What is the diagnosis and treatment for a 15-year-old male with hypothyroid-stimulating hormone (TSH) levels, elevated free triiodothyronine (free T3) levels, low free thyroxine (free T4) levels, and normal thyroglobulin and thyroglobulin antibody levels?

Diagnostic Evaluation for Thyroid Hormone Resistance (THR)

This 15-year-old male most likely has thyroid hormone resistance (THR), a rare genetic disorder where tissues are insensitive to thyroid hormone despite elevated T3 and T4 levels, and this should be confirmed with thyroid hormone receptor beta gene sequencing. 1, 2

Understanding the Laboratory Pattern

The combination of low TSH with high free T3 and low free T4 is highly unusual and does not fit typical thyroid disorders:

• Classic hyperthyroidism (Graves' disease, toxic nodular goiter) presents with low TSH, high free T4, and high free T3 3, 4
• Central hypothyroidism (hypophysitis) presents with low TSH, low free T4, and low free T3 5
• This patient's pattern (low TSH, high T3, low T4) suggests either thyroid hormone resistance or laboratory artifact 1, 2

Most Likely Diagnosis: Thyroid Hormone Resistance

Thyroid hormone resistance is characterized by:

• Elevated free T3 and free T4 levels with inappropriately normal or elevated TSH (though TSH can be low in some variants) 1, 2
• Mutations in the thyroid hormone receptor beta gene causing end-organ insensitivity to thyroid hormones 1
• Patients may have goiter, tachycardia, or palpitations despite the resistance 1
• The disorder is often misdiagnosed as Graves' disease due to similar clinical presentations 1, 2

However, the low free T4 in this case is atypical - classic THR presents with both elevated T3 and T4. This discrepancy requires careful consideration of:

• Laboratory error or interference - repeat all thyroid function tests including TSH, free T4, free T3, and total T4 6
• Binding protein abnormalities - measure thyroid binding globulin (TBG) directly 6
• Assay interference - some antibodies or medications can cause spurious results 6

Immediate Diagnostic Workup

Confirm the laboratory findings first:

• Repeat TSH, free T4, free T3, total T4, and total T3 in a different laboratory to rule out assay interference 6
• Measure thyroid binding globulin (TBG) levels directly 6
• Check thyroid peroxidase (TPO) antibodies and TSH receptor antibodies (TRAb) 5, 3

If abnormalities persist, proceed with:

• Thyroid ultrasound to assess gland size and structure 3
• Thyroid uptake scan (I-123 or Tc-99m) - high uptake suggests Graves' disease or THR, low uptake suggests thyroiditis 4
• Thyroid hormone receptor beta gene sequencing - this is the definitive test for THR 1, 2

Differential Diagnosis to Exclude

Graves' disease with concurrent THR:

• This rare combination has been reported and presents diagnostic challenges 1, 2
• Positive TSH receptor antibodies (TRAb) and thyroid-stimulating antibodies (TSAb) indicate Graves' disease 2
• High thyroid uptake on nuclear scan supports Graves' disease 1, 2
• Both conditions can coexist, requiring gene sequencing for definitive diagnosis 1

Central hypothyroidism (hypophysitis):

• Would present with low TSH, low free T4, and low free T3 (not high T3) 5
• Common with immune checkpoint inhibitors (ipilimumab, nivolumab) - not relevant in a 15-year-old without cancer treatment 5
• MRI of the sella would show pituitary enlargement or abnormalities 5

Thyrotoxicosis from thyroiditis:

• Presents with high free T4 and T3, low TSH, but low thyroid uptake on nuclear scan 3, 4
• Usually transient and self-limited 3

Treatment Approach

If thyroid hormone resistance is confirmed:

• No treatment is typically required if the patient is clinically euthyroid (no symptoms of hyper- or hypothyroidism) 1, 2
• Monitor thyroid function every 3-6 months initially to ensure stability 6
• Genetic counseling should be offered as THR is inherited in an autosomal dominant pattern 1

If Graves' disease coexists with THR (positive TRAb/TSAb, high uptake):

• Antithyroid drugs (methimazole) can induce remission even in patients with concurrent THR 2
• Treatment duration is typically 12-18 months, though longer courses (5-10 years) reduce recurrence rates 3
• Monitor for remission by checking TRAb and TSAb titers 2

Critical pitfall to avoid:

• Never start thyroid hormone replacement before ruling out adrenal insufficiency in cases of suspected central hypothyroidism, as this can precipitate adrenal crisis 5
• However, this patient's high T3 makes central hypothyroidism unlikely 5

When to Refer to Endocrinology

Immediate referral is warranted for:

• Persistent abnormal thyroid function tests after repeat testing 6
• Need for thyroid hormone receptor gene sequencing 1
• Presence of goiter, thyroid nodules, or other structural abnormalities 6
• Symptoms of thyrotoxicosis (palpitations, weight loss, heat intolerance) despite unclear diagnosis 3
• Consideration of radioactive iodine therapy or thyroidectomy if Graves' disease is confirmed 3, 4

Common Pitfalls

• Mistaking THR for Graves' disease - both can present with goiter, high thyroid hormones, and high uptake, but TSH is typically normal or elevated in THR (not suppressed) 1, 2
• Treating based on a single abnormal test - 30-60% of abnormal thyroid tests normalize on repeat testing 7
• Ignoring the low free T4 - this is atypical for both Graves' disease and classic THR, suggesting possible laboratory interference or binding protein abnormality 6
• Initiating treatment without confirming the diagnosis - inappropriate thyroid hormone or antithyroid drug therapy can cause significant morbidity 7, 3