Non-Autoimmune Hyperthyroidism Associated With a Novel Germline Mutation (D633N) in the TSH Receptor.

Area of Science:

• Endocrinology
• Genetics
• Internal Medicine

Background:

• Nonautoimmune hyperthyroidism due to activating germline TSHR mutations is rare and diagnostically challenging.
• The case involves a 75-year-old woman with a long history of goiter and subclinical hyperthyroidism who developed overt thyrotoxicosis.

Purpose of the Study:

• To report a case of nonautoimmune hyperthyroidism caused by a novel TSHR gene mutation.
• To emphasize the diagnostic considerations for antibody-negative hyperthyroidism, particularly in elderly patients.

Main Methods:

• Clinical case presentation and management.
• Laboratory testing including TSH, TRAb, and TSAb.
• Radioactive iodine therapy, methimazole, dexamethasone, and total thyroidectomy.
• Histopathological examination of thyroid tissue.
• Postoperative genetic analysis of peripheral blood DNA for TSHR mutations.
• Functional analysis of the identified TSHR variant.

Main Results:

• The patient presented with thyrotoxicosis, negative TRAb/TSAb, and resistance to initial potassium iodide treatment.
• Radioactive iodine therapy led to severe destructive thyroiditis and heart failure.
• Hormonal control with methimazole and dexamethasone, followed by thyroidectomy, normalized thyroid function.
• Histopathology showed adenomatous goiter.
• Genetic analysis revealed a novel heterozygous germline TSHR mutation (c.1897G > A, p.D633N).
• Functional analysis indicated modest constitutive activity of the TSHR variant.

Conclusions:

• The identified TSHR mutation expands the known spectrum of activating mutations causing nonautoimmune hyperthyroidism.
• The variant's modest constitutive activity may explain the late clinical onset.
• Considering nonautoimmune hyperthyroidism, including genetic causes, is crucial for antibody-negative hyperthyroidism, irrespective of age or family history.