Penetrance

The penetrance of heterozygous germline DICER1 pathogenic variants is reduced and age dependent. In a longitudinal natural history study of 145 individuals with a germline DICER1 pathogenic variant and 135 family controls, the cumulative incidence of MNG or thyroidectomy by age 40 years was 75% in women and 17% in men versus 8% and 0% in control women and men . Risk for cancers associated with DICER1 varies according to age and sex. In a study of 102 female and male non-proband individuals with a germline DICER1 pathogenic variant, by age ten years 5.3% (95% CI, 0.6% to 9.7%) had developed a neoplasm (females, 4.0%; males, 6.6%). By age 50 years 19.3% (95% CI, 8.4% to 29.0%) had developed a neoplasm (females, 26.5%; males, 10.2%).

Source: GeneReviews — "DICER1 Tumor Predisposition"

Diagnostic Criteria

Suggestive Findings

DICER1 tumor predisposition (DICER1) should be suspected in individuals with the following tumors and/or clinical features:

Source: GeneReviews — "DICER1 Tumor Predisposition"

Differential Diagnosis

Pleuropulmonary Blastoma (PPB)

Congenital pulmonary airway malformation (CPAM) or congenital cystic adenomatoid malformation (CCAM). Type I PPB cannot be distinguished radiographically from benign congenital cystic lung malformations; however, pneumothoraces and the presence of multifocal or bilateral cysts are more common in PPB than in other conditions. The difficulties in distinguishing PPB from CPAM have led some pediatric surgeons to advocate excision of all CCAMs . Pulmonary sequestrations and peripheral bronchogenic cysts are more complex lesions that are commonly diagnosed prenatally. Although their radiographic and histologic features should facilitate differentiation from PPB , there is one report of a pulmonary sequestration in an individual with DICER1 .

Source: GeneReviews — "DICER1 Tumor Predisposition"

Management Guidelines

Evaluations Following Initial Diagnosis

For an individual diagnosed with a DICER1 tumor predisposition (DICER1), the two considerations for evaluations following initial diagnosis are:

• The extent of disease spread (staging) for malignant or potentially malignant DICER1-associated tumors;

• The presence of other synchronous DICER1 conditions .

Extent of Disease Spread (Staging)

Pleuropulmonary blastoma types I and Ir. Initial imaging and follow-up imaging should include chest CT. No metastatic potential is associated with this type; thus, the only additional evaluation is for synchronous DICER1-associated tumors and clinical features .

Pleuropulmonary blastoma types II and III

• CT of the chest to evaluate extent of disease and completeness of resection

• Brain MRI to evaluate for metastatic disease. This should be performed at diagnosis and throughout treatment and follow up.

• Radionuclide bone scan and/or PET scan to evaluate for metastatic disease and as a baseline relative to follow-up imaging

• Echocardiography as needed to define intracardiac extension of tumor, tumor thrombi, or pericardial effusion

• Rarely, spine MRI for paraspinal or intraspinal extension

• In the event of systemic embolization and any suggestion of vascular involvement (facial plethora, vena cava syndrome, cardiac murmur), investigation with vascular ultrasound examination

• CT of the abdomen/pelvis to assess for liver or other intraabdominal metastases

Note: Bone marrow involvement is extremely rare.

Source: GeneReviews — "DICER1 Tumor Predisposition"

Surveillance Guidelines

Surveillance guidelines for individuals with a germline DICER1 pathogenic variant have been established . Provider and individual/family education is the cornerstone of surveillance. Individuals and caregivers should be advised of signs and symptoms of concern. Note that if signs of tumor are detected, additional evaluation will be needed. This table is not intended to address post-tumor surveillance.

Table 4.

Recommended Surveillance for Individuals with DICER1 Tumor Predisposition

System/Concern | Evaluation | Frequency

Pleuropulmonary

blastoma | Clinical eval as indicated for any signs/symptoms (e.g., tachypnea, cough, fever, pain, pneumothorax) | Prompt eval for any signs/symptoms of concern

Chest CT chest x-ray | • Chest x-ray at birth, every 4-6 mos until age 8 yrs, then annually until age 12

• Consider chest CT at age 3-6 mos. If initial CT normal: consider repeat CT at age 2.5-3 yrs.

• If diagnosed after age 12 yrs, consider baseline chest x-ray or chest CT.

Multinodular goiter /

thyroid gland neoplasia | Thyroid physical exam for thyroid gland asymmetry /or nodules | • At diagnosis (any age)

• Annually

Thyroid US | • Consider US by age 8 yrs.1 If normal, consider repeat US every 3-5 yrs.

• Earlier for thyroid gland asymmetry /or nodules

• Post-chemotherapy: By age 10 yrs or w/in 3-5 yrs of treatment

Thyroid function testing | If clinical signs/symptoms of hypo- or hyperthyroidism

Ovarian sex cord-

stromal tumors (

other tumors of the

female genital tract

Source: GeneReviews — "DICER1 Tumor Predisposition"