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

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

doi:10.1210/clinem/dgae098

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

J Clin Endocrinol Metab. 2024 Feb 19:dgae098. doi: 10.1210/clinem/dgae098. Online ahead of print.

Authors

Kanako Tanase-Nakao¹, Megumi Iwahashi-Odano¹, Chiho Sugisawa^{2

3}, Kiyomi Abe², Koji Muroya⁴, Yukiyo Yamamoto⁵, Yasusada Kawada⁶, Yuichi Mushimoto⁷, Kazuhiro Ohkubo⁷, Saori Kinjo⁸, Kazuhiro Shimura², Kohei Aoyama⁹, Haruo Mizuno⁹, Tomoyuki Hotsubo¹⁰, Chie Takahashi¹¹, Tsuyoshi Isojima¹¹, Yoko Kina¹², Satoshi Takakuwa¹², Junpei Hamada¹³, Miwa Sawaki¹⁴, Keiichi Shigehara¹⁵, Satoru Sugimoto¹⁵, Yuri Etani¹⁶, Hiroko Narumi-Wakayama¹⁷, Yusuke Mine¹⁸, Tomonobu Hasegawa², Akira Hishinuma¹⁹, Satoshi Narumi^{1

2}

Affiliations

¹ Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan.
² Department of Pediatrics, Keio University School of Medicine, 160-8582 Tokyo, Japan.
³ Department of Internal Medicine, Ito Hospital, Tokyo 150-0002, Japan.
⁴ Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama 232-8555, Japan.
⁵ Department of Medical Education, University of Occupational and Environmental Health, Japan, Kitakyushu 807-8555 Japan.
⁶ Department of Pediatrics, Kyushu Rosai Hospital, Kitakyushu 800-0296, Japan.
⁷ Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
⁸ Department of Pediatrics, Okinawa Chubu Hospital, Okinawa 904-2293, Japan.
⁹ Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
¹⁰ Department of Pediatrics, NTT East Japan Sapporo Hospital, Sapporo 060-0061, Japan.
¹¹ Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
¹² Division of Pediatric Endocrinology and Metabolism, Okinawa Prefectural Nanbu Medical Center and Children's Medical Center, Okinawa 901-1193, Japan.
¹³ Department of Pediatrics, Ehime University Graduate School of Medicine, Ehime 791-0295, Japan.
¹⁴ Department of Pediatrics, Nakatsu Municipal Hospital, Nakatsu 871-8511, Japan.
¹⁵ Department of Pediatrics, Ayabe City Hospital, Ayabe 623-0011, Japan.
¹⁶ Department of Pediatric Gastroenterology, Nutrition and Endocrinology, Osaka Women's and Children's Hospital, Osaka 594-1101, Japan.
¹⁷ Division of Endocrinology and Metabolism, Tokyo Metropolitan Children's Medical Center, Tokyo 183-8561, Japan.
¹⁸ Department of Pediatrics, Nihon University School of Medicine, Tokyo 173-8610, Japan.
¹⁹ Department of Infection Control and Clinical Laboratory Medicine, Dokkyo Medical University, Mibu, Tochigi 321-0293, Japan.

PMID: 38373250
DOI: 10.1210/clinem/dgae098

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.

Keywords: Congenital Hypothyroidism; Goiter; Thyroglobulin; Thyroid Dyshormonogenesis; Thyroid Neoplasms.