Publications by authors named "Ari J Wassner"

41 Publications

Belzutifan, a Potent HIF2α Inhibitor, in the Pacak-Zhuang Syndrome.

N Engl J Med 2021 11;385(22):2059-2065

From the Departments of Pediatric Oncology (J.K., K.V.H., J.A.P., C.M.C., A.I., C.B.W., K.A.J., S.G.D.) and Medical Oncology (W.G.K.), Dana-Farber Cancer Institute, Harvard Medical School, the Divisions of Hematology and Oncology (J.K., J.A.P., M.M.H., K.A.J., S.G.D.) and Endocrinology (A.J.W.) and the Departments of Surgery (B.R.W.), Pathology (S.O.V.), and Radiology (S.D.V.), Boston Children's Hospital, Harvard Medical School, and the Manton Center for Orphan Disease Research and the Division of Genetics and Genomics, Boston Children's Hospital (J.A.M., J.L.) - all in Boston; Howard Hughes Medical Institute, Chevy Chase, MD (W.G.K.); and Merck, Kenilworth, NJ (R.F.P., N.J.Z.).

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 . 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.).
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http://dx.doi.org/10.1056/NEJMoa2110051DOI Listing
November 2021

Re: "The Use of the Bethesda System for Reporting Thyroid Cytopathology in Pediatric Thyroid Nodules: A Meta-Analysis" by Vuong

Thyroid 2021 09 26;31(9):1441. Epub 2021 Apr 26.

Thyroid Center, Boston Children's Hospital, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1089/thy.2021.0116DOI Listing
September 2021

Predictors of Bilateral Disease in Pediatric Differentiated Thyroid Cancer.

J Clin Endocrinol Metab 2021 09;106(10):e4242-e4250

Thyroid Center, Boston Children's Hospital, Boston, MA, USA.

Context: Total thyroidectomy is recommended for children with papillary thyroid carcinoma, partly because of a high prevalence of bilateral disease. Identifying characteristics that predict bilateral disease might identify candidates for more limited surgery.

Objective: Investigate associations of preoperative or histopathological characteristics with bilateral disease in children with differentiated thyroid cancer.

Methods: Retrospective cohort study (1998-2020) at 2 academic hospitals. Patients <19 years who underwent total thyroidectomy for differentiated thyroid cancer were included. Clinical, sonographic, and histopathological characteristics were evaluated. The presence of bilateral disease on histopathology was assessed by univariable analysis and multivariable logistic regression.

Results: One hundred and fifteen subjects were analyzed (90% with papillary carcinoma). Median (range) age at diagnosis was 15.0 (8.1-18.9) years. Bilateral disease was present in 47/115 subjects (41%). Bilateral disease was associated with solid parenchyma, calcifications, irregular margins, and abnormal lymph nodes detected by ultrasound, Bethesda class V/VI cytology, papillary histology, tumor multifocality in the primary lobe, extrathyroidal extension, lymphovascular invasion, and nodal metastases. In multivariable analysis, only multifocality in the primary lobe was independently associated with bilateral disease (OR 7.61, 95% CI 2.44-23.8, P < .001). Among clinically node-negative subjects with papillary carcinoma who did not have tumor multifocality in the primary lobe, bilateral disease was present in 5/32 (16%).

Conclusions: In children with differentiated thyroid cancer, tumor multifocality in the primary lobe is associated with bilateral disease and should prompt consideration of completion thyroidectomy after initial lobectomy. Clinically node-negative children with tumors that are unifocal in the primary lobe have a low likelihood of contralateral disease.
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http://dx.doi.org/10.1210/clinem/dgab210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475192PMC
September 2021

Graves' disease in a five-month-old boy with an unusual treatment course.

J Pediatr Endocrinol Metab 2021 Mar 15;34(3):401-406. Epub 2020 Dec 15.

Division of Endocrinology, Boston Children's Hospital, Boston, MA, USA.

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 duplication of the 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.
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http://dx.doi.org/10.1515/jpem-2020-0549DOI Listing
March 2021

Clinical utility of sonographic features in indeterminate pediatric thyroid nodules.

Eur J Endocrinol 2021 May;184(5):657-665

Thyroid Center, Brigham and Women's Hospital.

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 (<19 years). We assessed the association of demographic and sonographic characteristics with malignancy risk among all indeterminate nodules and within each Bethesda category.

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.
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http://dx.doi.org/10.1530/EJE-20-1480DOI Listing
May 2021

Relationship of Preoperative Thyroid Dysfunction to Clinical Outcomes in Pediatric Cardiac Surgery.

J Clin Endocrinol Metab 2021 04;106(5):e2129-e2136

Division of Endocrinology, Boston Children's Hospital, Boston, MA, USA.

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 <19 years old who underwent cardiac surgery with cardiopulmonary bypass and had thyrotropin (TSH) measured within 14 days preoperatively. Exclusion criteria included neonates (≤30 days), preoperative extracorporeal life support, salvage operations, or transplantation procedures.

Main Outcome Measures: Subjects were stratified by preoperative TSH concentration (mIU/L): low (<0.5), normal (0.5-5), mildly high (5.01-10), or moderately high (>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.
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http://dx.doi.org/10.1210/clinem/dgab040DOI Listing
April 2021

Natural History of Thyroid Disease in Children with PTEN Hamartoma Tumor Syndrome.

J Clin Endocrinol Metab 2021 03;106(3):e1121-e1130

Thyroid Center, Boston Children's Hospital, Boston, MA, USA.

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.
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http://dx.doi.org/10.1210/clinem/dgaa944DOI Listing
March 2021

Severity of Proteinuria Is Directly Associated With Risk of Hypothyroidism in Adults.

J Clin Endocrinol Metab 2021 01;106(2):e757-e762

Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA.

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 < .001). The highest tertile had a greater prevalence of TSH greater than 5 mIU/L (17.2% vs 10.5%, 11.9%, P < .001) but a similar risk of TSH greater than 5 mIU/L (odds ratio [OR] 1.44; 95% CI, 0.67-3.09, P = .35). The highest tertile also had a higher prevalence (6.2% vs 3.4%, 2.6%, P = .003) and risk (OR 1.72; 95% CI, 1.05-2.84, P = .008) of TSH greater than 10 mIU/L. Similar results were observed when comparing samples with nephrotic-range proteinuria (> 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.
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http://dx.doi.org/10.1210/clinem/dgaa872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823239PMC
January 2021

Risk Stratification in Pediatric Thyroid Cancer: Growing Evidence for Individualized Therapy.

Authors:
Ari J Wassner

J Clin Endocrinol Metab 2021 03;106(3):e1471-e1472

Thyroid Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1210/clinem/dgaa705DOI Listing
March 2021

Undernutrition and Pubertal Timing in Female Survivors of Medulloblastoma and Other Embryonal Tumors.

J Clin Endocrinol Metab 2020 10;105(10)

Division of Endocrinology, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts.

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.
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http://dx.doi.org/10.1210/clinem/dgaa475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442276PMC
October 2020

Unraveling the Genetics of Congenital Hypothyroidism: Challenges and Opportunities.

Authors:
Ari J Wassner

J Clin Endocrinol Metab 2020 09;105(9)

Thyroid Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1210/clinem/dgaa454DOI Listing
September 2020

MCT8 deficiency: collaborative rare disease phenotyping for care and research.

Authors:
Ari J Wassner

Lancet Diabetes Endocrinol 2020 07;8(7):555-557

Thyroid Center, Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA. Electronic address:

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http://dx.doi.org/10.1016/S2213-8587(20)30186-8DOI Listing
July 2020

COINCIDENT SUPPURATIVE THYROIDITIS AND GRAVES DISEASE IN A PATIENT WITH INFECTED BRANCHIAL CLEFT CYST.

AACE Clin Case Rep 2019 Nov-Dec;5(6):e365-e368. Epub 2019 Aug 14.

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.
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http://dx.doi.org/10.4158/ACCR-2019-0236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873837PMC
August 2019

Assessment of American College of Radiology Thyroid Imaging Reporting and Data System (TI-RADS) for Pediatric Thyroid Nodules.

Radiology 2020 02 10;294(2):415-420. Epub 2019 Dec 10.

From the Department of Radiology, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115 (D.M.R., C.B.B., P.M.D., E.A., M.C.F.); and Thyroid Program, Division of Endocrinology, Boston Children's Hospital, Boston, Mass (A.J.W., C.E.C., J.R.S.).

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.
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http://dx.doi.org/10.1148/radiol.2019191326DOI Listing
February 2020

Update on congenital hypothyroidism.

Curr Opin Endocrinol Diabetes Obes 2020 02;27(1):63-69

Thyroid Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Purpose Of Review: The present review summarizes recent advances in the diagnosis and management of patients with congenital hypothyroidism.

Recent Findings: 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.

Summary: 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.
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http://dx.doi.org/10.1097/MED.0000000000000520DOI Listing
February 2020

A Novel Fusion in Pediatric Medullary Thyroid Carcinoma.

Thyroid 2019 11;29(11):1704-1707

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, Massachusetts.

Medullary thyroid carcinoma (MTC) is most commonly associated with gene mutations. fusions have rarely been described, although not previously in pediatrics and not previously partnered with in MTC or any other cancer. A 10-year-old boy with progressive stridor was found to have metastatic MTC, including lung, lymph node, and adrenal metastases. Baseline calcitonin was 6703 pg/mL. While molecular testing was pending, he was treated empirically with the investigational selective RET inhibitor, LOXO-292, without improvement. Molecular testing revealed a novel - fusion. His therapy was changed to crizotinib and then to alectinib for improved tolerability. Calcitonin decreased to 663 pg/mL after 6 days of ALK inhibition. He remains on alectinib with ongoing response. A novel - fusion has now been implicated in a pediatric case of metastatic MTC. This fusion has profound clinical sensitivity to ALK inhibitors. This report expands the spectrum of fusions seen in MTC, including the first pediatric case of translocated MTC. This novel fusion with has not previously been reported in other human cancers. Given the dramatic response to ALK inhibition in this case, identifying patients with fusion MTC has important therapeutic implications.
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http://dx.doi.org/10.1089/thy.2019.0041DOI Listing
November 2019

Thyroid hormone therapy in congenital hypothyroidism and pediatric hypothyroidism.

Endocrine 2019 10 26;66(1):51-62. Epub 2019 Jul 26.

Thyroid Program, Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, 333 Longwood Avenue, 2nd floor, Boston, MA, 02115, USA.

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.
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http://dx.doi.org/10.1007/s12020-019-02024-6DOI Listing
October 2019

Differences in Thyroid Nodule Cytology and Malignancy Risk Between Children and Adults.

Thyroid 2019 08;29(8):1097-1104

1Thyroid Program, Division of Endocrinology and Boston Children's Hospital, Boston, Massachusetts.

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. 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 (<19 years) and adult (≥19 years) patients. Four hundred thirty pediatric thyroid nodules and 13,415 adult nodules were analyzed. Pediatric nodules were more likely to be malignant than adult nodules (19% vs. 12%,  = 0.0002). Within cytological categories, malignancy rates were higher in pediatric nodules than in adult nodules that were cytologically nondiagnostic (11% vs. 4%,  = 0.03), atypia of undetermined significance (AUS; 44% vs. 22%,  = 0.004), or suspicious for follicular neoplasm (SFN; 71% vs. 28%,  = 0.001). There were no significant differences between children and adults in the types of thyroid cancers diagnosed in these cytological categories. Among cytologically benign nodules, the difference in malignancy rates was statistically significant but clinically minimal (0.7% vs. 1%,  = 0.001). Malignancy rates did not differ between children and adults among nodules with cytology suspicious for papillary carcinoma (73% vs. 68%,  = 0.67) or positive for malignancy (97% vs. 95%,  = 1). Among the subset of nodules that were resected, the malignancy rate was higher in children than in adults only in nodules that were SFN (71% vs. 36%,  = 0.007). Among thyroid nodules that are cytologically AUS, SFN, or nondiagnostic, malignancy rates are higher in children than in adults. These discrepancies likely represent true differences in malignancy risk between pediatric and adult patients, rather than differences in cytological interpretation. Our findings provide pediatric-specific data to inform the optimal management of thyroid nodules in children, which may differ from that of adult nodules with equivalent cytology.
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http://dx.doi.org/10.1089/thy.2018.0728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707031PMC
August 2019

Natural History and Outcomes of Cytologically Benign Thyroid Nodules in Children.

J Clin Endocrinol Metab 2018 09;103(9):3557-3565

Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts.

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 <25% cystic; nodules <2 cm grew similarly regardless of cystic content.

Conclusion: Benign cytology in pediatric thyroid nodules has a low false-negative rate similar to that in adults, and prognosis is excellent in the rare cases of malignancy. Resection of 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.
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http://dx.doi.org/10.1210/jc.2018-00895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126895PMC
September 2018

Thyroid Nodules in Pediatric Patients: Sonographic Characteristics and Likelihood of Cancer.

Radiology 2018 08 1;288(2):591-599. Epub 2018 May 1.

From the Department of Radiology, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115 (D.M.R., C.B.B., P.M.D., H.E.P., E.A., M.C.F.); and Thyroid Program, Division of Endocrinology, Boston Children's Hospital, Boston, Mass (S.A.H., A.J.W., J.R.S., C.E.C.).

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.
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http://dx.doi.org/10.1148/radiol.2018171170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369930PMC
August 2018

Congenital Hypothyroidism.

Authors:
Ari J Wassner

Clin Perinatol 2018 03;45(1):1-18

Thyroid Program, Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.clp.2017.10.004DOI Listing
March 2018

Congenital hypothyroidism: insights into pathogenesis and treatment.

Int J Pediatr Endocrinol 2017 2;2017:11. Epub 2017 Oct 2.

Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115 USA.

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 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.
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http://dx.doi.org/10.1186/s13633-017-0051-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625825PMC
October 2017

Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and nephrocalcinosis.

Kidney Int 2018 01 12;93(1):204-213. Epub 2017 Oct 12.

Division of Nephrology, Department of Pediatrics, Nationwide Children's Hospital/The Ohio State University, Columbus, Ohio, USA.

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.
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http://dx.doi.org/10.1016/j.kint.2017.06.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750088PMC
January 2018

Pediatric Hypothyroidism: Diagnosis and Treatment.

Authors:
Ari J Wassner

Paediatr Drugs 2017 Aug;19(4):291-301

Thyroid Program, Division of Endocrinology, Harvard Medical School, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA.

Thyroid hormone has important physiologic functions in nearly every organ system. The critical role of thyroid hormone in growth and in physical and neurologic development lends particular importance to the prompt diagnosis and appropriate treatment of hypothyroidism in infants and children. Congenital hypothyroidism is common and has potentially devastating neurologic consequences. While the approach to diagnosis and treatment of severe congenital hypothyroidism is well established, data continue to emerge about the genetic causes, clinical significance, and prognosis of the milder forms of congenital hypothyroidism that are increasingly being diagnosed by newborn screening. Similarly, the diagnosis and treatment of severe acquired hypothyroidism is straightforward and clearly of clinical benefit, but uncertainty remains about the optimal management of mild subclinical hypothyroidism. This review summarizes current knowledge of the causes, clinical manifestations, diagnosis, treatment, and prognosis of hypothyroidism in infants and children, with a focus on recent developments and areas of uncertainty in this field.
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http://dx.doi.org/10.1007/s40272-017-0238-0DOI Listing
August 2017

Prevalence and Significance of Thyroglobulin Antibodies in Pediatric Thyroid Cancer.

J Clin Endocrinol Metab 2017 09;102(9):3146-3153

Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts 02115.

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.
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http://dx.doi.org/10.1210/jc.2017-00286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6283415PMC
September 2017

Myocardial Induction of Type 3 Deiodinase in Dilated Cardiomyopathy.

Thyroid 2017 05 5;27(5):732-737. Epub 2017 Apr 5.

1 Thyroid Program, Division of Endocrinology, Boston Children's Hospital , Boston, Massachusetts.

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.
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http://dx.doi.org/10.1089/thy.2016.0570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5421592PMC
May 2017

Mutations in SLC26A1 Cause Nephrolithiasis.

Am J Hum Genet 2016 06 19;98(6):1228-1234. Epub 2016 May 19.

Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ajhg.2016.03.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908148PMC
June 2016

Liothyronine Improves Biochemical Control of Congenital Hypothyroidism in Patients with Central Resistance to Thyroid Hormone.

J Pediatr 2016 08 11;175:167-172.e1. Epub 2016 May 11.

Division of Endocrinology, Boston Children's Hospital, Boston, MA. Electronic address:

Objective: To assess whether adding liothyronine (LT3) to levothyroxine (LT4) monotherapy normalizes serum thyrotropin (TSH) and thyroxine (T4) concentrations in children with congenital hypothyroidism and central resistance to thyroid hormone.

Study Design: We retrospectively studied 12 patients with congenital hypothyroidism and central resistance to thyroid hormone (6 treated with LT3+LT4 combined therapy and 6 treated with LT4 monotherapy). In patients receiving combined therapy, we compared serum concentrations of TSH, T4, and triiodothyronine before and after addition of LT3. We used repeated measures analysis to compare thyroid function in participants receiving combined therapy vs monotherapy, while accounting for age and intrasubject correlation.

Results: In patients receiving combined therapy, the addition of LT3 was associated with normalization of mean TSH (9.2 vs 4.5 mIU/L, P = .002), a lower proportion of TSH values greater than 10 mIU/L (35% vs 8%, P = .03), and a decrease in mean serum T4 by 23 ± 9% (P < .001). Compared with patients receiving LT4 monotherapy, patients receiving combined therapy had lower mean TSH (8.5 ± 0.9 vs 4.3 ± 0.4, P < .001), lower odds of TSH elevation greater than 10 mIU/L (OR 0.20, 95% CI 0.10-0.41, P < .001), and lower odds of T4 elevation (OR 0.21, 95% CI 0.04-1.09, P = .06). LT3 treatment did not increase serum T3 levels significantly.

Conclusion: The addition of LT3 to LT4 monotherapy facilitates normalization of both serum TSH and T4 in patients with congenital hypothyroidism and central resistance to thyroid hormone. Larger prospective studies are needed to confirm these findings and to determine the effect of combined therapy on neurodevelopmental outcomes.
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http://dx.doi.org/10.1016/j.jpeds.2016.04.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981539PMC
August 2016

Prevalence of Monogenic Causes in Pediatric Patients with Nephrolithiasis or Nephrocalcinosis.

Clin J Am Soc Nephrol 2016 Apr 19;11(4):664-72. Epub 2016 Jan 19.

Division of Nephrology, Department of Medicine and Howard Hughes Medical Institute, Chevy Chase, Maryland

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 <18 years of age, with nephrolithiasis (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.
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http://dx.doi.org/10.2215/CJN.07540715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822665PMC
April 2016

Subclinical Hypothyroidism in Infancy: To Treat or Not to Treat, That Is the Question.

J Pediatr 2016 Mar 23;170:17-9. Epub 2015 Dec 23.

Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts. Electronic address:

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http://dx.doi.org/10.1016/j.jpeds.2015.12.001DOI Listing
March 2016
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