Can thyroxine (T4) resistance syndrome occur in patients with a negative genetic test?

Can Thyroid Hormone Resistance Syndrome Occur with Negative Genetic Testing?

Yes, thyroid hormone resistance syndrome can absolutely occur despite negative genetic testing, as approximately 10-15% of patients meeting clinical criteria for resistance to thyroid hormone (RTH) have no identifiable mutation in the THRB or THRA genes, often due to somatic mosaicism or limitations in current testing methods. 1, 2

Understanding the Genetic Limitations

The genetic basis of RTH is well-established, with mutations in the thyroid hormone receptor beta (THRB) gene responsible for the vast majority of cases—specifically, 122 different mutations have been identified across 300 families 3. However, the detection rate is imperfect:

• Mutation detection occurs in only 74-82% of clinically diagnosed cases 1, 2
• In one study of 58 patients with biochemical patterns suggesting RTH, only 26% (15/58) had confirmed THRB mutations 1
• Mosaicism can result in pathogenic variants present at very low allele frequencies (1-2%), which may be missed by standard genetic testing 4
• The pathogenic variant may be present only in specific tissues, making blood-based genetic testing falsely negative 4

Clinical Diagnosis Remains Paramount

The diagnosis of RTH is fundamentally clinical and biochemical, not purely genetic:

Diagnostic Criteria

• Elevated serum free T4 and free T3 concentrations 3, 2
• Normal or slightly elevated TSH levels (not suppressed as expected with thyrotoxicosis) 3, 1
• Goiter present in most cases 3, 2
• Absence of typical symptoms and metabolic consequences of thyroid hormone excess 3

When to Suspect RTH Despite Negative Genetics

• Family history of thyroid abnormalities is present in 77.3% of cases 2
• Patients are often asymptomatic or have minimal symptoms despite markedly elevated thyroid hormones 1
• Previous inappropriate treatments (thyroidectomy, radioablation) due to misdiagnosis as primary thyrotoxicosis 3, 2

Critical Differential Diagnosis Steps

Before concluding a patient has RTH with negative genetics, you must systematically exclude:

1. Analytical Interference (Most Common Alternative)

• Repeat thyroid function tests using a different immunoassay platform (e.g., if initial testing on Roche, repeat on Siemens ADVIA Centaur) 1
• In one series, 26% of suspected RTH cases were actually due to analytical interference that resolved with alternative testing methods 1
• Biological interference from thyroid hormone transport protein variants (albumin, transthyretin, thyroxine-binding globulin) accounts for 24% of cases with discordant results 1

2. TSH-Secreting Pituitary Adenoma

• This is the most critical alternative diagnosis to exclude 3
• Requires pituitary MRI imaging
• Failure to differentiate RTH from TSH-secreting adenoma has resulted in inappropriate treatment in nearly one-third of patients 3

3. Familial Dysalbuminemic Hyperthyroxinemia

• Screen for mutations in ALB, TTR, and SERPINA7 genes 1
• These patients are typically completely asymptomatic 1

Recommended Diagnostic Algorithm

For patients with elevated free T4/T3 and non-suppressed TSH:

1. Repeat thyroid function tests (TSH, free T4, free T3) using a different analytical platform 1

2. If discordance persists, obtain:

   • Pituitary MRI to exclude TSH-secreting adenoma 3
   • Family history assessment (77% have positive family history) 2
   • Clinical assessment for goiter and symptoms 3, 2

3. Genetic testing sequence:

   • First-line: THRB gene sequencing 1, 2
   • If negative and clinical suspicion remains high: Consider high-sensitivity genetic analysis to detect mosaicism at allele frequencies as low as 1-2% 4
   • Screen for transport protein variants: ALB, TTR, SERPINA7 1

4. If all genetic testing is negative but clinical picture strongly suggests RTH:

   • The diagnosis of RTH can still be made on clinical and biochemical grounds alone 3
   • Document the clinical classification (generalized resistance vs. pituitary resistance) 3
   • Provide genetic counseling regarding the 1-2% risk of germline mosaicism affecting future offspring 4

Management Implications

The absence of a genetic mutation does not change clinical management:

• No specific treatment is typically required for RTH 3
• The primary value of diagnosis is preventing inappropriate treatment (thyroidectomy, radioiodine ablation) that has occurred in 18.2% of cases due to misdiagnosis 2
• Genetic counseling should still be offered, as familial transmission can occur even without identified mutations 3, 2
• Family screening is warranted given the high rate of familial cases 2

Common Pitfalls to Avoid

• Never assume negative genetics excludes RTH—10-15% of clinical cases have no identifiable mutation 1, 2
• Always repeat testing with a different assay before pursuing extensive genetic workup, as analytical interference is common 1
• Do not treat elevated thyroid hormones with antithyroid drugs or ablation without excluding RTH, as this has led to inappropriate thyroidectomy in multiple reported cases 3, 2
• Remember that older patients (mean age 24.8 years in one series, range 22 days to 70 years) may present later in life, and age alone does not exclude the diagnosis 2