Detection of neonates with mild congenital hypothyroidism (primary) or isolated hyperthyrotropinemia: an increasingly common management dilemma

Abstract

Anywhere from 10% to 40% of neonates detected by newborn screening programs have mild congenital hypothyroidism (thyroid-stimulating hormone [TSH] 6 to 20 mU/l with borderline low free T4) or isolated hyperthyrotropinemia. The increasing frequency of such cases appears to be chiefly the result of lowering screening TSH cutoffs. In some cases, the etiology is a mild form of dysgenesis or dyshormonogenesis; most cases, however, on imaging have gland in situ of unexplained etiology. Re-evaluation after age 3 years shows some with transient hypothyroidism, a minority with permanent hypothyroidism, while the majority have persistent, mild TSH elevation and normal free T4. There is limited data on neurodevelopmental outcome to guide management. In cases where the TSH is trending down and free T4 is normal, we recommend re-checking serum TSH and free T4 at weekly intervals. If serum TSH does not normalize by 4 weeks of age, we recommend treatment, with re-evaluation after age 2–3 years.

Keywords::

• congenital hypothyroidism
• gland in situ
• hyperthyrotropinemia
• newborn screening
• serum free T4
• serum TSH
• subclinical hypothyroidism
• thyroid
• thyroid dysgenesis
• thyroid dyshormonogenesis
• thyroid-stimulating hormone cutoff

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Neonates with mild hypothyroidism, which we define as a serum thyroid-stimulating hormone (TSH) between 6 and 20 mU/l with a borderline low free T4 level, or isolated hyperthyrotropinemia, make up between 10 and 40% of cases detected by some NBS programs.

• The increasing frequency of such cases appears primarily to be the result of lowering of the screening TSH cut-off, which, for example, in some programs has dropped from 40 mU/l in serum (20 mU/l whole blood) to 20 mU/l (10 mU/l whole blood).

• Lowering the screening TSH cut-off will increase the rate of false positives; in the Lombardy NBS program, when the TSH cut-off was lowered from 20 mU/l (whole blood) to 12 mu/l and then to 10 mU/l, the recall rate increased from 0.08 to 0.87% [5].

• Infants born preterm and Down syndrome babies often have mild thyroid dysfunction, though preterm infants have an atypical pattern of thyroid dysfunction characterized by delayed TSH elevation.

• Imaging studies show a eutopic thyroid ‘gland in situ’ in many/most of these mild congenital hypothyroidism (CH) cases (including babies born preterm and those with Down syndrome).

• Re-evaluation of thyroid function after age 3 years shows that, while these cases are more likely to have transient hypothyroidism, most will have a persistent, but mild form of SCH characterized by mild TSH elevation (5–10 mU/l) and normal free T4 levels.

• The underlying etiology of the thyroid defect has been established in some cases, for example, mild dysgenesis due to TSH receptor mutations, thyroid ectopy, hypoplasia or hemiagenesis and mild forms of dyshormonogenesis, caused by partial iodide organification defects due to DUOX2 gene mutations; however, the etiology of the majority of cases with gland in situ remains unexplained.

• The limited data on outcome in these cases appear to show that most have normal neurodevelopment, but there are some reports (with no controls) of mildly impaired cognition.

• Treatment decisions are difficult; in cases with a serum TSH between 6 and 20 mU/l and a subnormal free T4, we recommend treatment. In cases where the serum TSH appears to be trending down and free T4 is normal, we recommender re-checking serum TSH and free T4 at weekly intervals. If serum TSH remains elevated beyond 4 weeks of age, we recommend treatment, with re-evaluation planned after age 2–3 years.

• Ultimately, the best way to determine management will depend on randomized controlled trials comparing neurodevelopmental outcome with thyroid hormone versus placebo treatment. NBS programs need to balance the goal of detecting those newborns that clearly benefit from early diagnosis and treatment versus the cost burden and unnecessary testing and anxiety created by detecting other neonates with mild, short-lived hypothyroidism that appear not to benefit from treatment.

Notes