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.

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.

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.

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.

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.

Between hyperfiltration and impairment: demystifying early renal functional changes in diabetic nephropathy.

Renal functional changes in diabetic nephropathy conventionally have been linked to progression of urinary albumin excretion. This paradigm was based on historic evidence noting that hyperfiltration occurred in the setting of normoalbuminuria and microalbuminuria and that loss of renal function began in the context of proteinuria. More contemporaneous research findings, using serum cystatin-C-based estimates of glomerular filtration rate (cC-GFR), have challenged this paradigm. Rather, the process of renal function loss appears to begin prior to the onset of proteinuria. In the 2nd Joslin Kidney Study on the Natural History of Microalbuminuria, over one-third of type 1 diabetes (T1DM) patients with microalbuminuria at the time of enrollment already had evidence of mild (cC-GFR<90) or moderate (cC-GFR<60 ml/min) renal function impairment. Understanding the mechanisms underlying this phenomenon of early renal function impairment may allow for interventions directed at altering or retarding early renal function decline. To date, serum uric acid and components of the TNFalpha pathway appear to be involved.

High-normal serum uric acid is associated with impaired glomerular filtration rate in nonproteinuric patients with type 1 diabetes.

BACKGROUND AND OBJECTIVES: Early renal function decline begins before the onset of proteinuria in patients with type 1 diabetes. The association of elevated serum uric acid with advanced impaired renal function prompts an examination of its role in early renal function decline in patients before proteinuria develops. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients with type 1 diabetes and normoalbuminuria or microalbuminuria were recruited to the Second Joslin Kidney Study. A medical history and measurements of BP, hemoglobin A1c, albumin excretion rate, and serum concentrations of uric acid and cystatin C were obtained. Estimated glomerular filtration rate was measured by a cystatin C-based formula. RESULTS: We studied 364 patients with normoalbuminuria and 311 patients with microalbuminuria. Mean glomerular filtration rate in these groups was 119 and 99 ml/min, respectively. Mildly or moderately impaired renal function (<90 ml/min) was present in 10% of those with normoalbuminuria and 36% of those with microalbuminuria. In univariate and multivariate analyses, lower glomerular filtration rate was strongly and independently associated with higher serum uric acid and higher urinary albumin excretion rate, older age, and antihypertensive treatment. CONCLUSIONS: Serum uric acid concentration in the high-normal range is associated with impaired renal function in patients with type 1 diabetes. Follow-up studies are needed to confirm that this level of serum uric acid is a risk factor for early renal function decline in type 1 diabetes and to determine whether its reduction would prevent the decline.