Molar pregnancy is an abnormal pregnancy in
which the embryo does not develop or develops
abnormally, but proliferation and hydropic
degeneration of the placenta villi is seen. Complete
hydatidiform moles usually have a 46XX
karyotype, and the molar chromosomes are entirely
of paternal origin (Androgenic moles).
Molar pregnancy in next gestation is rare; Its
probability of occurrence is approximately 1%
in sporadic partial or complete hydatidiform
moles of androgenic origin (
Most subsequent pregnancies following a sporadic
hydatidiform mole will be full term normal
pregnancies. Recurrent molar pregnancy may even
be familial, but this is an exceedingly rare condition (
Here we present the outcome of subsequent pregnancies in two cases of familial recurrent hydatidiform.
The first case is a member of the family K,
whom we previously reported as a case of familial
molar pregnancy comprising five affected
members, each with at least one hydatidiform
Our patient has two children. The first child is
a healthy boy, but the second one suffers from
congenital heart disease of ventricular septal
defect (VSD) and also Down syndrome (
However, mutation of C6orf221 has not been investigated in this family. The second case is a member of family (S) in which two sisters of the family are affected. The first sister has had recurrent pregnancy loss for four times, including complete molar pregnancies. The younger sister has had two complete molar pregnancies. Genetic analysis of her second molar pregnancy revealed it to be diploid but biparental in origin. Her third pregnancy resulted in a partly molar pregnancy with an apparently normal fetus with XX karyotype in amniocentesis.
Karyotype of the infant from FRHM family (K) diagnosed with Down syndrome.
This mother had preterm labor that could not be prevented due to signs of preeclampsia (proteinurea 3+ and hypertension (140/90 mmhg)). In addition, the mother had significant manifestations of molar pregnancy, including hyperemesis, hyper thyroidism (higher than normal free T4 and suppressed TSH), theca lutein ovarian cysts, and an enlarged partly molar placenta. At 25-weeks-ofpregnancy an apparently normal female was born but resuscitation was not successful. Amniotic fluid was more than normal (approximately 2 liters), that may be due to large placenta. After delivery, the mother had early post partum hemorrhage and received misoprostol (400 μm, sublingual), but she showed adverse reactions to this medicine with tachycardia (heart rate:120), fever (39˚C), and urticaria. After ruling out thyroid storm, it was controlled by symptomatic treatments.
Samples of placenta and cord blood were preserved
for further investigation and the newborn
with placenta were sent for pathologic evaluations.
Pathology revealed a partial molar pregnancy (
Pathology of partly molar change associated with a normal fetus in family (S).
The mother came back for follow up by monitoring of β-hCG. The level of β-hCG was 64000 mIU/ml at the time of admission and 10 days after delivery it was 550 mIU/ml and now it is negative.
Ultrasound on her first trimester, illustrated a singleton
pregnancy by an irregular gestational sac. In
serial ultra-sound, the placenta has been larger with
cystic area sounds like molar changes with large bilateral
ovarian cysts, most probably theca lutein cysts
First trimester ultra-sound of partly molar change accompanying a normal fetus in family (S).
Evaluation of her previous hydatidiform mole
(HM). and recent partial moles revealed a diploid
complete hydatidiform mole that are biparental in
origin suggesting that like her elder sister she has
FRHM. Surprisingly both sisters were not found
to have a mutation in NLRP7, the gene most common
mutated in this condition (
Overall, these families have had 26 pregnancies including twelve molar pregnancies (complete or partial), and three abortions.
Complete hydatidiform mole or androgenic origin
usually results from an excess of paternal genomes.
In this condition, complete hydatidiform
moles are mostly diploid, but biparental in origin
and the outcome of subsequent pregnancies is
likely to be a hydatidiform mole or other types of
reproductive loss (
Today, molar pregnancies are assumed to be rare due to early detection of abnormal pregnancies by ultra sound. Nutritional improvement has contributed to the decline of molar pregnancy as well.
Coexistence of molar changes with an apparently
healthy fetus is unusual in a case of
FRHM. However, it has been reported in other
situations, it could be due to a mole and a normal
fetus in twin pregnancy, partial mole, partly
molar changes, and also mesenchymal dysplasia
There are both diverse and heterogeneous causes of FRHM, such as in family K, in which both genetic and environmental factors may interact with causative mutations in FRHM and affect the reproductive outcomes in different pregnancies (even normal full term pregnancy).
With the exception of a mutated C6orf221 in family S, the causes of different pregnancy outcomes in these families have not yet been determined and more investigation is required to clarify these issues. We know that the mutation of NLRP7 is responsible for adverse pregnancy outcomes, however, the mutation was absent in both families. Although environmental and nutritional factors may overcome the effects of other responsible mutant genes, especially in the family K with several term pregnancies, detection of other chromosomal and genetic factors responsible for abnormal offspring should always be taken into consideration. The mutation of C6orf221 has not yet been evaluated in family K.
Since the members of this family mostly have
had term pregnancies in their subsequent pregnancies,
we can assume that a temporary factor,
such as environmental conditions, affect their
reproduction in a period of time. In a case-control
study, investigators revealed an association
between the occurrence of mole hydatidiform
pregnancies and the exposure of their husbands
to soil and dust (
Existence of a chromosomal abnormality (Down syndrome) in the child of one of the members could be coincidental, but we cannot rule out any relationship between genetical and chromosomal abnormalities in FRMH.
Therefore, further studies are required to detect other mutations and integrate the puzzle of causes responsible for familial molar pregnancies in order to manage these adverse reproductive outcomes.