Mutation of a Gene for Thyroid Transcription Factor-1 (TITF1) in a Patient with Clinical Features of Resistance to Thyrotropin

Abstract

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 (ΔFT3, 0.4 pg/ml; ΔT3, 13 ng/dl; and ΔTSH, 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.

Lethal Respiratory Failure and Mild Primary Hypothyroidism in a Term Girl with a de Novo Heterozygous Mutation in the TITF1/NKX2.1 Gene

“…It is conceivable that the actual TITF1/NKX2.1 targets would be differentially affected by the mutation. In the developing thyroid, the TSH receptor gene seems to be controlled by TITF1/NKX2.1, which accounts for the partial resistance to TSH observed in human (23) and murine heterozygotes for loss-of-function TITF1/NKX2.1 mutations (24) and likely accounting for the compensated hypothyroidism of the present patient. A similar situation with a more pronounced effect on a lung-specific gene could provide an explanation to the phenotype of our patient.…”

“…Pertinent to this discussion is the extremely wide panel of thyroid phenotypes displayed by patients harboring a heterozygous loss-offunction mutation of TITF1/NKX2.1. This goes from mild hyperthyrotropinemia with normal-sized thyroid to profound hypothyroidism associated with hypoplasia or apparent athyreosis (23,27,28). Interestingly, there is no simple relation between the thyroid, neurological, and respiratory phenotypes of individual mutants (24).…”

Respiratory insufficiency in a newborn with congenital hypothyroidism due to a new mutation of TTF‐1/NKX2.1 gene

“…Heterozygous loss of function of the gene can cause a phenotype with only mild hypothyroidism and later neurological phenotype in childhood and also mild hypothyroidism and lethal neonatal respiratory distress with a pulmonary morphology suggestive of surfactant deficiency …”

A Novel NKX2.1 Mutation in a Family with Hypothyroidism and Benign Hereditary Chorea

“…Mutations that produce major alterations in the protein structure may be associated with only minor neurological signs (10,21). Primary hypothyroidism has been linked to NKX2.1 mutations in 73% (16=22) of the cases (6,7,(10)(11)(12)14,15,17,19,20,22). This and the different severity of thyroidal manifestations indicate that other genetic and=or environmental factors, at present unknown, may modulate the expressivity of the phenotype.…”

“…The association of choreoathetosis, hypothyroidism, and pulmonary alterations has recently been linked to mutations in the gene encoding NKX2.1. So far, 21 mutations in the NKX2.1 gene have been identified (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22).…”