Nineteen years of national screening for congenital hypothyroidism: Familial cases with thyroid dysgenesis suggest the involvement of genetic factors

Although a few familial forms of congenital hypothyroidism (CH) due to thyr oid dysgenesis (TD) have been reported, this disorder is usually considered to be sporadic. Recently, we reported that 2% of CH patients with TD have a positive familial history. The aim of this study was to describe the clin ical characteristics of these familial cases and to compare them with spora dic cases. We used the French national population-based registry of the first 19-yr sc reening program, which included 14,416,428 screened neonates with a 100% re covery rate. Familial history of CH with TD was investigated by means of a questionnaire sent to the pediatricians (n = 592) who provided ongoing clin ical care for the 4049 CH patients detected during this period, including 2 863 CH cases due to TD. Information was obtained from 73% of these pediatri cians who were following up 2472 CH patients with TD (86%). In all, 67 patients with a positive family history of CH with TD were refer red, belonging to 32 multiplex families (i.e. including at least 2 affected members). Families were identified with ectopic gland (n = 12), athyreosis (n = 7), or both (n = 13). Comparison of familial with isolated cases show ed a similar etiological diagnosis distribution of CH (40% vs. 33% for athy reosis and 60% us. 67% for ectopic thyroid gland, respectively), whereas a significantly lower predominance of females was found in familial than in i solated cases (1.4 us. 2.7; P < 0.03). Extrathyroidal congenital malformati ons were found with a similarly higher incidence in familial and isolated C H populations compared with the general population (respectively, 9% and 8. 2% vs. 2.5%). In conclusion, although familial cases represent a minority of cases of'con genital hypothyroidism caused by thyroid dysgenesis, they were observed in a significantly higher proportion (> 15-fold) than would be expected from c hance alone. This familial clustering, including athyreosis and ectopic thy roid gland, strongly suggests that genetic factors could be involved in thy roid dysgenesis with a common underlying mechanism for both etiological gro ups. Moreover, the high proportion of extrathyroidal congenital malformatio ns in a population affected by CH due to TD suggests that the potential gen etic factors involved in thyroid gland organogenesis are also involved in t he development of other organs.