Abstract 503

Background : Permanent primary congenital hypothyroidism (CH) is a heterogeneous condition. Its three main causes, which can be distinguished by scintigraphy, are: 1)incomplete or aberrant thyroid migration leading to an ectopic gland; 2) defective thyroid development resulting in athyreosis; or 3) enzymatic defects causing goiter. Goiters follow an autosomal recessive pattern of inheritance. Ectopy and athyreosis are generally sporadic with a female predominance. On the other hand, population-based studies have suggested a higher incidence of birth defects among children with CH, but the type of CH (permanent vs transient) was not always specified and the etiology was documented by scintigraphy in at most 50% of the cases. Rationale: A precise description of what type of CH is associated with which malformation is important because it may lead to the identification of the molecular mechanisms involved in thyroid gland migration and development in humans. Methods and Results: We reviewed the charts of all patients (N=272) who had been referred over the last 10 years to a pediatric endocrinology clinic in the province of Quebec on the basis of screening at day 2-3 using TSH as the primary test. These patients represent 94% of the patients identified by the Quebec Network of Genetic Medicine. We excluded patients with transient CH (N=37) and patients who had not had a scintigraphy at diagnosis (N=4). There were 139 patients with etocopy (101 girls), 36 with athyreosis (20 girls) and 43 with goiter (19 girls). In addition, scintigraphy showed: in 2 unrelated girls, left thyroid hemiagenesis; in 11 patients (4 girls), a gland a normal shape, position and size. The sex ratio was significantly different from 1 only in patients with ectopies (Chi-square, p<0.001). Extra-thyroid anomalies found in the records of children who had been followed for at least 8 months were: persistent isolated ventricular septal defects (VSD)(2 ectopies), other cardiac defects (4 ectopies-including one who also had a duplication of the urinary collecting ducts-, 2 athyreoses), cleft lip/palate with dextrocardia and imperforate anus (1 athyreosis), and septo-optic dysplasia (1 ectopy). Summary: Children with ectopies constitute the only group: a) with a significant female predominance and b) in whom persistent isolated VSDs were observed with a frequency (2/139 or 1.4%) higher than in the general population (0.25%).

Conclusion : The development and migration of the thyroid: a) may be differently modulated by the genetic makeup or hormonal milieu of the fetus; b) may be due to abnormalities in molecular interactions that can also lead to defective septation of the fetal heart; because the genes critical for thyroid development or migration (PAX 8, TTF-1, and TSH-R) are known to be involved in cardiac morphogenesis, other genes must be implicated in those cases.