Clin Genet 2007: 71: 25–34Printed in Singapore. All rights reserved

# 2006 The Authors

Journal compilation # 2006 Blackwell Munksgaard

CLINICAL GENETICS

doi: 10.1111/j.1399-0004.2006.00697.x

Developmental Biology: Frontiers for Clinical Genetics

Section Editors:

Roderick R. McInnes, email: mcinnes@sickkids.ca

Jacques L. Michaud, email: jacques.michaud@recherche-ste-justine.qc.ca

The genetics of hydatidiform moles: newlights on an ancient disease

Slim R, Mehio A. The genetics of hydatidiform moles: new lights on anancient disease.Clin Genet 2007: 71: 25–34. # Blackwell Munksgaard, 2007

Hydatidiform mole (HM) is a human pregnancy with no embryo butcystic degeneration of chorionic villi. The common form of this conditionoccurs in 1 in every 1500 pregnancies in western societies and at a higherincidence in some geographic regions and populations. Recurrent molesaccount for 2% of all molar cases and a few of them occur in more thanone family member. By studying a familial form of recurrent moles,a recessive maternal locus responsible for this condition was mapped to19q13.4 and causative mutations identified. The defective protein,NALP7, is part of the CATERPILLAR protein family with roles inpathogen-induced inflammation and apoptosis. The exact role of NALP7in the pathophysiology of molar pregnancies is unknown yet. NALP7could have a role either in oogenesis or in the endometrium duringtrophoblast invasion and decidualization. In this review, we outlinedrecent advances in the field of HMs and reviewed the literature in thelight of the new data.

R Slima,b and A Mehioc

aDepartments of Human Genetics,bObstetrics and Gynecology, andcDepartment of Pathology, McGillUniversity Health Center, MontrealH3G 1A4, Canada

Key words: Hydatidiform moles –spontaneous abortions – NALP7 –inflammation – molar pregnancies –recurrent hydatidiform moles – familialhydatidiform moles

Corresponding author: Rima Slim,Montreal General Hospital ResearchInstitute, Room L12-132, 1650 CedarAvenue, Montreal H3G 1A4, Canada.Tel.: 1514 934 1934x44550;fax: 1514 934 8261;e-mail: rima.slim@muhc.mcgill.ca

Received 31 July 2006, revised andaccepted for publication 3 August 2006

Hydatidiform mole (HM) (OMIM 231090) is adisease of ancient recognition. It has fascinatedand puzzled biologists for the last two millen-niums. Hippocrates in his treatise on �Air, Waterand Places’ described this condition, �The womenappear to be with child, . this happens from thedropsy of the uterus,’ and attributed its occur-rence to the drinking of unhealthy water frommarshes. It is not clear in his monograph towhich factor in the water he was alluding. But, hewas definitely talking about the sporadic, non-recurrent form of this condition. According toBrews, the first time the terms �hydatids’ and�moles’ were used together is in William Smelliecollection of cases and observations in mid-wifery; collection VIII entitled ‘‘Of what iscommonly called the false conception, Molesand Hydatides’’ (1, 2). In Table 1 we outlinedforgotten dates of interest in the history of HMs

that have led to their current definition, benigntumors of the trophoblast resulting from aber-rant human pregnancies with no embryos butcystic degeneration of chorionic villi.

Epidemiology

HMs are relatively common and occur in approx-imately 1 in every 1500 pregnancies in Europe andNorth America (3–10). This incidence variesbetween ethnic groups and is 2–10 times higher insome countries of Latin America, theMiddle East,and the Far East with the highest frequencies beingin Mexico, Iran, and Indonesia (3–10). Severalstudies have been performed to correlate the higherincidence of moles in particular racial groups withgenetic and various environmental factors such asfood preferences, vitamin A deficiency, and viral

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factors. These studies demonstrated that women ofAsian origin are at higher risk of developing molesthan others (11, 12). Besides ethnicity, the onlyconsistent correlation found in several countries isthe increased incidence of moles in women over45 and teenagers (4, 5, 7, 8, 10, 11, 13–17). Molarpregnancies are usually not recurrent. However,women with a previous HM are at higher risk ofhaving a secondmole thanwomen from the generalpopulation (4, 5, 7, 8, 10, 17), indicating theirgenetic susceptibility. After a priormole, the risk ofhaving a second one is 5–40 times that of womenfrom the general population. This risk increasesafter a secondmole and decreases if thewomanhadhad one or more normal pregnancies. RecurrentHMs (RHMs) in a single-family member occur in0.6–2.57% of all molar cases (18, 19) and in rarecases in at least two related women from the samefamily (familial cases) (20–34).

Clinical presentation

In the past, the first manifestation of a typicalHM used to be vaginal bleeding in the middletrimester of the pregnancy, which may beaccompanied by the passage of grape-like struc-tures from the vagina. Other signs may includelarger than normal growth of the uterus,abdominal pain, severe nausea, and vomiting(hyperemesis gravidarum) associated with a highlevel of human chorionic gonadotropin (hCG),a hormone normally produced during pregnancybut present at much higher levels in patients withHMs. Nowadays, because of the routine use ofultrasonography in monitoring pregnancies start-ing from the eighth week of gestation, HMs arebeing diagnosed at an earlier gestational age.Consequently, a HM rarely presents with theclassic signs and symptoms of excessive uterine

size. The majority of patients present withvaginal bleeding or are discovered after ultraso-nography (35, 36). After diagnosis, moles areevacuated by dilatation and suction curettageand the patients followed up with a series ofserum hCG estimations until the hCG level fallsto a normal, non-pregnant state. Complicationsmay develop in up to 15% of cases where re-maining molar tissues invade the wall of theuterus leading to an invasive mole or in rare cases(2–5%) to a choriocarcinoma, a malignant,rapidly growing, and metastatic cancer.

Histopathology

Based on the histopathology of the evacuatedmolar tissues, HMs are divided into two types:complete hydatidiform moles (CHMs) and par-tial hydatidiform moles (PHMs). CHMs arecharacterized by hydropic degeneration of allvilli and absence of embryo, cord, and amnioticmembranes. In CHMs, all the villi are enlargedwith cisternae, avascular (no fetal vessels), andsurrounded by areas of excessive trophoblastic pro-liferation (Figs 1 and 2). PHMs are characterizedby focal trophoblastic proliferation with a mix-ture of normal-sized villi and edematous villi.The trophoblastic proliferation is less pro-nounced than in complete moles. An embryo,cord, and amniotic membranes are usuallypresent in partial moles (3, 6). In a minority ofcases, moles are not easily divisible into partialand complete moles because embryonic tissuesare also found in rare cases of complete moles(37) and now in some cases of moles evacuatedearly (38, 39). We note that in the past, whenarrested pregnancies used to be histologicallyexamined at the time of their spontaneousmanifestation, cystic changes of chorionic villi

Table 1. History of hydatidiform moles

Year Author Description

470–410 BC Hippocrates Dropsy of the uterus from drinking unhealthy water425–565 Aetius of Amida Hydropic uterus with small bladder-like objects1276 Story of the Countess

Margaret of HennebergSupernatural infliction leading to the birth of 365 children

1752 William Smellie Bunch of grapes of different sizesCollection VIII, �. false conception,Moles and Hydatids’

�.. round fleshy substance ..’

in which he citesMr. Lamotte’s XVIth observation

�. delivered a mole .’

1827 Velpeau and Mme Boivin The first recognition that the grape-structure aredilated cystic chorionic villi

1853 Virchow Degeneration affecting the stroma of the villi1895 Marchand Proliferation of syncytial and Larghan’s cell1925 Rossler and Zondek Excess of gonadotropic hormone in urine

Table adapted form Brews (1939).

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were found in 66% of early arrested pregnancies(40). Hertig in his review on the genesis of HMsbelieves that blighted ova, which constitute 50%of cases of spontaneous abortions, are at theorigin of HMs. Indeed, a blighted ovum (whosename is misleading and not accurate) is a productof conception of biparental origin. A blightedovum does not contain an embryo but displaysfrequent early hydatidiform degeneration of itschorionic villi (Fig. 3) and several karyotypeabnormalities (41–43). The relationship betweenblighted ova and HMs is not clear, but somepatients with RHMs have also had blighted ova[(30); and unpublished observations].

Cytogenetics

The first karyotype studies on molar pregnanciesgoback to the earliest days of cytogeneticswith thediscovery of sex chromatin or Barr body that wasshown to be present in most complete moles (44).This was an intriguing observation because theratio of male to female should be 50:50. Theexplanationof this observationwas providedKajiiand Ohama (45) who confirmed the presence oftwo X chromosomes in most moles and demon-strated their androgenetic and monospermicnature. However, dispermic moles with 46,XY

karyotype were also shown to occur in rare cases(4%) (46). PHMs are in general triploid with 69chromosomes and usually contain two sets ofpaternal chromosomes and one set of maternalchromosomes (diandric).The most recent reports, although done on a

limited number of cases, estimate that 80% ofCHMshaveadiploidgenomeandareandrogenetic.Among those, 60% are monospermic and 20% aredispermic (47, 48). The remaining 20% havea biparental genomic contribution to their genome.

A maternal locus responsible for recurrent HMs

The molecular analysis of familial forms isrelatively recent. In 1999, the first familial caseof recurrent moles was analyzed and the molartissues were found diploid with biparentalcontribution to their genome (49). This familyas well as another one from a different ethnicgroup led to mapping a maternal defective locusresponsible for this condition to 19q13.4 (50). Atthat time, only seven familial cases of moles wererecorded in the OMIM database and the EnglishPubMed literature. Since 1999, 14 new familieswith RHMs have been reported indicating thatthis disease is more frequent than originallythought. The analysis of these families reducedthe size of the candidate region (27, 31, 51) and

Fig. 2. Histology of chorionic villi in a complete hydatidiform mole and a normal pregnancy. (a) Complete hydatidiformmole. Microphotographs showing two chorionic villi with hydropic changes and abnormal circumferential proliferation of thetrophoblast surrounding the chorionic villi. Note the presence of a cistern in the left villus and the absence of fetal vesselsin the two villi. (b) A normal pregnancy of similar gestational age. Note the normal polar arrangements of proliferatingtrophoblastic cells and the presence of fetal vessels (arrows).

Fig. 1. Gross morphology of a hyda-tidiform mole. (a) Photograph takendirectly after the evacuation of thetissue showing hydropic degenerationof chorionic villi with visible vesicles.(b) Photograph of another hydatidi-form mole after washes and lyses ofred blood cells.

Genetics of hydatidiform moles

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demonstrated the genetic heterogeneity of famil-ial RHMs (28, 52).

Epigenetics of HMs

Historical view

The role of epigenetics in the pathology of HMsemerged after the demonstration that CHMs areandrogenetic by Kajii and Ohama in 1977 (45).Their findings brought to light the comparison ofandrogenetic moles with another human pathol-ogy, ovarian teratoma, which are parthenoge-netic tumors of germ cell origin that developfrom maternal ovarian tissues without thecontribution of males (53). As opposed toandrogenetic HMs which do not contain embry-onic tissues, ovarian teratomas as well as othergerm cell tumors, contain highly differentiatedtissues such as hair, teeth, cartilage, bones, andthyroid follicles. At that time, there were a lot ofinterests in the scientific community in under-standing cell pluripotency and differentiationand consequently why mammalian parthenoge-nones, gynogenones, and androgenones do notdevelop to term. The answers to these questionscame essentially from the work of Surani et al.(54) and from that of Solter (55) who havetremendously contributed to our current under-standing of the different roles of the maternaland paternal genomes. The work of Surani andBarton onmouse pronuclear transplantation haveled to the conclusion that the paternal genome isessential for the development of extra-embryonictissues while the maternal genome is essential forthe development of the embryo itself. Theseobservations were in agreement with observationson triploid embryos and fetuses where diandricembryo, with 46 paternal and 23 maternalchromosomes lead to PHMs while digynicembryos, with 46 maternal and 23 paternalchromosomes lead to abortions with well-formedembryos without excessive development of thetrophoblast (for review see Ref. (56)). Altogetherthese studies have led to a common belief thatthe excessive development of the trophoblast in

HMs is caused by the expression of two doses ofimprinted, paternally expressed genes while theabsence of embryo in CHMs is caused by theabsence of imprinted, maternally expressed genes.Various groups confirmed the androgenetic

nature of most moles and hypothetical mecha-nisms were proposed to explain the absence of thematernal genome in the molar tissues; Wake et al.postulated that androgenetic moles are the resultof fertilized ova in which the maternal nucleus waseither eliminated or inactivated (57) and Jacobset al. (58) proposed that HMs originate from thefertilization of an empty egg by a haploid spermthat duplicates without cytokinesis to reconstitutea diploid genome. Out of 24 moles analyzed byJacobs et al. (58), two were diploids and bi-parental with maternal and paternal genetic com-plements. However, the authors did not commenton them; they designated one as an atypical moleand could not reach a conclusion regarding thesecond. Indeed, biparental moles are undistin-guishable at the clinical and pathological levelsfrom their androgenetic counterparts; they areonly discovered after the analysis of polymorphicmarkers.

Deregulation of imprinted genes in biparental HMs

The original 19q13.4 HM candidate region was4.8-Mb and contained several Kruppel-type(C2H2) zinc finger genes with roles as trans-acting regulator of the transcription of othergenes. In addition, the presence in the HMcandidate region of an imprinted gene, PEG3,and possibly others based on their occurrence inclusters, fostered the belief that the causalmutations responsible for biparental RHMsderegulate the expression of several imprintedgenes. Attractive examples of such genes are twoKruppel-type (C2H2) zinc finger genes, the CTCF(chromosome 16) and BORIS (chromosome 20)(59), with the former being involved in thesilencing the imprinted H19-Igf2 (for review seeRefs. (60, 61), b-globin (62), and Tsix (63)). Thishas led Judson et al. (28) to look at the

Fig. 3. Histopathology of blightedovum. (a) Chorionic villi with hy-dropic changes and mild sclerosis.Note the absence of excessive tropho-blastic cell proliferation around thechorionic villi. (b) Lower magnifica-tion of the same sample showing thepresence of an empty gestational sacwith the two characteristic layers,chorion (the outer membrane) andamnion (the inner membrane).

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methylation of several imprinted genes in onebiparental HM. The authors demonstrated theabsence of methylation marks on six of the eightanalyzed paternally expressed genes and the gainof methylation marks on one of two maternallyexpressed genes. They suggested that the causa-tive gene leading to RHMs in their family, whichis not linked to 19q13.4, is a trans-acting factorresponsible for imprint establishment. In anotherstudy, the methylation of four imprinted geneswas analyzed in two molar tissues from a familywith linkage to 19q13.4 and led to the same trendof results, a lack of methylation marks onpaternally expressed genes and gain of methyla-tion marks on maternally expressed genes (64).Using DNA polymorphisms, the lack and gain ofDNA methylation was shown to occur only onthe maternal alleles. To investigate whether thisgain of methylation is the result of an abnormalerasure of the grandparental marks in theprimordial germ cells of the patients, we tracedthe inheritance of the abnormally methylatedalleles to the molar tissues and found that thegain of methylation occurred in two cases onunmethylated alleles in the patients. This indi-cated that the abnormal methylation, at least onthese two genes, was acquired de novo either inthe maternal germline or post-zygotically beforeor after implantation (65). So far, only one studyaddressed by immunohistochemistry the expres-sion of an imprinted gene, p57KIP2, in RHMscaused by defect in 19q13.4 and showed itsunderexpression (29), which is in agreement withthe above-mentioned methylation data.

Normal post-zygotic DNA methylation inbiparental HMs

Biparental molar tissues caused by defect in19q13.4 were further analyzed to investigate thestatus of DNA methylation at other types ofCpG-rich regions. This analysis demonstratednormal DNA methylation at repetitive elementsand satellite sequences; the promoters of inactivegenes on the inactive X chromosome; and 13major CpG-rich regions surrounding the differ-entially methylated region of the imprinted,paternally expressed PEG3. These data indicatethat post-zygotic DNA demethylation, de novomethylation, and X-inactivation occur normallyin biparental RHMs. In addition, three cancer-related genes known to be abnormally hyper-methylated in several sporadic HMs were alsonormally methylated (66). However, the analysisof this limited number of non-imprinted genesdoes not allow reaching a general conclusion on

their methylation status in molar tissues. Weexpect that other non-imprinted genes be abnor-mally methylated in these tissues. We were notsuccessful in identifying such genes in the globalmethylation assessment we performed usingrestriction landmark genome scan; only a fewloci were predicted by this method and none ofthem could be confirmed by other approaches.Assessing gene transcription using microarrays,in cases where RNAs from the molar tissues areavailable, will be a better approach to identifysingle copy genes that are deregulated in cho-rionic villi of RHMs.

Immunology and HMs

Long before the emergence of the role of epi-genetics in the pathology of moles, immunologyhas been recognized as a cause of various forms ofpregnancy loss including HMs. The roots of thesethoughts date back to the beginning of the 20thcentury and were formulated in Medawar’shypothesis in 1953 to explain how the mammalianfetus escapes the maternal immune system (67).Medawar’s hypothesis gave rise to the proposalsthat an abnormal immune relationship betweenthe mother and her fetus may underlie pathologicpregnancies such as HMs, choriocarcinoma, andchronic abortions (68–71). In some studies, thisabnormal immune relationship was attributed toan insufficient fetal antigenic stimulus caused bythe sharing of several HLA antigens between thepatients and their partners (72). In cases where thesegregation of the parental HLA was investigated,the shared alleles were found in the androgeneticmoles indicating either a preferential fertilizationof a spermatozoon carrying the shared antigen orthe maternal selection and delayed elimination ofHLA compatible conceptuses (73). Indeed, thespontaneous delayed elimination of typical HMsrelative to abortions with cystic changes wasoriginally noted by Hertig and Edmonds (40) andelaborated by Takeuchi (74). Based on these dataand on the similarity between vascular lesionsobserved in rejected renal and cardiac transplantsand those in the placenta of chronic abortions,preeclampsia, idiopathic intrauterine growthretardation, HMs, Labarrere and Althabe (75)proposed a unifying immune cause underlyingthese various forms of abnormal pregnancies.

Maternal mutations in NALP7 cause RHMs

The search for the 19q13.4 gene causing RHMswas hampered mainly by the scarcity of familialforms of this condition and the richness of

Genetics of hydatidiform moles

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human chromosome 19 in genes. Recently the19q13.4 gene, NALP7, causing RHMs wasidentified by the finding of five different muta-tions including two splice donor site mutations(Fig. 4) (76). Women with recurrent HMs are ho-mozygous or compound heterozygous for muta-tions in NALP7. This gene is transcribed ina variety of human tissues including unfertilizedoocytes at the germinal vesicle and metaphase Istages and also in the endometrium. NALP7 ispart of the CATERPILLER protein family withroles in inflammation and apoptosis during thecell’s response to infections (77). NALP7 isupregulated in testicular seminoma tumors whereits down-regulation with small interfering RNAresults in growth suppression (78). In vitro studieshave shown that NALP7 interacts physicallywith procaspase-1, inhibits its processing, andconsequently inhibits the secretion of IL-1b (79).

Biology has more imagination than biologists:possible roles of NALP7

The identity of the gene causing familial RHMswas a surprise in the imprinting field (80).NALP7 has no known role in DNA methylationand does not contain any DNA-binding domain.The abnormal DNA methylation in biparentalmolar tissues caused by truncated NALP7 pro-tein seems to be a consequence and not a cause ofthe defect. This reminds us of an old say that�hydatidiform mole is two diseases in one’ in thesense that abnormal maternal inflammation isthe cause while abnormal methylation is theconsequence. The exact role of NALP7 in RHMsand where the abnormal DNA methylation startsare currently unknown based on experimentalevidence. From the above-mentioned data, theknown role of NALP7 in cytokine secretion is themost likely explanation by which defects inNALP7 could lead to HMs since IL-1b is apleiotropic cytokine known to activate a number ofinflammatory and apoptotic pathways involved

in normal folliculogenesis, ovulation, blastocystimplantation, and trophoblast invasion.

Role in oogenesis

NALP7 could have a role as a maternal effectgene. Maternal effect genes are defined as geneswhose products are needed in the oocytes tosupport early embryonic development until theactivation of the embryonic genome. Such genesare not supposed to affect ovulation andfertilization, but their absence would lead toearly embryo arrest. This hypothesis is supportedby the expression of NALP7 in unfertilizedoocytes. A potential role of NALP7 in oogenesiswould explain the absence of maternal methyla-tion marks on paternally expressed genes ana-lyzed in molar tissues from patients with NALP7defect. Another argument in favor of thishypothesis is the fact that another NALP gene,Nalp5, has been shown in mice to be a maternaleffect gene (81). Nalp5-null mouse females havenormal ovaries, their oocytes fertilize normallybut the embryos stop to develop at the two-cellstage. Two other NALP genes, NALP9 (82) andNALP14 (83), show oocyte-restricted expressionand are believed to play a role in reproduction.

Role in post-implantation development

The second possible role of NALP7 is afterimplantation and is supported by the followingobservations. First, NALP7 is transcribed inhuman endometrium and has been shown toplay a role in IL-1b secretion, a cytokine involvedin decidualization and trophoblast invasion (84,85). The NALP7 inflammatory pathway is partof the cellular immune response, a well-knowncause of repeated spontaneous abortions andvarious forms of reproductive failure. SinceMedawar’s hypothesis in 1953, a large numberof studies have documented an abnormalimmune response in women with reproductive

Fig. 4. NALP7 protein structure andpositions of the reported mutations.PYD, pyrin domain (also calledDAPIN domain) found in all NALPproteins; NACHT domain found inneuronal apoptosis inhibitor proteins(NAIP), the major histocompatibilitycomplex class II transactivator (CIITA),HET-E and TP1 proteins all involved insensing intracellular pathogens or theirderived molecules; and LRR, leucine-rich repeats.

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wastage of unexplained clinical origin. Despitethe contradictory results obtained in thesestudies, the general consensus is that an embryois bathing in a sea of cytokines (for review seeRef. (86)); a dysregulated cytokine production inthe endometrium of women with RHMs wouldbe very harmful for the embryo. Second, a longtime ago, pathologists have noted that the firstrecognizable change in the degeneration of theHM chorionic villi is the disappearance of fetalvessels, which differentiate at the same time aschorionic villi around the fifth week of pregnancy(menstrual age) (40). It is therefore possible thatpatients with RHMs have a dysregulated endo-metrial inflammation that affects decidualizationand at the same time the formation of fetalvessels. Consequently, the villus fluid that wouldbe normally carried away by the fetal circulationaccumulates and leads to the cystic degenerationof the villi. Third, inflammation and leukocyteinfiltration of the decidua in the common molarpregnancies have been documented in severalstudies (40, 87–89). Fourth, so far, patients withthe reported mutations in NALP7 ovulatednaturally and had several pregnancies. It wasonly after 7–14 weeks of gestation that the defectmanifested itself. Fifth, the wide variability in the

phenotype of the conceptuses of patients withNALP7 mutations, ranging from moles tonormal pregnancies and including stillbirths,makes it unlikely for NALP7 to a have a roleonly in oogenesis.Alternatively, a double role of NALP7, with

a first one in the oocytes and a second afterimplantation is also a possible scenario (Fig. 5).

Conclusions

Familial RHMs is a rare monogenic Mendelianform of a complex disorder with probably singlegene predisposition, other host genetic factors andenvironmental factors contributing to its patho-genesis. The identification of NALP7 pinpointsthe role of maternal inflammation in the commonform of HMs. Dissecting the NALP7 inflamma-tory pathway using functional studies and modelanimals will reveal other susceptibility genes andtriggering environmental factors causing thecommon form of this condition (Fig. 4). Interest-ingly, regions with higher incidence of non-recurrent HMs are those with higher incidence ofvarious infectious diseases. Revisiting severalaspects of the pathology of HMs (Table 2) in the

Table 2. Suggestions that will contribute to the dissection of the genetic complexity of common HMs

Clinical Search for blood inflammatory markers at the time of molar manifestationNote the reproductive history of the patient including infertility and all pregnancy outcomesNote the reproductive history of all other family membersCheck for consanguinity between the parents of the patient and between the patient and her partner

Epidemiology Determine which patients are at higher risk of a second mole?–Patients with CHMs

Androgenetic monospermicAndrogenetic dispermicBiparental

–Patients with PHMs

Pathology Analyze the implantation sites of HMsSearch for inflammatory markers in the deciduaSearch for pathogens (parasites, bacteria, viruses) and pathogen-derived molecules

Familial RHMs: rare Mendelianform of a complex disease

Identification of NALP7

Dissecting the NALP7 inflammatory pathwayAnimal models

Susceptibility to infection,triggers: Parasites,bacteria, viruses, etc.

RHMs in single familymembers (2 of moles)

Non-recurrentHMs (1/1000)

New candidate genes

?

Fig. 5. Current understanding of familialRHMs and strategy to study the commonforms.

Genetics of hydatidiform moles

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light of the new data will continue to add pieces tothe intricate puzzle that is HMs and contribute tothe elucidation of molecular mechanisms under-lying their formation.

Acknowledgements

We thank Ugljesa Djuric for his comments and assistance in thepreparation of the figures. R. S. is supported by the Fonds de laRecherche en Sante du Quebec and by an operating (MOP-67179) and an international development (OPD-73018) grantsfrom the Canadian Institute of Health Research.

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