Resistance to thyroid hormone (RTH) is a rare hereditary syndrome with impaired sensitivity to thyroid hormones (TH) and reduced intracellular action of triiodothyronine (T3) caused by genetic variants of TH receptor beta (TRB) or alpha (TRA). RTH type beta (RTHβ) due to dominant negative variants in the TRB gene usually occurs with persistent elevation of circulating free TH, non-suppressed serum TSH levels responding to a thyrotropin-releasing hormone (TRH) test, an absence of typical symptoms of hyperthyroidism and goiter. Here, we present a rare variant in the TRB gene reported for the first time in an Italian patient with generalized RTHβ syndrome. The patient showed elevated TH, with non-suppressed TSH levels and underwent thyroid surgery two different times for multinodular goiter. The genetic test showed a heterozygous mutation in exon 9 of the TRB gene resulting in the replacement of threonine (ACG) with methionine (ATG) at codon 310 (p.M310T). RTHβ syndrome should be considered in patients with elevated TH, non-suppressed TSH levels and goiter.
Learning points
• Resistance to thyroid hormone (RTH) is a rare autosomal dominant hereditary syndrome with impaired tissue responsiveness to thyroid hormones (TH).
• Diagnosis of RTH is usually based on the clinical finding of discrepant thyroid function tests and confirmed by a genetic test.
• RTH is a rare condition that must be considered for the management of patients with goiter, elevation of TH and non-suppressed serum TSH levels in order to avoid unnecessary treatments.
Keywords: Adult; Female; White; Italy; Thyroid; Thyroid; Oncology; Unique/unexpected symptoms or presentations of a disease; May; 2021
Thanks for posting. There are a number of similar case studies. RTH due to mutations of the TH receptor beta (TRB) gene usually presents with elevated free thyroid hormones and a non-suppressed TSH. Sometimes the thyroid fails from the stress of excess secretion or concurrent autoimmune thyroiditis, in these cases there may not be elevated thyroid hormones but elevated TSH. It's worth noting that in about 15% of cases a mutation is not found. RTH TRB was discovered by Sam Refetoff, his colleague Roy Weiss gives a very good overview here ncbi.nlm.nih.gov/pmc/articl... .
The very rare cases of RTH due to TH receptor alpha (TRA) gene are usually very severe with bone deformations and mental retardation.
I believe a much more common form of RTH is caused by endocrine disrupting chemicals which can disrupt thyroid hormone binding in peripheral tissues with negligible effect on the pituitary. This is an artifact of testing of potential EDCs which includes feeding them to rodents and running TFTs. Substances which cause abnormal TFTs do not get approval, thus only harmful substances which cannot be detected with TFTs are approved! I call this 'Acquired Resistance to Thyroid Hormone (ARTH)'.
Thanks for posting. I’m always interested in these new findings as I’m someone with non-suppressed TSH along with elevated thyroid hormones. I’ve had genetic testing for variants in the beta receptor, but none have been detected. So now I’m awaiting further DNA phenotyping, which may be a fairly long wait!
There are many mutations on the gene. The same mutation in a family may have different presentations in individuals and no mutation is found in some cases. There's a whole load of technical stuff on the mutations which I'm not into.
I can look up SNPs on my raw data in 23& me but the ways the genes are usually described means nothing to me and is not useful for searching the raw data. I do have one mutation for it.
I have never got into the specific mutations, they are on a particular region of the gene. I don't think it matters from a practical viewpoint as there are so many mutations with slightly varying effects.
As for 23&me I place more reliance on the fortune teller at the local fair.
But the raw data can be checked against snps it can’t all be nonsense or made up, surely. The one supposedly close relative I have in there led to naught but she was not exactly forthcoming to try and find any link. Most of my own relatives are a sight brighter than she seemed to be and who knows what skeletons in cupboards might exist in a family? I do have a friend who discovered who her real father was by registering with it and that was without a doubt. She was gobsmacked to discover her father was Pakistani (& her mother Israeli but that was discovered through tracing not genetic testing) . She could never have found out all that without it and there is no doubt whatsoever it is correct. It was deffo more than a bit better than any fortune teller at a local fair in her case, I’d say.
My brother ran a test. We are half English half Irish but the test said we had lots of ancestors from South America and no Irish ancestors. I also did a simple course on genetics at the Royal Institution and the teacher said these sorts of tests are not much use.
The tests for specific e.g. DIO2 polymorphisms no doubt work (but not much use) but the ones aimed at the general public are more for amusment than science.
They were of use to my pal and in my case have revealed some interesting data that could explain some of my problems with my thyroid and poor response to T4. The ancestry info seems to fit with what I know of my maternal line. It shows genetic links in an area where I know I had an ancestor many generations back. Unless they were properly independently investigated for quality and accuracy it’s anyone’s guess if it’s a good sound genetic analysis or not. It’s not my area but it was spot on with my friend’s paternal ancestry. Do you think they mixed up your brother’s sample with someone else or it’s just 💩? Maybe if the genetics are really closely related like in her case they do get it right sometimes.
It’s the only article I can find giving some detail of why the tests are not so good as say you’d get on the NHS. I’ve had two on NHS, but I don’t know if I could access them .
I have underactive thyroids doctors said I have mutations gene, from my patients. I have both of them had 2 different genes which is y I'm on 200mg levothyroxine a day and 20mg Atorvastin, my cholesterol isn't bad because of diet its because I was born with this mutation. Found out that I had underactive thyroid 8 years ago. I have learnt this information from my doctor after more tests. I new to no if I have passed it on to my children. 2 years ago my daughter was 20 and she suddenly got ill were i rushed her to hospital. I thought she was dieing,She was diagnosed with type 1 DIABETES, and she her pancreas was the size of a 82 Yr old.
It took weeks in hospital until doctors found out I gave it to her.
I really need to no more about wot I should do with my other 3 children. Do I need to get them tested or is it kk not 2 x
Your genetic issues are way beyond the experience of most members - certainly far beyond what I know anything about.
I think you need proper genetic counselling - for which start by talking to your GP. There are genetic counselling services within at least some parts of the NHS.
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