Faculty Bibliography

Pancreatic neuroendocrine tumors (PNETs) occur in the context of tuberous sclerosis complex (TSC). To date, PNETs in association with TSC have been described almost exclusively in adults and in the context of TSC2. We present the evaluation of a PNET in a young child with TSC1. A 3-year, 6-month-old boy with TSC1 was found on surveillance to have a small pancreatic lesion measuring 0.4 cm on magnetic resonance imaging (MRI). The lesion showed interval enlargement to 1 cm on serial MRI studies during the ensuing 16 weeks. Endocrine laboratory tests did not reveal a functional tumor. The patient underwent enucleation of the pancreatic lesion. Microscopic examination defined a well-differentiated PNET, grade II/intermediate grade with a mitotic rate of two mitotic figures per 10 high-powered field and Ki-67 proliferation index of ∼15%. The tumor was positive for the TSC1 gene mutation. The patient was free of tumor recurrence at the 5-year follow-up examination, as determined by endocrine surveillance and annual MRI of the abdomen. In the reported data, PNET in patients with TSC has been primarily reported in association with TSC2. Our case demonstrates that patients with TSC1 can develop PNETs, even at an early age. The international TSC consensus group 2012 recommendation was to obtain MRI of the abdomen every 1 to 3 years for surveillance of renal angiomyolipomas and renal cystic disease. It might be beneficial to add a pancreatic protocol to the surveillance guidelines to evaluate for PNET.

Context: Common environmental contaminants can disrupt normal thyroid function, which plays essential but varying roles at different ages. Objective: To evaluate the relationship of perchlorate, thiocyanate, and nitrate, three sodium-iodide symporter (NIS) inhibitors, and thyroid function in different age-sex-stratified populations. Design, Setting, Participants, and Intervention: This was a cross-sectional analysis of data from the 2009-2012 National Health and Nutrition Examination Surveys (NHANES) evaluating the exposure to perchlorate, thiocyanate, and nitrate in 3,151 participants aged 12-80. Main Outcome Measure: Blood serum free thyroxine (FT4) as both a continuous and categorical variable. We also assessed blood serum thyroid stimulating hormone (TSH). Results: Controlling for serum cotinine, BMI, total daily energy consumption, race/ethnicity, and poverty-to-income ratio, for each log unit increase in perchlorate, FT4 decreased by 0.03 ng/dL in both the general population (p=0.004) and in all women (p=0.005), and by 0.06 ng/dL in adolescent girls (p=0.029), corresponding to 4% and 8% decreases relative to median FT4, respectively. For each log unit increase thiocyanate, FT4 decreased by 0.07 ng/dL in adolescent boys (p=0.003), corresponding to a 9% decrease relative to median FT4, respectively. Conclusions: Our results indicate that adolescent boys and girls represent vulnerable subpopulations to the thyroid-blocking effects of NIS symporter inhibitors. These results suggest a valuable screening and intervention opportunity.

Type 1 diabetes mellitus (T1DM) is one of the most common chronic diseases diagnosed in childhood. Childhood and adolescent years are also the most important period for growth in height and acquisition of skeletal bone mineral density (BMD). The growth hormone (GH)/insulin like growth factor -1 (IGF-1) axis which regulates growth, is affected by T1DM, with studies showing increased GH and decreased IGF-1 levels in children with T1DM. There is conflicting data as to whether adolescents with TIDM are able to achieve their genetically-determined adult height. Furthermore, data support that adolescents with T1DM have decreased peak BMD, although the pathophysiology of which has not been completely defined. Various mechanisms have been proposed for the decrease in BMD including low osteocalcin levels, reflecting decreased bone formation; increased sclerostin, an inhibitor of bone anabolic pathways; and increased leptin, an adipocytokine which affects bone metabolism via central and peripheral mechanisms. Other factors implicated in the increased bone resorption in T1DM include upregulation of the osteoprotegerin/ receptor-activator of the nuclear factor-kappaB ligand pathway, elevated parathyroid hormone levels, and activation of other cytokines involved in chronic systemic inflammation. In this review, we summarize the clinical studies that address the alterations in the GH/IGF-I axis, linear growth velocity, and BMD in children and adolescents with T1DM; and we review the possible molecular mechanisms that may contribute to an attenuation of linear growth and to the reduction in the acquisition of peak bone mass in the child and adolescent with T1DM.

This review highlights the presentations of myopathy in children in both hypothyroid and hyperthyroid states with an emphasis on the pathophysiology, diagnosis and treatment. Based on our review of the literature data, myopathy should be considered in all children presenting with muscular weakness or altered muscle enzymes in the context of thyroid disease.

Background MEN-2B syndrome is comprised of the association of MTC, PHEOs and multiple mucosal neuromas. The latter is a phenotype pathognomonic of this syndrome, but expressivity of the mucosal neuroma phenotype is less than 100%. The RET genotype-phenotype correlations are well recognized. MEN-2B is transmitted as an autosomal dominant trait. The germline point mutations are gain-of-function, causing RET activation. Most cases of MEN-2B have a codon 918 mutation (exon 16) of the intracellular tyrosine kinase domain of RET proto-oncogene. Recently, classification based on the pathogenesis and molecular correlation of the mutations involved in MEN-2A and MEN-2B places these mutations into a cluster 2 (kinase receptor signaling) and its downstream pathway: the mutated protein RET interacts with and alters the activity of several effector proteins of the receptor kinase intracellular signaling pathway. Case presentation 9 year old female presenting with 2 weeks of neck pain and left anterior neck mass. No history of radiation exposure to the head or neck; no family history of thyroid cancer or pheochromocytoma. VS: BP 90/60 mm Hg, HR 85 bpm, height 130 cm (-1.1 SD). Phenotype: long faces, lingual mucosal neuromas with involvement of the lips, pectus excavatum, and arachnodactyly. Thyroid exam: left, firm ~ 2cm x 2cm-sized thyroid nodule, not fixed. Laboratory studies: Calcitonin: 226 pg/mL (0-5)- high; Chromogranin A: 8 nmol/L (0 - 5) elevated; CEA: 4.4 ng/ml (0 - 4.7) borderline high. Thyroid US: left thyroid lobe hypoechoic complex nodule 1.5 x 1.8 x 2.8 cm with coarse calcifications. US-guided FNAB, cytology: atypical cells, salt/pepper chromatin, amyloid (+). Immunohistochemical staining (+) for calcitonin. Diagnosis: MTC (Medullary Thyroid Carcinoma). Pheochromocytoma screen: plasma free metanephrine: 33 pg/mL (0-62), pelvic MRI with/without contrast and I-123 MIBG were normal. Genetic study: germline mutation, RET M918T (highest aggressiveness). Total thyroidectomy with central compartment lymph node dissection was performed. Pathology: pT1b (> 1 cm, < 2 cm), no nodal extension. Postoperative Calcitonin: < 2.0 pg/mL. Conclusions Identification of the mucosal neuroma phenotype in a child should alert the clinician to the diagnosis of MTC, a rare aggressive cancer syndrome. The diagnosis of MTC is made from calcitonin measurements and FNAB. Confirmation by positive immunostaining of tumor tissue for calcitonin is necessary with exclusion of pheochromocytoma. The finding of a germline mutation (sporadic/hereditary) in the RET gene in proband necessitates genetic testing in all first-degree relatives. After surgical intervention (in accordance to genotype-phenotype stratification), surveillance with calcitonin levels (as a marker of persistent/recurrent disease), CEA, Chromogranin A, and thyroid US along with plasma free metanephrines is recommended

Introduction: Vitamin D intoxication is a rare cause of hypercalcemia. There is a recent increase in reports of pediatric cases of hypercalcemia, secondary to vitamin D intoxication. This trend is attributable to the growing popularity of vitamin D supplements, especially as Vitamin D is being marketed as a "panacea" for a number of medical problems.Immigrant families often travel to their countries of origin, where vitamin supplements are available in formulations different from the US. Parents may not report using supplements to their child's pediatrician, as these supplements are perceived "safe" with no dangerous side effects.Case Presentation: A three year old toddler presented to the emergency room with emesis, polyuria, and lethargy. On inquiry, the family reported use of a multivitamin gel (made in Ecuador) dispensed at 1 tsp bid. Per the manufacturer's label, 5 grams (aD;one teaspoon) contains 0.096 mg (aD;100 IU) of cholecalciferol. A standard conversion of 1mug of cholecalciferol equals 40 IU1, secondary to conversion error this patient received 7,680 IU per day and 108,000 IU total vitamin D3 over 14 days, which is toxic. "Teaspoon" dosage inaccuracies and potentially excessive administration by caretakers compounded vitamin D toxicity.Initial lab values revealed Ca 16 mg/dl, iPTH 2.25 pg/mL (15-65), 25 OH vit D3: >512ng/mL(30-100), and UCa/UCreatinine 1.14mg/mg(<0.2). Hydration, lasix, calcitonin (6 days), and prednisolone (7 days) were used to manage the hypercalcemia. After 15 days of treatment, the 25 OH vitamin D3 was 324 ng/ml and the calcium decreased to 11.2 mg/dL. Conclusion s: In our case, dispensing and labeling errors led the parents to administer high doses of vitamin D to their toddler, leading to hypercalcemia. This highlights several issues regarding vitamin supplement usage.First, physicians should be aware of the dosage conversion of vitamin D in terms of IU, mg and mcg to calculate if the prescribed dose is appropriate for their patients. In addition, as there are no established manufacturing standards for certain vitamin supplement formulations-such as gels-caution should be exercised as more reports are emerging of toxic ingestion from overzealous supplementation. Verification of supplement source and composition is essential. Lastly, educating parents about the safe use of vitamin D supplements-emphasizing the need to report imported supplements to the patient's pediatrician-is important to avoiding erroneous toxic ingestion