Prenatal diagnosis and genetic analysis of type I and type II thanatophoric dysplasia.

Thanatophoric dysplasia (TD) is one of the most common neonatal lethal skeletal dysplasias. Prenatal sonographic and molecular genetic diagnoses of three cases of TD type I (TD1) and one case of TD type II (TD2) are presented here. Two fetuses of TD1 were characterized by polyhydramnios, macrocephaly, short limbs, a narrow thoracic cage and curved short femora, but without a cloverleaf skull at 27 and 31 weeks' gestation, respectively. The third fetus with TD1 was, however, not associated with macrocephaly, polyhydramnios, chest narrowing and severe femoral bowing on prenatal ultrasound at 18 weeks' gestation. The TD2 fetus was characterized by polyhydramnios, short limbs, a narrow thoracic cage, straight short femora, hydrocephalus and a cloverleaf skull at 24 weeks' gestation. Three-dimensional ultrasound was able to enhance the visualization of thickened, redundant skin folds and craniofacial and limb deformities associated with TD. Molecular analysis of the fibroblast growth factor receptor 3 (FGFR3) gene by restriction enzyme digestion analysis and direct sequencing using cultured amniotic fluid cells or cord blood cells revealed a missense mutation of 742C-->T (Arg248Cys) in all cases with TD1 and a missense mutation of 1948A-->G (Lys650Glu) in the case with TD2. The present report shows that adjunctive applications of molecular genetic analysis of the FGFR3 gene and three-dimensional ultrasound are useful for prenatal diagnosis of TD.

Prenatal diagnosis and genetic analysis of double trisomy 48,XXX,+18.

Prenatal diagnosis of simultaneous occurrence of double trisomy involving chromosomes 18 and X is extremely rare. We report on the prenatal diagnosis, genetic analysis and clinical manifestations of a fetus with both trisomy 18 and trisomy X. A 26-year-old, para 1 woman was referred for genetic counselling at 36 weeks' gestation with the sonographic findings of intrauterine growth retardation (IUGR), polyhydramnios, ventricular septal defect, and an enlarged cisterna magna. Both cordocentesis and amniocentesis revealed a consistent karyotype of 48,XXX,+18. Quantitative fluorescent polymerase chain reaction using polymorphic small tandem repeat markers specific for chromosomes 18 and X rapidly determined that both aneuploidies arose as a result of non-disjunction in maternal meiosis II. Our case shows that two non-disjunction events can occur not only in the same parent, but also in the same cell division. Our case also shows that double trisomy, 48,XXX,+18, can demonstrate an enlarged cisterna magna, IUGR and polyhydramnios in prenatal ultrasound.

A fetus with VACTERL association, unilateral aplasia of the humerus and partial hemihypoplasia.

We report simultaneous occurrence of right partial hemihypoplasia and ipsilateral aplasia of humerus in a fetus with VACTERL association. Our case has further demonstrated the overlap between VACTERL and body hemihypoplasia.

Thyroxine, renal beta-adrenergic receptors, and dipsogenesis in food-deprived rats.

The effect of thyroxine (T4) replacement on the increased renal beta-adrenergic receptor number and the increased beta-adrenergic dipsogenic responsiveness of fasted rats was studied in male Sprague-Dawley rats. Food deprivation significantly decreased serum thyroxine (T4) and triiodothyronine (T3) levels, increased the dipsogenic response to isoproterenol, and elevated renal beta-adrenergic receptor concentration. Daily administration of T4 (40 micrograms/kg) to food-deprived rats restored serum thyroid levels to normal. Thyroxine replacement also reduced the increased beta-adrenergic dipsogenic responsiveness in the food-deprived rats to control levels. In addition, daily administration of thyroxine reduced the beta-adrenergic receptor concentration in renal cortices to that observed in controls. Thyroid treatment tended to decrease the isoproterenol-induced renin release in food-deprived rats and increase the response in the control rats. These results suggest that the relative hypothyroid state observed in the food-deprived rat may be responsible for the increased concentration of renal beta-receptors and the associated activation of the renin-angiotensin system, which may be partially responsible for the observed increased dipsogenic response induced by isoproterenol. Collectively, the data reaffirm the interaction of thyroid hormone and beta-adrenergic responsiveness, although it is of interest that, in regard to renal beta-receptors, the concentrations are decreased to normal by thyroid treatment, whereas previous studies in hypothyroid rats demonstrate an increase to normal of cardiac beta-receptors. This would suggest thyroid hormone may normalize a response in an opposite direction depending on the direction of the disturbance.

Possible mechanism for increased beta-adrenergic dipsogenic response in food-deprived rats.

The dipsogenic responsiveness to isoproterenol was studied in food-deprived male rats. Unstimulated water intake was similar between control and fasted groups, and parallel dose-response curves for the dipsogenic response induced by isoproterenol (10-50 micrograms/kg) were observed. A twofold elevation in dipsogenic responsiveness was observed in the fasted rats, and this enhanced response was correlated with a dose-dependent increase in plasma renin activity when compared with the control rats after administration of isoproterenol. beta-Adrenergic receptor binding assays were performed on both heart and renal cortical tissues. In the heart the receptor concentration was decreased after food deprivation, whereas the affinity of the receptor for the beta-adrenergic antagonist [125I]CYP remained unchanged. On the other hand, an increased beta-adrenergic receptor concentration without change in affinity was found in renal cortices of fasted rats. Results from these receptor binding studies correlated with the attenuated chronotrophic response and the increased dipsogenic response to beta-adrenergic stimulation in the fasted rat. Therefore stimulation of these increased renal receptors by isoproterenol could result in an enhanced activation of the renin-angiotensin system and thus be a factor responsible for the increased dipsogenic response induced by isoproterenol observed in the fasted rats.