Clinical characteristics: DICER1 tumor predisposition (DICER1) is characterized by an increased risk for pleuropulmonary blastoma (PPB), pulmonary cysts, thyroid gland neoplasia (multinodular goiter, adenomas, and/or thyroid cancer), ovarian tumors (Sertoli-Leydig cell tumor, gynandroblastoma, and sarcoma), and cystic nephroma. Less commonly observed tumors include ciliary body medulloepithelioma, nasal chondromesenchymal hamartoma, embryonal rhabdomyosarcoma, pituitary blastoma, pineoblastoma, central nervous system (CNS) sarcoma, other CNS tumors, and presacral malignant teratoid tumor. The majority of tumors occur in individuals younger than age 40 years. PPB typically presents in infants and children younger than age six years. Ovarian sex cord-stromal tumors are most often diagnosed before age 40 years. Cystic nephroma generally presents in young children but has also been reported in adolescents. Additional clinical features that may be seen include macrocephaly, ocular abnormalities, structural anomalies of the kidney and collecting system, and dental anomalies (bulbous crowns).

Diagnosis/testing: The diagnosis of DICER1 is established by identification of a heterozygous germline DICER1 pathogenic variant that is known or suspected to cause loss of function.

Management: Treatment of manifestations: Treatment for DICER1-associated malignant tumors is dependent on tumor type and stage. Most often treatment involves surgical resection with or without chemotherapy. The treatment of PPB may also include radiation, primarily to treat residual disease or recurrence. Thyroid nodules that have concerning features may require biopsy and/or surgical resection. Ovarian tumors require surgery and may also require chemotherapy. Ciliary body medulloepithelioma has been treated with resection or plaque brachytherapy.

Surveillance: Chest radiograph shortly after birth is recommended for infants at risk for a germline DICER1 pathogenic variant. In individuals with confirmed DICER1, clinical examination and imaging-based surveillance for signs and symptoms of PPB, thyroid gland neoplasia, ovarian sex cord-stromal tumors, and other DICER1-associated tumors is recommended. Current imaging guidelines include chest radiograph every four to six months until age eight years, and every 12 months from age eight to 12 years. Chest CT at age three to six months with repeat chest CT at age 30 months to three years should be considered. Baseline chest radiograph or chest CT should be considered in those diagnosed after age 12 years. Thyroid ultrasound is recommended beginning at age eight years with subsequent ultrasounds every three to five years. Individuals with a history of chemotherapy exposure should begin thyroid ultrasound within three to five years of treatment. Thyroid function testing is recommended for individuals with symptoms of thyroid dysfunction. Pelvic ultrasounds for surveillance for gynecologic tumors in females are recommended every six to 12 months beginning at age eight years and extending until at least age 40 years. Screening for cystic nephroma and other renal tumors includes abdominal ultrasounds every six months until age eight years and then annually until age 12 years. Visual acuity measurement and dilated ophthalmology examination for ciliary body medulloepithelioma is recommended annually from age three years until at least age ten years. Annual physical examination should include assessment of extraocular movements, assessment of red reflex, neurologic examination, and thyroid palpation. Family education is the cornerstone of surveillance.

Evaluation of relatives at risk: If a germline DICER1 pathogenic variant has been identified in an affected family member, it is reasonable to offer molecular genetic testing to at-risk relatives of all ages to clarify their genetic status and to provide recommendations for age-appropriate surveillance and early intervention.

Pregnancy management: In rare instances large lung cysts may cause respiratory distress in newborns, and thus a third-trimester ultrasound is recommended for pregnancies in which the fetus is at risk for a DICER1 pathogenic variant. If lung cysts are identified, consultation with specialists in high-risk obstetrics and fetal medicine is recommended.

Genetic counseling: DICER1 is inherited in an autosomal dominant manner with reduced penetrance. In individuals with PPB with a detectable germline DICER1 pathogenic variant, approximately 80% of the germline pathogenic variants were inherited from a parent and approximately 20% were de novo. Each child of an individual with a DICER1 germline pathogenic variant has a 50% chance of inheriting the variant. Given the reduced penetrance, many individuals with a germline DICER1 pathogenic variant remain clinically unaffected. Once a germline DICER1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.