Increasing Incidence of Congenital Hypothyroidism: Some Answers, More Questions

In 2007, Harris and Pass (1) reported that the incidence (birth prevalence) of congenital hypothyroidism (CH) detected by newborn screening programs in the United States had nearly doubled over the previous two decades, increasing from 1:3985 (in 1987) to 1:2273 (in 2002). In an analysis of data from their state of New York, Harris and Pass (1) found an even higher incidence, increasing from 1:3373 (in 1978) to 1:1415 (in 2005). The report of an apparent doubling was not limited to the United States. Newborn screening programs in Western Australia (1: 5747 to 1:2825) (2), Italy (1:2654 to 1:1154) (3), the northern region of the United Kingdom (1:2702 to 1:1078) (4), and Greece (1:3384 to 1:1749) (5) also reported an increasing incidence of CH. After these reports, questions naturally arose. Was this increasing incidence real, signaling an increase in the underlying etiology(ies) of CH? Or was the increasing incidence an artifact, explained by modifications of screening programs such as a change in test cutoffs? Furthermore, did the additional babies benefit from detection and early treatment? What do we know about the etiology of CH? CH is a heterogeneous disorder, with a spectrum of underlying etiologies. The most common cause is thyroid dysgenesis (ectopy, aplasia, hypoplasia, or hemiagenesis); historically, dysgenesis accounts for approximately 85% of cases. The next most common cause is thyroid dyshormonogenesis (defects in thyroid hormone biosynthesis), accounting for 10–15% of cases. Defects in thyroid hormone biosynthesis are familial, generally inherited in an autosomal recessive manner. Determination of an underlying defect is generally made by an imaging study, either ultrasonography or thyroid scintigraphy. Although imaging can determine thyroid anatomy and, if radionuclide uptake is done, some information on function, it does not elucidate the exact etiology. In fact, the underlying etiology of thyroid dysgenesis remains unknown for the vast majority of cases. Mutations in transcription factors that regulate thyroid gland development [thyroid transcription factor 2 (TTF-2), NKX2.1 (also termed TTF-1), or PAX-8] are found in only 2% of cases shown to have thyroid dysgenesis by imaging (6). Most cases of thyroid dysgenesis appear to be sporadic. It has long been known that there is a 2:1 female-to-male ratio in thyroid dysgenesis. Although this would seem to be a clue to the underlying etiology, its significance remains unknown. Previous studies from the screening program in Quebec report that the incidence of thyroid dysgenesis has remained relatively stable over the last few decades (7). Of note, with reports of increasing incidence, imaging studies now find a thyroid problem not reported in older studies—a normal-appearing thyroid gland in a eutopic location, so-called “thyroid in situ” (3, 5). Because this is associated with hypothyroidism, thyroid in situ is thought to be the result of a “functional abnormality.” Some cases of thyroid in situ have been shown to be the result of resistance to TSH binding (TSH receptor mutation), or signaling (G protein defect) (8), or to mild forms of dyshormonogenesis (hydrogen peroxide generation or maturation defects) (9). However, the exact etiology remains unknown for most cases. Hypothyroidism tends to be milder with thyroid in situ, and some cases are transient, with recovery to euthyroidism (9). Other cases of transient CH have a known etiology. Examples include babies born to mothers with Graves’ disease on antithyroid drugs, babies exposed to excess iodine (either maternal transmission or postnatal, usually from topical iodine antiseptics), and babies born to mothers with autoimmune thyroid disease