DICER1 Syndrome

DICER1 syndrome is a genetic disorder associated with an increased risk for developing tumors in the lungs, kidneys, ovaries, thyroid, and several other locations in the body. These growths may be benign (non-cancerous) or malignant (cancerous).

DICER1 syndrome is also known as DICER1-related disorders and DICER1-pleuropulmonary blastoma familial tumor predisposition syndrome

Individuals with DICER1 syndrome are at increased risk of developing:

• Pleuropulmonary blastoma, a cystic lung tumor that may transform into an invasive tumor that spreads if it is not diagnosed and treated early. These lung tumors are often diagnosed at birth or within the first few months of life. These tumors rarely develop after the age of 7. This is the most common type of DICER1-associated tumor to affect infants and preschool-aged children.
• Multinodular goiter (MNG), and less commonly, differentiated thyroid cancer. MNG is a non-cancerous thyroid condition in which there are multiple nodules throughout the thyroid. The types of thyroid cancer that may develop include follicular and papillary thyroid cancer.
• Cystic nephroma, a non-cancerous kidney tumor, and less commonly, Wilms’ tumor or anaplastic sarcoma of the kidney.
• Ovarian tumors, most commonly Sertoli-Leydig cell tumor.
• Embryonal rhabdomyosarcoma of the uterine cervix (and less commonly, other locations).

Less commonly, children with DICER1 syndrome may develop:

• Certain types of brain tumors, such as pineoblastoma and pituitary blastoma
• Nasal chondromesenchymal hamartoma, a type of nose tumor
• Ciliary body medulloepithelioma, a type of eye tumor

Symptoms of DICER1 syndrome include abnormal growths in the lungs, kidneys, thyroid and ovaries (for females).

The lung lesions may be identified on prenatal ultrasound or diagnosed after a baby is born and found to have difficulty breathing. The thyroid tumors present as an asymptomatic “lump” (nodule) in the lower third of the neck. The ovarian tumors present with acne, increased body hair in an adult male pattern (face, chest, abdomen), and irregular periods secondary to increased production of the male hormone testosterone.

Tumors in the brain may present with increasing weight, weakness, and bruising secondary to increased production of cortisol (Cushing’s syndrome). Tumors in other areas of the body may be noticed based on history, physical exam, laboratory and radiologic evaluation.

DICER1 syndrome is caused by abnormality in the DNA code, also known as a “mutation." The role of the DICER1 gene is to regulate the expression of other genes. It is thought that by regulating the expression of multiple genes, DICER1 aids in the prevention of tumors. When the DICER1 gene is mutated within a cell, the affected cell may grow in an uncontrolled fashion, allowing tumors to form.

With the exception of egg and sperm cells, each cell of our bodies normally has two working copies of the DICER1 gene. In individuals with DICER1 syndrome, however, each cell contains only one working copy of the DICER1 gene. If the second copy is present, it is altered and does not function properly.

The DICER1 gene mutation is inherited in an autosomal dominant fashion, meaning that a person carrying a mutation in one copy of the DICER1 gene has a 50 percent chance of passing this same alteration onto each of their future children. Children who inherit the altered gene copy have DICER1 syndrome; however, not all will develop the tumors typically associated with the syndrome (referred to as “variable penetrance”). Because of this variation, if you or a family member is found to have a DICER1 mutation, it is extremely important to find a knowledgeable physician and genetic counselor.

As many as 80 percent of patients with DICER1 syndrome inherit a mutated copy of the DICER1 gene from a parent who also has the syndrome. In the remaining 20 percent of patients, DICER1 syndrome results from the occurrence of a “new” mutation in the DICER1 gene in one of the father’s sperm, mother’s eggs or in a cell of the developing fetus. Although these individuals will be the first in their family to carry the mutated gene, each of their future children will have a 50 percent chance of inheriting the same genetic alteration.

The diagnosis of DICER1 syndrome may be suspected based on:

• The presence of certain types of tumors, such as pleuropulmonary blastoma, cystic nephroma, multinodular goiter, and other tumors in the ovaries (Sertoli-Leydig cell tumors) and brain (pituitary blastoma and pineoblastoma)
• An individual’s family history that shows other family members diagnosed with the types of cancers mentioned above

It is estimated that 70 percent of people diagnosed with pleuropulmonary blastoma (PPB) will be identified to have a DICER1 gene mutation.

If there is any indication your child may have DICER1 syndrome, they should be referred to a facility that has the experience, expertise and resources to fully evaluate your child and best plan for their care. At Children’s Hospital of Philadelphia (CHOP), a diagnosis of DICER1 syndrome involves evaluation by our Cancer Predisposition Program and the Pediatric Thyroid Center. 

A doctor or genetic counselor will construct a pedigree — a multi-generational family tree — indicating which family members have developed certain tumors or cancer, taking note of the types of cancer and the age of onset.

If the pattern of clinical features and/or tumors is suggestive of a DICER1 mutation, the physician or genetic counselor will recommend genetic testing be performed. A sample of your child’s blood will be collected, then their DNA will be isolated and analyzed to determine if there are any alternations to or deletion (loss) of a DICER1 gene.

DICER1 genetic test results can provide valuable information to determine if screening for additional tumors should be pursued over the lifetime of the patient, as well as for other family members.

It is important to note that an identical DICER1 mutation can be manifested differently in each person affected — even within the same family. For example, one sibling with the DICER1 gene may develop numerous tumors, while a sibling with the same mutation may never develop a tumor over their lifetime. There are likely other genetic and environmental factors that contribute to these differences, but currently these factors remain unknown.

For patients with DICER1-syndrome, surveillance testing should include:

• Chest imaging: A chest CT should be performed when the child is 3-6 months old. If results are normal, a second chest CT should be performed between 2.5-3 years of age, and a chest X-ray should also be performed every six months until the child is 8 years old; then decrease in frequency to every 12 months until the child is 12 years old.
• Thyroid examination and thyroid ultrasound: A thyroid ultrasound should be performed by age 8, and if the initial ultrasound is normal, then every two to three years based on the results of the child’s physical exam. For patients treated with chemotherapy for pleuropulmonary blastoma, a thyroid ultrasound should be obtained annually for the first five years after treatment, and then decreased to every two to three years if the ultrasound is normal.
• Renal ultrasound: An abdominal ultrasound should be performed every six months until age 8; then decreased to every 12 months until the child is 12 years old.
• Pelvic ultrasound: A pelvic ultrasound should be performed once or twice a year starting in early childhood and continuing into adulthood (usually to age 40).
• Screening evaluations for other tumors is based on clinical signs and symptoms.
  • Brain MRI is performed if the child is experiencing headaches, vomiting, decreased or double vision, difficulty with upward gaze, early puberty or is diagnosed with Cushing’s syndrome.
  • Head and neck imaging is performed if the child has nasal obstruction.

There is no cure for DICER1 syndrome. Instead, the focus of medical care for most individuals with DICER1 syndrome is on cancer surveillance and screening to allow clinicians to discover tumors at their earliest, most treatable stages.

Treatment for individuals who develop tumors is based on the location, stage and type of the DICER1-associated tumors, and may include:

• Surgery to remove the tumor(s) or growth(s)
• Chemotherapy
• Radiation

Individuals with DICER1 syndrome should receive ongoing monitoring. When patients reach young adulthood (early 20s) they will be transitioned to an adult tumor predisposition program.

Reproductive options 

As individuals with DICER1 syndrome grow into adulthood, they may consider starting a family of their own.

Children born to a parent with DICER1 syndrome each have a 50 percent chance of inheriting the genetic abnormality in the DICER1 gene; however, with early detection and surveillance, children can lead healthy, happy and productive lives. For families that are interested, reproductive options exist for individuals with an alteration in the DICER1 gene who do not wish to pass this alteration onto future children.

In families with known DICER1 gene mutations, early screening for pleuropulmonary blastoma has been associated with improved health and survival of babies that inherit the DICER1 gene mutation.

Prenatal diagnosis

DNA is isolated from the cells of the developing baby through one of two procedures (chorionic villus sampling [CVS] or amniocentesis) and 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.

Pre-implantation genetic diagnosis (PGD)

For couples using in vitro fertilization 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.

Before an individual or couple can proceed with prenatal testing or PGD, a DICER1 mutation must be identified in one of the parents.

The long-term outlook for patients with DICER1 syndrome is highly variable and much remains unknown about this syndrome.

Patients and families with DICER1 syndrome will be provided information to voluntarily join an international registry, such as the Ovarian and Testicular Stromal Tumor Registry or the International Pleuropulmonary Blastoma Registry. These registries and others continue to provide us with information on the behavior and risks of this syndrome, as well as give families an opportunity to join the DICER1 syndrome support group community.

Individuals with DICER1 syndrome have a 50 percent chance of passing along their genetic mutation to their children, so family planning should be carefully considered.