Can incorporating molecular testing improve the accuracy of newborn screening for congenital adrenal hyperplasia?

BACKGROUND: Single-tier newborn screening (NBS) for CAH using 17-hydroxyprogesterone (17OHP) measured by fluoroimmunoassay (FIA) in samples collected at 24-48 hours produces a high false-positive rate (FPR). 2nd tier steroid testing can reduce the FPR and has been widely implemented. We investigated the accuracy of an alternative multi-tier CAH NBS protocol that incorporates molecular testing of the CYP21A2 gene and reduces the 1st tier 17OHP cutoff to minimize missed cases. METHODS: Created a Minnesota-specific CYP21A2 pathogenic variants panel; develop a rapid, high-throughput multiplex, allele-specific-primer-extension assay; perform 1-year retrospective analysis of Minnesota NBS results comparing metrics between a conventional steroid-based two-tier protocol and a molecular-based multi-tier NBS protocol, applied post-hoc. RESULTS: CYP21A2 gene sequencing of 103 Minnesota families resulted in a Minnesota-specific panel of 21 pathogenic variants. Centers for Disease Control and Prevention (CDC) created a molecular assay with 100% accuracy and reproducibility. Two-tier steroid-based screening of 68,659 live births during 2015 resulted in 2 false negatives (FNs), 91 FPs, and 1 true positive (TP). A three-tier protocol with a lower 1st-tier steroid cutoff, 2nd-tier 21-variant CYP21A2 panel and 3rd-tier CYP21A2 sequencing would have resulted in 0 FNs, 52 FPs and 3 TPs. CONCLUSIONS: Incorporation of molecular testing could improve the accuracy of CAH NBS, although some distinct challenges of molecular testing may need to be considered before implementation by NBS programs.

Implementation of genomic medicine for rare disease in a tertiary healthcare system: Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD).

BACKGROUND: In the United States, rare disease (RD) is defined as a condition that affects fewer than 200,000 individuals. Collectively, RD affects an estimated 30 million Americans. A significant portion of RD has an underlying genetic cause; however, this may go undiagnosed. To better serve these patients, the Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD) was created under the auspices of the Center for Individualized Medicine (CIM) aiming to integrate genomics into subspecialty practice including targeted genetic testing, research, and education. METHODS: Patients were identified by subspecialty healthcare providers from 11 clinical divisions/departments. Targeted multi-gene panels or custom exome/genome-based panels were utilized. To support the goals of PRaUD, a new clinical service model, the Genetic Testing and Counseling (GTAC) unit, was established to improve access and increase efficiency for genetic test facilitation. The GTAC unit includes genetic counselors, genetic counseling assistants, genetic nurses, and a medical geneticist. Patients receive abbreviated point-of-care genetic counseling and testing through a partnership with subspecialty providers. RESULTS: Implementation of PRaUD began in 2018 and GTAC unit launched in 2020 to support program expansion. Currently, 29 RD clinical indications are included in 11 specialty divisions/departments with over 142 referring providers. To date, 1152 patients have been evaluated with an overall solved or likely solved rate of 17.5% and as high as 66.7% depending on the phenotype. Noteworthy, 42.7% of the solved or likely solved patients underwent changes in medical management and outcome based on genetic test results. CONCLUSION: Implementation of PRaUD and GTAC have enabled subspecialty practices advance expertise in RD where genetic counselors have not historically been embedded in practice. Democratizing access to genetic testing and counseling can broaden the reach of patients with RD and increase the diagnostic yield of such indications leading to better medical management as well as expanding research opportunities.

Copeptin levels in hospitalized infants and children with suspected vasopressin-dependent disorders: a case series.

OBJECTIVES: There have been recent advances assessing copeptin levels in adults with suspected disorders of vasopressin release. Very limited data exits on copeptin levels in children and infants, especially in a critically-ill hospitalized population where hyper- and hypo-natremia are very common. Our objective is to describe the institutional experience assessing copeptin levels in hospitalized infants and children with hyper- or hypo-natremia. METHODS: We performed a single-center retrospective case series of all infants, children, and adolescents who had an ultrasensitive plasma copeptin level obtained between 2019-2021. RESULTS: A total of 29 critically ill patients (6 infants) were identified with 38 % of patients having copeptin levels after neurosurgical procedures for tumors or trauma. Approximately 13/17 children with hypernatremia had central diabetes insipidus (central diabetes insipidus) to diagnose CDI, A copeptin level ≤ 4.9 pmol/L resulted in an 88 % sensitivity (95 % CI 47-99 %), and 66 % specificity (95 % CI 30-93 %). Amongst those with hyponatremia levels were more variable, 8/12 children had syndrome of inappropriate antidiuresis (SIAD) with copeptin levels ranging 4.7-72.6 pmol/L. CONCLUSIONS: While difficult to conclude due to multiple limitations, this case series highlights that typical copeptin cutoffs used to diagnose DI in adults in an ambulatory setting may also translate to a critically-ill pediatric population. Large prospective studies are needed to confirm this observation. In addition, postoperative copeptin levels could potentially be utilized as an additional marker to predict permanent from transient DI, but much larger studies are needed. Further work is needed to establish normative copeptin levels in infants and patients with SIAD.

Initiation of Gender-Affirming Testosterone Therapy in a Lactating Transgender Man.

INTRODUCTION: Transgender and gender diverse individuals may choose to provide their infants with human milk. Lactating transgender men may experience gender dysphoria and desire to initiate or reinitiate gender-affirming testosterone therapy. However, there is limited safety data regarding use of testosterone during lactation. MAIN ISSUE: A 30-year-old G2P2 transgender man with gender dysphoria sought to initiate gender-affirming testosterone therapy while lactating. MANAGEMENT: Subcutaneous testosterone was self-administered beginning at 13 months post-partum. We prospectively collected data on circulating testosterone concentrations in parent serum, milk, and infant serum over 5 months until the infant self-weaned. The infant was monitored for growth and development at routine pediatric outpatient appointments. Parent serum testosterone concentrations rose with the initiation of testosterone therapy, reaching therapeutic concentrations by Day 14. Milk testosterone concentrations also increased with a maximum concentration of 35.9 ng/dl when the lactating parent was on a dose of 80 mg subcutaneous testosterone cypionate weekly. The calculated milk/plasma ratio remained under 1.0 and the calculated relative infant dose remained under 1%. The infant had no observable side effects, and his serum testosterone concentrations remained undetectable throughout the study period. CONCLUSION: This is the first study with data regarding human milk and infant serum testosterone concentrations during the initiation of gender-affirming testosterone therapy in a lactating individual. This evidence can help families and clinicians with decisions regarding lactation and testosterone use.

Risk of substance use disorders among adolescents and emerging adults with type 1 diabetes: A population-based cohort study.

BACKGROUND: Adolescents and emerging adults with chronic health conditions such as type 1 diabetes mellitus (T1D) are more likely to engage in high-risk behaviors. Previous studies regarding substance use in adolescents and emerging adults with T1D are mostly derived from cross-sectional studies utilizing self-administered questionnaires and are limited by lack of population-based comparison groups. In addition, despite the rising popularity of vaping, little is known about the incidence of vaping in adolescents and emerging adults with T1D. METHODS: We explored the incidence and prospective risk of substance use disorders (SUD) and vaping in adolescents and emerging adults with T1D compared to age and gender matched nondiabetic referents residing in Olmsted County, Rochester, MN. RESULTS: Risk of incident SUD was higher in those with T1D compared to matched referents with alcohol, marijuana, and smoked tobacco being most common substances. When stratified by gender, these differences remained significant in males, but not females. CONCLUSIONS: While further work is needed to delineate the causative relationships between T1D, mental health, and substance abuse, our findings confirm the critical need for substance use screening and mental health support for adolescents and emerging adults with T1D.

Ovarian Steroid Cell Tumor Masquerading as Steroid-Unresponsive Congenital Adrenal Hyperplasia.

OBJECTIVE: Ovarian neoplasms in children are rare. The objective of this report is to emphasize the importance of considering those neoplasms in the differential diagnosis of hyperandrogenism even with negative diagnostic imaging. METHODS: We report the case of a 12-year-old girl who presented with virilization and elevated 17 hydroxyprogesterone (17-OHP) and who was subsequently diagnosed with an ovarian neoplasm. RESULTS: The patient was initially seen for hirsutism and deepening of the voice. Elevated 17-OHP, androstenedione, and testosterone prompted the initial diagnosis of nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, but those levels failed to suppress on corticosteroid therapy. Ultrasound, computed tomography scan, and magnetic resonance imaging of the abdomen and pelvis were normal. Genetic testing for congenital adrenal hyperplasia was negative. Bilateral selective adrenal and ovarian venous sampling confirmed the ovarian origin of her hyperandrogenism. A unilateral salpingo-oophorectomy revealed a steroid cell tumor. Postoperatively there was normalization of testosterone and 17-OHP. CONCLUSION: This report highlights the utility of selective adrenal and ovarian sampling when suspecting a primary androgen-secreting neoplasm, even in the setting of elevated 17-OHP levels and negative imaging studies, as early diagnosis can prevent manifestation of irreversible symptoms of virilization.

Pediatric Endocrinology: Perspectives of Pediatric Endocrinologists Regarding Career Choice and Recruitment of Trainees.

OBJECTIVES: To examine main factors that influence the decision to choose pediatric endocrinology as a career among pediatric endocrinologists and assess their work satisfaction or stress level and suggested strategies to increase interest in subspecialty training in pediatric endocrinology. METHODS: A workforce survey was distributed among 1470 members of the Pediatric Endocrine Society. RESULTS: The response rate was 37.4%, with 550 members responding. The most common reasons for the respondents choosing pediatric endocrinology were intellectual stimulation (79%), exposure to endocrinology during residency (57%) or medical school (43%), and ability to establish relationships with patients with chronic disorders (54%). Of the respondents, 97% considered intellectual stimulation as the most favorable aspect of the specialty, and 84% considered financial compensation as the most unfavorable aspect of pediatric endocrinology. Majority (77%) were satisfied or very satisfied with their work environment. The mean work-related stress score (0 [none] to 10 [worst]) was 5.7, standard deviation was 2.1, and median was 6 (Q1, Q3: 4, 7). Increased financial compensation for the services and loan payment or forgiveness option were the top strategies suggested to enhance interest among residents for training in the subspecialty. One third (37%) felt that reducing the duration of the fellowship to 2 years would increase interest in training in pediatric endocrinology. CONCLUSION: The pediatric endocrinologists reported overall excellent career satisfaction, indicating the potential to attract high-quality doctors to the specialty. Improving reimbursement and loan forgiveness were the top strategies suggested for increasing interest in subspecialty training in pediatric endocrinology.

Vasopressin-Dependent Disorders: What Is New in Children?

Arginine vasopressin (AVP)-mediated osmoregulatory disorders, such as diabetes insipidus (DI) and syndrome of inappropriate secretion of antidiuretic hormone (SIADH) are common in the differential diagnosis for children with hypo- and hypernatremia and require timely recognition and treatment. DI is caused by a failure to concentrate urine secondary to impaired production of or response to AVP, resulting in hypernatremia. Newer methods of diagnosing DI include measuring copeptin levels; copeptin is AVP's chaperone protein and serves as a surrogate biomarker of AVP secretion. Intraoperative copeptin levels may also help predict the risk for developing DI after neurosurgical procedures. Copeptin levels hold diagnostic promise in other pediatric conditions, too. Recently, expanded genotype and phenotype correlations in inherited DI disorders have been described and may better predict the clinical course in affected children and infants. Similarly, newer formulations of synthetic AVP may improve pediatric DI treatment. In contrast to DI, SIADH, characterized by inappropriate AVP secretion, commonly leads to severe hyponatremia. Contemporary methods aid clinicians in distinguishing SIADH from other hyponatremic conditions, particularly cerebral salt wasting. Further research on the efficacy of therapies for pediatric SIADH is needed, although some adult treatments hold promise for pediatrics. Lastly, expansion of home point-of-care sodium testing may transform management of SIADH and DI in children. In this article, we review recent developments in the understanding of pathophysiology, diagnostic workup, and treatment of better outcomes and quality of life for children with these challenging disorders.

Brain functions and cognition on transient insulin deprivation in type 1 diabetes.

BACKGROUNDType 1 diabetes (T1D) is a risk factor for dementia and structural brain changes. It remains to be determined whether transient insulin deprivation that frequently occurs in insulin-treated individuals with T1D alters brain function.METHODSWe therefore performed functional and structural magnetic resonance imaging, magnetic resonance spectroscopy, and neuropsychological testing at baseline and following 5.4 ± 0.6 hours of insulin deprivation in 14 individuals with T1D and compared results with those from 14 age-, sex-, and BMI-matched nondiabetic (ND) participants with no interventions.RESULTSInsulin deprivation in T1D increased blood glucose, and ß-hydroxybutyrate, while reducing bicarbonate levels. Participants with T1D showed lower baseline brain N-acetyl aspartate and myo-inositol levels but higher cortical fractional anisotropy, suggesting unhealthy neurons and brain microstructure. Although cognitive functions did not differ between participants with T1D and ND participants at baseline, significant changes in fine motor speed as well as attention and short-term memory occurred following insulin deprivation in participants with T1D. Insulin deprivation also reduced brain adenosine triphosphate levels and altered the phosphocreatine/adenosine triphosphate ratio. Baseline differences in functional connectivity in brain regions between participants with T1D and ND participants were noted, and on insulin deprivation further alterations in functional connectivity between regions, especially cortical and hippocampus-caudate regions, were observed. These alterations in functional connectivity correlated to brain metabolites and to changes in cognition.CONCLUSIONTransient insulin deprivation therefore caused alterations in executive aspects of cognitive function concurrent with functional connectivity between memory regions and the sensory cortex. These findings have important clinical implications, as many patients with T1D inadvertently have periods of transient insulin deprivation.TRIAL REGISTRATIONClinicalTrials.gov NCT03392441.FUNDINGClinical and Translational Science Award (UL1 TR002377) from the National Center for Advancing Translational Science; NIH grants (R21 AG60139 and R01 AG62859); the Mayo Foundation.

PANCYTOPENIA SECONDARY TO AUTOIMMUNE VITAMIN B12 DEFICIENCY IN GRAVES DISEASE.

OBJECTIVE: To describe a case of Graves disease (GD) and coexistent pancytopenia associated with autoimmune vitamin B12 deficiency. While thyrotoxicosis and antithyroid drugs can cause pancytopenia, other autoimmune conditions such as vitamin B12 deficiency can occur, leading to severe anemia and pancytopenia. METHODS: A 19-year-old female with GD treated with methimazole presented with thyrotoxicosis and evidence of pancytopenia. Diagnostic studies included a complete blood cell count, peripheral blood smears, thyroid function tests, and a bone marrow biopsy. RESULTS: White blood cells were 2.4 × 109 cells/L (reference range [RR] is 3.4 to 9.6 × 109 cells/L), hemoglobin was 7.9 g/dL (RR is 11.6 to 15.0 g/dL), neutrophil count was 1.2 × 109 cells/L, and platelets were 84 × 109 cells/L (RR is 157 to 371 × 109 cells/L). Thyroid-stimulating hormone was <0.01 mIU/L (RR is 0.50 to 4.30 mIU/L), free thyroxine was 3.7 ng/dL (RR is 1.0 to 1.6 ng/dL), and total triiodothyronine was 221 ng/dL (RR is 91 to 218 ng/dL). Due to suspicion for drug-induced pancytopenia, methimazole was discontinued. Three days later, she was hospitalized for a syncopal episode with a further decline in hemoglobin to 6.7 g/dL, neutrophils to 0.68 × 109 cells/L, and platelets to 69 × 109 cells/L. Bone marrow biopsy findings showing marrow hypercellularity and hypersegmented neutrophils suggested vitamin B12 deficiency. Vitamin B12 was <70 ng/L (RR is 180 to 914 ng/L). Intramuscular vitamin B12 injections were initiated, and pancytopenia resolved within 1 month. CONCLUSION: Although rarely described in the literature, autoimmune vitamin B12 deficiency can be missed as an underlying etiology for pancytopenia in patients with GD. The clinical picture can be further confounded when these patients are treated with antithyroid drugs known to cause bone marrow suppression.

A community-based study of demographics, medical and psychiatric conditions, and gender dysphoria/incongruence treatment in transgender/gender diverse individuals.

BACKGROUND: Current understanding about health care in the gender diverse population is limited by the lack of community-based, longitudinal data, especially in the USA. We sought to characterize a community-based cohort of transgender individuals including demographics, gender identities, social characteristics, psychiatric and medical conditions, and medical therapy for gender dysphoria/incongruence. PATIENTS AND METHODS: We performed a retrospective chart review of gender diverse residents of Olmsted County, Minnesota, who sought gender-specific healthcare from January 1, 1974, through December 31, 2015, using an infrastructure that links medical records of Olmsted County residents from multiple institutions. RESULTS: The number of patients seeking gender-specific healthcare increased from 1 to 2 per 5-year interval during the 1970s-1990s to 41 from 2011 to 2015 (n = 82). Forty-nine (59.8%) were assigned male sex at birth (AMAB), 31 (37.8%) were assigned female (AFAB), and 2 (2.4%) were intersex. Gender identities evolved over time in 16.3% and 16.1% of patients AMAB and AFAB, respectively, and at most recent follow-up, 8.2% and 12.9% of patients AMAB and AFAB, respectively, were non-binary. Depression affected 78%, followed by anxiety (62.2%), personality disorder (22%), and post-traumatic stress disorder (14.6%). 58.5% experienced suicidal ideation, 22% attempted suicide, and 36.6% were victims of abuse. The most prevalent medical conditions and cardiovascular (CV) risk factors included obesity (42.7%), tobacco use (40.2%), fracture [34.1% (86.2% traumatic)], hypertension (25.6%), hyperlipidemia (25.6%), and hypertriglyceridemia (15.9%). 67.3% of patients AMAB used feminizing and 48.4% of patients AFAB used masculinizing hormone therapy. When compared to US CDC National Health Statistics, there was a significantly greater prevalence of depression and anxiety but no difference in the prevalence of obesity, hypertension, hypercholesterolemia, type 2 diabetes, or stroke. CONCLUSION: Transgender and gender diverse individuals represent a population who express various gender identities and are seeking gender-specific healthcare at increasing rates. Psychiatric illness is highly prevalent compared to the US population but there is no difference in the prevalence of CV risk factors including obesity, type 2 diabetes, hypertension, and dyslipidemia.

Use of Copeptin Levels to Predict the Resolution of Transient Postoperative SIADH.

BACKGROUND: Copeptin levels reflect vasopressin activity and help classify osmoregulatory disorders. There is limited pediatric experience using copeptin to diagnose and manage diabetes insipidus, syndrome of inappropriate antidiuretic hormone secretion (SIADH), and bi- or tri-phasic postsurgical osmoregulatory disorders. In this report, we describe serial copeptin levels in an infant who developed transient SIADH after neurosurgery. CASE DESCRIPTION: A 4-month-old infant with no prior pituitary dysfunction underwent endoscopic fenestration of a large arachnoid cyst (3.5 × 4.7 × 3.8 cm). He developed SIADH on postoperative day 4 with seizures, hyponatremia (sodium 121 mmol/L), and concentrated urine (535 mOsm/kg). His initial copeptin level was inappropriately high in the context of his hyponatremia. Copeptin levels decreased as his SIADH resolved. Serial copeptin levels correlated to the infant's increased ability to dilute urine. CONCLUSION: Copeptin levels in this infant are consistent with levels described in adults and older children. Obtaining copeptin levels may improve providers' ability to quickly diagnose and manage SIADH amongst other heterogeneous causes of hyponatremia. Lastly, trending copeptin levels improved providers' ability to monitor SIADH progression, and may allow preemptive fluid titration for children with bi- or tri-phasic shifts in osmoregulation after neurological procedures.

Pediatric applications of Dotatate: early diagnostic and therapeutic experience.

In recent years, new somatostatin receptor agents (SSTRs) have become available for diagnostic imaging and therapy in neuroendocrine tumors. The novel SSTR ligand DOTA-DPhel-Tyr3-octreotate (Dotatate) in particular can be linked with 68Gallium for diagnostic imaging purposes, and with the ß-emitter 177Lutetium for radiotherapy in the setting of neuroendocrine tumors. Dotatate imaging offers distinct advantages in the evaluation of neuroendocrine tumors compared to standard techniques, including greater target-to-background ratio and lesion conspicuity, high sensitivity/specificity, improved spatial resolution with positron emission tomography (PET)/CT or PET/MR, and decreased radiation exposure. Although currently off-label in pediatrics, Dotatate theranostics in children are being explored, most notably in the setting of neuroblastoma and hereditary neuroendocrine syndromes. This article provides a multicenter case series of Dotatate imaging and therapy in pediatric patients in order to highlight the spectrum of potential clinical applications.

Bilateral pheochromocytoma: Clinical characteristics, treatment and longitudinal follow-up.

OBJECTIVE: Comprehensive data about patients with bilateral pheochromocytoma are limited. We aimed to describe the clinical presentation, genetic analysis, treatment and outcomes of patients with bilateral pheochromocytoma. DESIGN: A retrospective study at a tertiary care centre. PATIENTS: All patients with bilateral pheochromocytoma evaluated at Mayo Clinic in Rochester, Minnesota between January 1951 and December 2015. MEASUREMENTS: Tumour size, genetic testing, plasma/urine metanephrines and catecholamines. RESULTS: A total of 94 patients (51% women) were diagnosed with bilateral pheochromocytoma at a median age at first presentation of 31 years (range, 4-70). Bilateral disease was noted in 8.0% of pheochromocytoma patient overall and 37.5% of patients 18 years of younger. Most patients presented with synchronous tumours (80%). Median time to metachronous tumours was 4.5 years (range, 1-38). Genetic disease was identified in 75 (80%) patients, including MEN 2A (42.6%), VHL (19.1%), MEN 2B (9.6%) and NF1 (8.5%). Excess catecholamines were present in 97% of patients. Patients with synchronous pheochromocytoma commonly underwent simultaneous bilateral adrenalectomy (99%), and 18 (24%) had cortical-sparing surgery. Multicentric tumours were reported in 23 of 77 (30%) patients with available data. Recurrent disease was found in 9.6% of patients, and 8.5% developed metastatic disease. Median follow-up was 8.5 years. At the study conclusion, 4 patients had died due to pheochromocytoma or adrenalectomy. CONCLUSIONS: Bilateral pheochromocytoma occurred in 7.0% of adults with pheochromocytoma and 37.5% of paediatric patients. Genetic disease was identified in 80% of patients, predominantly MEN2A. Multicentric tumours were common, but most were still cured following adrenalectomy.

Association of Adverse Childhood Experiences with Glycemic Control and Lipids in Children with Type 1 Diabetes.

Adverse childhood experiences (ACE) have been associated with a greater prevalence of risky behaviors and chronic health conditions, such as diabetes in adulthood. While adolescents with risk taking behaviors experience worsening of diabetic metabolic control, it is yet to be determined whether glycemic management in children and adolescents is negatively and independently influenced by ACEs. This study examines the relationship between ACEs in children and adolescents with type 1 diabetes (T1DM) and glycemic control, BMI and lipids. For such children, we hypothesized that hemoglobin A1c (HbA1c) is positively correlated with ACE scores. Parents of children (age 2-18 years) with T1DM completed a validated ACE questionnaire. The associations between parent and child ACE score and HbA1c, lipids and BMI z-scores were assessed using linear regression. The prevalence of any ACE was 27.9% among children and 49.0% among parents. HbA1c was significantly higher in children who had exposure to three or more ACEs (ß:0.63 (4.5 mmol/mol); p = 0.02), in those who had a parent exposed to four or more ACEs (ß:0.87 (7.2 mmol/mol); p = 0.03), in children who had exposure to household incarceration (ß:0.62 (4.4 mmol/mol); p = 0.05) and children who witnessed or had been victim of violence in the neighborhood (ß:0.71 (5.4 mmol/mol); p = 0.02). ACEs were highly prevalent among children with T1DM and had a positive association with glycemic control.

Association between mild hyperthyrotropinemia and hypercholesterolemia in children with severe obesity.

Background Severe obesity is associated with a number of cardiometabolic risk factors. Thyroid-stimulating hormone (TSH) levels are often slightly increased in children with obesity. The clinical significance of the mild elevation in TSH in children with obesity is unclear. Objective To examine the association between TSH and lipids in children with severe obesity. Methods We performed a retrospective analysis of records of children with severe obesity with simultaneous measurements of TSH and lipids. Children with TSH <0.3 mIU/L and ≥10 mIU/L were excluded. The relationship between TSH and lipids was evaluated using univariate/multiple variable linear and logistic regression. Results The study included 834 children (age 13.8 ± 4.1 years, males 46%, body mass index [BMI]: 36.9 ± 7.6 kg/m2; BMI z-score 2.6 ± 0.4). Seventy-four (8.9%) children had TSH between 5 and <10 mIU/L (high TSH [HTSH]). TSH was positively associated with non-high-density lipoprotein (HDL) cholesterol (ß: 1.74; 95% confidence interval [CI] 0.29-3.20, p = 0.02). Total cholesterol and non-HDL cholesterol were higher in males with HTSH compared to those with normal TSH (175.5 vs. 163.5 mg/dL, p = 0.02 and 133.7 vs. 121.4 mg/dL, p = 0.02, respectively). The odds of elevated non-HDL cholesterol (≥145 mg/dL) was higher in males with HTSH relative to those with normal TSH (odds ratio [OR]: 2.78; 95% CI 1.35-5.69, p = 0.005). Conclusions TSH levels were positively associated with non-HDL cholesterol in children with severe obesity. Males with mildly elevated TSH had higher total cholesterol and non-HDL cholesterol compared to males with normal TSH. Further studies are warranted to determine if levothyroxine therapy would result in improvement in total cholesterol or non-HDL cholesterol in children with severe obesity with mildly elevated TSH.

Patterns of amiodarone-induced thyroid dysfunction in infants and children.

BACKGROUND: Heart Rhythm Society guidelines recommend obtaining thyroid function tests (TFTs) at amiodarone initiation and every 6 months thereafter in adults, with no specific pediatric recommendations. Untreated hypothyroidism in young children negatively affects brain development and somatic growth, yet the optimal screening frequency for pediatric patients remains unclear, and limited data exist on pediatric amiodarone-induced thyroid dysfunction. OBJECTIVE: The purpose of this study was to describe the patterns of amiodarone-induced thyroid dysfunction in pediatric patients. METHODS: We established a retrospective cohort of 527 pediatric patients who received amiodarone between 1997 and 2017. We defined amiodarone therapy lasting 3-30 days as "short term" and >30 days as "long term." RESULTS: The final cohort (n = 150) consisted of 27 neonates (18%), 25 infants (16%), 27 young children (18%), and 71 children (47%). Of the children in whom TFTs were checked, half (50.8%) developed a thyroid-stimulating hormone (TSH) value above the reference for age. Neonates had the highest median peak TSH values in both short- and long-term groups: 23.5 mIU/L (interquartile range 11.4-63.1) and 28.8 mIU/L (interquartile range 11.4-34.4), respectively. Although concurrent use of inotropic support was significantly associated with lower initial TSH values, no variable related to cardiac illness or type of heart disease was associated with peak TSH values. CONCLUSION: Neonates and infants receiving amiodarone had more thyroid dysfunction with greater degrees of TSH elevation than older children. TSH elevations occurred early, even with short-term exposure. Given the concern for brain development and growth in hypothyroid children, our results suggest the need for more rigorous pediatric-specific thyroid monitoring guidelines.

Improved utilization of waist-to-height ratio in cardiometabolic risk counselling in children: Application of DMAIC strategy.

RATIONALE, AIMS, AND OBJECTIVES: Waist circumference (WC) and waist-to-height ratio (WHtR) are superior surrogate markers of central obesity than body mass index. However, WC is not measured routinely in paediatric clinics. The objective of this study was to implement measurement of WC during routine assessment of children in an ambulatory outpatient clinic setting and subsequent dissemination of cardiometabolic risk counselling in children with central obesity (defined as WHtR ≥0.5). METHOD: Prospective cohort of patients aged 6 to 20 years. Study period was divided into three phases: baseline (3 months), process improvement (2 months), and implementation (6 months). Define-Measure-Analyse-Improve-Control (DMAIC) strategy was applied. Measurement of WC was implemented as a component of the physical examination in patients. Outcome measures were (1) improvement in frequency of WC measurement and (2) utilization of WHtR in cardiometabolic risk counselling. RESULTS: Waist circumference was not measured in any patient during baseline phase (n = 551). During process improvement phase, of the total 347 patients, WC was measured in 35% vs target of 30%. In the implementation phase, WC was measured in 37% patients (365 out of 964). Of these 365 patients, 175 (48%) had elevated WHtR, and 73% of them (n = 128) were counselled about their increased cardiometabolic risk. CONCLUSIONS: Application of an evidence-based DMAIC protocol led to significant improvement in assessment for central obesity in an ambulatory clinic practice and appropriate counselling regarding cardiometabolic risk reduction in children and adolescents with central obesity over an 8-month period. Meticulous planning and execution, frequent reinforcement, and integrating feedback from the involved multi-disciplinary team were important factors in successful implementation of this quality improvement project.

Mild subclinical hypothyroidism is associated with paediatric dyslipidaemia.

BACKGROUND: There is a lack of consensus on the cardiometabolic consequences of mild subclinical hypothyroidism (SCH) among children. The objective of the current study was to compare lipid profiles in children with mild SCH with those of euthyroid children. STUDY DESIGN: Retrospective medical record review. PATIENTS: Children (ages 2-18 years) who had undergone simultaneous measurement of TSH, free thyroxine (T4) and lipids. Lipids in children with mild SCH (TSH 5-<10 mIU/L and normal free T4, n = 228) were compared with those in euthyroid children (n = 1215). RESULTS: TSH level was positively associated with total cholesterol and nonhigh density lipoprotein (non-HDL) cholesterol [ß 0.05(0.03-0.08), P < .0001 and ß 0.05(0.03-0.08), P < .0001, respectively]. Total cholesterol was significantly higher in children and adolescents with mild SCH compared with euthyroid children (4.43 ± 1.14 mmol/L vs 4.2 ± 0.85 mmol/L, P = .0005). Similarly, non-HDL cholesterol level was also higher in children with mild SCH relative to euthyroid children (3.08 ± 1.14 mmol/L vs 2.91 ± 0.8 mmol/L, P = .001). The adjusted odds ratio of having elevated total cholesterol and elevated non-HDL cholesterol was greater in children with mild SCH compared with euthyroid children (OR 1.88, 95% CI; 1.28-2.73; P = .001 and 1.72, 95% CI 1.2-2.5; P = .003, respectively). The presence of thyroid autoimmunity was not associated with higher rates of dyslipidaemia. CONCLUSIONS: Mild SCH in children and adolescents was associated with higher rates of elevated total cholesterol and elevated non-HDL cholesterol. Randomized placebo controlled studies are warranted to determine if treatment of mild SCH in children leads to improvement in lipid profile.