title: Mutation of a gene for thyroid transcription factor-1 (TITF1) in a patient with clinical features of resistance to thyrotropin.
abstract: Resistance to TSH (RTSH [MIM 275200]) is a heterogeneous condition defined by variable degree of insensitivity to biologically active TSH. While this condition is classically caused by loss-of-function mutations of the TSH receptor gene (TSHR), several patients have exhibited RTSH-like phenotype in the apparent absence of TSHR mutations, and some of them have mutations of PAX8 or GNAS1. We identified a Japanese boy with congenital hypothyroidism who suffered from recurrent lower respiratory infection during infancy and choreoathetosis at a later age. At 14 years of age, he was diagnosed as having RTSH, on the basis of compensated hypothyroidism (TSH, 30.2 mU/L; FT4, 1.2 ng/dl), disproportionate increments of thyroid hormones and TSH during a TRH test (DeltaFT3, 0.4 pg/ml; DeltaT3, 13 ng/dl; and DeltaTSH, 88.3 mU/L), and normal ultrasound thyroid image and radioactive iodine uptakes. Molecular analysis for TITF1 revealed a novel de novo heterozygous deletion/insertion mutation (c.470_479delinsGCG,) that is predicted to lose the entire homeodomain and the NK2-specific domain. We suggest that a heterozygous loss-of-function TITF1 mutation can also cause RTSH-compatible phenotype.
authors.affiliation: Division of Pediatrics, Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medicine and Dental Sciences, Niigata, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Nagasaki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Narumi
authors.forename: Tadashi
authors.initials: T
authors.lastname: Asami
authors.forename: Toru
authors.initials: T
authors.lastname: Kikuchi
authors.forename: Tomonobu
authors.initials: T
authors.lastname: Hasegawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Uchiyama
mesh_terms: D000293:Adolescent; D001426:Bacterial Proteins; D003409:Congenital Hypothyroidism / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics*; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics*; D000074482:Thyroid Nuclear Factor 1; D013972:Thyrotropin / Q000097:blood; D013973:Thyrotropin-Releasing Hormone; D013974:Thyroxine / Q000097:blood; D014157:Transcription Factors / Q000235:genetics*; D014284:Triiodothyronine / Q000097:blood
chemical_list: D001426:Bacterial Proteins; C424710:HetF protein, Nostoc punctiforme; C000614412:NKX2-1 protein, human; D009687:Nuclear Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D014284:Triiodothyronine; D013973:Thyrotropin-Releasing Hormone; D013972:Thyrotropin; D013974:Thyroxine