Alice O. Martin

Frequency of diabetes mellitus in mothers of probands with gestational diabetes: Possible maternal influence on the predisposition to gestational diabetes

Interviews for genetic histories were conducted prior to delivery in 166 pregnant diabetic probands and 83 control gravidas with normal carbohydrate metabolism throughout gestation. A significant association was observed between parental diabetic phenotypes and type of diabetes in the probands (chi 2(12)) = 32.413; p less than 0.001). In particular a higher than expected number of mothers with diabetes was encountered in 91 probands with gestational diabetes mellitus. The findings are examined in relationship to the hypothesis that vulnerability to gestational diabetes may be increased by exposure to an abnormal environment during intrauterine development.

Cytogenetic results of chorionic villus sampling: high success rate and diagnostic accuracy in the United States collaborative study.

Cytogenetic results of first-trimester chorionic villus sampling are reported from seven U.S. medical centers. For 6033 patients who had a successful chorionic villus sampling procedure, the rate for obtaining a cytogenetic diagnosis was 99.6% with the direct method, long-term culture, or both. There were no incorrect sex predictions and no diagnostic errors involving trisomies 21, 18, or 13, sex chromosome aneuploidies, or structural abnormalities. There were no cases of normal cytogenetic diagnosis followed by birth of a cytogenetically abnormal infant. Three cases of unusual aneuploidies (tetraploidy, trisomy 16, and trisomy 22) detected by the direct method only were not confirmed by cytogenetic follow-up. Mosaic cytogenetic abnormalities were observed in 0.83% of all cases in which chorionic villus sampling was done but were confirmed by amniocentesis or in fetal tissues in only 7 of 30 cases (23.3%). Maternal cell contamination occurred in 1.9% of long-term cultures, although this did not present any cytogenetic diagnostic difficulties. Overall, a very high degree of laboratory success and diagnostic accuracy was observed with either cytogenetic method, although fewer predictive errors were observed with the long-term culture method and none were observed when both methods were used.

Diabetes in pregnancy, Northwestern University series (1977–1981): I. Prospective study of anomalies in offspring of mothers with diabetes mellitus☆☆☆

Offspring of mothers with diabetes mellitus were examined prospectively with the use of a detailed checklist. Diabetic women were usually identified in the late first or early second trimester and thereafter rigorously managed in hopes of achieving euglycemia. The frequency of infants with major anomalies was higher (9/106, 8.5%) in White Classes B to F than in either the general population or in a small group of concurrently gathered control subjects (1/41, 2.4%). The frequency of anomalies in Class A diabetes was 3/76 (3.9%), a rate that may or may not be increased. Of the 12 major anomalies observed in diabetic offspring, six involved the heart and three involved the skeletal system. No pattern of minor anomalies appeared to exist. Limited data failed to reveal a specific HLA type that conferred increased risk for anomalies, and chromosomal abnormalities were not increased in frequency. If hyperglycemia is indeed the mechanism responsible for anomalies in offspring of mothers with diabetes mellitus, our observations suggest that rates will be reduced only by achieving optimal control in the first trimester.

XY gonadal dysgenesis: Genetic heterogeneity based upon clinical observations, H-Y antigen status and segregation analysis

SummaryClinical observations and segregation analysis indicate that XY gonadal dysgenesis is characterized by genetic heterogeneity. In addition to the type inherited in X-linked recessive fashion, segregation analysis of other families suggested another type by revealing that the proportion of affected sibs did not differ from that expected on the basis of a male-limited autosomal recessive inheritance. Further heterogeneity may be deduced on the basis of coexisting campomelic dwarfism or possibly also renal parenchymal abnormalities. These observations of genetic heterogeneity must be considered when interpreting studies in which individuals with XY gonadal dysgenesis may or may not show H-Y antigen.

Translocations are infrequent among couples having repeated spontaneous abortions but no other abnormal pregnancies

During the years 1977 to 1986, cytogenetic studies were performed on 342 women and 297 men whose reproductive history included one or more first trimester spontaneous abortions. Thirty-nine women and 35 men experienced not only early fetal losses but also one or more stillborn infants, liveborn anomalous infants, or early neonatal deaths. Among the 303 women and 262 men evaluated solely because of repetitive abortions, only 1 woman and 1 man showed a translocation. Two translocations were detected among the 39 women and 35 men having not only repetitive abortions but also a stillborn infant, anomalous liveborn, or unexplained neonatal death. Only among the 25 women having abortions and other abnormal perinatal events was the frequency of translocations high (2/25 or 8%). Our data continue to indicate that balanced chromosomal translocations are relatively infrequent in individuals having repeated abortions but no other adverse perinatal outcome.

Cancers of the breast and female genital system: Search for recessive genetic factors through analysis of human isolate

To investigate the importance of recessive genes in female breast and genital cancers, we have conducted investigations in the Hutterites, a highly inbred genetic isolate in North America. The homogeneous life style of this group, which lives on communal farms, also facilitates distinction between shared environmental and genetic factors. We ascertained 177 cases of cancer (all organ systems) through Canadian and United States cancer registries, field trips, and searches of death certificates. Breast cancer and endometrial cancer mortalities were those expected for 1970 United States whites, but no deaths due to squamous cervical carcinoma were ascertained in this monogamous population. Inbreeding coefficients (F) for cases were higher than means for matched controls for each of the four cases of breast cancers that occurred in younger women (less than 45 years of age), for four of five cases of endometrial cancer, and for the single cases of uterine leiomyosarcoma, dysgerminoma, and ovarian adenocarcinoma. By contrast, in cases of breast cancer that occurred in women 45 years of age or older, only four of 15 Fs were above those for controls. There is a significant difference between the two breast cancer age groups with respect to the likelihood that the F of cases was higher than the F of controls (chi 2 = 6.99, p less than 0.01). However, grouping cases by type, none of the F distributions were significantly different from those of their matched controls. These preliminary genetic investigations thus conform certain concepts concerning breast and female genital cancer but also suggest the desirability of further studies to elucidate the role of genetic factors in premenopausal breast cancer.

Parental chromosomal rearrangements associated with repetitive spontaneous abortions

Parental chromosomal rearrangements represent a well-established cause of repetitive spontaneous abortions. However, the frequent of parental translocations varies widely in reported series, suggesting differences in ascertainment. For this reason a sample of individuals (120 women, 104 men) who had experienced spontaneous abortions but neither stillborn nor anomalous liveborn infants was investigated. Only one translocation was detected (0.4% of individuals). The relatively low frequency of translocations in this series of probably a reflection of not only lack of coexisting stillborn or anomalous infants but also the referral pattern in this unit that facilitates routine analysis of all couples experiencing repetitive abortions. In addition, one women showed a pericentric inversion.

Chromosome analysis of ectopic human conceptuses

Maternal factors (e.g. salpingitis) are known to be associated with ectopic gestations; however, few studies have considered the chromosomal complements or morphologic features of ectopic conceptuses. We studied 23 ectopic conceptuses removed from fallopian tubes during surgical resection. The chromosomal complements were normal (four with 46,XY; four with 46,XX) in all cases in which an intact embryo was identified, as well as in the single case characterized by disorganized embryonic tissue. Ten of the 14 ectopic conceptuses in which only a gestational sac and placental villi were identified also show normal chromosomal complements (seven with 46,XX; three with 46,XY); in the remaining four cases, variations from the normal chromosomal complement were found (46,XX/47,XX,+9; 45,X/46,XX; 46,XX/47,XX,+mar; and 92,XXXX). The former two probably signify underlying fetal abnormalities; however, the latter two could have reflected, respectively, in vitro aberrations or tetraploidy characteristic of normal amnion. Pooled data from this study and two previous reports indicate that ectopic conceptuses probable have no higher frequency of chromosomal abnormalities than in utero conceptuses of comparable embryonic ages.

Chorionic villus sampling in continuing pregnancies II. Cytogenetic reliability

Cytogenetic analysis was performed on 103 chorionic villus samples. Analysis of the 103 samples revealed six abnormalities. In three of the six the abnormalities were confirmed in fetal or neonatal tissue (47,XY, + 13; 46,XY, t(13q13q); 45,X). In three samples the abnormalities detected were not confirmed; in two of the three the abnormalities were detected only in long-term cultures, whereas in the other samples the abnormality was restricted to direct analysis of the villi after overnight incubation. Our initial experience leads us to conclude that certain abnormalities in chorionic villus sampling may not be indicative of fetal abnormalities; 45,X/46,XX or 45,X/46,XY mosaicism is such a complement. Discrepancies between cytogenetic analysis of intact villi processed soon after sampling and of cells grown in culture can be managed by adhering to several suggested guidelines and by liberal use of confirmatory amniocentesis.

Chorionic villus sampling for first-trimester Prenatal diagnosis: Northwestern University Program

We present our initial experience in developing a chorionic villus sampling program at Northwestern University. In phase 1, we performed chorionic villus sampling in 58 patients prior to elective first-trimester abortion, assessing the reliability and reproducibility of obtaining adequate villus samples and performing cytogenetic analysis by means of both the direct and culture methods. Specimens were categorized according to quality: class I, multiple identifiable villi (n = 20); class II, few villi or villi mixed with decidua (n = 15); class III, no villi (n = 23). There was a positive trend between operator experience, amount of villi obtained, and quality of cytogenetic preparations. In March, 1984, we received Institutional Review Board approval to perform chorionic villus sampling in continuing pregnancies (phase 2). Among the first 20 cases we found two abnormalities (47,XY, + 13; 45,X). The remaining 18 pregnancies were continuing. Recommendations are made for developing a chorionic villus sampling program.