Recurrent hydatidiform mole is a condition that affects women and is characterized by the occurrence of at least two abnormal pregnancies that result in the formation of hydatidiform moles. A hydatidiform mole is a mass that forms early in pregnancy and is made up of cells from an abnormally developed embryo and placenta. Normally, the embryo would develop into a fetus and the placenta would grow to provide nutrients to the growing fetus. When a hydatidiform mole occurs once, it is known as sporadic hydatidiform mole; if it happens again, the condition is known as recurrent hydatidiform mole.

The first symptom of a hydatidiform mole is often vaginal bleeding in the first trimester of pregnancy. During an ultrasound examination, the abnormal placenta appears as numerous small sacs, often described as resembling a bunch of grapes.

Hydatidiform moles are not naturally discharged from the body and must be surgically removed, typically by the end of the first trimester. After removal, there is up to a 20 percent risk that any tissue left behind will continue to grow and become a cancerous (malignant) tumor called a persistent mole. If the tumor invades the surrounding tissue of the uterus, it is called an invasive mole. In rare cases, this malignant tumor can transform into a different form of cancer called gestational choriocarcinoma that can spread (metastasize) to other tissues such as the liver, lungs, or brain.

Molar pregnancy is a condition in which the placenta does not develop properly. The symptoms of molar pregnancy, which may include vaginal bleeding, severe morning sickness, stomach cramps, and high blood pressure, typically begin around the 10th week of pregnancy. Because the embryo does not form or is malformed in molar pregnancies, and because there is a small risk of developing a cancer called choriocarcinoma, a D&C is usually performed.

Hydatidiform moles occur in 1 in 600 to 1,000 pregnancies in western countries. One to six percent of previously affected women will have a recurrent hydatidiform mole. Gestational choriocarcinoma occurs in 1 in 20,000 to 50,000 pregnancies in the United States.

Mutations in multiple genes have been found to cause recurrent hydatidiform mole. About 55 percent of cases of this condition are caused by NLRP7 gene mutations and about 5 percent of cases are caused by KHDC3L gene mutations. Mutations in other genes each account for a small percentage of cases.

The proteins produced from the NLRP7 and KHDC3L genes are critical for normal egg cell (oocyte) development, which impacts embryonic development. Within oocytes, the exact role of NLRP7 and KHDC3L proteins are not known. However, they are thought to play a role in a phenomenon known as genomic imprinting. Through genomic imprinting certain genes are turned off (inactivated) based on which parent the copy of the gene came from. For most genes, both copies of the gene (one copy inherited from each parent) are active in all cells. However, for a small subset of genes, only one of the two copies is active and the other is turned off. For some of these genes, the copy from the father is normally active, while for others, the copy from the mother is normally active.

NLRP7 or KHDC3L gene mutations result in the production of proteins with impaired function. As a result, oocytes do not develop normally. A pregnancy that results from an abnormal oocyte cannot develop properly, resulting in recurrent hydatidiform mole. NLRP7 or KHDC3L gene mutations can also prevent proper imprinting of multiple genes that contribute to a developing embryo, leading to abnormal gene activity (expression). It is not clear if problems with imprinting also contribute to the development of a hydatidiform mole. In women with NLRP7 or KHDC3L gene mutations, a hydatidiform mole will develop in every pregnancy that occurs with her egg cells.

A small number of cases of recurrent hydatidiform mole have been found to be caused by mutations in genes that play important roles in the production of oocytes and sperm cells. The proteins produced from these genes are involved in the normal process of exchanging genetic material between chromosomes in preparation for cell division during oocyte and sperm cell production. These proteins are needed to make breaks in the chromosomes so that genetic information can be exchanged.

Mutations in these genes prevent the normal function of the proteins involved in the exchange of genetic material. Without the exchange of genetic material, cell division is often stopped. In affected women, this can lead to the production of abnormal oocytes that do not contain chromosomes. When a normal sperm cell fertilizes one of these oocytes, the resulting embryo has only one set of chromosomes. Because the embryo has no genes from the mother, the pregnancy cannot develop normally, resulting in a hydatidiform mole. In women with these rare gene mutations, every pregnancy that occurs with her egg cells will result in a hydatidiform mole or pregnancy loss (miscarriage).

In some cases of recurrent hydatidiform mole, no mutations in any of the genes associated with the condition have been identified. In these instances, the cause of the condition is unknown.

Normal Function

The KHDC3L gene provides instructions for making a protein whose role is not known. The KHDC3L protein is thought to be involved in regulating gene activity (expression) through a phenomenon known as genomic imprinting. Through genomic imprinting, certain genes are turned off (inactivated) based on which parent the copy of the gene came from. For most genes, both copies of the gene (one copy inherited from each parent) are active in all cells. However, for a small subset of genes, only one of the two copies is active and the other is turned off. For some of these genes, the copy from the father is normally active, while for others, the copy from the mother is normally active.

It is likely that the KHDC3L protein has additional roles in egg cell (oocyte) and embryonic development; however, its exact functions are unclear.

Health Conditions Related to Genetic Changes

Recurrent hydatidiform mole

At least six mutations in the KHDC3L gene have been found to cause a pregnancy-related condition known as recurrent hydatidiform mole. A hydatidiform mole is a mass that forms early in pregnancy and is made up of cells from an abnormally developed embryo and placenta. The placenta, a structure in the uterus that normally provides nutrients to a growing fetus, is dysfunctional and appears as numerous small sacs, often described as resembling a bunch of grapes. When a hydatidiform mole develops more than once, the condition is known as recurrent hydatidiform mole. KHDC3L gene mutations account for recurrent hydatidiform mole in about 5 percent of women with this condition.

KHDC3L gene mutations result in the production of a protein with reduced function. As a result, oocytes do not develop normally. A pregnancy that results from an abnormal oocyte cannot develop properly, resulting in recurrent hydatidiform mole. KHDC3L gene mutations can also prevent proper imprinting of multiple genes that contribute to a developing embryo, leading to abnormal gene activity (expression). It is not clear if problems with imprinting also contribute to the development of a hydatidiform mole. In women with KHDC3L gene mutations, a hydatidiform mole will develop in every pregnancy that occurs with her egg cells.

Other Names for This Gene

• C6orf221
• ECAT1
• ES cell-associated transcript 1 protein
• HYDM2
• KH domain containing 3-like, subcortical maternal complex member
• KHDC3-like protein

Genomic Location

Normal Function

The NLRP7 gene provides instructions for making a protein whose role is not known. The NLRP7 protein is thought to be involved in regulating gene activity (expression) through a phenomenon known as genomic imprinting. Through genomic imprinting, certain genes are turned off (inactivated) based on which parent the copy of the gene came from. For most genes, both copies of the gene (one copy inherited from each parent) are active in all cells. However, for a small subset of genes, only one of the two copies is active and the other is turned off. For some of these genes, the copy from the father is normally active, while for others, the copy from the mother is normally active.

Research suggests that the NLRP7 protein also plays a role in egg cell (oocyte) and embryonic development as well as inflammation and other immune responses by regulating the release of an immune protein called interleukin-1 beta.

Health Conditions Related to Genetic Changes

Recurrent hydatidiform mole

More than 75 mutations in the NLRP7 gene have been found to cause a pregnancy-related condition called recurrent hydatidiform mole. A hydatidiform mole is a mass that forms early in pregnancy and is made up of cells from an abnormally developed embryo and placenta. The placenta, a structure in the uterus that normally provides nutrients to a growing fetus, is dysfunctional and appears as numerous small sacs, often described as resembling a bunch of grapes. When a hydatidiform mole occurs more than once, the condition is known as recurrent hydatidiform mole. NLRP7 gene mutations account for recurrent hydatidiform mole in about 55 percent of women with this condition.

The NLRP7 gene mutations that cause recurrent hydatidiform mole lead to production of a protein with reduced function or prevent production of any protein at all. As a result, oocytes do not develop normally. A pregnancy that results from an abnormal oocyte cannot develop properly, resulting in recurrent hydatidiform mole. NLRP7 gene mutations can also prevent proper imprinting of multiple genes that contribute to a developing embryo, leading to abnormal gene activity (expression). It is not clear if problems with imprinting also contribute to the development of a hydatidiform mole. In women with NLRP7 gene mutations, a hydatidiform mole will develop in every pregnancy that occurs with her egg cells. Additionally, NLRP7 gene mutations result in slowed release of interleukin-1 beta. A shortage of this protein disrupts the normal immune response that would remove the hydatidiform mole from the body. Instead, the hydatidiform mole must be removed surgically.

Other disorders

Some rare and common variations (polymorphisms) in the NLRP7 gene are associated with an increased risk for early pregnancy loss, such as miscarriages and nonrecurrent (sporadic) hydatidiform mole. The polymorphisms are found in one copy of the NLRP7 gene in each cell. Unlike women with recurrent hydatidiform mole (described above), women with these polymorphisms are able to have normal pregnancies.

Other Names for This Gene

• CLR19.4
• NACHT, leucine rich repeat and PYD containing 7
• NACHT, LRR and PYD containing protein 7
• NACHT, LRR and PYD domains-containing protein 7
• NALP7
• NLR family, pyrin domain containing 7
• NOD12
• nucleotide-binding oligomerization domain protein 12
• nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 7
• PAN7
• PYPAF3
• PYRIN-containing Apaf1-like protein 3

Genomic Location

Recurrent hydatidiform mole is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. Recurrent hydatidiform mole seems to have an autosomal recessive inheritance pattern even when the genetic cause of the condition is unknown.

Treatment of a hydatidiform mole may include the following:

• Surgery (Dilatation and curettage with suction evacuation) to remove the tumor.

After surgery, beta human chorionic gonadotropin (β-hCG) blood tests are done every week until the β-hCG level returns to normal. Patients also have follow-up doctor visits monthly for up to 6 months. If the level of β-hCG does not return to normal or increases, it may mean the hydatidiform mole was not completely removed and it has become cancer. Pregnancy causes β-hCG levels to increase, so your doctor will ask you not to become pregnant until follow-up is finished.

For disease that remains after surgery, treatment is usually chemotherapy.