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Cited by 75Thyroid Disorders and TreatmentsGenomics and Rare DiseasesGrowth Hormone and Insulin-like Growth Factors

A Novel Mutation in THRA Gene Associated With an Atypical Phenotype of Resistance to Thyroid Hormone

Espiard, Stéphanie, Savagner, Frédérique, Flamant, Frédéric, Vlaeminck-Guillem, Virginie, Guyot, Romain, Munier, Mathilde, d'Herbomez, Michele, Bourguet, William +4 more·2015·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.2015-1120
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Abstract

CONTEXT: RTHα is a recently discovered resistance to thyroid hormone (RTH) due to mutation of THRA, the gene encoding TRα1, the thyroid hormone receptor. It has been described in a few patients with growth retardation, short stature, and a low free T4/free T3 (FT4/FT3) ratio. OBJECTIVE: A 27-year-old patient presenting with dwarfism and a low FT4/FT3 ratio was investigated. DESIGN: Clinical, biochemical, and radiological data were collected. Whole exome sequencing was performed in the patient and her relatives. RESULTS: The patient exhibited congenital macrocytic anemia and severe bone malformation with growth retardation, dwarfism, clavicular agenesis, and abnormalities of the fingers, toes, and elbow joints. In adulthood, she presented with active behavior, chronic motor diarrhea, and hypercalcemia. Treatment with T3 led to heart rate acceleration, worsening of diarrhea, and TSH suppression. Low resting energy expenditure normalized on T3. rT3, SHBG, and IGF-1 remained normal. A de novo monoallelic missense mutation in THRA was discovered, the N359Y amino acid substitution (c.1075A>T), which affected both the TRα1 and the non-receptor isoform TRα2. The mutant TRα1 had a decrease in transcriptional activity related to decreased T3 binding and a dominant-negative effect on the wild-type receptor. CONCLUSIONS: This patient presents a new phenotype including more significant bone abnormalities, lower TSH, and higher FT3 levels, without certainty of all her symptoms with the TRα1(N359Y) mutation. This case suggests that patients with a low FT4/FT3 ratio should be screened for THRA mutations, even if clinical and biological features differ from previous reported cases of RTHα.

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  • The 27-year-old woman with an N359Y substitution affecting both TRα1 and TRα2 had a unique combination of skeletal abnormalities including intrauterine growth retardation and failure to thrive, macrocephaly, hypertelorism, micrognathia, short and broad nose, agenesis of the clavicles and 12th ribs, elongated thorax, ovoid vertebrae, scoliosis, congenital hip dislocation, short limbs and dwarfism,单

    “Her unique combination of skeletal abnormalities includes intrauterine growth retardation and failure to thrive, macrocephaly, hypertelorism, micrognathia, short and broad nose, agenesis of the clavicles and 12th ribs, elongated thorax, ovoid vertebrae, scoliosis, congenital hip dislocation, short limbs and dwarfism, unilateral humero-radial synostosis, elbow dislocation and syndactyly.”

    From Thyroid diseases and bone health (2018) · cites this paper as [68]

  • The TRα1N359Y mutant protein had impaired T3 binding and transactivation function with moderate dominant-negative activity.

    “The TRα1N359Y mutant protein had impaired T3 binding and transactivation function with moderate dominant-negative activity, while no clear functional abnormality of the TRα2N359Y mutant was identified [68, 79].”

    From Thyroid diseases and bone health (2018) · cites this paper as [68]

  • A severe and atypical phenotype was described in a 27-year-old woman with an N359Y substitution affecting both TRα1 and TRα2.

    “Nevertheless, a severe and atypical phenotype was described in a 27-year-old woman with an N359Y substitution affecting both TRα1 and TRα2 [68].”

    From Thyroid diseases and bone health (2018) · cites this paper as [68]

  • No clear functional abnormality of the TRα2N359Y mutant was identified.

    “The TRα1N359Y mutant protein had impaired T3 binding and transactivation function with moderate dominant-negative activity, while no clear functional abnormality of the TRα2N359Y mutant was identified [68, 79].”

    From Thyroid diseases and bone health (2018) · cites this paper as [68]

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Authors
Espiard, S., Savagner, F., Flamant, F., Vlaeminck-Guillem, V., Guyot, R., Munier, M., d'Herbomez, M., Bourguet, W., Pinto, G., Rose, C., Rodien, P., & Wémeau, J.-L.
Affiliations
Lyon 1 Université (FR)
Corresponding author
Espiard, Stéphanie
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2015-08
Volume
100
Issue
8
Pages
2841-2848
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jc.2015-1120
OpenAlex
W1951445306
Cited by
75
References
32
Citations by year
2026: 3 · 2025: 2 · 2024: 6 · 2023: 3 · 2022: 8 · 2021: 4 · 2020: 7 · 2019: 10 · 2018: 5 · 2017: 13 · 2016: 7 · 2015: 7
FWCI
9.25
Type
journal article
Language
en
Open access
closed
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
Keywords
thyroid hormone resistance, thyroid hormone receptor alpha 1, TRα2, de novo missense variant, dwarfism, growth retardation, bone malformations, macrocytic anemia, hypercalcemia, dominant negative effect, TSH suppression, resting energy expenditure, phenotypic variability
MeSH terms
Adult, Diarrhea, Dwarfism, Female, Humans, Hypercalcemia, Musculoskeletal Abnormalities, Phenotype, Germ-Line Mutation, Thyroid Hormone Resistance Syndrome, Genes, erbA, Amino Acid Substitution

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