Congenital Hypothyroidism: Screening and Management.

ABSTRACT: Untreated congenital hypothyroidism (CH) leads to intellectual disabilities. Prompt diagnosis by newborn screening (NBS) leading to early and adequate treatment results in grossly normal neurocognitive outcomes in adulthood. However, NBS for hypothyroidism is not yet established in all countries globally. Seventy percent of neonates worldwide do not undergo NBS.The initial treatment of CH is levothyroxine, 10 to 15 mcg/kg daily. The goals of treatment are to maintain consistent euthyroidism with normal thyroid-stimulating hormone and free thyroxine in the upper half of the age-specific reference range during the first 3 years of life. Controversy remains regarding detection of thyroid dysfunction and optimal management of special populations, including preterm or low-birth weight infants and infants with transient or mild CH, trisomy 21, or central hypothyroidism.Newborn screening alone is not sufficient to prevent adverse outcomes from CH in a pediatric population. In addition to NBS, the management of CH requires timely confirmation of the diagnosis, accurate interpretation of thyroid function testing, effective treatment, and consistent follow-up. Physicians need to consider hypothyroidism in the face of clinical symptoms, even if NBS thyroid test results are normal. When clinical symptoms and signs of hypothyroidism are present (such as large posterior fontanelle, large tongue, umbilical hernia, prolonged jaundice, constipation, lethargy, and/or hypothermia), measurement of serum thyroid-stimulating hormone and free thyroxine is indicated, regardless of NBS results.

Congenital Hypothyroidism: Screening and Management.

Untreated congenital hypothyroidism (CH) leads to intellectual disabilities. Newborn screening (NBS) for CH should be performed in all infants. Prompt diagnosis by NBS leading to early and adequate treatment results in grossly normal neurocognitive outcomes in adulthood. However, NBS for hypothyroidism is not yet practiced in all countries globally. Seventy percent of neonates worldwide do not undergo NBS. The recommended initial treatment of CH is levothyroxine, 10 to 15 mcg/kg daily. The goals of treatment are to maintain consistent euthyroidism with normal thyroid-stimulating hormone and with free thyroxine in the upper half of the age-specific reference range during the first 3 years of life. Controversy remains regarding the detection of thyroid dysfunction and optimal management of special populations, including preterm or low-birth-weight infants and infants with transient or mild CH, trisomy 21, or central hypothyroidism. NBS alone is not sufficient to prevent adverse outcomes from CH in a pediatric population. In addition to NBS, the management of CH requires timely confirmation of the diagnosis, accurate interpretation of thyroid function testing, effective treatment, and consistent follow-up. Physicians need to consider hypothyroidism in the face of clinical symptoms, even if NBS thyroid test results are normal. When clinical symptoms and signs of hypothyroidism are present (such as large posterior fontanelle, large tongue, umbilical hernia, prolonged jaundice, constipation, lethargy, and/or hypothermia), measurement of serum thyroid-stimulating hormone and free thyroxine is indicated, regardless of NBS results.

Ultrasound determination of pediatric thyroid mass.

BACKGROUND: Radioiodine therapy for Graves disease can be achieved with dosing based on estimated thyroid gland mass. Thyroid mass can be estimated using linear ultrasound measurements, and conversion factors for volume and density. The choice of conversion factors could impact estimated thyroid mass and thus administered radioiodine dose. OBJECTIVE: The objective of this study was to define the relationship between thyroid mass estimated by ultrasound and measured thyroid mass following thyroidectomy. MATERIALS AND METHODS: This was a retrospective, exempt study that included patients < 18 years of age with < 6 months between thyroid ultrasound and thyroidectomy January 2010-June 2020. Thyroid dimensions by ultrasound, thyroid mass at thyroidectomy and histopathological diagnosis were collected. Published conversion factors were used to estimate thyroid volume with conversion to mass using a density of 1.05 g/cm3. Pearson correlations and Bland-Altman difference analyses were used to define the relationship between estimated mass and specimen weight. Linear regression was used to calculate an optimal conversion factor for estimating thyroid mass. RESULTS: We included 86 patients, 67 female (78%), with a mean age of 14.5 ± 3.15 years. Mass estimated using all tested conversion factors had similar strong, positive correlation with specimen weight (r = 0.95). The mean difference between thyroid mass estimated by ultrasound and measured mass ranged from - 0.34 g (conversion factor = 0.523) to 1.69 g (conversion factor = 0.554). The optimal simplified factor for estimation of thyroid mass for the study sample was 0.537. CONCLUSION: All published conversion factors for estimating thyroid mass based on linear ultrasound measurements produce good estimates of thyroid mass. Errors in estimated mass are less than 2 g on average.

Frequency and Severity of Hypothyroidism During TKI Therapy in the Pediatric and Young Adult Population.

Tyrosine kinase inhibitors that target vascular endothelial growth factor receptor [VEGFR-TKI] are a class of targeted therapies approved for treatment of several malignancies and are increasingly used in the pediatric population. Development of hypothyroidism during VEGFR-TKI therapy is well described in adults; however, there are no available data in children. Importantly, hypothyroidism during childhood can negatively impact growth and neurodevelopment. This retrospective study is the first to document frequency and severity of VEGFR-TKI induced hypothyroidism in pediatric and young adult patients. Patients included were ≤25 years of age and treated with at least one VEGFR-TKI between 2010 and 2018 at Cincinnati Children's Hospital Medical Center. After review of clinical and demographic data, 69 patients were identified. Of these, 19 (27.5%) developed thyroid dysfunction defined as Thyroid-stimulating hormone≥5 mIU/mL during therapy. Twelve of those patients had overt hypothyroidism with documentation of low free thyroxine and/or levothyroxine initiation. Mean exposure time to VEGFR-TKI before thyroid dysfunction was 2.8 (0.5-10.4) months. These results suggest moderate risk of developing thyroid dysfunction during VEGFR-TKI therapy in pediatric and young adult patients. Baseline thyroid hormone screening should be performed and repeated frequently during the first year of therapy in the pediatric population.

Utility of Continuous Glucose Monitoring vs Meal Study in Detecting Hypoglycemia After Gastric Bypass.

CONTEXT: Gastric bypass (GB) increases postprandial glucose excursion, which in turn can predispose to the late complication of hypoglycemia. Diagnosis remains challenging and requires documentation of symptoms associated with low glucose and relief of symptom when glucose is normalized (Whipple triad). OBJECTIVE: To compare the yield of mixed meal test (MMT) and continuous glucose monitoring system (CGMS) in detecting hypoglycemia after GB. SETTING: The study was conducted at General Clinical Research Unit, Cincinnati Children's Hospital (Cincinnati, OH, USA). METHODS: Glucose profiles were evaluated in 15 patients with documented recurrent clinical hypoglycemia after GB, 8 matched asymptomatic GB subjects, and 9 healthy weight-matched nonoperated controls using MMT in a control setting and CGMS under free-living conditions. RESULTS: Patients with prior GB had larger glucose variability during both MMT and CGMS when compared with nonsurgical controls regardless of their hypoglycemic status. Sensitivity (71 vs 47%) and specificity (100 vs 88%) of MMT in detecting hypoglycemia was superior to CGMS. CONCLUSIONS: Our findings indicate that a fixed carbohydrate ingestion during MMT is a more reliable test to diagnose GB-related hypoglycemia compared with CGMS during free-living state.

Primary thyroid dysfunction after single intravenous iodinated contrast exposure in young children: a propensity score matched analysis.

BACKGROUND: Data suggest an increased risk of thyroid dysfunction following iodine-based contrast material (IBCM) in children. OBJECTIVE: To estimate the prevalence of thyroid stimulating hormone (TSH) abnormalities following exposure to a single dose of intravenous IBCM during computed tomography (CT) in young children. MATERIALS AND METHODS: Inpatients ≤24 months of age who underwent a single CT with intravenous IBCM (exposed cohort) or abdominal ultrasound (US) (unexposed cohort) examination and had a TSH value obtained within 90 days after imaging between January 2009 to November 2018 were identified. Propensity score matching with 20 variables was performed. Primary thyroid dysfunction was defined by abnormally high or low TSH value. Multivariable logistic regression identified risk factors, including intravenous IBCM, for thyroid dysfunction. RESULTS: From the eligible 4,215 imaging examinations, 114 unique patients were included in the propensity matched population (n=57 per group). Thyroid dysfunction was identified in 14% (8/57) and 7% (4/57) of the IBCM-exposed and IBCM-unexposed cohorts, respectively. No patient in either cohort was started on thyroid hormone supplementation within the 3 months after imaging. Intravenous IBCM exposure was not a significant predictor of thyroid dysfunction on univariable (odds ratio [OR]=2.16, 95% confidence interval [CI]=0.61-7.64, P=0.23) or multivariable (OR=2.61, 95% CI=0.65-10.55, P=0.18) analyses. Significant independent predictors of post-imaging thyroid dysfunction included height (OR=1.25, P=0.0095) and trisomy 21 (OR=4.04, P=0.019). CONCLUSION: Hospitalized children ≤24 months of age who received a single dose of intravenous IBCM for CT examination had a similar prevalence of TSH abnormalities compared to a propensity score matched group who underwent abdominal US. One dose of intravenous IBCM likely does not cause prolonged TSH abnormalities; however, larger studies are needed.

Improving Malignancy Prediction in AUS/FLUS Pediatric Thyroid Nodules with the Aid of Ultrasound.

INTRODUCTION: The standard workup of thyroid nodules concerning for malignancy includes fine-needle aspiration (FNA). In 2015, the American Thyroid Association (ATA) guidelines for the management of pediatric thyroid nodules recommended that all nodules with a Bethesda III cytology undergo surgical resection. OBJECTIVES: To correlate a Bethesda III cytology with histologic and clinical outcomes to determine the relevance of the ATA recommendations, and to evaluate whether Thyroid Imaging Reporting and Data System (TI-RADS) scoring could identify Bethesda III nodules at a lower risk of malignancy. METHODS: A retrospective chart review of patients who had undergone thyroid nodule FNA from 2008 to 2018 was performed. Malignancy rates were determined for each Bethesda category. The reference standard was histopathology or 2-year follow-up of imaging outcomes for nonoperative cases. Ultrasound exams of Bethesda III nodules were reviewed and TI-RADS scores assigned. RESULTS: A total of 143 FNA samples from 128 patients were identified. The mean age was 14.9 years (range 7-22). Twenty-two (15%) of the FNA samples were Bethesda III; the malignancy rate was 38%. A TI-RADS score was assigned in 20 of the 22 Bethesda III nodules. ROC analysis found an optimal cut-off for malignancy prediction of ≥7 points (risk category TR5). The negative predictive value was 85.7% (95% CI 35.9-99.6) and the positive predictive value was 83.3% (95% CI 57.2-98.2). CONCLUSION: Although, at baseline, thyroid nodules with a Bethesda III classification carry a moderate risk of malignancy in the pediatric population, TI-RADS scoring can identify nodules with a lower risk within this group. If validated by larger studies, this can inform decision making and reduce unneeded surgery.

Differentiated Thyroid Cancer in the Pediatric/Adolescent Population: Evolution of Treatment.

Differentiated thyroid cancer (DTC) is the most common cancer in adolescents and young adults. In 2015, the American Thyroid Association published guidelines for management of pediatric DTC. We report our institutional experience and highlight changing practices and new opportunities. A retrospective analysis of all patients diagnosed with DTC from 2001 to 2016 was performed. Among 59 eligible patients, 31 (53%), 15 (25%), and 13 (22%) had low-risk, intermediate-risk, and high-risk disease, respectively. Half (15/31) of low-risk and all intermediate-risk/high-risk patients received radioactive iodine (I-131) ablation. For low-risk patients, average I-131 dose decreased from 80 to 42.05 mCi, and the percentage of patients who received I-131 decreased over time. Eleven of 16 patients with tumor genomic data were found to have somatic targetable (n=6) or germline (n=5) mutations. Persistent/recurrent disease was only present in high-risk (n=8) and intermediate-risk (n=1) patients. Two patients with iodine-refractory disease received trametinib to enhance radioiodine uptake. All patients were alive at follow-up (median, 5 y; range, 1 to 15 y). Coincident with the recent American Thyroid Association guidelines, the use of I-131 in low-risk patients has decreased over time in our practice. Tumor sequencing and cancer genetic evaluation may help redefine opportunities for treatment of high-risk patients and family counseling.

Complexities of gender assignment in 17ß-hydroxysteroid dehydrogenase type 3 deficiency: is there a role for early orchiectomy?

BACKGROUND: 17ß-Hydroxysteroid dehydrogenase type-3 (17ßHSD-3) deficiency is a rare cause of 46,XY disorders of sex development. The enzyme converts androstenedione to testosterone, necessary for masculinization of male genitalia in utero. 17ßHSD-3 deficiency is frequently diagnosed late, at puberty, following virilization, with consequent female-to-male gender reassignment in 39-64%. The decision for sex of rearing is difficult, especially if diagnosed in early childhood. Consensus guidelines are equivocal or support male gender assignment. Long-term outcomes data to guide decisions are also lacking; however, in the few cases of early diagnosis and orchiectomy, female gender retention appears more likely.We report two patients with 17ßHSD-3 deficiency, who presented at unusual ages, in whom female gender was chosen. We performed a focused literature review and summary of gender outcomes in 17ßHSD-3 deficiency following early orchiectomy. CASES: Patient A was a phenotypic female who presented at one year of age with bilateral inguinal hernias and external female genitalia. Testes were identified at surgery. The karyotype was 46,XY. She was initially diagnosed with complete androgen insensitivity syndrome; however, androgen receptor mutation analysis was negative. Human chorionic gonadotropin stimulation yielded a low testosterone: androstenedione ratio (0.6, normal >0.8). Genetic testing demonstrated compound heterozygosity for two known mutations of the HSD17B3 gene. She underwent bilateral orchiectomy at two years of age.Patient B was born with female genitalia and virilized at 13 years of age. She did not seek evaluation until 22 years of age. Her karyotype was 46,XY. She had bilateral inguinal testes and low testosterone: androstenedione ratio (0.3). HSD17B3 gene sequencing showed her to be a compound heterozygote for two known mutations. She identified herself as female and underwent bilateral orchiectomy and estrogen replacement therapy. CONCLUSIONS: These two patients highlight the complexities of diagnosis and management in 17ßHSD-3 deficiency. Although existing data are limited, early orchiectomy is likely to result in retention of female gender identity, avoiding the complications related to virilization in adolescence. As such, it is important to pursue a definitive diagnosis to guide clinical decisions, and to have the support and long term follow up with an inter-disciplinary disorders of sex development team.

Bariatric surgery for severe obesity in two adolescents with type 1 diabetes.

Bariatric surgery has been effective in treating type 2 diabetes mellitus (T2DM); it has not been used frequently in obese patients with type 1 diabetes mellitus (T1DM). This is the first case series reporting on the effect of bariatric surgery on diabetes control in adolescents with T1DM. Patient A is a 19-year-old obese man with T1DM who underwent vertical sleeve gastrectomy. At 12 months after surgery he demonstrated 28% reduction in BMI. His daily total insulin requirement had decreased; however, hemoglobin A1c remained primarily unchanged at 8.8%. Patient B is a 13-year-old obese girl with an initial clinical diagnosis of T2DM controlled on only metformin. She underwent Roux-en-Y gastric bypass; at 1 month after surgery she presented in diabetic ketoacidosis and was found to have positive islet cell antibodies, which were also present before surgery. Her diagnosis was revised to T1DM, and she was started on insulin. By 28 months after surgery her BMI had decreased by 42%. Since initiation of insulin, her daily total insulin requirement had decreased, but hemoglobin A1c had significantly worsened from 6.3% to 10%. We found that despite significant weight loss, improvements in cardiovascular risk factors (dyslipidemia and obstructive sleep apnea), and quality of life in our patients, bariatric surgery does not necessarily lead to improved glycemic control of T1DM. Patients with T1DM have ongoing dependency on exogenous insulin, and optimal glycemic control still depends on patient compliance with diabetes care.