Discordance of monozygotic twins for thyroid dysgenesis: implications for screening and for molecular pathophysiology.

Since the advent of biochemical screening for congenital hypothyroidism, the majority of monozygotic twins reported with thyroid dysgenesis have been discordant, and most were missed on neonatal screening, presumably due to fetal blood mixing. We hypothesized that there may be bias leading to preferential reporting of discordant twins and/or of false negative screening results. Therefore, we performed a systematic search for twins in two congenital hypothyroidism screening centers, Quebec and Brussels, that use a primary TSH approach. In Quebec, 10 pairs of twins were identified, all discordant for congenital hypothyroidism due to thyroid dysgenesis (4 monozygotic and 4 dizygotic pairs) and dyshormonogenesis (2 dizygotic pairs). The 6 pairs identified in the Brussels database were also all discordant for congenital hypothyroidism due to thyroid dysgenesis (1 monozygotic and 3 dizygotic pairs) and dyshormonogenesis (2 dizygotic pairs). The median increase in TSH between screening and diagnosis was 7-fold in the monozygotic twins vs. 2-fold in matched singletons (P = 0.02), suggesting fetal blood mixing between the twins. In summary, discordance for thyroid dysgenesis is the rule in monozygotic twins, and fetal blood mixing may result in delayed or missed diagnoses. We therefore conclude that 1) a second sample for congenital hypothyroidism screening at 14 d of age should be considered for all same-sex twins; and 2) thyroid dysgenesis generally results from epigenetic phenomena, early somatic mutations, or postzygotic stochastic events.

Influence of LDL receptor gene mutation and apo E polymorphism on lipoprotein response to simvastatin treatment among adolescents with heterozygous familial hypercholesterolemia.

The efficacy of the inhibitors of HMG CoA reductase shows considerable interindividual variation and intense research has focused in the recent years to identify the genetic loci and environmental factors responsible for this variability. A randomized, double-blind, placebo-controlled clinical trial with simvastatin, an HMG CoA reductase inhibitor, was conducted in 63 adolescents (47 treated versus 17 controls) with heterozygous FH. The patients were grouped according to known low-density lipoprotein (LDL) receptor gene mutation class. After 6 weeks of treatment with 20 mg/d of simvastatin, the mean reduction in plasma LDL-cholesterol in patients with a receptor-negative mutation (n=33) was 39% whereas, in the receptor-defective mutation group (n=14), it was 31% (P=0.01). Multiple regression analyses showed that there was a significant association between the apo E polymorphism and LDL-cholesterol response to simvastatin only among heterozygotes for a receptor-negative mutation. In subjects carrying a receptor-defective mutation, however, we observed that 51% of the variability in LDL-cholesterol response was explained by variations in the dosage of simvastatin expressed in mg/kg/day (P=0.0028). There was no significant association between LDL-cholesterol response and the dosage of simvastatin among heterozygotes for a receptor-negative mutation. The results of the present study have shown that the contribution of apo E polymorphism and the dosage of simvastatin to the LDL-cholesterol responsiveness is influenced by the nature of the LDL receptor gene mutation.