Evaluation of the First Three Years of Treatment of Children with Congenital Hypothyroidism Identified through the Alberta Newborn Screening Program.

The effectiveness of newborn screening (NBS) for congenital hypothyroidism (CH) relies on timely screening, confirmation of diagnosis, and initiation and ongoing monitoring of treatment. The objective of this study was to ascertain the extent to which infants with CH have received timely and appropriate management within the first 3 years of life, following diagnosis through NBS in Alberta, Canada. Deidentified laboratory data were extracted between 1 April 2014 and 31 March 2019 from Alberta Health administrative databases for infants born in this time frame. Time to lab collection was anchored from date of birth. Timeliness was assessed as the frequency of monitoring of Thyroid Stimulating Hormone (TSH) and appropriateness as the frequency of children maintaining biochemical euthyroidism. Among 160 term infants, 95% had confirmation of diagnosis by 16 days of age. The cohort had a median of 2 (range 0-5) TSH measurements performed in the time interval from 0 to 1 month, 4 (0-12) from 1 to 6 months, 2 (0-10) from 6 to 12 months, and 7 (0-21) from 12 to 36 months. Approximately half were still biochemically hypothyroid (TSH > 7 mU/L) at 1 month of age. After becoming euthyroid, at least some period of hypo- (60%) or hyperthyroidism (TSH < 0.2 mU/L) (39%) was experienced. More work needs to be performed to discern factors contributing to prolonged periods of hypothyroidism or infrequent lab monitoring.

Cardiac MRI evaluation of aortic biophysical properties in paediatric Turner syndrome.

BACKGROUND: Aortopathy in Turner syndrome is associated with aortic dilation, and the risk of dissection is increased when the aortic size index is ≥ 2-2.5 cm/m2. We evaluated the aortic biophysical properties in paediatric Turner syndrome using cardiac MRI to determine their relationship to aortic size index. METHODS: Turner syndrome patients underwent cardiac MRI to evaluate ventricular function, aortic dimensions, and biophysical properties (aortic stiffness index, compliance, distensibility, pulse wave velocity, and aortic and left ventricular elastance). Spearman correlation examined correlations between these properties and aortic size index. Data was compared to 10 controls. RESULTS: Of 25 Turner syndrome patients, median age 14.7 years (interquartile range: 11.0-16.8), height z score -2.7 (interquartile range: -2.92 - -1.54), 24% had a bicuspid aortic valve. Turner syndrome had increased diastolic blood pressure (p < 0.001) and decreased left ventricular end-diastolic (p < 0.001) and end-systolic (p = 0.002) volumes compared to controls. Median aortic size index was 1.81 cm/m2 (interquartile range: 1.45-2.1) and 7 had an aortic size index > 2 cm/m2. Aortic and left ventricular elastance were greater in Turner syndrome compared to controls (both p < 0.001). Increased aortic size index correlated with increased aortic elastance (r = 0.5, p = 0.01) and left ventricular elastance (r = 0.59, p = 0.002) but not aortic compliance. Higher ascending aortic areas were associated with increased aortic compliance (r = 0.44, p = 0.03) and left ventricular elastance (r = 0.49, p = 0.01). CONCLUSION: Paediatric Turner syndrome with similar aortic size index to controls showed MRI evidence of abnormal aortic biophysical properties. These findings point to an underlying aortopathy and provide additional parameters that may aid in determining risk factors for aortic dissection.

X-linked hypophosphatemia caused by a deep intronic variant in PHEX identified by PCR-based RNA analysis of urine-derived cells.

X-linked hypophosphatemia (XLH) is caused by dominant inactivating mutations in the phosphate regulating endopeptidase homology, X-linked (PHEX), resulting in elevated fibroblast growth factor 23 (FGF23), hypophosphatemia, rickets and osteomalacia. PHEX variants are identified in approximately 85 % of individuals with XLH, which leaves a substantial proportion of patients with negative DNA-based genetic testing. Here we describe a 16-year-old male who had typical features of XLH on clinical and radiological examination. Genomic DNA sequencing of a hypophosphatemia gene panel did not reveal a pathogenic variant. We therefore obtained a urine sample, established cell cultures and obtained PHEX cDNA from urine-derived cells. Sequencing of exon-spanning PCR products demonstrated the presence of an 84 bp pseudoexon in PHEX intron 21 due to a deep intronic variant (c.2147+1197A>G), which created a new splice donor site in intron 21. The corresponding PHEX protein would lack 33 amino acids on the C-terminus and instead include an unrelated sequence of 17 amino acids. The patient and his affected mother both had this variant. This report highlights that individuals with the typical clinical characteristics of XLH and negative genomic DNA sequence analysis can have deep intronic PHEX variants that are detectable by PCR-based RNA diagnostics.

Canadian Cystic Fibrosis-related Diabetes Clinical Practice Survey: Analysis of Current Practices and Gaps in Clinical Care.

OBJECTIVES: Our aim in this study was to identify challenges and gaps in Canadian practices in screening, diagnosis, and treatment of cystic fibrosis-related diabetes (CFRD), with the goal of informing a Canadian-specific guideline for CFRD. METHODS: We conducted an online survey of health-care professionals (97 physicians and 44 allied health professionals) who care for people living with CF (pwCF) and/or CFRD (pwCFRD). RESULTS: Most pediatric centres followed <10 pwCFRD and adult centres followed >10 pwCFRD. Children with CFRD are usually followed at a separate diabetes clinic, whereas adults with CFRD may be followed by respirologists, nurse practitioners, or endocrinologists in a CF clinic or in a separate diabetes clinic. Less than 25% of pwCF had access to an endocrinologist with a special interest or expertise in CFRD. Many centres perform screening oral glucose tolerance testing with fasting and 2-hour time points. Respondents, especially those working with adults, also indicate use of additional tests for screening not currently recommended in CFRD guidelines. Pediatric practitioners tend to only use insulin to manage CFRD, whereas adult practitioners are more likely to use repaglinide as an alternative to insulin. CONCLUSIONS: Access to specialized CFRD care may be a challenge for pwCFRD in Canada. There appears to be wide heterogeneity of CFRD care organization, screening, and treatment among health-care providers caring for pwCF and/or pwCFRD across Canada. Practitioners working with adult pwCF are less likely to adhere to current clinical practice guidelines than practitioners working with children.

Use of glucagon-like peptide-1 receptor agonists for pediatric patients with obesity and diabetes: The providers' perspectives.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RA) have been widely used in adults with Type 2 diabetes (T2D) and obesity. We sought to evaluate the experience of pediatric endocrinology providers with GLP-1RA and factors that guide them on whether and how to prescribe these medications. METHODS: We surveyed the members of the Pediatric Endocrine Society regarding the use of GLP-1RA in their practice. RESULTS: The respondents (n = 102) were predominantly from academic centers (84%) and 75%reported using GLP-1RA in pediatric patients, mostly to treat T2D and obesity. Patient tolerance for the medication was reported to be the driving factor determining the duration of treatment. Gastrointestinal side effects were observed more commonly than local reactions or elevation of pancreatic enzymes. Lack of clinical experience was reported to be a major barrier for prescribing GLP-1RA, particularly among those with more than 5 years of clinical experience. Finally, liraglutide was used more often (93%) than other GLP-1RA. CONCLUSIONS: The use of GLP-1RA has increased in pediatric patients. Recent Food and Drug Administration approval of liraglutide for pediatric obesity will likely further increase its prescription rate. Providers should be vigilant about side effects and adjust the doses of GLP-1RA accordingly. More efforts should be made by professional societies to educate pediatric endocrinology providers about the proper use of GLP-1RA and enhance their confidence in prescribing these medications.

Diabetic ketoacidosis at type 1 diabetes diagnosis in children during the COVID-19 pandemic.

OBJECTIVE: The COVID-19 pandemic has led to significant public health measures that have resulted in decreased acute pediatric care utilization. We evaluated whether the rate of severe presentations of new onset type 1 diabetes (DM1), such as, diabetic ketoacidosis (DKA) has changed since the COVID-19 public health measures were enacted. RESEARCH DESIGN AND METHODS: A retrospective chart review of children less than 18 years of age presenting with new onset DM1 during the pandemic period of March 17, 2020 to August 31, 2020 was conducted at two tertiary care pediatric hospitals in Alberta, Canada. Rates of DKA and severe DKA were compared to the same time period in the year 2019 (pre-pandemic control). RESULTS: The number of children presenting with newly diagnosed DM1 was similar during the pandemic year of 2020 compared with 2019 (107 children in 2020 vs. 114 in 2019). The frequency of DKA at DM1 onset was significantly higher in the pandemic period (68.2% vs 45.6%; p < 0.001) and incidence of severe DKA was also higher (27.1% in 2020 vs 13.2% in 2019; p = 0.01). CONCLUSIONS: There was a significant increase in DKA and severe DKA in children presenting with new onset DM1 during the COVID-19 pandemic period. This emphasizes the need for educating health care professionals and families to be aware of the symptoms of hyperglycemia and the importance of early diagnosis and treatment even during public health measures for COVID-19.

Revision of Alberta's Provincial Insulin Pump Therapy Criteria for Adults and Children With Type 1 Diabetes: Process, Rationale and Framework for Evaluation.

OBJECTIVES: Insulin pump therapy is a valuable, but costly approach, with public funding in Alberta for eligible individuals since 2013. The Provincial Insulin Pump Therapy Program Clinical Advisory Committee has revised and updated the clinical criteria, integrating current literature, best practice and feedback from clinicians. The objective was to develop criteria that would: 1) optimize safety and effectiveness of insulin pump therapy, while 2) carefully stewarding resources available to care for people with type 1 diabetes. METHODS: The Clinical Advisory Committee comprised health-care professionals with expertise in pump therapy and included adult and pediatric endocrinologists, an internist, a pediatrician, certified pump trainers, diabetes educators and clinic managers. The group meets regularly by teleconference. Decisions are made by consensus. RESULTS: Indications for insulin pump therapy for adults and children with insulin-deficient diabetes were divided into 4 hierarchical levels: 1) problematic hypoglycemia, inability to achieve acceptable control or progressive complications; 2) unpredictable activity, dawn phenomenon or children for whom use of multiple daily injections is not appropriate; 3) individual preference and 4) clinical exception, with priority given to indications with clear evidence of benefit. The criteria emphasize the importance of: 1) adequate education in diabetes self-management; 2) adequate trial of flexible insulin therapy with modern analogues and 3) evidence of active, safe diabetes self-management. Tools to facilitate effective and efficient annual review and surveillance were developed incorporating biological, behavioural evaluation and self-reflection to provide a framework for program evaluation. The recommendations were implemented in January 2019. CONCLUSIONS: The process and revised criteria may be valuable for jurisdictions considering how to develop and implement a publicly funded insulin pump program.

Incidence and Risk Factors for Hypoglycemia During Fetal-to-Neonatal Transition in Premature Infants.

Objective: To determine the incidence and risk factors associated with neonatal hypoglycemia in the premature population <33 weeks' gestation. Methods: This was a secondary retrospective analysis from previous infants enrolled in randomized controlled trials. A total of 255 infants <33 weeks' gestation were born during the study period. Eight infants were excluded due to missing glucose or maternal data and 175 infants were analyzed. Main outcome measures: Primary outcome was hypoglycemia (blood glucose <2.6mmol/L) determined via glucose oxidase method on arterial or venous blood gas. Birth weight subgroups: small for gestational age (SGA, birth weight <10%ile for gestational age) and large for gestational age (LGA, birth weight >90%ile for gestational age). Maternal hypertension was systolic blood pressure >140mmHg. Results: 175 infants <33 weeks' gestational age (89 male, 84 female) were analyzed. Hypoglycemia occurred in 59 infants (33.7%). Maternal hypertension (OR 3.07, 95% CI 1.51-6.30, p = 0.002) was the sole risk factor for neonatal hypoglycemia. Protective factors for hypoglycemia included labor at time of delivery (OR 4.51, 95% CI 2.29-9.18, p <0.0001) and antenatal magnesium sulfate (OR 2.53, 95% CI 1.23-5.50, p = 0.01). There were no significant differences between hypoglycemic and euglycemic infants in sex, gestational age, LGA infants, antenatal steroids, vaginal birth, or maternal diabetes. SGA infants were excluded from analysis due to sample size. Conclusions: Premature infants <33 weeks' gestation have increased risk of hypoglycemia. Maternal hypertension increases hypoglycemia risk. Antenatal magnesium sulfate administration or labor at time of delivery decrease hypoglycemia risk.

Marked phenotypic variable expression among brothers with duplication of Xq27.1 involving the SOX3 gene.

We describe four phenotypically different brothers who share the same microduplication of Xq27.1, which contains the SOX3 gene. SOX3 mutations have been associated with growth hormone deficiency, variable degrees of additional pituitary hormone deficiencies, and mental retardation. SOX3 also appears to play an important role in pharyngeal arch segmentation that gives rise to craniofacial structures. While these four brothers have inherited the same mutation, they manifest a spectrum of phenotypes, ranging from complete, multiple pituitary hormone deficiencies to no apparent pituitary hormone deficiency with or without craniopharyngeal/facial dysmorphisms. We look to the literature to provide putative explanations for the variable expression of the brothers' shared SOX3 mutation.

Growth hormone treatment of Canadian children: results from the GeNeSIS phase IV prospective observational study.

BACKGROUND: Country-specific data on outcomes of treatment with recombinant human growth hormone are lacking. We present such data for children treated with growth hormone in Canada. METHODS: We describe characteristics and outcomes of 850 children (mean age at baseline 8.5 yr) treated with growth hormone constituting the Canadian cohort of the multinational phase IV prospective observational Genetics and Neuroendocrinology of Short-stature International Study (GeNeSIS). The diagnosis associated with short stature was as determined by the investigator. Auxological data were evaluated yearly until near-adult height. Adverse events were assessed in all growth-hormone-treated patients. RESULTS: The diagnosis ascribed as the cause of short stature was growth hormone deficiency in 526 children (61.9%), predominantly organic rather than idiopathic, particularly congenital pituitary abnormalities and intracranial tumours. All diagnostic groups with sufficient patients for analysis had increased height velocity standard deviation score (SDS) and height SDS during growth hormone treatment. For patients who reached near-adult height (n = 293), the mean height SDS was within the normal range for about 80% of patients with organic growth hormone deficiency (n = 131) or idiopathic growth hormone deficiency (n = 50), 50% of patients with idiopathic short stature (n = 10) and 46% of patients with Turner syndrome (n = 79). Eleven deaths were reported, 7 in patients with organic growth hormone deficiency. Serious adverse events considered related to growth hormone treatment (n = 19) were isolated except for medulloblastoma recurrence (n = 2) and adenoidal hypertrophy (n = 2). INTERPRETATION: Growth hormone treatment was effective and had a good safety profile in Canadian children. Growth hormone dosages were lower than in the US and global GeNeSIS cohorts, and a greater proportion of treated Canadian children had organic growth hormone deficiency. STUDY REGISTRATION: ClinicalTrials.gov, no. NCT01088412.

Pediatric Type 1 Diabetes: Patients' and Caregivers' Perceptions of Glycemic Control.

OBJECTIVES: (1) to describe pediatric patients with T1D and their caregivers' perceptions of measures of glycemic control (hemoglobin [A1C] and blood glucose [BG] levels) and (2) to determine the relationship between patients' and caregivers' perceptions of measures of glycemic control with actual A1C levels and adherence to diabetes self-care behaviors. METHODS: Patients (8 to 18 years) with T1D and caregivers completed questionnaires that queried their perceptions of (1) what the A1C level assesses, (2) the ideal A1C target, and (3) the ideal BG range. Point-of-care A1C levels were measured for each patient. They also completed the Self-Care Inventory Revised (SCI-R) to assess adherence to diabetes self-care behaviors. RESULTS: Among 253 dyads, the frequencies of patients compared to caregivers who could accurately describe what the A1C level assesses, identify the ideal A1C target, and identify the ideal BG range were 20 vs. 66, 31 vs. 56, and 72 vs. 76%, respectively. Patients' accuracy in reporting ideal targets for glycemic control was significantly associated with caregivers' accuracy. There was a trend for lower median A1C levels in patients who were part of a dyad wherein both had accurate perceptions of glycemic control. CONCLUSIONS: Patients and caregivers had accurate knowledge of ideal BG range but were less knowledgeable about the meaning of A1C levels and ideal A1C targets. Nevertheless, whether glycemic control was perceived as an A1C measurement or a BG range, A1C levels trended lower for patients when both they and their caregivers had accurate perceptions of glycemic control.

46,XY disorder of sex development due to 17-beta hydroxysteroid dehydrogenase type 3 deficiency: a plea for timely genetic testing.

BACKGROUND: 17ß-hydroxysteroid dehydrogenase type 3 (17ßHSD3) deficiency is a rare cause of disorder of sex development (DSD) due to impaired conversion of androstenedione to testosterone. Traditionally, the diagnosis was determined by ßHCG-stimulated ratios of testosterone:androstenedione < 0.8. CASE PRESENTATION: An otherwise phenotypically female infant presented with bilateral inguinal masses and a 46,XY karyotype. ßHCG stimulation (1500 IU IM for 2 days) suggested 17ßHSD3 deficiency although androstenedione was only minimally stimulated (4.5 nmol/L to 5.4 nmol/L). Expedient genetic testing for the HSD17B3 gene provided the unequivocal diagnosis. CONCLUSION: We advocate for urgent genetic testing in rare causes of DSD as indeterminate hormone results can delay diagnosis and prolong intervention.

Cardiac Magnetic Resonance Imaging in Pediatric Turner Syndrome.

OBJECTIVE: To compare the detection of cardiac lesions with the use of cardiac magnetic resonance imaging (CMR) and conventional echocardiography in children with Turner syndrome. STUDY DESIGN: Twenty-four girls with Turner syndrome, 8-18 years of age, were recruited through the Pediatric Endocrinology Program. Participants underwent CMR and echocardiography within a 2-year period, and discrepancies between the results of each modality were identified. RESULTS: Fifteen of 24 (63%) girls had a cardiac lesion identified on CMR or echocardiography. Both modalities identified the same lesion in 10 of 15 (67%); however, 6 of 15 (40%) participants had a lesion identified on CMR but not echocardiography. Participants with a missed lesion had a trend towards greater body mass index. Aortic dilation and bicuspid aortic valve were the most commonly missed lesions by echocardiography. CONCLUSIONS: CMR identifies significant cardiac lesions missed by echocardiography in pediatric patients with Turner syndrome, particularly along the aorta. These findings support the current guidelines that recommend screening CMR in addition to echocardiogram. Early identification of cardiac abnormalities in patients with Turner syndrome will allow for a greater understanding of the natural history in these patients and potentially identify candidates for earlier intervention.

Risk for ESRD in type 1 diabetes remains high despite renoprotection.

Historically, patients with type 1 diabetes and macroalbuminuria had high competing risks: cardiovascular death or renal failure. Here, we assessed these risks in patients receiving therapies implemented during the last 30 years. Between 1991 and 2004, we enrolled 423 white patients with type 1 diabetes who developed macroalbuminuria (albumin excretion rate, ≥300 µg/min). With follow-up for 98% through 2008, ESRD developed in 172 patients (incidence rate, 5.8/100 person-years), and 29 died without ESRD (mortality rate, 1/100 person-years). The majority of these outcomes occurred between ages 36 and 52 years with durations of diabetes of 21 to 37 years. The 15-year cumulative risks were 52% for ESRD and 11% for pre-ESRD death. During the 15 years of follow-up, the use of renoprotective treatment increased from 56 to 82%, and BP and lipid levels improved significantly; however, the risks for both ESRD and pre-ESRD death did not change over the years analyzed. There were 70 post-ESRD deaths, and the mortality rate was very similar during the 1990s and the 2000s (11/100 person-years versus 12/100 person-years, respectively). Mortality was low in patients who received a pre-emptive kidney transplant (1/100 person-years), although these patients did not differ from dialyzed patients with regard to predialysis eGFR, sex, age at onset of ESRD, or duration of diabetes. In conclusion, despite the widespread adoption of renoprotective treatment, patients with type 1 diabetes and macroalbuminuria remain at high risk for ESRD, suggesting that more effective therapies are desperately needed.

High-normal serum uric acid increases risk of early progressive renal function loss in type 1 diabetes: results of a 6-year follow-up.

OBJECTIVE: We previously described a cross-sectional association between serum uric acid and reduced glomerular filtration rate (GFR) in nonproteinuric patients with type 1 diabetes. Here, we prospectively investigated whether baseline uric acid impacts the risk of early progressive renal function loss (early GFR loss) in these patients. RESEARCH DESIGN AND METHODS: Patients with elevated urinary albumin excretion (n = 355) were followed for 4-6 years for changes in urinary albumin excretion and GFR. The changes were estimated by multiple determinations of albumin-to-creatinine ratios (ACRs) and serum cystatin C (GFRcystatin). RESULTS: At baseline, the medians (25th-75th percentiles) for uric acid, ACR, and GFRcystatin values were 4.6 mg/dl (3.8-5.4), 26.2 mg/g (15.1-56.0), and 129 ml/min per 1.73 m(2) (111-145), respectively. During the 6-year follow-up, significant association (P < 0.0002) was observed between serum uric acid and development of early GFR loss, defined as GFRcystatin decline exceeding 3.3% per year. In baseline uric acid concentration categories (in mg/dl: <3.0, 3.0-3.9, 4.0-4.9, 5.0-5.9, and >or=6), the risk of early GFR loss increased linearly (9, 13, 20, 29, and 36%, respectively). This linear increase corresponds to odds ratio 1.4 (95% CI 1.1-1.8) per 1 mg/dl increase of uric acid. The progression and regression of urinary albumin excretion were not associated with uric acid. CONCLUSIONS: We found a clear dose-response relation between serum uric acid and risk of early GFR loss in patients with type 1 diabetes. Clinical trials are warranted to determine whether uric acid-lowering drugs can halt renal function decline before it becomes clinically significant.

Serum concentrations of markers of TNFalpha and Fas-mediated pathways and renal function in nonproteinuric patients with type 1 diabetes.

BACKGROUND AND OBJECTIVES: The aim of our study was to examine serum markers of the TNF and Fas pathways for association with cystatin-C based estimated glomerular filtration rate (cC-GFR) in subjects with type 1 diabetes (T1DM) and no proteinuria. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The study group (the 2nd Joslin Kidney Study) comprised patients with T1DM and normoalbuminuria (NA) (n = 363) or microalbuminuria (MA) (n = 304). Impaired renal function (cC-GFR <90 ml/min) was present in only 10% of patients with NA and 36% of those with MA. We measured markers of the tumor necrosis factor alpha (TNFalpha) pathway [TNFalpha, soluble TNF receptor 1 (sTNFR1), and 2 (sTNFR2)], its downstream effectors [soluble intercellular and soluble vascular adhesion molecules (sICAM-1 and sVCAM-1), interleukin 8 (IL8/CXCL8), monocytes chemoattractant protein-1 (MCP1), and IFNgamma inducible protein-10 (IP10/CXCL10)], the Fas pathway [soluble Fas (sFas) and Fas ligand (sFasL)], CRP, and IL6. RESULTS: Of these, TNFalpha, sTNFRs, sFas, sICAM-1, and sIP10 were associated with cC-GFR. However, only the TNF receptors and sFas were associated with cC-GFR in multivariate analysis. Variation in the concentration of the TNF receptors had a much stronger impact on GFR than clinical covariates such as age and albumin excretion. CONCLUSIONS: Elevated concentrations of serum markers of the TNFalpha and Fas-pathways are strongly associated with decreased renal function in nonproteinuric type 1 diabetic patients. These effects are independent of those of urinary albumin excretion. Follow-up studies are needed to characterize the role of these markers in early progressive renal function decline.