CLINICAL, PATHOLOGICAL, AND MOLECULAR STUDIES OF 2 FAMILIES WITH IODIDE ORGANIFICATION DEFECT

Two unrelated families (CA and NA) in which an iodide organification d efect (IOD) was present in two siblings of each family were studied. T hese patients had congenital goiters with hypothyroidism and a positiv e perchlorate discharge test. Examination of the thyroid tissue reveal ed no thyroid peroxidase (TPO) activity. Histologic findings were cons istent with a microfollicular pattern of hyperplasia. Moderate cellula r atypia was present, characterized by nuclear pleomorphism and hyperc hromatism. Full length thyroglobulin was purified by gel filtration, b ut was not iodinated. Immunohistochemical studies using a polyclonal a nti-human thyroid peroxidase (hTPO) antibody confirmed the presence of immunoreactive TPO protein in the thyroid tissues. Samples of normal and affected individuals were studied with respect to the presence of various fragments using TPO probes of varying sizes. The two affected siblings from family CA were homozygous for fragments 3.9, 4.6, and 7. 0 kb (Bg/II) and 2.3 and 2.9 kb (Taql), whereas the parents were heter ozygous. In the other family (NA), the Bg/II digestion and TPO-31 hybr idization revealed an interesting and informative polymorphism. The pa rents showed two different polymorphic patterns: the father had a 5.0/ 4.6 kb pattern and the mother a 4.7/4.5 kb pattern. However, the two a ffected siblings showed the same heterozygotic allelic pattern at 4.5/ 4.6 kb. The restriction fragment length polymorphism detected in these two families suggests an association between the TPO gene and an IOD. Results suggest that in these dyshormonogenetic tissues an altered TP O protein molecule is being synthesized, without detectable in vitro a ctivity, but visible by immunostaining techniques in the goitrous tiss ue. Mutations in the TPO gene sequence are most likely associated with these changes.