DICER1 syndrome: Approach to testing and management at a large pediatric tertiary care center

Abstract

Background: To expand the current knowledge of DICER1 syndrome and to propose criteria for genetic testing based on experience at a pediatric tertiary care center.Procedure: This study involved a retrospective chart review of the 78 patients (47 probands and 31 family members) seen in the Cancer Genetics Program at The Hospital for Sick Children (SickKids) who were offered genetic testing for DICER1. Results:Of 47 probands offered genetic testing for DICER1, 46 pursued testing: 11 (23.9%) carried a pathogenic variant and one proband (2.1%) carried a missense variant of uncertain significance with evidence for pathogenicity. Thirty-one family members of variant-positive probands were offered testing: eight of the 25 who agreed to testing carried their familial variant (32.0%).Overall, 20 patients were identified to have a variant in DICER1 (eight males, 12 females). Of these, 13 (65.0%) presented with clinical manifestations associated with the syndrome. The most common lesions were pleuropulmonary blastoma (PPB) (five of 20 patients, 25.0%) and pineoblastoma (three of 20 patients, 15.0%). The average age at which individuals were diagnosed with a primary neoplasm was 5.2 years (range 0.8-20 years, median 3.0). Surveillance at our institution, with a median follow-up time of 23 months, has identified PPB in two asymptomatic individuals. These lesions were identified at early stages, thus potentially reducing treatment-related morbidity and mortality.

Ten years of DICER1 mutations: Provenance, distribution, and associated phenotypes

“…PPB, which is most often diagnosed before age 6 years, is plausibly the greatest threat to patient well‐being, particularly Types II and III which have 5‐year overall survival rates of 71% and 53%, respectively (Messinger et al, ). As such, and given the possible progression of some of the tumor types to fulminant disease (including cystic PPB to the solid variants, and possibly, more rarely, MNG to DTC, and pCN to anaplastic sarcoma of the kidney), it is advised that identification and screening of DICER1 pathogenic variant heterozygotes be implemented as early as possible with the aim of detecting precancerous or lower‐stage lesions that may be more amendable to treatment (Schultz et al, ; van Engelen et al, ). Timely counseling, genetic testing, and accurate variant classification are therefore of significant clinical importance.…”

“…given the possible progression of some of the tumor types to fulminant disease (including cystic PPB to the solid variants, and possibly, more rarely, MNG to DTC, and pCN to anaplastic sarcoma of the kidney), it is advised that identification and screening of DICER1 pathogenic variant heterozygotes be implemented as early as possible with the aim of detecting precancerous or lower-stage lesions that may be more amendable to treatment (Schultz et al, 2018;van Engelen et al, 2018). In this mutation update, we have provided a comprehensive summary of all DICER1 alterations published before January 31st, 2019.…”

“…While most individuals with DICER1 syndrome are heterozygous for a germline loss‐of‐function DICER1 pathogenic variant, other predisposing DICER1 alterations have also been documented. These include deletion of the entire DICER1 locus (de Kock, Geoffrion, et al, ; de Kock et al, ; Herriges et al, ; van Engelen et al, ), in‐ and out‐of‐frame intragenic deletions involving one or more exons (Apellaniz‐Ruiz et al, ; Brenneman et al, ; Sabbaghian et al, ), and somatic mosaicism, which is observed in a small fraction of syndromic patients (Brenneman et al, ; de Kock et al, ; Klein et al, ). Individuals with mosaicism for loss‐of‐function mutations tend to exhibit one or two foci of disease; in contrast, mosaicism for RNase IIIb hotspot mutations results in a greater number of disease foci at significantly younger ages than is typical (Brenneman et al, ; de Kock et al, ).…”

Primary Lung Tumors in Children: Radiologic-Pathologic CorrelationFrom the Radiologic Pathology Archives

“…PPB is associated with germline variants in the DICER1 gene located on chromosome 14q32. 13. DICER1 syndrome predisposes individuals to both benign and malignant neoplasms and has been described previously as PPB familial tumor and dysplasia syndrome.…”

Further evidence that full gene deletions of DICER1 predispose to DICER1 syndrome

“…2 Three additional patients with DICER1 syndrome caused by germline 14q32 deletions have since been described (Supporting Information Figure S1). 3,4 Here, we report a fifth patient with a DICER1 syndrome phenotype and a germline 14q32 deletion ( Figure 1A). Details of sample and consent ascertainment and materials and methods are provided in the Supporting…”