DICER1 Syndrome

  • 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. The most frequently reported are:

    • 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)
    • Certain types of ovarian tumors (including Sertoli-Leydig cell tumors)
  • Causes

    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 our bodies need to perform different functions.

    There is a specific gene known as DICER1, located on chromosome 14 at position q32.13, which is altered in children 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 mutated and does not function properly.

    How is DICER1 syndrome inherited?

    Some children with DICER1 syndrome inherit an altered copy of the DICER1 gene from a parent who carries the same genetic mutation. In other children, 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 these "new" mutation situations, the affected child will be the first one in his family to carry this genetic change.

    People who carry an alteration in one copy of the DICER1 gene in all the cells of their body have a 50 percent — or one in two — chance of passing this same alteration on to each of their 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.

  • Diagnosis

    The diagnosis of DICER1 syndrome may be suspected in individuals who develop pleuropulmonary blastoma (PPB), cystic nephroma, ovarian Sertoli-Leydig tumor, and/or other tumors associated with DICER1 mutations. It is estimated that 40-60 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 cystic nephroma. (Bahubeshi et al., 2010).

    Testing for DICER1 syndrome

    To identify whether an individual has DICER1 syndrome, it is important to perform genetic testing using a small sample of blood. Clinicians can then isolated the white blood cells and use them 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 onto 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:

    • Prenatal diagnosis: DNA is obtained from the cells of the embryo through chorionic villus sampling (CVS) or amniocentesis. The DNA is analyzed for alterations in the DICER1 gene. With appropriate counseling, a parent can then decide whether to carry the pregnancy to term or to end the pregnancy.
    • Preimplantation Genetic Diagnosis (PGD): For couples using in vitro fertilization (IVF) to become pregnant, embryos can be tested for genetic disorders before transferring them into the uterus. Only healthy embryos carrying two working copies of the DICER1 gene would be implanted.
  • Tumor risks

    People with DICER1 syndrome are at an increased risk of developing certain tumors, including:

    • Pleuropulmonary blastoma
    • Cystic nephroma
    • Ovarian Sertoli-Leydig tumor
    • Multinodular goiter
    • 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.

    Tumor screening protocol

    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.

  • 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 tumor predisposition syndrome. J Med Genet, 48, 273-278.

Reviewed by Kristin Zelley, MS, Kim E. Nichols, MD on March 04, 2013