DICER1- Related Tumor Predisposition

Excerpt

Clinical characteristics: DICER1-related tumor predisposition (DICER1) is characterized by an increased risk for a spectrum of malignancies, benign neoplasms, and other clinical findings. The most common features are lung cysts and thyroid nodules. DICER1-related neoplasms include pleuropulmonary blastoma (PPB), Sertoli-Leydig cell tumor (SLCT), including gynandroblastoma, pediatric cystic nephroma (CN), and differentiated thyroid carcinoma. Less commonly observed neoplasms include ciliary body medulloepithelioma, nasal chondromesenchymal hamartoma, pituitary blastoma, pineoblastoma, DICER1-associated central nervous system (CNS) sarcoma, embryonal tumor with multilayered rosettes (without somatic alterations of chromosome 19 microRNA cluster), pulmonary blastoma, well-differentiated fetal lung adenocarcinoma, embryonal rhabdomyosarcoma (primarily of the female reproductive tract), anaplastic sarcoma of the kidney, primary ovarian sarcoma, PPB-like peritoneal sarcoma, extraovarian SLCT, multicystic neoplasms of the liver, and Wilms tumor. Additional clinical features can include macrocephaly, retinal abnormalities, structural anomalies of the urinary collecting system or kidney (including kidney cysts), hamartomatous polyps, and liver cysts. The majority of tumors occur in individuals younger than age 40 years. PPB typically presents in infants and children younger than age seven years. Ovarian sex cord-stromal tumors are most often diagnosed before age 40 years. Pediatric CN generally presents in young children but has also been reported in adolescents.

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 type II or III PPB and certain other malignant tumors may also include radiation, primarily to treat residual disease or recurrence. Thyroid nodules that have concerning features may require biopsy (generally fine-needle aspiration [FNA]) and/or surgical resection. Thyroid carcinoma may require specific treatment in addition to surgery depending on certain characteristics. Ovarian tumors require surgery and may also require chemotherapy depending on stage and histology, with radiation generally reserved for relapsed disease. Ciliary body medulloepithelioma has been treated with resection, cryotherapy, or plaque brachytherapy. Pineoblastoma and DICER1-associated CNS sarcoma are treated with resection, radiotherapy, and chemotherapy.

Surveillance: Family education regarding signs and symptoms of DICER1-related tumors is the cornerstone of surveillance. Clinical evaluation for manifestations of DICER1-related tumors every six months or at each visit; chest radiograph at birth, every six months until age eight years, then annually until age 12 years. Chest CT at age three months and age 30 months. Consider baseline chest radiograph or CT in those diagnosed after age 12 years. Thyroid ultrasounds every three years beginning at age eight years. Consider annual thyroid ultrasound for five years following the completion of chemotherapy for individuals who have received chemotherapy. FNA following age-appropriate guidelines for evaluating thyroid nodules. Pelvic ultrasounds for gynecologic tumors in females every six months until at least age 40 years. Abdominal ultrasounds for pediatric CN and other kidney tumors every six months until age eight years and then annually until age 12 years. Consider baseline abdominal ultrasound in those diagnosed after age 12 years. Monitor for decreased visual acuity and leukocoria at each visit. Assess visual acuity and dilated ophthalmology examination annually from age three to ten years. Urgent evaluation for any concerning ocular symptoms. Monitor for signs and symptoms of CNS malignancy. Urgent brain MRI for any concerning neurologic symptoms. Consider shared decision making about screening brain MRI in the absence of symptoms in late adolescence and early adulthood. Assess for manifestations of intestinal obstruction as needed.

Evaluation of relatives at risk: Clarify the genetic status of first-degree relatives (of all ages) – with cascade testing as indicated (including parents, children, and sibs) – of an individual with DICER1 by molecular genetic testing for the DICER1 pathogenic variant in the family in order to provide recommendations for age-appropriate surveillance and early intervention. As screening recommendations begin in infancy, testing at-risk individuals soon after birth is recommended.

Pregnancy management: Symptom-directed surveillance for DICER1-associated conditions. SLCT has been reported during pregnancy in individuals with DICER1; therefore, up-to-date screening prior to conception is recommended. If concerns arise during pregnancy, prompt consultation with specialists in high-risk obstetrics and fetal medicine is indicated to support pregnancy monitoring and delivery planning.

Genetic counseling: DICER1 is inherited in an autosomal dominant manner with reduced, age-related penetrance. Approximately 85% of individuals diagnosed with DICER1-associated PPB are thought to have inherited a DICER1 germline pathogenic variant from a parent who may or may not have PPB or other DICER1-associated findings. Each child of an individual with a germline constitutional DICER1 pathogenic variant has a 50% chance of inheriting the pathogenic variant. Because the penetrance of heterozygous germline DICER1 pathogenic variants is reduced, 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, predictive testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.