Genetic Analysis of Repeated, Biparental, Diploid, Hydatidiform Moles Lone Sunde, Lars O. Vejerslev, Mie P. Jensen, S0ren Pedersen, Jens Michael Hertz, and Lars Bolund ABSTRACT: A woman presented with five consecutive pregnancies displaying molar morphology. In the fifth pregnancy, a non-malformed, liveborn infant was delivered. Genetic analyses (RFLP analysis, cytogenetics, flow cytometry) were performed in pregnancies II-V. It was demonstrated that these preg- nancies originated in separate conceptions, all conceptuses were diploid, and all had maternally as well as paternally derived genetic markers. By cytogenetic analysis, aberrant heteromorphisms were noted; no other abnormalities were observed in chromosome structure or in DNA sequence. Many different causes for the abnormal development can be envisaged, environmental as well as genetic. To conform to current ideas of molar pathogenesis, it is suggested that the present conceptuses might have arisen from imbalances in imprinted genomic regions. This could be a consequence of uniparental disomy in critical regions gener- ated by somatic crossing over. Alternatively, it could be caused by a malfunction in the generation or main- tenance of imprinting. INTRODUCTION Hydatidiform mole is a morphologic entity with well estab- lished genetic correlations. A widely accepted definition of a hydatidiform mole is a "human conceptus displaying macroscopically visible vesicular villi and trophoblastic hyperplasia." In the complete mole, no signs of fetus, cord, amniotic membrane, or normal villi are noted, whereas one or more of these features are present in the partial mole [1]. In general, a correlation between the relative amount of paternal contribution to the genome and the extent of molar changes is noted: The complete moles are diploid, with both chromosome sets paternally derived. The partial moles most often are triploid (rarely tetraploid) and two of the three (three of the four) chromosome sets are paternally derived [2]. Ex- ceptions to these rules have been noted, but until now radi- cal changes in the classification system have not been re- quired [3]. However, observations of diploid conceptuses displaying the morphology of partial hydatidiform moles are recurrent. Szulman suggested the existence of a separate entity, the diploid partial mole, but he and others also draw attention From the Institute of Human Genetics, University of Aarhus (L. S., M. P. J., S. E, J. M. H., L. B.); the Department of Medical Genetics, The John F. Kennedy Institute (L. O. V.), Glostrup/Copenha- gen; and the Department of Obstetrics and Gynaecology, Hvidovre Hospital (L. O. V.), University of Copenhagen, Denmark. Address reprint requests to: Lone Sunde, Institute of Human Genetics, The Bartholin Building, University of Aarhus, DK-8000, Aarhus C, Denmark. Received May 18, 1992; accepted October 19, 1992. 16 Cancer Genet Cytogenet 66:16-22 (1993) 0165-4608/93/$06.00 to the possibility of twin gestations, one molar and one non- molar [4-6]. When the hydatidiform change is scattered throughout a single placenta attached to a normal fetus or when genetic markers are identical in normal and molar parts of a pregnancy, biparental diploid genetic constitution of one conceptus seems more likely than dizygotic twinning. Four reports of such pregnancies are given in Table 1. We have encountered a case of repeated, biparental, diploid, hydatidiform moles in one patient. Clinical, histo- pathologic, and genetic observations of three of the pregnan- cies have been published elsewhere [7]. In the present pa- per, we report a more detailed genetic analysis of four of the pregnancies and the results are discussed with reference to pathogenesis. A possible pathogenetic mechanism involves abnormal patterns of imprinting in critical loci. This, for in- stance, could be caused by an increased frequency of somatic crossing over or a defect in the imprinting mechanism. CASE REPORT The patient presented with repeated moles; in all of her five pregnancies, with the same spouse, placental gross vesicles were noted. The patient and the spouse were consanguine- ous, having the same grandfather. Both the woman and her husband were born in the Middle East, but emigrated to Northern Europe after the first pregnancy. Clinical and mor- phologic data of the pregnancies are summarized in Table 2. MATERIALS AND METHODS Restriction fragment-length polymorphism (RFLP) analysis was performed on DNA prepared from vesicular villi from © 1993 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas. New York, NY 10010