2. Academic Validation
  3. Central Hypothyroidism and Novel Clinical Phenotypes in Hemizygous Truncation of TBL1X

Central Hypothyroidism and Novel Clinical Phenotypes in Hemizygous Truncation of TBL1X

  • J Endocr Soc. 2018 Nov 23;3(1):119-128. doi: 10.1210/js.2018-00144.
Marta García 1,  Ana C Barreda-Bonis 2,  Paula Jiménez 1,  Ignacio Rabanal 3,  Arancha Ortiz 4,  Elena Vallespín 5,  Ángela Del Pozo 6,  Juan Martínez-San Millán 7,  Isabel González-Casado 2,  José C Moreno 1
Affiliations

Affiliations

  • 1 Thyroid Molecular Laboratory, Institute for Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Autonomous University of Madrid, Madrid, Spain.
  • 2 Pediatric Endocrinology, La Paz University Hospital, Madrid, Spain.
  • 3 Pediatric Otorhinolaryngology, La Paz University Hospital, Madrid, Spain.
  • 4 Child and Adolescent Psychiatry, La Paz University Hospital, Madrid, Spain.
  • 5 Functional and Structural Genomics, Institute for Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Madrid, Spain.
  • 6 Bioinformatics Unit, Institute for Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Madrid, Spain.
  • 7 Department of Radiology, Ramón y Cajal Hospital, Madrid, Spain.
PMID: 30591955 DOI: 10.1210/js.2018-00144
Abstract

Transducin β-like 1 X-linked (TBL1X) gene encodes a subunit of the nuclear corepressor-silencing mediator for retinoid and Thyroid Hormone Receptor complex (NCoR-SMRT) involved in repression of thyroid hormone action in the pituitary and hypothalamus. TBL1X defects were recently associated with central hypothyroidism and hearing loss. The current study aims to describe the clinical and genetic characterization of a male diagnosed with central hypothyroidism through thyroid hormone profiling, TRH test, brain MRI, audiometry, and psychological evaluation. Next-generation Sequencing of known genes involved in thyroid disorders was implemented. The 6-year-old boy was diagnosed with central hypothyroidism [free T4: 10.42 pmol/L (normal: 12 to 22 pmol/L); TSH: 1.57 mIU/L (normal: 0.7 to 5.7 mIU/L)], with a mildly reduced TSH response to TRH. He was further diagnosed with attention-deficit/hyperactivity disorder (ADHD) at 7 years, alternating episodes of encopresis and constipation, and frequent headaches. MRI showed a normal pituitary but detected a Chiari malformation type I (CMI). At 10 years, audiometry identified poor hearing threshold at high frequencies. Sequencing revealed a nonsense hemizygous mutation in TBL1X [c.1015C>T; p.(Arg339Ter)] largely truncating its WD-40 repeat domain involved in nuclear protein-protein interactions. In conclusion, to our knowledge, we identified the first severely truncating TBL1X mutation in a patient with central hypothyroidism, hypoacusia, and novel clinical features like ADHD, gastrointestinal dysmotility, and CMI. Given the relevance of TBL1X and NCoR-SMRT for the regulation of transcriptional programs at different tissues (pituitary, cochlea, brain, fossa posterior, and cerebellum), severe mutations in TBL1X may lead to a distinct syndrome with a phenotypic spectrum wider than previously reported.

Keywords

22 hearing loss; Chiari malformation type I; TBL1X gene; attention deficit hyperactivity disorder; central hypothyroidism.

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