The Genetics and Biology of TRH Resistance
At a Glance
TRH resistance syndrome results from changes in both copies of the TRHR gene. The pituitary cannot respond properly to TRH, so it releases too little TSH and Free T4 falls. Because TSH may be normal or only slightly abnormal, TSH-only newborn screening can miss the condition.
Understanding the biology of TRH Resistance Syndrome requires looking at the communication lines between the brain and the body. In most cases of thyroid disease (primary hypothyroidism), the problem is in the thyroid gland itself. In your child’s case, the thyroid gland is structurally capable of working, but the signaling pathway it uses to receive instructions is malfunctioning [1][2].
The TRHR Gene: An Impaired Antenna
The instructions for building the “antenna” on your pituitary gland are found in the TRHR gene [1]. This antenna is officially called the Thyrotropin-Releasing Hormone Receptor. Normally, when the brain senses that thyroid levels are low, it sends out a signal called TRH (Thyrotropin-Releasing Hormone) [3]. This signal lands on the receptor, triggering an internal process that tells the pituitary gland to release TSH (Thyroid-Stimulating Hormone), which finally stimulates the thyroid [4].
In TRH Resistance, the child has inherited two non-working copies of the TRHR gene (a biallelic defect) [1]. Because of these mutations, the antenna might:
- Fail to catch the signal: The receptor is present, but it cannot bind effectively to the TRH hormone [1].
- Fail to send the internal message: The receptor binds the signal, but the internal “wiring” is broken, so the message never reaches the rest of the cell [4].
Because the pituitary gland can’t process the brain’s call for more thyroid hormone, it doesn’t release enough TSH. Without TSH, the thyroid gland remains under-stimulated, leading to low levels of the vital hormone Free T4 [1][5].
Why Standard Screening Often Fails
Many newborn screening programs use a TSH-only test [6]. This test is designed to find primary hypothyroidism. In primary cases, the pituitary gland is working perfectly and screaming for more hormone, which makes TSH levels skyrocket [5].
However, in TRH Resistance (a form of central hypothyroidism), the TSH levels are often:
- Normal: The pituitary is doing its baseline job but isn’t ramping up like it should [1].
- Mildly Low or Slightly Elevated: Even if TSH is slightly high, it is “inappropriately normal or low” compared to how low the Free T4 is [5][7].
Because the TSH number doesn’t look like a typical thyroid problem, many babies with this condition pass their newborn screening and are only diagnosed later when a doctor evaluates growth delays or checks a full thyroid panel that includes Free T4 [1][8].
Comparing Genetic Causes
TRH Resistance is one of several genetic reasons for central hypothyroidism. Your doctors may consider other conditions when making a diagnosis:
- TSHB Deficiency: This often presents with very severe hypothyroidism soon after birth [9].
- IGSF1 Deficiency: This is the most common recognized genetic cause of central congenital hypothyroidism to date, usually affecting boys. It can also involve low prolactin or changes in how the child goes through puberty [10][11].
- TBL1X Deficiency: This condition is often linked to hearing loss alongside thyroid issues [12].
TRH Resistance is an isolated disorder, meaning it typically only impacts the thyroid signaling system rather than multiple hormone systems [4][11].
Understanding Genetic Testing Terms
When discussing genetics, your doctor may use specific terms:
- Biallelic: Having two variant copies of a gene, one inherited from each parent.
- Segregation Testing: Testing the parents and other family members to confirm exactly how the gene mutations were passed down. This helps confirm the diagnosis and assess risks for future pregnancies.
Common questions in this guide
What gene is involved in TRH resistance syndrome, and how is it inherited?
Why might a baby with TRH resistance pass newborn screening?
How do TRHR mutations affect thyroid hormone production?
How is TRH resistance different from other genetic forms of central hypothyroidism?
Could other pituitary hormones be affected in TRH resistance?
What do biallelic variants and segregation testing mean?
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References
References (12)
- 1
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Biochemical and physiological insights into TRH receptor-mediated signaling.
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Frontiers in cell and developmental biology 2022; (10()):981452 doi:10.3389/fcell.2022.981452.
PMID: 36147745 - 3
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Nature reviews. Endocrinology 2017; (13(10)):588-598 doi:10.1038/nrendo.2017.47.
PMID: 28549061 - 4
Central Hypothyroidism Due to a TRHR Mutation Causing Impaired Ligand Affinity and Transactivation of Gq.
García M, González de Buitrago J, Jiménez-Rosés M, et al.
The Journal of clinical endocrinology and metabolism 2017; (102(7)):2433-2442 doi:10.1210/jc.2016-3977.
PMID: 28419241 - 5
Neonatal screening for primary and central congenital hypothyroidism: is it time to go Dutch?
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European thyroid journal 2023; (12(4)).
PMID: 37326450 - 6
DIAGNOSIS OF ENDOCRINE DISEASE: Congenital hypothyroidism: update and perspectives
Peters C, van Trotsenburg ASP, Schoenmakers N
European journal of endocrinology 2018; (179(6)):R297-R317 doi:10.1530/EJE-18-0383.
PMID: 30324792 - 7
TSH and FT4 Concentrations in Congenital Central Hypothyroidism and Mild Congenital Thyroidal Hypothyroidism.
Zwaveling-Soonawala N, van Trotsenburg ASP, Verkerk PH
The Journal of clinical endocrinology and metabolism 2018; (103(4)):1342-1348 doi:10.1210/jc.2017-01577.
PMID: 29325028 - 8
Critical evaluation of the newborn screening for congenital hypothyroidism in the Netherlands.
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European journal of endocrinology 2020; (183(3)):265-273.
PMID: 32580148 - 9
Molecular spectrum of TSHβ subunit gene defects in central hypothyroidism in the UK and Ireland.
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Clinical endocrinology 2017; (86(3)):410-418 doi:10.1111/cen.13149.
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IGSF1 Deficiency: Lessons From an Extensive Case Series and Recommendations for Clinical Management.
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The Journal of clinical endocrinology and metabolism 2016; (101(4)):1627-36 doi:10.1210/jc.2015-3880.
PMID: 26840047 - 11
Recent advances in research on isolated congenital central hypothyroidism.
Tajima T, Nakamura A, Oguma M, Yamazaki M
Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology 2019; (28(3)):69-79 doi:10.1297/cpe.28.69.
PMID: 31384098 - 12
Mutations in TBL1X Are Associated With Central Hypothyroidism.
Heinen CA, Losekoot M, Sun Y, et al.
The Journal of clinical endocrinology and metabolism 2016; (101(12)):4564-4573 doi:10.1210/jc.2016-2531.
PMID: 27603907
This page explains the genetics and biology of TRH resistance syndrome for informational purposes only and does not constitute medical advice. Your child’s pediatric endocrinologist and genetics team should interpret genetic tests, thyroid results, and treatment needs.