Biomedical subjects
Publications and source records attributed to J L Simpson.
Elevated amniotic fluid alpha-fetoprotein and presence of acetylcholinesterase were detected in a pregnancy that resulted in an infant whose only abnormality was a hydrocele. Although these amniotic fluid findings are usually indicative of a serious fetal anomaly, our report indicates that this is not always the case.
In the present investigation we test the hypothesis that deficiencies of the X chromosome affect sister chromatid exchange (SCE) frequencies in human fibroblast cell lines. Our results show increased mean SCE frequencies in cell lines with abnormalities of the X chromosome: 45,X; 46,X,del(X) (q13), 46,X,del(X)(p11), and 46,X,i(Xq); control cell lines were 46,XX. In only one abnormal line [46,X,del(X)(p11)] was the increase not significant after correcting for multiple comparisons. If SCE formation is replication-dependent, the increased SCE frequencies might merely reflect the prolonged cell cycle we reported previously in cell lines with X chromosome abnormalities (Simpson and LeBeau 1981). Other explanations for differences between cell lines are possible, e.g., that deleted loci on the X chromosome affect cellular uptake of bromodeoxyuridine (BrDU). However, specific mechanisms were not explored directly.
No formal genetic studies of incomplete müllerian fusion anomalies have been conducted previously, despite several reports of familial aggregates. Accordingly, the authors sought to determine the frequency with which symptomatic müllerian fusion anomalies occurred in relatives of a small but genetically unbiased sample of 24 probands. Only one of 37 (2.7%) female sibs over age 16 appeared to have a symptomatic uterine anomaly; none of 24 mothers, none of 45 maternal aunts, and none of 50 paternal aunts appeared affected. Such a low frequency of affected relatives is more consistent with polygenic/multifactorial etiology than with other genetic etiologies.
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.
The hypothesis that variation in Y-chromosome length is associated with repetitive fetal wastage was tested. Chromosome lengths were objectively quantitated by scanning photographic negatives of metaphases with a computer programmed to (1) select boundary thresholds and (2) construct and measure centerlines with a cubic spline-fitting algorithm. Variation in Y length among cells of different individuals was standardized by use of the ratio of the length of the Y to the average of the lengths of the No. 20s (20) in the same cell. Three groups were studied: (1) men whose wives had three or more spontaneous abortions and no live-born infants, (2) men whose wives had both abortions and normal live-born infants, and (3) control men whose wives had normal live-born infants only. Although central tendencies were similar in the three groups, the distributions of Y lengths among the three groups were significantly different (chi 2(6) = 15.33, 0.025 greater than p greater than 0.010). This difference was primarily because more of the subjects with only repetitive loss had Y lengths in the "tails" of the distribution rather than in the center. Our observations suggest the existence of an optimal Y length with respect to reproductive performance.
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Familial aggregates of incomplete Müllerian fusion have been reported, but the role of genetic factors has not been elucidated. In the last several years, we have fortuitously encountered three families in which several members were affected with Müllerian fusion anomalies. In two families, several members had incomplete Müllerian fusion as traditionally described. In the third family, several members had the hand-foot-genital syndrome, a rare autosomal dominant disorder characterized not only by Müllerian fusion defects but also by skeletal (hand and foot) malformations. The etiologic heterogeneity of Müllerian fusion defects is considered.
Chromosomal inversions are being detected in humans with increasing frequency due to the application of chromosomal banding techniques. Inversions have occurred in all chromosomal groups. These structural aberrations may lead to infertility, reproductive loss, or abnormal offspring. To illustrate their clinical significance, we report a family in which an inversion in chromosome No. 18 is segregating. This family was ascertained through a proband whose anomalies were consistent with the deletion 18q syndrome. The chromosomal imbalance originated by recombination within the parental inversion during meiosis. Consideration of this family and 6 others with similar breakpoints (18p11 and 18q12 or q21) suggests that the risk of unbalanced (recombinant) livebirths may be higher for female inv(18) heterozygotes than for males. The paucity of male carriers detected could be due to prenatal selection or chance. Overall, there may be preferential segregation for the aberrant chromosomes (inversions plus recombinants). Amniocentesis and cytogenetic analysis of pregnancy losses is recommended for families in which inversions are detected.
We studied a 3-generation kindred to determine whether the gene responsible for one form of von Willebrand disease (vWD) is linked to 1) the HLA locus, or 2) a polymorphic locus for a serum enzyme or red cell antigen. HLA haplotypes were determined in 12 affected family members, in 10 cases by direct analysis and in 2 cases by deduction. Seven of 12 affected individuals were A2, B7, as compared to 0 of 9 unaffected. However, the maximum lod score was only 0.41 at a recombination frequency of 0.2. Of the 17 serum red cell and plasma protein markers studied, 5 (Kell, ADA, AK1, BF, GC) did not segregate, and 12 (ABO, Rh, JK, Fy, P, PGM1, ACP1, ESD, GLO1, MN, HP, GPT) gave lod scores less than + 1.0. We conclude that there is no strong evidence for linkage between the locus for vWD and any of the markers studied.
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Shared histocompatibility antigens between spouses may affect reproductive outcome adversely as a result of prenatal selection against compatible fetuses. Evidence from both animal and human studies suggest that histocompatible fetuses may not initiate a maternal immunologic response that prevents rejection of the embryo. Therefore, parents sharing HLA antigens may produce compatible fetuses and consequently experience a greater frequency of early fetal losses and show poorer reproductive outcome than couples not sharing antigens. In the Hutterites, an inbred human isolate that proscribes contraception, we tested the hypothesis that couples sharing HLA antigens have poorer reproductive outcomes than couples who do not. The Hutterites are characterized by high fertility and large family sizes. Couples that share zero (no. = 21), one (no. = 15), and more than one (no. = 10) HLA-A or HLA-B antigens were compared for reproductive performance. Median intervals between births were larger among couples that share more than one antigen in eight of 11 intervals examined. In addition, the median intervals from marriage to first, fifth, and tenth birth were consistently larger among couples that share more than one antigen. Differences among the groups appear to become larger with increasing parity, suggesting that the effect of histocompatibility on reproductive performance becomes more evident in later pregnancies. These differences in reproductive performance between couples that share zero, one, or more than one HLA-A or HLA-B antigens may have significant evolutionary consequences. However, our results demonstrate that sharing HLA antigens does not preclude normal pregnancy and caution should be exercised before concluding that shared HLA antigens are solely responsible for repeated fetal losses.
The genetics of Müllerian aplasia (absent fallopian tubes, absent or rudimentary uterine corpus and cervix, absent upper vagina) has never been investigated systematically. Some investigators believe the disorder is inherited in female-limited autosomal dominant fashion, males transmitting the mutant gene but, of course, not manifesting the trait. To investigate this possibility, we obtained pedigrees in 23 probands with Müllerian aplasia. None had an affected relative. The absence of affected individuals among 30 postpubertal sisters, 31 paternal aunts, and 40 maternal aunts makes it unlikely that a sex-limited autosomal dominant gene is a common cause of Müllerian aplasia in our population. Dominant genes might exist in other populations, and fresh dominant mutations cannot be excluded. However, polygenic/multifactorial inheritance is perhaps more plausible.
After observing abnormal offspring following artificial insemination by donor, several authors recently have proposed intensive genetic screening of donors. The screening would be beyond that practiced by most infertility specialists. To determine the necessity for formal genetic investigation of donors, the authors analyzed the outcome of artificial insemination pregnancies in which donors were screened with careful medical and family histories, but were not subjected to formal pedigree analysis, karyotyping, or extensive metabolic screening. Fewer than 10% of potential donors were disqualified for genetic reasons. The study, limited to ascertaining the presence or absence of overt anomalies evident at birth, showed that such malformations were not more frequent in artificial insemination pregnancies (1.7%) than in controls (2.3%). It is concluded that extensive and formalized genetic screening is probably not necessary provided a thorough medical history is obtained. In addition, a practical approach to identifying donors at increased risk for siring abnormal offspring is offered.
Specimens of amniotic fluid were studied to assess the frequency of hypermodal cells and their significance. Multiple cultures were initiated on each specimen, and thorough cytogenetic analysis was performed routinely. Of 1,000 specimens, 59 (5.9%) contained a total of 64 hypermodal cells. However, true fetal mosaicism was not detected. An additional structurally abnormal chromosome accounted for 32 of the 64 hypermodal cells, and, in each case, cytogenetic analysis offered an explanation that obviated clinical concern. In 17 of the 32 cases, hypermodality was only apparent, the result of a single chromosome broken into two parts to produce a spuriously elevated count; in the other 15 cases, the extra chromosome was an unidentified fragment. In the 32 other hypermodal cells, an additional morphologically normal chromosome was present; however, in each case, failure to detect similar aberrations in other cultures initiated from the same specimen minimized the possibility that such cells reflected true fetal mosaicism. Indeed, clinical outcome was normal in all cases. Thus, for clinical purposes, routine banding techniques and analysis of multiple cultures seem to be adequate to exclude fetal mosaicism; laborious in situ methodology seems to be unnecessary. Future cytogenetic efforts should emphasize processing of more specimens of amniotic fluid, rather than more detailed analysis of individual specimens.
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