Genetics of Congenital Isolated TSH Deficiency: Mutation Screening of the Known Causative Genes and a Literature Review

Chiho Sugisawa, Tetsuya Takamizawa, Kiyomi Abe, Tomonobu Hasegawa, Kentaro Shiga, Hidenori Sugawara, Koji Ohsugi, Koji Muroya, Yumi Asakura, Masanori Adachi, Takashi Daitsu, Chikahiko Numakura, Akemi Koike, Junko Tsubaki, Kazuteru Kitsuda, Nobuo Matsuura, Matsuo Taniyama, Sumiyasu Ishii, Tetsurou Satoh, Masanobu YamadaSatoshi Narumi

Research output: Contribution to journalArticle

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Abstract

CONTEXT: Congenital isolated TSH deficiency (i-TSHD) is a rare form of congenital hypothyroidism. Five genes (IGSF1, IRS4, TBL1X, TRHR, and TSHB) responsible for the disease have been identified, although their relative frequencies and hypothalamic/pituitary unit phenotypes have remained to be clarified. OBJECTIVES: To define the relative frequencies and hypothalamic/pituitary unit phenotypes of congenital i-TSHD resulting from single gene mutations. PATIENTS AND METHODS: Thirteen Japanese patients (11 boys and 2 girls) with congenital i-TSHD were enrolled. IGSF1, IRS4, TBL1X, TRHR, and TSHB were sequenced. For a TBL1X mutation (p.Asn382del), its pathogenicity was verified in vitro. For a literature review, published clinical data derived from 74 patients with congenital i-TSHD resulting from single-gene mutations were retrieved and analyzed. RESULTS: Genetic screening of the 13 study subjects revealed six mutation-carrying patients (46%), including five hemizygous IGSF1 mutation carriers and one hemizygous TBL1X mutation carrier. Among the six mutation carriers, one had intellectual disability and the other one had obesity, but the remaining four did not show nonendocrine phenotypes. Loss of function of the TBL1X mutation (p.Asn382del) was confirmed in vitro. The literature review demonstrated etiology-specific relationship between serum prolactin (PRL) levels and TRH-stimulated TSH levels with some degree of overlap. CONCLUSIONS: The mutation screening study covering the five causative genes of congenital i-TSHD was performed, showing that the IGSF1 defect was the leading genetic cause of the disease. Assessing relationships between serum PRL levels and TRH-stimulated TSH levels would contribute to predict the etiologies of congenital i-TSHD.

Original languageEnglish
Pages (from-to)6229-6237
Number of pages9
JournalThe Journal of clinical endocrinology and metabolism
Volume104
Issue number12
DOIs
Publication statusPublished - 2019 Dec 1

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Hypothyroidism
Screening
Genes
Mutation
Prolactin
Hypothalamo-Hypophyseal System
Phenotype
Defects
Genetics
Congenital Hypothyroidism
Inborn Genetic Diseases
Genetic Testing
Serum
Intellectual Disability
Virulence
Obesity

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

Genetics of Congenital Isolated TSH Deficiency : Mutation Screening of the Known Causative Genes and a Literature Review. / Sugisawa, Chiho; Takamizawa, Tetsuya; Abe, Kiyomi; Hasegawa, Tomonobu; Shiga, Kentaro; Sugawara, Hidenori; Ohsugi, Koji; Muroya, Koji; Asakura, Yumi; Adachi, Masanori; Daitsu, Takashi; Numakura, Chikahiko; Koike, Akemi; Tsubaki, Junko; Kitsuda, Kazuteru; Matsuura, Nobuo; Taniyama, Matsuo; Ishii, Sumiyasu; Satoh, Tetsurou; Yamada, Masanobu; Narumi, Satoshi.

In: The Journal of clinical endocrinology and metabolism, Vol. 104, No. 12, 01.12.2019, p. 6229-6237.

Research output: Contribution to journalArticle

Sugisawa, C, Takamizawa, T, Abe, K, Hasegawa, T, Shiga, K, Sugawara, H, Ohsugi, K, Muroya, K, Asakura, Y, Adachi, M, Daitsu, T, Numakura, C, Koike, A, Tsubaki, J, Kitsuda, K, Matsuura, N, Taniyama, M, Ishii, S, Satoh, T, Yamada, M & Narumi, S 2019, 'Genetics of Congenital Isolated TSH Deficiency: Mutation Screening of the Known Causative Genes and a Literature Review', The Journal of clinical endocrinology and metabolism, vol. 104, no. 12, pp. 6229-6237. https://doi.org/10.1210/jc.2019-00657
Sugisawa, Chiho ; Takamizawa, Tetsuya ; Abe, Kiyomi ; Hasegawa, Tomonobu ; Shiga, Kentaro ; Sugawara, Hidenori ; Ohsugi, Koji ; Muroya, Koji ; Asakura, Yumi ; Adachi, Masanori ; Daitsu, Takashi ; Numakura, Chikahiko ; Koike, Akemi ; Tsubaki, Junko ; Kitsuda, Kazuteru ; Matsuura, Nobuo ; Taniyama, Matsuo ; Ishii, Sumiyasu ; Satoh, Tetsurou ; Yamada, Masanobu ; Narumi, Satoshi. / Genetics of Congenital Isolated TSH Deficiency : Mutation Screening of the Known Causative Genes and a Literature Review. In: The Journal of clinical endocrinology and metabolism. 2019 ; Vol. 104, No. 12. pp. 6229-6237.
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T2 - Mutation Screening of the Known Causative Genes and a Literature Review

AU - Sugisawa, Chiho

AU - Takamizawa, Tetsuya

AU - Abe, Kiyomi

AU - Hasegawa, Tomonobu

AU - Shiga, Kentaro

AU - Sugawara, Hidenori

AU - Ohsugi, Koji

AU - Muroya, Koji

AU - Asakura, Yumi

AU - Adachi, Masanori

AU - Daitsu, Takashi

AU - Numakura, Chikahiko

AU - Koike, Akemi

AU - Tsubaki, Junko

AU - Kitsuda, Kazuteru

AU - Matsuura, Nobuo

AU - Taniyama, Matsuo

AU - Ishii, Sumiyasu

AU - Satoh, Tetsurou

AU - Yamada, Masanobu

AU - Narumi, Satoshi

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N2 - CONTEXT: Congenital isolated TSH deficiency (i-TSHD) is a rare form of congenital hypothyroidism. Five genes (IGSF1, IRS4, TBL1X, TRHR, and TSHB) responsible for the disease have been identified, although their relative frequencies and hypothalamic/pituitary unit phenotypes have remained to be clarified. OBJECTIVES: To define the relative frequencies and hypothalamic/pituitary unit phenotypes of congenital i-TSHD resulting from single gene mutations. PATIENTS AND METHODS: Thirteen Japanese patients (11 boys and 2 girls) with congenital i-TSHD were enrolled. IGSF1, IRS4, TBL1X, TRHR, and TSHB were sequenced. For a TBL1X mutation (p.Asn382del), its pathogenicity was verified in vitro. For a literature review, published clinical data derived from 74 patients with congenital i-TSHD resulting from single-gene mutations were retrieved and analyzed. RESULTS: Genetic screening of the 13 study subjects revealed six mutation-carrying patients (46%), including five hemizygous IGSF1 mutation carriers and one hemizygous TBL1X mutation carrier. Among the six mutation carriers, one had intellectual disability and the other one had obesity, but the remaining four did not show nonendocrine phenotypes. Loss of function of the TBL1X mutation (p.Asn382del) was confirmed in vitro. The literature review demonstrated etiology-specific relationship between serum prolactin (PRL) levels and TRH-stimulated TSH levels with some degree of overlap. CONCLUSIONS: The mutation screening study covering the five causative genes of congenital i-TSHD was performed, showing that the IGSF1 defect was the leading genetic cause of the disease. Assessing relationships between serum PRL levels and TRH-stimulated TSH levels would contribute to predict the etiologies of congenital i-TSHD.

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