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The integration of genomic testing into clinical care enables the use of individualized approaches to the management of rare diseases. We describe the use of belzutifan, a potent and selective small-molecule inhibitor of the protein hypoxia-inducible factor 2α (HIF2α), in a patient with polycythemia and multiple paragangliomas (the Pacak-Zhuang syndrome). The syndrome was caused in this patient by somatic mosaicism for an activating mutation in EPAS1. Treatment with belzutifan led to a rapid and sustained tumor response along with resolution of hypertension, headaches, and long-standing polycythemia. This case shows the application of a targeted therapy for the treatment of a patient with a rare tumor-predisposition syndrome. (Funded by the Morin Family Fund for Pediatric Cancer and Alex's Lemonade Stand Foundation.).

Ultrasound screening for thyroid cancer is recommended in familial adenomatous polyposis (FAP). This study investigated the prevalence of thyroid neoplasia in children with FAP.Cross-sectional study of children with FAP at an academic hospital. Clinical and ultrasound data were analyzed for the prevalence of thyroid nodules and cancer.Of 37 children with FAP, 8 (22%) had thyroid nodules and 2 (5%) had thyroid cancer. Nodules (30%) and cancer (9%) were more common among female subjects and rare among male subjects.Thyroid ultrasound screening in adolescence may benefit female subjects with FAP but has limited utility in male subjects.

Objective Surgical resection is recommended for cytologically indeterminate pediatric thyroid nodules due to their intermediate malignancy risk. We evaluated the utility of ultrasound characteristics for refining malignancy risk to inform the management of these nodules. Design Retrospective cohort study (2004–2019). Methods We analyzed consecutive thyroid nodules with indeterminate fine-needle aspiration cytology (Bethesda category III, IV, or V) in pediatric patients ( Results Eighty-seven cytologically indeterminate nodules were identified in 78 patients. Bethesda category was III in 56 nodules (64%), IV in 12 (14%), and V in 19 (22%). The malignancy rate was 46/87 (53%) overall, and 23/56 (41%), 8/12 (75%), and 15/19 (79%) in Bethesda III, IV, and V nodules, respectively. Malignancy rate was higher in solitary nodules (67% vs 37%, P = 0.004) and nodules with irregular margins (100% vs 44%, P < 0.001) or calcifications (82% vs 43%, P = 0.002). American College of Radiology Thyroid Imaging, Reporting and Data System (ACR TI-RADS) risk level TR5 was associated with a higher rate of malignancy than lower TI-RADS risk levels (80% vs 42%, P = 0.002). Within individual Bethesda categories, TI-RADS risk level was not associated with malignancy. No sonographic feature had a negative predictive value for malignancy greater than 80%. Conclusions In pediatric thyroid nodules with indeterminate cytology, some sonographic features – including higher ACR TI-RADS risk level – are associated with malignancy, but these associations are unlikely to alter clinical management in most cases.

On March 30, 2022, the U.S. FDA issued a drug safety communication recommending that infants and young children through 3 years of age undergo monitoring of thyroid function within 3 weeks of intravascular administration of iodine-based contrast media. This article considers the literature that was referenced for this decision and provides an outlook on thyroid monitoring after diagnostic imaging from pediatric radiology and pediatric endocrinology perspectives.

OBJECTIVES To provide a clinical disease state review of recent relevant literature and to generate expert consensus statements regarding the breadth of pediatric thyroid cancer diagnosis and care, with an emphasis on thyroid surgery. To generate expert statements to educate pediatric practitioners on the state-of-the-art practices and the value of surgical experience in the management of this unusual and challenging disease in children. METHODS A literature search was conducted and statements were constructed and subjected to a modified Delphi process to measure the consensus of the expert author panel. The wording of statements, voting tabulation, and statistical analysis were overseen by a Delphi expert (J.J.S.). RESULTS Twenty-five consensus statements were created and subjected to a modified Delphi analysis to measure the strength of consensus of the expert author panel. All statements reached a level of consensus, and the majority of statements reached the highest level of consensus. CONCLUSION Pediatric thyroid cancer has many unique nuances, such as bulky cervical adenopathy on presentation, an increased incidence of diffuse sclerosing variant, and a longer potential lifespan to endure potential complications from treatment. Complications can be a burden to parents and patients alike. We suggest that optimal outcomes and decreased morbidity will come from the use of advanced imaging, diagnostic testing, and neural monitoring of patients treated at high-volume centers by high-volume surgeons.

Objectives Graves’ disease (GD) is rare in children under age five years. Antithyroid drugs are typically first-line therapy but carry the risks of agranulocytosis and liver dysfunction. Case presentation A male infant with multiple congenital anomalies, left ventricular hypertrophy, and neurologic dysfunction developed GD at five months of life. The presence of chronic hepatitis complicated medical management. Potassium iodide was effective temporarily, but urgent thyroidectomy was required at nine months of age. Postoperatively, the patient developed a thyroid function pattern consistent with impaired pituitary sensitivity to thyroid hormone (TH) that responded to the addition of liothyronine. Exome sequencing revealed a heterozygous de novo duplication of the ATAD3 gene cluster, suggesting a possible mitochondrial disorder. Conclusions This case describes the youngest child to date to be diagnosed with endogenous GD and to successfully undergo definitive treatment with thyroidectomy. An underlying defect in mitochondrial function is suspected, suggesting a potential novel pathophysiologic link to early-onset thyroid autoimmunity. Additionally, this case illustrated the development of impaired pituitary sensitivity to TH following thyrotoxicosis of postnatal onset, which may contribute to our understanding of hypothalamic-pituitary-thyroid (HPT) axis development.

This cross-sectional study examines whether body mass index in children with thyroid nodules is associated with thyroid cancer and a greater likelihood of undergoing thyroid surgery.

Context Children with brain tumors may have pubertal onset at an inappropriately young chronologic age. Hypothalamic-pituitary irradiation ≥18Gy has been found to be a risk factor; age at irradiation is associated with pubertal timing. However, the underlying mechanisms are unknown. Objective To determine the impact of body mass index (BMI) and catch-up growth on pubertal timing in females treated for medulloblastoma and other embryonal tumors. Design, Setting, and Patients Retrospective cohort analysis of 90 female patients treated for medulloblastoma and other embryonal tumors at Dana-Farber Cancer Institute/Boston Children’s Hospital from 1996 to 2016. Eighteen individuals met inclusion criteria, with a mean ± SD follow-up period of 11.9 ± 3.4 years. Main Outcome Measures Multiple linear regression models for age at pubertal onset and bone age discrepancy from chronologic age at pubertal onset assessed the joint influences of age at irradiation, hypothalamic irradiation dose, undernutrition duration, BMI standard deviation score (SDS) at pubertal onset, and catch-up BMI SDS. Results The mean ± SD age of pubertal onset was 9.2 ± 1.3 years and hypothalamic radiation dose was 31.9 ± 9.9 Gy. There was a direct relationship between age at irradiation and age at pubertal onset (β = 0.323 ± 0.144 [standard error] year per year; P = 0.04) that was significantly attenuated after adjusting for BMI SDS at pubertal onset (P = 0.5) and catch-up BMI SDS (P = 0.08), suggesting that BMI is a mediator. Conclusions Both absolute and catch-up BMI SDS at pubertal onset are significant mediators of pubertal timing and bone age discrepancy in pediatric medulloblastoma and other embryonal tumors, and thus, are targetable risk factors to optimize pubertal timing.

Background The American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TI-RADS) is a recognized tool for management of thyroid nodules in adults but has not been validated in pediatric patients. Purpose To assess the performance of the ACR TI-RADS criteria for guiding decisions on whether to biopsy thyroid nodules in pediatric patients in a single referral center. Materials and Methods In this retrospective study, a database of thyroid nodules in patients younger than 19 years who underwent fine-needle aspiration (FNA) biopsy between January 2004 and July 2017 was analyzed. ACR TI-RADS criteria were applied to each nodule, and an ACR TI-RADS score was created to determine how the nodule would be managed. The number of nodules that would be biopsied with FNA on the basis of ACR TI-RADS was compared with the total number of nodules biopsied with FNA in this clinic to determine if the use of ACR TI-RADS would have changed the rate of FNA (eg, decreased the number of procedures) and whether that change would have affected the timely diagnosis of cancer. Results A total of 314 patients (mean age, 14.9 years; age range, 2-18 years; 28 prepubertal patients; 286 postpubertal patients; 260 female patients) were evaluated. In these 314 patients, 404 thyroid nodules were scored, of which 19.1% (77 of 404) were malignant. Most cancers were papillary carcinoma (68 [88.3%] of 77). The use of ACR TI-RADS criteria for management of nodules in this pediatric study sample would have resulted in 17 (22.1%) of 77 cancers being missed at the patient's initial visit. Conclusion Use of the current American College of Radiology Thyroid Imaging Reporting and Data System criteria for management of pediatric thyroid nodules is inadequate because a high percentage of cancers would be missed at the initial encounter. © RSNA, 2019.

Thyroid cancer is rare in children but its incidence is increasing. Recent data have clarified important similarities and differences between thyroid cancers originating in childhood and in adulthood. The genetic drivers of pediatric thyroid cancers are similar to those in adult tumors but comprise more gene fusions and fewer point mutations. Clinically, despite frequent metastatic spread, pediatric thyroid cancer has an excellent prognosis and mortality is rare. Therefore, treatment approaches must weigh carefully the morbidity of thyroid cancer treatments against their benefits. Current key questions include which children require total thyroidectomy rather than more limited-and safer-lobectomy, and in which children does the benefit of radioactive iodine therapy outweigh its risk of inducing a secondary malignancy. Finally, molecular therapies targeting genetic drivers of thyroid cancer now provide effective treatment for children with progressive, radioiodine-refractory disease, as well as opportunities to explore novel neoadjuvant uses that facilitate therapeutic surgery or radioactive iodine.

Medullary thyroid carcinoma (MTC) is most commonly associated with RET gene mutations. ALK fusions have rarely been described, although not previously in pediatrics and not previously partnered wit...

Thyroid nodules with atypia of undetermined significance (AUS) are challenging to manage because of their intermediate risk of malignancy. Subclassification of atypia can refine malignancy risk in adult AUS nodules but has not been evaluated in children.This was a retrospective cohort study of pediatric patients (19 years old) who underwent fine-needle aspiration (FNA) of a thyroid nodule with resulting AUS cytology. Atypia was subclassified as nuclear only, architectural only, nuclear and architectural, or oncocytic. The primary outcome was the association between atypia subtype and malignancy. A secondary outcome was the association of atypia subtype with repeat FNA cytology.Sixty-eight AUS nodules in 61 patients were analyzed. The median age at FNA was 16.2 years (range, 9.8-18.9 years). Twenty-four nodules (35%) were malignant. Nuclear atypia only was present in 17 nodules (25%), architectural atypia only was present in 27 nodules (40%), nuclear and architectural atypia was present in 20 nodules (29%), and predominantly oncocytic features were present in 4 nodules (6%). The presence of nuclear atypia was associated with a significantly increased rate of malignancy (22 of 37 [59%] vs 2 of 31 [6.5%]; P.001), whereas architectural atypia was not associated with malignancy (P = .8). Repeat FNA was performed in 42 of 68 nodules (62%). In nodules with initial nuclear and architectural atypia, benign repeat cytology had a high false-negative rate (3 of 6; 50%).Pediatric AUS nodules with nuclear atypia have a high rate of malignancy, but architectural atypia is not associated with malignancy. In nodules with nuclear atypia, repeat FNA may inform clinical decisions regarding the need for resection. In the absence of suspicious clinical features, nodules without nuclear atypia might be considered for observation rather than resection or repeat FNA.

Background: The Bethesda System for Reporting Thyroid Cytopathology (BSRTC) is used to interpret fine-needle aspiration (FNA) cytology of thyroid nodules in children and adults. Nodule management is guided by the implied malignancy risk of each cytological category, which has been derived from adult populations. Whether these implied risks are applicable to pediatric thyroid nodules remains uncertain. We compared malignancy rates between pediatric and adult thyroid nodules within each cytological category. Methods: We evaluated consecutive thyroid nodules ≥1 cm that underwent FNA at the Boston Children's Hospital and Brigham and Women's Hospital from 1998 to 2016. All cytology was interpreted by a single cytopathology group according to the BSRTC. Malignancy rates were compared between pediatric (

Thyroid hormones have long been known to have a range of effects on the cardiovascular system. However, significant knowledge gaps exist concerning the precise molecular and biochemical mechanisms governing these effects and the optimal strategies for management of abnormalities in thyroid function in patients with and without preexisting cardiovascular disease. In September 2017, the National Heart, Lung, and Blood Institute convened a Working Group with the goal of developing priorities for future scientific research relating thyroid dysfunction to the progression of cardiovascular disease. The Working Group reviewed and discussed the roles of normal thyroid physiology, the consequences of thyroid dysfunction, and the effects of therapy in 3 cardiovascular areas: cardiac electrophysiology and arrhythmias, the vasculature and atherosclerosis, and the myocardium and heart failure. This report describes the current state of the field, outlines barriers and challenges to progress, and proposes research opportunities to advance the field, including strategies for leveraging novel approaches using omics and big data. The Working Group recommended research in 3 broad areas: (1) investigation into the fundamental biology relating thyroid dysfunction to the development of cardiovascular disease and into the identification of novel biomarkers of thyroid hormone action in cardiovascular tissues; (2) studies that define subgroups of patients with thyroid dysfunction amenable to specific preventive strategies and interventional therapies related to cardiovascular disease; and (3) clinical trials focused on improvement in cardiovascular performance and cardiovascular outcomes through treatment with thyroid hormone or thyromimetic drugs.

Objectives To provide a clinical disease state review of recent relevant literature and to generate expert consensus statements regarding the breadth of pediatric thyroid cancer diagnosis and care, with an emphasis on thyroid surgery. To generate expert statements to educate pediatric practitioners on the state-of-the-art practices and the value of surgical experience in the management of this unusual and challenging disease in children. Methods A literature search was conducted and statements were constructed and subjected to a modified Delphi process to measure the consensus of the expert author panel. The wording of statements, voting tabulation, and statistical analysis were overseen by a Delphi expert (J.J.S.). Results Twenty-five consensus statements were created and subjected to a modified Delphi analysis to measure the strength of consensus of the expert author panel. All statements reached a level of consensus, and the majority of statements reached the highest level of consensus. Conclusion Pediatric thyroid cancer has many unique nuances, such as bulky cervical adenopathy on presentation, an increased incidence of diffuse sclerosing variant, and a longer potential lifespan to endure potential complications from treatment. Complications can be a burden to parents and patients alike. We suggest that optimal outcomes and decreased morbidity will come from the use of advanced imaging, diagnostic testing, and neural monitoring of patients treated at high-volume centers by high-volume surgeons.

Context Thyroid function may be assessed in children before cardiac surgery because of concerns that hypothyroidism or thyrotoxicosis might adversely affect cardiac function perioperatively. However, the relationship between preoperative thyroid dysfunction and surgical outcomes is unknown. Objective Determine the relationship between preoperative thyroid dysfunction and outcomes of pediatric cardiac surgery. Methods Retrospective cohort study (January 2005 to July 2019). Setting Academic pediatric hospital. Patients All patients Main Outcome Measures Subjects were stratified by preoperative TSH concentration (mIU/L): low (10). Outcomes were compared among subjects with normal TSH (control) and each group with abnormal TSH concentrations. The primary outcome was 30-day mortality. Secondary outcomes included time to extubation, intensive care unit and hospital length of stay, and operative complications. Results Among 592 patients analyzed, preoperative TSH was low in 15 (2.5%), normal in 347 (58.6%), mildly high in 177 (29.9%), and moderately high in 53 (9.0%). Free thyroxine was measured in 77.4% of patients and was low in 0 to 4.4% of subjects, with no differences among TSH groups. Thirty-day mortality was similar among TSH groups. There were no differences in any secondary outcome between patients with abnormal TSH and patients with normal TSH. Conclusion Preoperative mild to moderate subclinical hypothyroidism was not associated with adverse postoperative outcomes in children undergoing cardiopulmonary bypass procedures.

Context Thyroid ultrasound screening is recommended in children with PTEN hamartoma tumor syndrome (PHTS) due to increased risk of thyroid neoplasia, but the natural history of thyroid disease in children with PHTS is unclear. Objective Determine the prevalence and natural history of thyroid disease in children with PHTS. Methods Retrospective cohort study (1998-2019) in an academic pediatric hospital of individuals with genetically confirmed PHTS diagnosed before age 19 years. Clinical, thyroid ultrasound, and laboratory characteristics are described. Primary outcomes were the prevalence of thyroid nodules ≥10 mm diameter and time course and risk factors for nodule development assessed by Cox regression analysis. Secondary outcomes included thyroid nodule requiring biopsy, other ultrasound findings, and prevalence of autoimmune thyroid disease. Results Among 64 subjects with PHTS, 50 underwent thyroid ultrasound. A thyroid nodule ≥10 mm was diagnosed in 22/50 (44%) subjects at median (range) age 13.3 (7.0-22.9) years. Nodules were diagnosed earlier in females than in males (10.8 [7.0-17.9] vs 14.2 [9.9-22.9] years, P = .009). In multivariate analysis, risk of thyroid nodules was significantly associated with female sex (hazard ratio 2.90, 95% CI 1.16-7.27, P = .02) and inversely associated with the presence of neurologic findings of PHTS (HR 0.27, 95% CI 0.10-0.69, P = .007). Abnormal-appearing lymph nodes with echogenic foci were observed by ultrasound in 20% of subjects, but these were not associated with malignancy. Autoimmune thyroid disease was present in 10/33 (30.3%) of subjects in whom it was assessed. Conclusion Thyroid disease is common in children with PHTS. This study supports current consensus recommendations for ultrasound screening.

Context Proteinuria can cause or exacerbate hypothyroidism, possibly due to urinary loss of protein-bound thyroid hormone. However, the precise relationship between proteinuria and hypothyroidism remains unclear. Objective This work aimed to determine the prevalence of hypothyroidism in patients with proteinuria and the relationship between hypothyroidism and degree of proteinuria. Design A retrospective cohort study was conducted from December 1979 to March 2015. Setting This study was conducted at a large academic hospital. Patients All paired samples of urine protein and serum thyrotropin (TSH), measured within 24 hours, were obtained from adults (age > 18 years) with at least one instance of urine protein greater than 0.2 g/day or mg/mg creatinine. Main Outcome Measures Samples were stratified by urine protein tertile. Mean TSH and risk of TSH elevation were compared among tertiles using analysis of covariance and generalized estimating equations controlled for age, sex, samples per patient, and levothyroxine treatment. Results A total of 2676 samples were identified from 2136 patients. Mean ± SE TSH (mIU/L) was increased in the highest tertile of urine protein (> 1.75g/day) compared to the lower 2 tertiles (2.09 ± 0.07 vs 1.59 ± 0.07, 1.59 ± 0.06, P 3.5g/day) to those with lesser proteinuria. Conclusion Hypothyroidism is common among adults with proteinuria, and the risk of hypothyroidism is directly related to the severity of proteinuria.

BACKGROUND: Disordered thyroid hormone transport, due to mutations in monocarboxylate transporter 8 (MCT8), is characterized by intellectual and motor disability due to cerebral hypothyroidism and chronic peripheral thyrotoxicosis. Phenotypic characteristics and natural history of MCT8 deficiency have not been systematically evaluated. METHODS: In this international, multicentre, study, retrospective data (2003 to 2019) from patients with MCT8 deficiency followed in 47 centres, was analysed. Our primary objectives were to determine neurocognitive outcomes and overall survival. We also assessed clinical parameters, including anthropometric characteristics, biochemical markers and neuroimaging findings. RESULTS: 151 subjects with 73 different MCT8 mutations were included. 21·2% (32/151) of patients died at a median age of 10·5 years (range 1·6-71·0), with main causes of mortality being pulmonary infection (18·8%) and sudden (cardiac) death (18·8%). Survival differed significantly between individuals who attained head control or not (log-rank test: p=0·002; hazard ratio 3·99 95%CI 1·89-8·76). The limited motor and cognitive abilities of patients did not improve with age. T3 concentrations were elevated in 95·1% (96/101) and total T4 concentrations were reduced in 89·5% (94/105) of patients. 71·1% (59/83) patients were underweight (

The present review summarizes recent advances in the diagnosis and management of patients with congenital hypothyroidism.Although most newborn screening strategies are designed to detect severe primary hypothyroidism that presents shortly after birth, some infants display a pattern of delayed TSH rise despite normal initial newborn screening. Recent studies suggest that delayed TSH rise may be more common and more severe than previously recognized. Although much less common than primary hypothyroidism, central congenital hypothyroidism is as likely to be of moderate or severe degree, which has implications for its detection and treatment. The discovery of new genetic causes of central congenital hypothyroidism, including the X-linked genes IGSF1, TBL1X, and IRS4, has begun to expand our understanding of thyroid axis regulation. Recent long-term data indicate that current treatment recommendations for congenital hypothyroidism result in grossly normal neurocognitive outcomes even in severely affected patients, and that overtreatment may not be as harmful as previously suspected. Liquid levothyroxine is now commercially available in the United States, but more studies are needed to determine optimal dosing using this formulation.Prompt identification and adequate treatment of patients with congenital hypothyroidism is critical to optimize outcomes. New information continues to accumulate about how to improve detection of congenital hypothyroidism in specific subgroups of infants (particularly those with delayed TSH rise and central hypothyroidism) and about treatment of patients with this disorder.

The incidence of nephrolithiasis continues to rise. Previously, we showed that a monogenic cause could be detected in 11.4% of individuals with adult-onset nephrolithiasis or nephrocalcinosis and in 16.7-20.8% of individuals with onset before 18 years of age, using gene panel sequencing of 30 genes known to cause nephrolithiasis/nephrocalcinosis. To overcome the limitations of panel sequencing, we utilized whole exome sequencing in 51 families, who presented before age 25 years with at least one renal stone or with a renal ultrasound finding of nephrocalcinosis to identify the underlying molecular genetic cause of disease. In 15 of 51 families, we detected a monogenic causative mutation by whole exome sequencing. A mutation in seven recessive genes ( AGXT, ATP6V1B1, CLDN16, CLDN19, GRHPR, SLC3A1, SLC12A1 ), in one dominant gene ( SLC9A3R1 ), and in one gene ( SLC34A1 ) with both recessive and dominant inheritance was detected. Seven of the 19 different mutations were not previously described as disease-causing. In one family, a causative mutation in one of 117 genes that may represent phenocopies of nephrolithiasis-causing genes was detected. In nine of 15 families, the genetic diagnosis may have specific implications for stone management and prevention. Several factors that correlated with the higher detection rate in our cohort were younger age at onset of nephrolithiasis/nephrocalcinosis, presence of multiple affected members in a family, and presence of consanguinity. Thus, we established whole exome sequencing as an efficient approach toward a molecular genetic diagnosis in individuals with nephrolithiasis/nephrocalcinosis who manifest before age 25 years.

Background: The thyroid hormone–inactivating enzyme type 3 deiodinase (D3) is induced during hypertrophic and ischemic cardiomyopathy, leading to a state of local cardiac hypothyroidism. Whether D3 induction occurs in dilated cardiomyopathy is unknown. Methods: This study characterized changes in cardiac D3 and thyroid hormone signaling in a transgenic model of progressive dilated cardiomyopathy (TG9 mice). Results: Cardiac D3 was dramatically induced 15-fold during the progression of dilated cardiomyopathy in TG9 mice. This D3 induction localized to cardiomyocytes and was associated with a decrease in myocardial thyroid hormone signaling. Conclusions: Cardiac D3 is induced in a mouse model of dilated cardiomyopathy, indicating that D3 induction may be a general response to diverse forms of cardiomyopathy.

Context Circulating thyroglobulin antibodies (TgAb) can confound measurement of serum thyroglobulin and impair thyroid cancer surveillance. Few data exist on the significance of TgAb in pediatric thyroid cancer. Objective To describe the prevalence, natural history, and clinical significance of TgAb in children with thyroid cancer. Design Retrospective cohort study. Setting Single academic pediatric center. Patients Seventy-three consecutive children (≤18 years) with nonmedullary thyroid cancer who had serum TgAb measured within 6 months after diagnosis. Main outcome measures Prevalence and natural history of TgAb; association of TgAb status and resolution with patient and disease characteristics. Results TgAb were detected in 41% of subjects (30 of 73) and were associated with lymph node metastasis (83% vs 53%, P = 0.01) but not distant metastasis. In patients with TgAb, resolution occurred in 44% (11 of 25) over a median follow-up of 3.8 years. Median time to clear TgAb was 10.7 months, and 10 of 11 patients who cleared (91%) did so within 2 years. Resolution of TgAb was associated with lower initial TgAb level (median 4.5 vs 76 normalized units, P = 0.003). TgAb positivity at diagnosis was not independently associated with persistent or recurrent disease (odds ratio 3.20, 95% confidence interval 0.95 to 10.80, P = 0.06). Conclusions TgAb are common at diagnosis in children with thyroid cancer but resolve in nearly half of patients within 1 to 2 years. TgAb are associated with the presence of lymph node metastasis at diagnosis, but the long-term prognostic significance remains to be determined.

Medullary thyroid carcinoma (MTC) is most commonly associated with

Objective: Acute suppurative thyroiditis (AST) is frequently caused by anatomic abnormalities, including branchial cleft cysts. Patients with AST are typically euthyroid, but thyrotoxicosis may occur. Thyroid antibodies are usually not present in AST. Our objective is to describe a teenage male who presented with concomitant suppurative thyroiditis and Graves disease (GD). Methods: We report a case of an infected left branchial cleft cyst with AST and concurrent GD in an adolescent male. Thyroid function tests and thyroid imaging were used for diagnostic evaluation, and the patient was managed with antibiotics, analgesia, and surgery. Results: A 17-year-old male with a history of an infected left fourth branchial cleft cyst presented with recurrence of neck pain, odynophagia, and fever. Serum labs showed thyrotoxicosis and elevated thyroid antibodies and inflammatory markers. Magnetic resonance imaging showed an abscess adjacent to the left thyroid lobe. Symptoms resolved after antibiotic therapy, but laboratory tests showed persistent subclinical thyrotoxicosis. Four months later, he underwent excision of the branchial cleft cyst and left thyroid lobe. Two months after surgery, evaluation showed overt thyrotoxicosis with laboratory tests confirming GD. Methimazole was initiated and thyroid function subsequently normalized. Conclusion: This patient manifested a rare coincidence of AST due to a branchial cleft cyst and autoimmune thyroid disease. Further studies are needed to determine if there is any relationship between AST and development of thyroid autoimmunity. Assessment of thyroid autoimmunity may be considered in patients with prior or recurrent AST.

The evaluation and management of hypothyroidism in children are similar to adults, but there are important differences based on the dependence on normal thyroid function for neurocognitive and physical development. In the pediatric population, hypothyroidism is frequently categorized as congenital or acquired hypothyroidism, depending on the age of presentation and the underlying etiology. The evaluation and management of children and adolescents with hypothyroidism are determined by the etiology as well as by the age at diagnosis, severity of the hypothyroidism, and the response to thyroid hormone replacement therapy. Children and adolescents require higher weight-based doses for thyroid hormone replacement than do adults, likely due to a shorter half-life of thyroxine (T4) and triiodothyronine (T3) in children, but weight-based dose requirements decrease as the child advances into adulthood. Multiple gaps in knowledge remains regarding how to optimize the treatment of hypothyroidism in pediatric patients, including (but not limited to) the selection of patients with subclinical hypothyroidism for treatment, and the potential benefit of combined LT3/LT4 therapy for patients with persistent symptoms and/or low T3 on LT4 monotherapy. The life-long impact on growth and development, and potentially on long-term cardiovascular and psychosocial health, are significant and highlight the importance of future prospective studies in pediatric patients to explore these areas of uncertainty.

Thyroid nodules are uncommon in children. Most pediatric thyroid nodules are benign, but the risk of malignancy is higher than in adults. Papillary thyroid carcinoma is the most common type of thyroid cancer in children, followed by follicular carcinoma. Risk factors for thyroid cancer in children include radiation exposure and certain genetic syndromes. The evaluation and management of pediatric thyroid nodules and cancer is similar to that in adults. While children frequently have more advanced disease at diagnosis than adults, their long-term prognosis is excellent. Medullary thyroid carcinoma is rare in children and usually occurs in the syndrome of multiple endocrine neoplasia type 2.

Nephrolithiasis, a condition in which urinary supersaturation leads to stone formation in the urinary system, affects about 5%-10% of individuals worldwide at some point in their lifetime and results in significant medical costs and morbidity. To date, mutations in more than 30 genes have been described as being associated with nephrolithiasis, and these mutations explain about 15% of kidney stone cases, suggesting that additional nephrolithiasis-associated genes remain to be discovered. To identify additional genes whose mutations are linked to nephrolithiasis, we performed targeted next- generation sequencing of 18 hypothesized candidate genes in 348 unrelated individuals with kidney stones. We detected biallelic mutations in SLC26A1 (solute carrier family 26 member 1) in two unrelated individuals with calcium oxalate kidney stones. We show by immunofluorescence, immunoblotting, and glycosylation analysis that the variant protein mimicking p.Thr185Met has defects in protein folding or trafficking. In addition, by measuring anion exchange activity of SLC26A1, we demonstrate that all the identified mutations in SLC26A1 result in decreased transporter activity. Our data identify SLC26A1 mutations as causing a recessive Mendelian form of nephrolithiasis.

Purpose To determine the relationship between demographic and sonographic characteristics of thyroid nodules and malignancy in a pediatric population. Materials and Methods All thyroid nodules in patients younger than 19 years that underwent ultrasound (US)-guided fine-needle aspiration biopsy between January 2004 and July 2017 were retrospectively identified. Age, sex, and background appearance of the thyroid gland were recorded for each patient, and sonographic characteristics and pathologic diagnosis were recorded for each nodule. Demographic and sonographic characteristics were assessed to determine which were associated with malignancy. Categorical and continuous variables and interobserver variability were assessed. Results A total of 404 nodules in 314 patients (82.8% female) (age range, 2-18 years; mean age, 14.9 years) were analyzed. A total of 77 nodules (19.1%) were malignant, the majority of which were papillary thyroid carcinoma (n = 68 [88.3%]). The likelihood of malignancy did not differ between boys and girls (27.8% vs 22.7%, P = .64), nor did it differ between prepubertal and pubertal patients (18.8% vs 19.1%, P.99). The cancer rate in patients with a solitary nodule was higher than that in patients with multiple nodules (29.4% vs 14.2%, P = .003). Sonographic characteristics associated with malignant nodules included larger size, solid parenchyma, taller-than-wide shape, presence of speckled calcifications, lack of a smooth margin, and presence of abnormal lymph nodes. Interobserver variability for assessment of sonographic characteristics ranged from moderate to very strong. Conclusion In children with thyroid nodules, solitary nodules, larger nodule size, solid parenchyma, taller-than-wide shape, speckled calcifications, irregular margins, and abnormal lymph nodes raise concern for malignancy.

CONTEXT: Most pediatric thyroid nodules are cytologically benign, but few data exist to guide treatment. OBJECTIVE: To describe the natural history and outcomes of cytologically benign, pediatric thyroid nodules. DESIGN: Cohort study. SETTING: Multidisciplinary thyroid clinic at an academic medical center. PATIENTS: Consecutive pediatric patients (≤18 years old) with cytologically benign thyroid nodules evaluated between 1998 and 2016. RESULTS: Cytologically benign nodules (N = 237) in 181 patients were followed by ultrasound (median follow-up, 3.4 years; range, 0.5 to 13.9 years) or to resection. Thyroid cancer was diagnosed in six nodules (2.5%), and all six patients were disease free after median follow-up of 4.9 years. Malignancy was more common in nodules >4 cm (15.4%; P = 0.037) or that grew during follow-up (6.0%; P = 0.048). The likelihood of nodule growth (±SE) was 15% ± 3%, 24% ± 4%, and 49% ± 10% at 6, 12, and 24 months, respectively. Among nodules >2 cm, those with ≥25% cystic content grew more slowly than nodules 4 cm, combined with surveillance of smaller nodules and repeated aspiration for growth, detects most false-negative results. Follow-up ultrasound in 12 months is appropriate for most cytologically benign pediatric nodules, but delaying surveillance up to 24 months may be reasonable in large, predominantly cystic nodules.

Congenital hypothyroidism is common and can cause severe neurodevelopmental morbidity. Prompt diagnosis and treatment are critical to optimizing long-term outcomes. Universal newborn screening is an important tool for detecting congenital hypothyroidism, but awareness of its limitations, repeated screening in high-risk infants, and a high index of clinical suspicion are needed to ensure that all affected infants are appropriately identified and treated. Careful evaluation will usually reveal the etiology of congenital hypothyroidism, which may inform treatment and prognosis. Early and adequate treatment with levothyroxine results in excellent neurodevelopmental outcomes for most patients with congenital hypothyroidism.

Nephrolithiasis is a prevalent condition with a high morbidity. Although dozens of monogenic causes have been identified, the fraction of single-gene disease has not been well studied. To determine the percentage of cases that can be molecularly explained by mutations in 1 of 30 known kidney stone genes, we conducted a high-throughput mutation analysis in a cohort of consecutively recruited patients from typical kidney stone clinics. The cohort comprised 272 genetically unresolved individuals (106 children and 166 adults) from 268 families with nephrolithiasis ( n =256) or isolated nephrocalcinosis ( n =16). We detected 50 likely causative mutations in 14 of 30 analyzed genes, leading to a molecular diagnosis in 14.9% (40 of 268) of all cases; 20 of 50 detected mutations were novel (40%). The cystinuria gene SLC7A9 ( n =19) was most frequently mutated. The percentage of monogenic cases was notably high in both the adult (11.4%) and pediatric cohorts (20.8%). Recessive causes were more frequent among children, whereas dominant disease occurred more abundantly in adults. Our study provides an in-depth analysis of monogenic causes of kidney stone disease. We suggest that knowledge of the molecular cause of nephrolithiasis and nephrocalcinosis may have practical implications and might facilitate personalized treatment.

Congenital hypothyroidism occurs in approximately 1 in 2000 newborns and can have devastating neurodevelopmental consequences if not detected and treated promptly. While newborn screening has virtually eradicated intellectual disability due to severe congenital hypothyroidism in the developed world, more stringent screening strategies have resulted in increased detection of mild congenital hypothyroidism. Recent studies provide conflicting evidence about the potential neurodevelopmental risks posed by mild congenital hypothyroidism, highlighting the need for additional research to further define what risks these patients face and whether they are likely to benefit from treatment. Moreover, while the apparent incidence of congenital hypothyroidism has increased in recent decades, the underlying cause remains obscure in most cases. However, ongoing research into genetic causes of congenital hypothyroidism continues to shed new light on the development and physiology of the hypothalamic-pituitary-thyroid axis. The identification of IGSF1 as a cause of central congenital hypothyroidism has uncovered potential new regulatory pathways in both pituitary thyrotropes and gonadotropes, while mounting evidence suggests that a significant proportion of primary congenital hypothyroidism may be caused by combinations of rare genetic variants in multiple genes involved in thyroid development and function. Much remains to be learned about the origins of this common disorder and about the optimal management of less severely-affected infants.

Type 1 diabetes mellitus (T1DM) is one of the most common chronic diseases in children and is frequently encountered in pediatric surgical practice. The annual incidence of diabetes in the United States is about 1/4000 children, but the worldwide incidence varies markedly by geographic location and ethnicity. Diabetes will be encountered frequently in pediatric surgical practice, and familiarity with the principles of its pathophysiology, treatment, and potential complications is critical for providing optimal surgical care to these patients. Surgery in patients with diabetes is associated with a variety of special considerations and risks. Perioperative care of these patients requires an understanding of the pathophysiology and current treatment of this disease, which are reviewed in this chapter. Surgical planning, preoperative evaluation, and intraoperative and postoperative management are discussed in detail, including principles of glycemic control, insulin management, and nutrition. Relevant acute and chronic complications of diabetes are also discussed.

Thyroid cancer is the most common endocrine malignancy, but due to its rare occurrence in the pediatric population, the cancer risk of childhood thyroid nodules is incompletely defined, and optimal management of children with suspected nodules is debated.The aim was to study the presenting features and cancer risk of sporadic childhood thyroid nodules using a standardized clinical assessment and management plan.Boston Children's Hospital and Brigham and Women's Hospital collaborated to create a multidisciplinary pediatric thyroid nodule clinic and implement a standardized assessment plan. Upon referral for a suspected nodule, serum TSH was measured and hypothyrotropinemic patients underwent (123)I scintigraphy. All others underwent thyroid ultrasonography, and if this confirmed nodule(s) ≥ 1 cm, ultrasound-guided fine-needle aspiration was performed. Medical records were retrospectively reviewed and compared to a control population of 2582 adults evaluated by identical methods.Of 300 consecutive children referred for the initial evaluation of suspected thyroid nodules from 1997 to 2011, 17 were diagnosed with autonomous nodules by scintigraphy. Neck ultrasonography performed in the remainder revealed that biopsy was unnecessary in over half, either by documenting only sub-centimeter nodules or showing that no nodule was present. A total of 125 children met criteria for thyroid biopsy, which was performed without complication. Their rate of cancer was 22%, significantly higher than the adult rate of 14% (P = .02).Neck ultrasonography and biopsy were key to the evaluation of children with suspected thyroid nodules. Although the relative cancer prevalence of sonographically confirmed nodules ≥ 1 cm is higher in pediatric patients than adults, most children referred for suspected nodules have benign conditions, and efforts to avoid unnecessary surgery in this majority are warranted.

Background and objectives Nephrolithiasis is a prevalent condition that affects 10%–15% of adults in their lifetime. It is associated with high morbidity due to colicky pain, the necessity for surgical intervention, and sometimes progression to CKD. In recent years, multiple monogenic causes of nephrolithiasis and nephrocalcinosis have been identified. However, the prevalence of each monogenic gene in a pediatric renal stone cohort has not yet been extensively studied. Design, setting, participants, & measurements To determine the percentage of cases that can be explained molecularly by mutations in one of 30 known nephrolithiasis/nephrocalcinosis genes, we conducted a high-throughput exon sequencing analysis in an international cohort of 143 individuals n =123) or isolated nephrocalcinosis ( n =20). Over 7 months, all eligible individuals at three renal stone clinics in the United States and Europe were approached for study participation. Results We detected likely causative mutations in 14 of 30 analyzed genes, leading to a molecular diagnosis in 16.8% (24 of 143) of affected individuals; 12 of the 27 detected mutations were not previously described as disease causing (44.4%). We observed that in our cohort all individuals with infantile manifestation of nephrolithiasis or nephrocalcinosis had causative mutations in recessive rather than dominant monogenic genes. In individuals who manifested later in life, causative mutations in dominant genes were more frequent. Conclusions We present the first exclusively pediatric cohort examined for monogenic causes of nephrolithiasis/nephrocalcinosis, and suggest that important therapeutic and preventative measures may result from mutational analysis in individuals with early manifestation of nephrolithiasis or nephrocalcinosis.

Objective Subcutaneous fat necrosis (SCFN) is a rare form of panniculitis in infants that generally occurs following birth trauma, meconium aspiration, or therapeutic cooling. Severe hypercalcaemia occurs in a subset of patients, but data on its presentation, management and outcomes are limited. This report details the clinical course and complications of infants treated for severe hypercalcaemia (peak serum calcium ≥3.0 mmol/L) due to SCFN. Design Chart review of all infants with SCFN seen at a single paediatric centre over a 13-year period. Patients Seven infants with SCFN developed severe hypercalcaemia, with median peak serum calcium 4.1 mmol/L (range 3.3–5.1). Results Severe hypercalcaemia occurred before 6 weeks of age, and was asymptomatic in 3/7 patients (43%). Most patients were treated with intravenous hydration, furosemide, glucocorticoids and low-calcium formula, which restored normocalcaemia in a median of 9 days (range 2–42). Fever developed during treatment in 4/7 infants (57%): two patients had bacterial infections and two had no infectious source identified. Nephrocalcinosis was present in 5/6 patients (83%) who were evaluated by renal ultrasound. Nephrocalcinosis failed to resolve in all cases over a median follow-up of 20 months (range 8–48), but no renal dysfunction was observed. Eosinophilia, which has not been reported previously in SCFN, was present in 6/7 patients (86%). Conclusions In this largest series to date of infants with severe hypercalcaemia due to SCFN, novel findings include the common occurrence of fever and a high incidence of persistent nephrocalcinosis without evidence of adverse renal outcomes.

In a retrospective analysis of childhood thyroid nodules, 18% were radiographic incidentalomas and 41% were discovered by a clinician's palpation; 40% were discovered by patients' families. The latter group had the largest nodules and highest rates of thyroid cancer metastasis, suggesting opportunities for earlier detection through annual well-child visits.

This review summarizes significant recent advances in the epidemiology, pathophysiology, and treatment of congenital hypothyroidism.The apparent incidence of congenital hypothyroidism has more than doubled in recent years because of several factors, including more inclusive diagnostic criteria, shifting demographics, and increasing survival of preterm infants. The greatest increase has occurred in mildly affected patients, many of whom have a eutopic thyroid gland. Congenital hypothyroidism may be transient or persistent, but the natural history cannot be predicted by severity at diagnosis. In premature infants, who are especially vulnerable to hypothyroidism, the rise in thyroid-stimulating hormone may be delayed and therefore detected only by routine follow-up screening. Recent studies of defects in thyroid hormone synthesis have focused on the role of mutations in the dual oxidase system and of a novel apical iodide transporter, anoctamin 1. Finally, emerging data suggest that exposure to excess thyroid hormone may be as harmful as hypothyroidism to long-term cognitive development.Although newborn screening has virtually eradicated mental retardation due to congenital hypothyroidism in parts of the world, new information continues to accumulate and new questions to arise about the diagnosis, physiology, and optimal management of this disorder.

Subcutaneous fat necrosis (SCFN) is a rare form of panniculitis in infants that generally occurs following birth trauma, meconium aspiration, or therapeutic cooling. Severe hypercalcaemia occurs in a subset of patients, but data on its presentation, management and outcomes are limited. This report details the clinical course and complications of infants treated for severe hypercalcaemia (peak serum calcium ≥3.0 mmol/L) due to SCFN.Chart review of all infants with SCFN seen at a single paediatric centre over a 13-year period.Seven infants with SCFN developed severe hypercalcaemia, with median peak serum calcium 4.1 mmol/L (range 3.3-5.1).Severe hypercalcaemia occurred before 6 weeks of age, and was asymptomatic in 3/7 patients (43%). Most patients were treated with intravenous hydration, furosemide, glucocorticoids and low-calcium formula, which restored normocalcaemia in a median of 9 days (range 2-42). Fever developed during treatment in 4/7 infants (57%): two patients had bacterial infections and two had no infectious source identified. Nephrocalcinosis was present in 5/6 patients (83%) who were evaluated by renal ultrasound. Nephrocalcinosis failed to resolve in all cases over a median follow-up of 20 months (range 8-48), but no renal dysfunction was observed. Eosinophilia, which has not been reported previously in SCFN, was present in 6/7 patients (86%).In this largest series to date of infants with severe hypercalcaemia due to SCFN, novel findings include the common occurrence of fever and a high incidence of persistent nephrocalcinosis without evidence of adverse renal outcomes.

Type 3 deiodinase (D3), the physiologic inactivator of thyroid hormones, is induced during tissue injury and regeneration. This has led to the hypotheses that D3 impacts injury tolerance by reducing local T3 signaling and contributes to the fall in serum triiodothyronine (T3) observed in up to 75% of sick patients (termed the low T3 syndrome). Here we show that a novel mutant mouse with hepatocyte-specific D3 deficiency has normal local responses to toxin-induced hepatonecrosis, including normal degrees of tissue necrosis and intact regeneration, but accelerated systemic recovery from illness-induced hypothyroxinemia and hypotriiodothyroninemia, demonstrating that peripheral D3 expression is a key modulator of the low T3 syndrome.

Evaluation of suspected endocrine pathology in newborn infants requires knowledge of the dynamic changes that characterize normal hormonal function in the neonatal period. This article reviews normal endocrine physiology as it pertains to common clinical scenarios encountered in neonatal surgical patients. Topics covered include thyroid and adrenal function as well as glucose and calcium metabolism.