRHa) therapy, have been identified as risk factors for slipped capital femoral epiphysis (SCFE). Five of 7 reported cases describe SCFE in children shortly after GnRHa therapy cessation. METHODS: We report 3 cases of SCFE that occurred in children on GnRHa therapy for the treatment of central precocious puberty (CPP) and discuss possible promoting factors. RESULTS: An otherwise healthy 8.75-year-old girl [body mass index (BMI) Z score +1.75] developed SCFE 6.75 years into GnRHa therapy for idiopathic CPP. A second girl (with a history of acute lymphoblastic leukemia requiring total body irradiation) was 10.6 years old (BMI Z score +1.06) when she developed SCFE 3.3 years into GnRHa therapy. The third case was an 8.75-year-old female with CPP secondary to a hypothalamic hamartoma (BMI Z score +1.65) who developed bilateral SCFE 5.6 years into therapy. CONCLUSION: Increasing evidence suggests an association between GnRHa therapy for CPP and the occurrence of SCFE. We suggest that a lack of adequate sex hormone exposure at a 'critical period' of bone formation may result in a weakened epiphysis that becomes susceptible to slipping. © 2013 S. Karger AG, Basel.

Presentation and course of diabetes in children and adolescents with Alstrom syndrome.

Alstrom syndrome is characterized by childhood obesity, progressive retinal degeneration, and sensorineural hearing loss with diabetes mellitus (DM) developing later in childhood and adulthood. The course of diabetes in children with this condition has not been described. We aim to describe the diagnosis, management, and course of diabetes in a series of children followed in our center. A retrospective chart review of all seven children with Alstrom syndrome was performed. Patients, aged 4.5-22 yr, had typical features of Alstrom syndrome. Five were diagnosed with DM at a median age of 11.5 yr. At diagnosis of DM, mean fasting blood glucose (FBG) was normal at 82.8 ± 12.6 mg/dL (4.6 ± 0.7 mmol/L), but random or oral glucose tolerance test (OGTT) values were > 200 mg/dL (11.1 mmol/L). Two patients had periods of poor control despite high-dose insulin and show better A1C, off insulin and with other therapy. In our series, DM in Alstrom syndrome begins by age 14 yr. At diagnosis of DM, FBG was normal. Hence the diagnosis may be missed if screening is performed with FBG alone. We conclude that OGTT should be considered annually from age 6 to 7 yr and in established DM, if glycemic control is poor on insulin, escalating doses may not be effective.