Congenital hypothyroidism and apparent athyreosis with compound heterozygosity or compensated hypothyroidism with probable hemizygosity for inactivating mutations of the TSH receptor

Clin Endocrinol (Oxf). 2004 Feb;60(2):220-7. doi: 10.1111/j.1365-2265.2004.01967.x.


Objective: We wished to ascertain whether mutations in the TSH receptor (TSHR) gene were present in two siblings with congenital hypothyroidism with no parental consanguinity.

Design: The pituitary-thyroid axis and thyroid gland morphology were investigated in both affected siblings and their parents. The TSHR gene was analysed in each subject.

Measurements: Basal thyroid function together with circulating thyroglobulin levels were measured in each subject. In addition, a TRH stimulation test was undertaken in each parent. All family members underwent thyroid ultrasonography. The TSHR gene was amplified from genomic DNA using the polymerase chain reaction and receptor mutations were identified by sequence analysis.

Results: Two siblings were diagnosed with severe congenital hypothyroidism (total T4 19-21 nmol/l, TSH 160-230 mU/l on neonatal screening). Although radioiodine scanning showed no tracer uptake and ultrasound imaging in both individuals failed to demonstrate thyroid tissue, suggesting complete athyreosis, circulating thyroglobulin levels were measurable. The thyroid status of the parents was discordant: in the father, baseline thyroid function (FT4 13 pmol/l, TSH 4 mU/l), the peak TSH level after TRH stimulation (30 mU/l) were normal and he exhibited an appropriate rise in circulating thyroid hormones in response to the elevated TSH; in contrast, in the mother, baseline thyroid function was abnormal (FT4 10 pmol/l, TSH 15 mU/l), the TSH response to TRH was exaggerated (110 mU/l), with no subsequent rise in circulating thyroid hormones. An eutopic, slightly hypoplastic thyroid gland was visualized on ultrasonography in the mother and her thyroid antibody status was negative. Both children were compound heterozygotes for missense (alanine to threonine at codon 553, A553T) and premature stop (tryptophan at codon 546, W546X) mutations in the fourth transmembrane domain of the TSH receptor. The mother and father were heterozygous for W546X and A553T mutations, respectively. Each mutation is known to abolish the function or cellular surface expression of the TSH receptor.

Conclusions: Inactivating mutations in the TSH receptor can be associated with severe TSH resistance presenting as congenital hypothyroidism with apparent athyreosis. Our observations also suggest that heterozygosity for an inactivating TSHR mutation may be associated with compensated hypothyroidism and thyroid hypoplasia.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Congenital Hypothyroidism*
  • Female
  • Gene Deletion*
  • Heterozygote
  • Humans
  • Hypothyroidism / genetics
  • Hypothyroidism / physiopathology
  • Infant, Newborn
  • Male
  • Neonatal Screening
  • Pedigree
  • Receptors, Thyrotropin / genetics*
  • Sequence Analysis, DNA
  • Thyroid Function Tests
  • Thyroid Gland / abnormalities*
  • Thyroid Gland / diagnostic imaging
  • Thyroid Gland / physiopathology
  • Thyrotropin-Releasing Hormone
  • Ultrasonography


  • Receptors, Thyrotropin
  • Thyrotropin-Releasing Hormone