# Resistance to thyroid hormone beta (R243Q) with autoimmune primary hypothyroidism: report of a kindred

## TL;DR

A family with a rare thyroid hormone resistance mutation and autoimmune thyroid disease is reported, highlighting diagnostic challenges.

## Contribution

Reports a rare coexistence of RTHβ and autoimmune hypothyroidism in an Indian family with a novel THRB mutation.

## Key findings

- A THRB gene mutation (c.728 G>A; p.Arg243Gln) was identified in family members with RTHβ and autoimmune thyroid disease.
- High thyrotropin with normal or high-normal thyroid hormone levels indicated RTHβ in the presence of hypothyroidism.
- Levothyroxine and beta-blocker therapies were used to manage symptoms in affected family members.

## Abstract

The syndrome of resistance to thyroid hormone beta (RTHβ) is characterized
by impaired tissue responsiveness to thyroid hormone and manifests as
non-suppressed thyrotropin despite elevated thyroid hormone levels. RTHβ
is most often caused by missense mutations in the thyroid hormone receptor beta
(THRB) gene and is typically inherited in an autosomal
dominant manner. Autoimmune thyroid disease is the most common cause of primary
hypothyroidism worldwide. Association of RTHβ with autoimmune
hypothyroidism is extremely rare. We describe an Indian kindred with a similar
association. The proband, a 49-year-old female, manifested elevated
anti-thyroglobulin antibodies, with an unusual thyroid function test pattern,
suggesting mid-normal to high-normal free thyroid hormone levels despite a
significantly elevated thyrotropin (free T3 = 4.2 pg/mL; free T4 = 1.37 ng/dL;
thyrotropin = 91.82 mIU/L). Family screening revealed a biochemical picture
consistent with RTHβ in her elder sister, treated for hypothyroidism, and
a daughter who is presently euthyroid with raised anti-thyroglobulin
autoantibodies. Both the proband and her daughter harbored a missense mutation
in exon 8 of the THRB gene (c. 728 G>A; p. Arg243Gln) that
is known to impair TRβ function in experimental studies. Considering the
hypothyroid state, the proband was started on levothyroxine, with a target to
maintain thyrotropin in the normal range, while the daughter received
beta-blocker therapy, which relieved her palpitations. To conclude, the
coexistence of RTHβ and primary hypothyroidism can delay diagnosis as
thyroid hormone levels appear deceptively normal. A discordance between
thyrotropin and thyroid hormone, i.e., high thyrotropin with inappropriately
normal or high-normal thyroid hormone levels, should prompt this
association.