Population genetic screening efficiently identifies carriers of autosomal dominant diseases.

Three inherited autosomal dominant conditions-BRCA-related hereditary breast and ovarian cancer (HBOC), Lynch syndrome (LS) and familial hypercholesterolemia (FH)-have been termed the Centers for Disease Control and Prevention Tier 1 (CDCT1) genetic conditions, for which early identification and intervention have a meaningful potential for clinical actionability and a positive impact on public health1. In typical medical practice, genetic testing for these conditions is based on personal or family history, ethnic background or other demographic characteristics2. In this study of a cohort of 26,906 participants in the Healthy Nevada Project (HNP), we first evaluated whether population screening could efficiently identify carriers of these genetic conditions and, second, we evaluated the impact of genetic risk on health outcomes for these participants. We found a 1.33% combined carrier rate for pathogenic and likely pathogenic (P/LP) genetic variants for HBOC, LS and FH. Of these carriers, 21.9% of participants had clinically relevant disease, among whom 70% had been diagnosed with relevant disease before age 65. Moreover, 90% of the risk carriers had not been previously identified, and less than 19.8% of these had documentation in their medical records of inherited genetic disease risk, including family history. In a direct follow-up survey with all carriers, only 25.2% of individuals reported a family history of relevant disease. Our experience with the HNP suggests that genetic screening in patients could identify at-risk carriers, who would not be otherwise identified in routine care.

Hemochromatosis and male infertility.

BACKGROUND: The clinical association of hemochromatosis and infertility is rare. Hemochromatosis may affect fertility through a variety of mechanisms. CASE: A 44-year-old man and his 36-year-old wife presented with primary infertility of 7 years' duration. The husband was diagnosed as having idiopathic hemochromatosis, abnormal glucose tolerance, and hypogonadism accompanied by impotence, retrograde ejaculation, and azoospermia. Treatment consisted of phlebotomies followed by gonadotropins, which corrected retrograde ejaculation and improved semen characteristics. Concomitant pelvic factors in the woman were corrected endoscopically. After failure of pregnancy with ovulation stimulation and intrauterine inseminations, a singleton pregnancy was achieved by in vitro fertilization, augmented with intracytoplasmic sperm injection. CONCLUSION: This case underscores the need to consider advanced reproductive technologies after the failure of specific, first-line therapeutic options in infertile couples.

Erythropoietin does not cross the placenta into the fetus.

Erythropoiesis in the fetus is controlled by erythropoietin (Ep). To determine the role of maternal Ep in this process, we used catheterized preparations of sheep and monkey fetuses to assess the ability of Ep administered to the mother to cross the placental barrier into the fetus. Ep was injected into pregnant sheep (3,600 IU/sheep) or monkeys (800-2,000 IU/animal) as a single intravenous dose, or into sheep in intravenous doses of 2,000 IU once every 12 h for a total of 4 injections. Maternal and fetal blood samples for Ep and reticulocyte determinations were obtained before and at intervals after Ep injections. The administration of Ep resulted in significant increases in maternal circulating Ep levels in sheep and monkeys. Despite the presence of high levels of maternal Ep, however, no increase in fetal plasma Ep levels was detected. The administration of Ep to the mother caused significant increases in reticulocyte production in the mother but not the fetus; injection of Ep directly to the fetus stimulated fetal erythropoiesis. These results demonstrate that Ep does not cross the placenta into the fetus even under conditions of chronically elevated maternal Ep levels, and suggest that red cell production in the fetus is regulated by Ep produced from sites within the fetus.

Early experience with open fetal surgery for congenital hydronephrosis.

The fetus with severe bilateral hydronephrosis and associated oligohydramnios in the second trimester is doomed at birth by ongoing pulmonary and renal damage. Since decompression with percutaneously placed catheters anesthetic, surgical, and tocolytic techniques for open fetal anesthetic, surgical, and tocolytic techniques for open fetal urinary tract decompression in animals, and have now applied those techniques to a small group of five patients. One had bilateral ureterostomies and the subsequent four had marsupialization of the bladder. All pregnancies proceeded to cesarean delivery at 32 to 35 weeks' gestation. There was no long-term maternal morbidity, and two mothers have since experienced normal pregnancies. Three fetuses had return of normal amniotic fluid dynamics, and all three had adequate pulmonary function at birth, suggesting that fatal pulmonary hypoplasia associated with early severe oligohydramnios had been reversed. Two neonates died at birth with pulmonary hypoplasia. One had no amniotic fluid even after decompression, and the other had some amniotic fluid after decompression but a tiny chest cavity due to the long period of severe oligohydramnios before decompression. Of the three surviving infants, one had normal renal function when she died of unrelated causes at 9 months of age. One has normal renal function at 23 months and the third had failing renal function at 2 1/2 years and has grown and developed normally, but will require renal transplantation. We have now developed selection criteria that would exclude from treatment the two fetuses who died of pulmonary hypoplasia and the one who developed renal failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Sonography as a procedure complementary to alpha-fetoprotein testing for neural tube defects.

Forty-four fetuses were studied sonographically because of an elevated amniotic fluid alpha-fetoprotein level noted during routine amniocentesis, questionable findings during an ultrasound examination at another institution, or a history of a neural tube defect in prior pregnancy. Eleven neural tube defects, 16 non-neural tube defect anomalies, and 17 normal fetuses were all correctly identified by sonography. Ultrasound answers the need for a second diagnostic tool to complement the alpha-fetoprotein measurement.