Familial Recurrent Hydatidiform Moles

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Familial Recurrent Hydatidiform Moles
Rosemary Fisher
Institute for Reproductive and Developmental
Biology, Imperial College London
Charing Cross Hospital, London
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Familial Recurrent HM Syndrome
2 of women with a HM have a second HM
CHM - CHM
CHM - PHM
PHM - PHM
PHM - CHM
Small number of women who have an inherited
predisposition to CHM - recurrent molar
pregnancies
Associated with families where one or more women
are affected
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Familial Recurrent HM Syndrome
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Familial Recurrent HM Syndrome
AR condition in which women have a predisposition
to molar pregnancies
CHM in this condition are pathologically
indistinguishable from typical androgenetic CHM
The CHM in FRHM show abnormal imprinting
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p57KIP2 Expression in HM
PHM
CHM
CHM
Sporadic
FRHM
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Familial Recurrent HM Syndrome
AR condition in which women have a predisposition
to molar pregnancies
CHM in this condition are pathologically
indistinguishable from typical androgenetic CHM
The CHM in FRHM show abnormal imprinting
Hydatidiform moles are diploid but biparental in
origin
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Microsatellite Polymorphisms in PHM and CHM
PHM
CHM
Size (bps)
Arbitrary Units of Fluorescence
D15S659
D13S317
Microsatellite
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Microsatellite Polymorphisms in CHM
FRCHM
CHM
size (bp)
Maternal
Maternal
Maternal
Arbitrary Units of Fluorescence
CHM
CHM
CHM
Paternal
Paternal
Paternal
D12S391
D13S317
D10S179
Microsatellite
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Clinical Significance of Familial Recurrent HM
Subsequent pregnancies ?
Risk of persistent trophoblastic disease ?
What is the underlying gene defect ?
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Subsequent Pregnancies in Women with HM
2 of women with HM have a second HM
20 of women with 2 HM have a third HM
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Pregnancies in Women with Familial Recurrent HM
FRHM - 16 families - 45 affected women
Normal pregnancies Pregnancy losses PHM
CHM HM
- 10 - 30 - 7 - 119 - 8
( 6)
(17)
(77)
174
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Risk of Persistent Trophoblastic Disease
CHM - Approximately 10
FRHM - 14 families - 37 affected women
12 of 113 CHM (11) have not resolved
spontaneously
Fisher et al (2004)
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Mapping the Gene for Familial Recurrent HM
Chromosome 19
p13.3
p13.2
p13.1
p12
cen
q12
q13.1
q13.2
q13.3
q13.4
This region contains approximately 80 genes
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Familial Recurrent HM is a Single Gene Disorder
Murdoch et al 2006
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NLRP7 (NALP7)
NACHT, leucine rich repeat and PYD containing 7
PYD
NACHT
leucine rich repeat region
Immunity and inflammation - negative regulator of
IL1?
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Deletion in NLRP7 in Affected Individual
Case CXS04
CAACACCTCCTCAGAAAATTGGATAAG
DNA
control
Protein
Asn
Thr
Ser
Glu
Asn
Trp
Ile
Ser
affected individual
CAACACTCCTCAGAAAATTGGATAAG
DNA
Protein
Asn
Thr
Pro
Lys
Ile
Gly
stop
Gln
Exon 2
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Mutations in NLRP7 (NALP7)
L750V
stop
stop
R693W
R693P
stop
N913S
N657V
duplication
(Murdoch et al 2006 Qian et al 2007 Kou et al
2008)
12 families
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Mutations in NLRP7 (NALP7)
Several different mutations - many found in only
a single family
Mutations of NLRP7 have now been found in most -
not all - families with FRHM
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Diagnosis of Familial Recurrent HM
It is important to identify FRHM
- unlikely to have a normal pregnancy
- risk of developing a trophoblastic tumour
Fluorescent microsatellite genotyping - show that
CHM are biparental
Screening of families is feasible to identify
affected individuals and carriers
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Screening for Familial Recurrent HM
mother
father
G/C
G/C
proband/sister 1
sister 2
G/C
C
c.2078GgtC base change
Mutation
R693P protein change
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Familial Recurrent HM Syndrome
Risk of subsequent molar pregnancies
Significant risk of developing persistent
trophoblastic disease
IVF may not be appropriate
Embryo appears genetically normal
Diagnosis - showing molar tissue is diploid,
biparental
- screening for mutations in NLRP7
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Acknowledgements
Charing Cross Hospital, London
IRDB, Imperial College London
Michael Seckl
Mary Wang
Philip Savage
Peter Dixon
Neil Sebire
Shaun Decordova
Matt Hodges
Hammersmith Hospitals Trustees Research Committee
Cancer Treatment and Research Trust