Genotype-Phenotype Correlations in Thirty Japanese Patients with Congenital Hypothyroidism Attributable to TG Defects.

Abstract

CONTEXT:

Thyroglobulin (Tg), encoded by TG, is essential for thyroid hormone synthesis. TG defects result in congenital hypothyroidism (CH). Most reported patients were born before the introduction of newborn screening (NBS).

OBJECTIVE:

We aimed to clarify the phenotypic features of patients with TG defects diagnosed and treated since the neonatal period.

SUBJECTS AND METHODS:

We screened 1061 patients with CH for thirteen CH-related genes and identified thirty patients with TG defects. One patient was diagnosed due to hypothyroidism-related symptoms and the rest were diagnosed via NBS. Patients were divided into two groups according to their genotypes, and clinical characteristics were compared. We evaluated the functionality of the seven missense variants using HEK293 cells.

RESULTS:

Twenty-seven rare TG variants were detected, including fifteen nonsense, three frameshift, two splice-site, and seven missense variants. Patients were divided into two groups: thirteen patients with biallelic truncating variants and seventeen patients with monoallelic/biallelic missense variants. Patients with missense variants were more likely to develop thyroid enlargement with TSH stimulation than patients with biallelic truncating variants. Patients with biallelic truncating variants invariably required full hormone replacement, whereas patients with missense variants required variable doses of levothyroxine. Loss of function of the seven missense variants was confirmed in vitro.

CONCLUSION:

To our knowledge, this is the largest investigation on the clinical presentation of TG defects diagnosed in the neonatal period. Patients with missense variants showed relatively mild hypothyroidism with compensative goiter. Patients with only truncating variants showed minimal or no compensative goiter and required full hormone replacement.

• Authors: Kanako Tanase-Nakao, Megumi Iwahashi-Odano, Chiho Sugisawa, Kiyomi Abe, Koji Muroya, Yukiyo Yamamoto, Yasusada Kawada, Yuichi Mushimoto, Kazuhiro Ohkubo, Saori Kinjo, Kazuhiro Shimura, Kohei Aoyama, Haruo Mizuno, Tomoyuki Hotsubo, Chie Takahashi, Tsuyoshi Isojima, Yoko Kina, Satoshi Takakuwa, Junpei Hamada, Miwa Sawaki, Keiichi Shigehara, Satoru Sugimoto, Yuri Etani, Hiroko Narumi-Wakayama, Yusuke Mine, Tomonobu Hasegawa, Akira Hishinuma, Satoshi Narumi
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) (Feb 19 2024) ISSN: 1945-7197 [Electronic] United States
• PMID: 38373250 (Publication Type: Journal Article)
• Copyright: © The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: [email protected].