The nuclear-encoded subunit 4 of cytochrome c oxidase (COX4) plays a role in regulation of oxidative phosphorylation and contributes to cancer progression. We sought to determine the role of COX4 in differentiated (DTC) and medullary (MTC) thyroid cancers. We examined the expression of COX4 in human thyroid tumors by immunostaining and used shRNA-mediated knockdown of COX4 to evaluate its functional contributions in thyroid cancer cell lines. In human thyroid tissue, the expression of COX4 was higher in cancers than in either normal thyroid (p = 0.0001) or adenomas (p = 0.001). The level of COX4 expression correlated with tumor size (p = 0.04) and lymph-node metastases (p = 0.024) in patients with MTCs. COX4 silencing had no effects on cell signaling activation and mitochondrial respiration in DTC cell lines (FTC133 and BCPAP). In MTC-derived TT cells, COX4 silencing inhibited p70S6K/pS6 and p-ERK signaling, and was associated with decreased oxygen consumption and ATP production. Treatment with potassium cyanide had minimal effects on FTC133 and BCPAP, but inhibited mitochondrial respiration and induced apoptosis in MTC-derived TT cells. Our data demonstrated that metastatic MTCs are characterized by increased expression of COX4, and MTC-derived TT cells are vulnerable to COX4 silencing. These data suggest that COX4 can be considered as a novel molecular target for the treatment of MTC.
We describe a 21-month-old male with relapsed clear cell sarcoma of the kidney receiving enteral nutrition who experienced recurrent, ketotic hypoglycemia. During relapse therapy, he had recurrent hypoglycemia episodes, in the setting of hematochezia and diarrhea. Evaluation revealed low carnitine levels. He received supplementation with oral levocarnitine throughout the remainder of treatment, resulting in normalization of serum carnitine levels and no further hypoglycemia. We believe adverse effects of the chemotherapy on his single kidney and gastrointestinal insult resulted in hypoglycemia and carnitine deficiency. Our case highlights that carnitine deficiency should be considered when acute onset hypoglycemia without obvious cause occurs.
Background: Sporadic congenital non-autoimmune hyperthyroidism (SCNAH) causes permanent hyperthyroidism secondary to activating mutations in the TSHR gene. SCNAH usually presents during infancy and can be difficult to treat with antithyroid drugs or subtotal thyroidectomy.1 When adequate therapy is delayed, irreversible sequela such as craniosynostosis, growth failure, and cognitive delays may develop. Definitive therapy for children with SCNAH is recommended with no consensus on timing or type of intervention. Our case highlights the importance of early total thyroidectomy to optimize clinical outcomes in patients with SCNAH.
Clinical case: A now 3-year-old male was born small for gestational age (SGA) at 34 weeks gestation with biochemical and clinical signs of hyperthyroidism in the neonatal period. On day of life 6, his TSH was 0.02 mcU/mL (reference range 0.34-5.6 mcU/mL) and free thyroxine (T4) was 5.42 ng/dL (reference range 0.58-1.64 ng/dL). Methimazole (MMI) 0.3 mg/kg/day was started at that time, and the dose was titrated over 6 weeks of life to 0.8 mg/kg/day due to continued elevation of free T4 levels. Negative thyroid autoantibodies and normal maternal thyroid studies prompted genetic testing at 3 months of age. This testing revealed a heterozygous variant in the TSHR gene [c.842G->A (p.G116R)] that was determined to be pathologic. Despite frequent MMI dose changes and confirmation of medication adherence, high-dose MMI was not effective in consistently normalizing his TSH and free T4 levels in the first two years of life. Concerns for poor growth and hyperactive behavior were also present. A “block and replace” strategy was not feasible since the patient remained hyperthyroid even at MMI doses up to 0.8 mg/kg/day. Despite normal insulin-like growth factor 1 and insulin-like growth factor binding protein 3 levels, poor linear growth persisted with a height Z-score of -3.61 by age 3 years. While he was SGA at birth, his recurrent hyperthyroidism impeded catch-up growth potential, so treatment with growth hormone (rhGH) was initiated. His height Z-score improved to -2.39 after 9 months on rhGH dosed at 0.18 mg/kg/week. Due to the difficulty in consistently managing him medically with MMI, he underwent total thyroidectomy at age three.
Conclusion: There is currently no consensus on the timing of definitive therapy for children with SCNAH. This case highlights the importance of considering total thyroidectomy at an early age to avoid long-term sequela of persistent hyperthyroidism.
1. Gozu HI, Lublinghoff J, Bircan R, Paschke R. Genetics and phenomics of inherited and sporadic non-autoimmune hyperthyroidism. Mol Cell Endocrinol. 2010;322:125–34.
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