Hereditary Cancer Predisposition Program at the Cancer Center

DICER1 Syndrome or Pleuropulmonary Blastoma Family Tumor and Dysplasia Syndrome (PPB-FTDS)

What is DICER1 syndrome?

DICER1 Syndrome (also known as Pleuropulmonary Blastoma Family Tumor and Dysplasia syndrome) is a rare hereditary cancer syndrome characterized by the development of specific types of tumors, with pleuropulmonary blastoma (a rare type of lung tumor that typically occurs in childhood), cystic nephroma (a rare benign kidney tumor), multinodular goiter (enlarged thyroid with multiple growths or nodules), and certain types of ovarian tumors (including Sertoli-Leydig cell tumors) being the most frequently reported.

What causes DICER1 syndrome?

DICER1 syndrome is caused by alterations, also known as mutations, at specific areas in a person’s genetic information. Each of us has a large amount of genetic information that is organized into smaller segments known as genes. Genes provide the instructions that the cells of the body need to perform their different functions.

There is a specific gene known as DICER1, located on chromosome 14 at position q32.13, which is altered in people with DICER1 syndrome. The DICER1 gene functions to regulate the expression of other genes. It is believed that by regulating the expression of multiple genes, DICER1 aids in the prevention of tumors. With the exception of egg and sperm cells, each cell of the body normally has two working copies of the DICER1 gene, one copy that is inherited from the mother and one from the father. However, in people who have DICER1 syndrome, each cell contains only one working copy of the DICER1 gene. While the second copy is present, it is altered so that it does not function properly.

How is DICER1 syndrome inherited?

Some individuals with DICER1 syndrome inherit an altered copy of the DICER1 gene from a parent who carries the same genetic mutation. In the remaining individuals, DICER1 syndrome results from the development of a “new” mutation in one of the father’s sperm, mother’s eggs, or in a cell of the developing fetus. In the latter situations, the affected individuals will be the first ones in their family to carry this genetic change.

Individuals who carry an alteration in one copy of the DICER1 gene in all the cells of their body have a 50 percent, or 1 in 2, chance of passing this same alteration on to each of his or her children. Children who inherit the altered gene copy will have DICER1 syndrome and thus be at increased risk of developing the tumors associated with DICER1 syndrome.

When should DICER1 syndrome be considered?

The diagnosis of DICER1 syndrome may be suspected in individuals who develop pleuropulmonary blastoma (PPB), cystic nephroma (CN), ovarian Sertoli-Leydig tumor, and/or other tumors associated with DICER1 mutations. It is estimated that 40 to 60 percent of PPBs are due to a DICER1 mutation. In one study, a DICER1 mutation was found in 11 out of 11 families with a history of PPB (alone or in combination with lung cysts) and/or cystic nephroma (Hill et al., 2009). Mutations in the DICER1 gene were also identified in affected members from five families with multinodular thyroid goiter and ovarian Sertoli-Leydig cell tumor (Rio Frio et al., 2011) and in rare families with CN (Bahubeshi et al., 2010).

How do you test for DICER1 syndrome?

To identify whether an individual has DICER1 syndrome, it is important to perform genetic testing. To perform genetic testing, a small sample of blood is obtained. The white blood cells are isolated and used as a source of DNA. Subsequently, the two copies of the DICER1 gene are analyzed using a process known as DNA sequencing to look for possible changes in the normal lettering of one of the two copies of the DICER1 gene. If a change is identified, it can be further analyzed to determine whether it is causative of DICER1 syndrome or simply a normal variation in the gene.

Reproductive options

A person with DICER1 syndrome who is concerned about passing this disorder on to future children has several options regarding prenatal genetic testing. However, before one of these can be considered, the familial DICER1 mutation must be identified. The options currently available include:

What are the tumor risks in individuals with DICER1 Syndrome?

Individuals with DICER1 syndrome are at an increased risk of developing certain tumors, including pleuropulmonary blastoma, cystic nephroma, ovarian Sertoli-Leydig tumor and multinodular goiter, and less commonly, Wilms tumor (a childhood kidney tumor) and sarcoma (a tumor of the muscle). In individuals with DICER1 Syndrome, the risk of developing these tumors is believed to be low, with the majority of DICER1 mutation carriers never developing a tumor. When individuals with DICER1 syndrome develop a tumor, they usually do so within the first two decades of life.

It is important to note that the clinical findings may differ greatly between affected family members who carry the same DICER1 mutation. For example, some individuals with a DICER1 mutation may develop one or more tumors, while other mutation carriers in the same family may never develop tumors. It is not yet understood why some individuals with DICER1 syndrome develop tumors while others do not. There are probably other genetic and environmental factors that contribute to these differences, but currently these factors remain unknown.

DICER1 syndrome has only been described recently and further studies may clarify or expand on our current knowledge of the tumor risks and clinical features associated with DICER1 mutations.

Recommended tumor screening protocol for individuals with DICER1 syndrome

There are currently no standard screening recommendations for individuals with DICER1 syndrome. Screening for pleuropulmonary blastoma, lung cysts, or other tumors associated with DICER1 syndrome may be considered, although many questions remain about the correct age at which screening should begin, how long screening should continue, and the optimal methods to use for screening. Consideration of a tumor screening protocol for individuals with DICER1 syndrome should include a thorough discussion of the advantages and disadvantage of screening with a physician familiar with the condition.

Support resources

The International Pleuropulmonary Blastoma Registry
Pediatric Oncology
Children's Hospitals and Clinics of Minnesota
2545 Chicago Ave. S., Suite 412
Minneapolis, MN 55404
Phone: 612-813-7115
Fax: 612-813-7108
Contact: Gretchen Williams or Dr. Yoav Messinger

American Cancer Society
1599 Clifton Rd. NE
Atlanta, GA 30329
Phone: 1-800-227-2345

CancerCare
275 Seventh Avenue
New York, NY 10001
Phone: 1-800-813-HOPE (1-800-813-4673) or 212-712-8400
Fax: 212-712-8495
info@cancercare.org

International Ovarian & Testicular Stromal Tumor (OTST) Registry
Registry Coordinator: Anne K. Harris, CCRP
Principal Investigator: Kris Ann Schultz, MD
Children's Hospital and Clinics of Minnesota
2545 Chicago Avenue South, Suite 412
Minneapolis, MN 55404
Phone: 612-813-5861
Fax: 612-813-7108
OTST@childrensMN.org

National Cancer Institute
6116 Executive Boulevard
Room 3036A
Bethesda, MD 20892-8322
Phone: 1-800-4-CANCER (1-800-422-6237)

References

Bahubeshi A, Bal N, Frio TR, Hamel N, Pouchet C, Yilmaz A, Soglio DB, Williams GM, Tischkowitz M, Priest JR, Foulkes WD. 2010. Germline DICER1 mutations and familial cystic nephroma. J Med Genet, 47, 863-866.

Hill DA, Ivanovich J, Priest JR, et al. 2009. DICER1 Mutations in Familial Pleuropulmonary Blastoma. Science, 325, 965.

Rio Frio T, Bahubeshi A, Kanellopoulou C, et al. 2011. DICER1 Mutations in Familial Multinodular Goiter With and Without Ovarian Sertoli-Leydig Cell Tumors. JAMA, 305, 68-77.

Slade I, Bacchelli C, Davies H, et al. 2011. DICER1 syndrome: Clarifying the diagnosis, clinical features and management implications of a pleiotrophic tumour predisposition syndrome. J Med Genet, 48, 273-278.

Reviewed by: Kim Nichols, MD, Kristin Zelley, MS, Samantha Wiley, MS
Date: March 2013

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