TY - JOUR
T1 - Genetics of Congenital Isolated TSH Deficiency
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
N1 - Funding Information:
This work was supported by JSPS KAKENHI Grant 15K09630 to S.N. and Grant 26461353 to T.S. and a grant from MHLW [Jitsuyoka (Nanbyo)-Ippan-014] to T.H.
PY - 2019/12/1
Y1 - 2019/12/1
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.
AB - 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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U2 - 10.1210/jc.2019-00657
DO - 10.1210/jc.2019-00657
M3 - Review article
C2 - 31504637
AN - SCOPUS:85074377777
VL - 104
SP - 6229
EP - 6237
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
SN - 0021-972X
IS - 12
ER -