Paternally Inherited DIO3 Loss and Infantile-Onset Central Hypothyroidism: Human Evidence for a Novel Mechanism of Hypothalamic-Pituitary-Thyroid Axis Dysregulation.

Abstract

Background: DIO3 encodes type 3 iodothyronine deiodinase, the major thyroid hormone-inactivating enzyme, and is an imprinted gene with preferential paternal-allele expression demonstrated in human neonatal skin. Dio3-deficient mice develop neonatal thyrotoxicosis followed by central hypothyroidism, but human evidence has been lacking.

Patient findings: On newborn screening, thyrotropin (TSH) and free thyroxine (fT4) did not meet repeat-testing criteria, while T-cell lymphopenia was detected neonatally. From 5 months onward, fT4 progressively declined without compensatory TSH elevation. Chromosomal microarray identified a derivative chromosome 14 with a 14q32.31-q32.33 deletion encompassing DIO3 and TRAF3. The deletion originated from a paternal balanced 4p/14q translocation.

Summary: In this patient, delayed-onset central hypothyroidism was most consistent with paternal DIO3 loss, whereas the accompanying T-cell lymphopenia was consistent with TRAF3 haploinsufficiency.

Conclusions: This case provides the first human evidence linking paternal DIO3 loss to delayed-onset central hypothyroidism, supporting a novel developmental mechanism that may alter hypothalamic-pituitary-thyroid axis programming.