DOI: 10.1177/10507256261500920 ISSN: 1050-7256

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

Tomohiro Hori, Hiroshi Ito, Tatsuya Sakashita, Toshinari Koyama, Masahiro Shimozawa, Mai Mori, Saori Kadowaki, Hideki Matsumoto, Hideo Sasai, Fumiaki Sakura, Yutaka Yamamoto, Satoshi Okada, Hidenori Ohnishi
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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.

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