DICER1 tumor predisposition syndrome: an evolving story initiated with the pleuropulmonary blastoma

Abstract

DICER1 syndrome (OMIM 606241, 601200) is a rare autosomal dominant familial tumor predisposition disorder with a heterozygous DICER1 germline mutation. The most common tumor seen clinically is the pleuropulmonary blastoma (PPB), a lung neoplasm of early childhood which is classified on its morphologic features into four types (IR, I, II and III) with tumor progression over time within the first 4–5 years of life from the prognostically favorable cystic type I to the unfavorable solid type III. Following the initial report of PPB, its association with other cystic neoplasms was demonstrated in family studies. The detection of the germline mutation in DICER1 provided the opportunity to identify and continue to recognize a number seemingly unrelated extrapulmonary neoplasms: Sertoli-Leydig cell tumor, gynandroblastoma, embryonal rhabdomyosarcomas of the cervix and other sites, multinodular goiter, differentiated and poorly differentiated thyroid carcinoma, cervical-thyroid teratoma, cystic nephroma-anaplastic sarcoma of kidney, nasal chondromesenchymal hamartoma, intestinal juvenile-like hamartomatous polyp, ciliary body medulloepithelioma, pituitary blastoma, pineoblastoma, primary central nervous system sarcoma, embryonal tumor with multilayered rosettes-like cerebellar tumor, PPB-like peritoneal sarcoma, DICER1-associated presacral malignant teratoid neoplasm and other non-neoplastic associations. Each of these neoplasms is characterized by a second somatic mutation in DICER1. In this review, we have summarized the salient clinicopathologic aspects of these tumors whose histopathologic features have several overlapping morphologic attributes particularly the primitive mesenchyme often with rhabdomyoblastic and chondroid differentiation and an uncommitted spindle cell pattern. Several of these tumors have an initial cystic stage from which there is progression to a high grade, complex patterned neoplasm. These pathologic findings in the appropriate clinical setting should serve to alert the pathologist to the possibility of a DICER1-associated neoplasm and initiate appropriate testing on the neoplasm and to alert the clinician about the concern for a DICER1 mutation.

Two Genetic Mechanisms in Two Siblings with Intellectual Disability, Autism Spectrum Disorder, and Psychosis

“…In addition to cleaving the double-strand RNA in the RNAi biogenesis, DICER1 is involved in generating small RNAs and has non-endonuclease activities [ 75 ]. Mutations of DICER1 are associated with susceptibility to various cancers, which was named DICER1 syndrome [ 76 , 77 ]. Some patients with DICER1 mutations have additional phenotypes, such as global developmental delay, macrocephaly, ASD, and other physical abnormalities [ 78 , 79 , 80 , 81 , 82 ].…”

Hereditary Gynecologic Cancer Syndromes – A Narrative Review

“…That explains the possible presence of tumors in adolescence without a DICER 1 germline mutation. 91 , 92 …”

A 40‐year follow‐up of a patient with Graham–Boyle–Troxell syndrome

“…The similarity between the original hypothesis for the Graham-Boyle-Troxell syndrome resulting from an abnormality involving both pulmonary and ureteral bud during the fifth week of gestation, and the important developmental role of DICER1 in branching morphogenesis has to be noted. However, the pulmonary and renal pathology of hamartomatous cysts has not been described with the DICER1 syndrome (González et al, 2022). The patient underwent pulmonary resection three times over a 12-year period without pathology showing pleuropulmonary blastoma that would be indicative of a DICER1 syndrome.…”