Although there was a statistically significantly higher prevalence of goiter in the 6- to 9-year age group with zero SLC26A4
mutant alleles compared with the general population, this difference is likely due to the detection method (palpation) used to identify goiter in the control group.15
Manual palpation and routine clinical ultrasonographic examination of the 2 goitrous subjects with EVA in this age group did not detect thyroid enlargement. Thyroid enlargement was revealed only with quantitative volume measurements and comparison with age- and sex-specific normative data. Our algorithm for classifying goiter status in subjects younger than 6 years or 13 to 14 years old, for whom normative Tvol
data are not available, is probably too complex for routine clinical use. A more limited but practical approach would be comparison with adjacent age- and sex-specific normative data.18,19
The thyroid associated with PDS has been described as initially smooth and diffuse and later becoming multinodular.14
Those conclusions may not fully reflect the natural history as revealed by ultrasonographic investigation of a primarily pediatric population. Although our cross-sectional study design did not permit the definition of “pregoitrous” structural or volume changes in subjects with EVA, the possibility of presymptomatic detection and intervention warrants a longitudinal study. Follow-up of structural abnormalities should include periodic thyroid ultrasonography and may include other diagnostic tests or endocrinology consultation for atypical nodules, gland enlargement, or thyroid function abnormalities or symptoms.
Our data do not support the hypothesis that thyroid serologic test results can be used to distinguish among individuals with zero, 1, or 2 mutant SLC26A4
alleles. This may reflect the cross-sectional design of our study and the comparatively young age distribution (mean age, 11.5 years) of our cohort. Some studies have reported a significant prevalence of subclinical or frank hypothyroidism among individuals presumed to have 2 SLC26A4
mutant alleles, but they were largely based on adult populations.14,21
In contrast, none of our subjects had clinical evidence of frank hypothyroidism, even those who received levothyroxine therapy. For some subjects, the goal of levothyroxine therapy may have been to stop or retard goiter progression for cosmetic or compressive indications. Although our results indicate that thyroid serologic testing is not a useful initial diagnostic screen for PDS, it remains important in the evaluation and management of symptoms or signs of hypothyroidism, hyperthyroidism, goiter, or thyroid structural abnormalities.
There was 1 case of thyroid cancer in our series of 80 individuals. There are published case reports, but no estimates of the incidence, of thyroid cancer in individuals with PDS. It has been suggested that thyroid cancer in individuals with PDS and untreated goiter may be a result of chronic exposure to excessive thyrotropin.22,23
However, subject number 1556 had no history of elevated thyrotropin levels. Thyroid cancer is a comparatively common malignant neoplasm and may be a co-incidental comorbid condition in some individuals with PDS. Our cohort with 2 mutant alleles of SLC26A4
is too small and too young to test the hypothesis that PDS is associated with an increased risk of thyroid cancer.
Our current results confirm our previous observation of a strong correlation of 2 mutant alleles of SLC26A4
with a positive PDT result.11
The 2 exceptions to this association are subjects 1447 (p. E384G and p.L597S alleles of SLC26A4
) and 1847 (p.G209V and p.Q514R alleles of SLC26A4
). We classified subject 1447 as having 1 mutant allele, since p.E384G is a functional null mutation but p.L597S is a hypofunctional variant with indeterminate pathogenic potential.12
Her positive PDT result could thus reflect a pathogenic role for p.L597S in trans
configuration with a functional null allele.12
Alternatively, we cannot exclude the possibilities of a subtle but significant motion artifact for the 123
I measurements or that subject 1447 represents a genuine exception to the geno-type-phenotype correlation. In contrast, subject 1847 has 2 clearly pathogenic SLC26A4
alleles. However, some atypical aspects of her thyroid phenotype may confound the interpretation of the PDT result. She had decreased TSH levels, FT4
results within normal limits, negative results for antithyroid antibodies, and multiple solid nodules. A fine-needle aspiration revealed an adenomatoid nodule with cystic changes. The patient had no signs or symptoms of hyperthyroidism. She was counseled to have a thyroidectomy and has not returned to the NIH.
A baseline thyroid ultrasonogram at initial diagnosis, followed by regular ultrasonographic studies to monitor for enlargement, may be appropriate clinical surveillance for individuals with EVA and hearing loss. Perchlorate discharge testing is recommended for the diagnostic evaluation of goiter, nondiagnostic SLC26A4
genotypes (zero or 1 mutant alleles), or both in patients with EVA. Further study will be necessary to evaluate the natural history and prognostic significance of a slightly but significantly enlarged thyroid gland or a normally sized gland with evidence of structural abnormalities. The clinician must weigh the potential benefit of early identification of an enlarged gland and presymptomatic initiation of levothyroxine therapy24
against the cost of ultrasonography and the identification of thyroid nodules of indeterminate clinical significance. Levothyroxine therapy is more clearly indicated in an individual with goiter accompanied by evidence of functional hypothyroidism. Because SLC26A4
mutations may lower the threshold for goiter when there is a slight decrease in dietary iodine intake,25
iodine supplementation should be considered as a prophylactic treatment for goiter. Longitudinal ultrasonographic studies of the thyroid gland in patients with EVA would provide a foundation for the design and interpretation of those studies.