title: Resistance to Thyroid Hormone Alpha in an 18-Month-Old Girl: Clinical, Therapeutic, and Molecular Characteristics.
abstract: BACKGROUND
  Recently, the first patients with resistance to thyroid hormone alpha (RTHα) due to inactivating mutations in the thyroid hormone receptor alpha (TRα) were identified. These patients are characterized by growth retardation, variable motor and cognitive defects, macrocephaly, and abnormal thyroid function tests. The objective was to characterize a young girl (18 months old) with a mutation in both TRα1 and TRα2, and to study the effects of early levothyroxine (LT4) treatment.
  
  
  METHODS
  The patient was assessed clinically and biochemically before and during 12 months of LT4 treatment. In addition, the consequences of the mutation for TRα1/2 receptor function were studied in vitro.
  
  
  RESULTS
  At 18 months of age, the patient presented with axial hypotonia, delayed motor development, severe growth retardation, and abnormally elevated triiodothyronine (T3)/thyroxine (T4) ratios. RTHα was suspected, and concomitantly a c.632A>G/p.D211G missense mutation was identified, affecting both the TRα1 and TRα2 proteins. This mutation was also found in the girl's father. LT4 treatment was started, resulting in a marked improvement of her hypotonia, motor skills, and growth. Functionally, the missense mutation led to decreased transcriptional activity of TRα1, which could be overcome by higher T3 levels in vitro. The mutant TRα1 showed a moderate dominant negative activity on wild type (WT) TRα1. In contrast, WT TRα2 and mutant TRα2 had negligible transcriptional activity and showed no dominant-negative effect over TRα1.
  
  
  CONCLUSIONS
  This report describes the phenotype of a young RTHα patient with a mild TRα mutation before and during early LT4 treatment. Treatment had beneficial effects on her muscle tone, motor development, and growth.
authors.affiliation: 1 Department of Internal Medicine, Erasmus University Medical Center , Rotterdam, The Netherlands .|2 Rotterdam Thyroid Center, Department of Internal Medicine, Erasmus University Medical Center , Rotterdam, The Netherlands .
authors.forename: Anja L M
authors.initials: AL
authors.lastname: van Gucht
authors.affiliation: 1 Department of Internal Medicine, Erasmus University Medical Center , Rotterdam, The Netherlands .|2 Rotterdam Thyroid Center, Department of Internal Medicine, Erasmus University Medical Center , Rotterdam, The Netherlands .
authors.forename: Marcel E
authors.initials: ME
authors.lastname: Meima
authors.affiliation: 3 Department of Pediatric Endocrinology, Emma Children's Hospital, Academic Medical Center , Amsterdam, The Netherlands .
authors.forename: Nitash
authors.initials: N
authors.lastname: Zwaveling-Soonawala
authors.affiliation: 1 Department of Internal Medicine, Erasmus University Medical Center , Rotterdam, The Netherlands .|2 Rotterdam Thyroid Center, Department of Internal Medicine, Erasmus University Medical Center , Rotterdam, The Netherlands .
authors.forename: W Edward
authors.initials: WE
authors.lastname: Visser
authors.affiliation: 4 Department of Endocrinology and Metabolism, Amsterdam University Medical Center , Amsterdam, The Netherlands .
authors.forename: Eric
authors.initials: E
authors.lastname: Fliers
authors.affiliation: 5 Department of Pediatrics, St. Lucas Andreas Hospital , Amsterdam, The Netherlands .
authors.forename: Johanna M B
authors.initials: JM
authors.lastname: Wennink
authors.affiliation: 6 Practice of Pediatric Physiotherapy, Sport Medical Center , Amsterdam, The Netherlands .
authors.forename: Civile
authors.initials: C
authors.lastname: Henny
authors.affiliation: 1 Department of Internal Medicine, Erasmus University Medical Center , Rotterdam, The Netherlands .|2 Rotterdam Thyroid Center, Department of Internal Medicine, Erasmus University Medical Center , Rotterdam, The Netherlands .
authors.forename: Theo J
authors.initials: TJ
authors.lastname: Visser
authors.affiliation: 1 Department of Internal Medicine, Erasmus University Medical Center , Rotterdam, The Netherlands .|2 Rotterdam Thyroid Center, Department of Internal Medicine, Erasmus University Medical Center , Rotterdam, The Netherlands .
authors.forename: Robin P
authors.initials: RP
authors.lastname: Peeters
authors.affiliation: 3 Department of Pediatric Endocrinology, Emma Children's Hospital, Academic Medical Center , Amsterdam, The Netherlands .
authors.forename: A S Paul
authors.initials: AS
authors.lastname: van Trotsenburg
mesh_terms: D002460:Cell Line; D002657:Child Development; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D013960:Thyroid Function Tests; D037021:Thyroid Hormone Receptors alpha / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D018382:Thyroid Hormone Resistance Syndrome / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D013974:Thyroxine / Q000627:therapeutic use; D014162:Transfection; D016896:Treatment Outcome
chemical_list: D037021:Thyroid Hormone Receptors alpha; D013974:Thyroxine