wdt_ID Phenotype and Relative Frequency Notation Does this disease by itself suggests DICER1 Mutation Testing? Approximate Ages of Susceptibility, range (peak). Malignant or Benign Deaths recorded in cases with DICER1 syndrome
3 Most Frequent Phenotypes
4 pleuropulmonary blastoma PPB yes
5 Type I (cystic) PPB 0 - 24 m (8 m ) M y, if progresses to Type II or III
6 Type II (cystic/solid) PPB 12 - 60 m (31 m) M y, ~40%
7 Type III (solid) PPB 18 - 72 m (44 m) M y, ~60%
9 Type Ir (cystic) PPB any age B or M none observed
10 multinodular goiter MNG no 5 - 40 y (10 - 20 y) B n
11 cystic nephroma CN yes 0 - 48 m (undetermined) B n (see anaplastic sarcoma of kidney below)
12 Sertoli-Leydig cell tumor of ovary SLCT yes 2 - 45 y (10 - 25 y) M y, < 5% of cases
13 Moderate Frequency Phenotypes
Pleuropulmonary blastoma (PPB)

PPB is a rare tumor that arises during fetal and infant lung development. It is thought to be the most common life-threatening manifestation of DICER1 syndrome. From birth until approximately age 2, PPB typically presents as a cystic mass (Type I PPB). From approximately age 2 to age 6, PPB may present as a combination of lung cysts and solid tumor (Type II PPB), or as purely solid tumor (Type III PPB). Types II and III PPB are highly malignant tumors with cure rates that are much lower than in Type I PPB. Type I PPB is capable of progressing to Types II and Types III, emphasizing the importance of early detection and resection. Children with PPB may present with shortness of breath and pneumothorax due to cyst rupture. In cases of advanced disease, they may additionally present with weight loss and fever. PMID: 8636815, 2520924219556464.

Cystic nephroma

CN is generally considered a benign renal dysplasia, consisting of multiple thin-walled multilocular cysts. It is one of the more frequent manifestations of DICER1 syndrome, typically occurring below the age of 4 years in mutation carriers, presenting as a painless abdominal or flank mass. While non-neoplastic, partial or total nephrectomy may be required due to a mass effect, or because of impairment of renal function. In very rare cases, CN has been observed to evolve into anaplastic sarcoma of the kidney, a malignant neoplasm. PMID: 21036787171379062448100128177962

Multinodular Goiter (MNG)

MNG is characterized by nodular enlargement of the thyroid gland. MNG is the most frequent manifestation of DICER1 syndrome, and presents as a palpable neck mass, typically from childhood to early adulthood. MNG and thyroid disease is common in the general population, and therefore DICER1 syndrome should be considered for MNG only in the presence of additional DICER1-related tumors in the individual or family. Differentiated thyroid cancer is a rare manifestation of DICER1 syndrome, and has been observed in children who have been heavily treated (chemotherapy, radiotherapy) for a previous diagnosis of PPB, as well as in those with no prior risk factors for thyroid cancer. PMID: 21205968, 2461771227459524.

Ovarian sex cord-stromal tumor (OSCST)

OSCSTs are a group of uncommon non-epithelial ovarian cancers, and include granulosa cell tumors, gynandroblastomas and Sertoli-Leydig cell tumors (SLCT). SLCT is the most commonly observed OSCST in DICER1 syndrome. While SLCT is a malignant tumor, associated mortality is low. SLCT frequently presents with signs of virilisation (hirsutism, voice changes), along with typical features of an ovarian neoplasm, including abdominal distension and pain. PMID: 21205968, 21501861, 25844550, 27858560.

Pituitary blastoma (PitB)

PitB is an extremely rare primitive tumor of the pituitary gland typically presenting by age 24 months, often with Cushings syndrome, or with opthalmoplegia, and/or hydrocephalus. PitB is a life-threatening tumor. It is a very rare but very highly characteristic manifestation of DICER1 syndrome. PMID: 24839956.

Pineoblastoma (PinB)

PinB is a rare primitive neuroectodermal tumor of the pineal gland. Presenting features include symptoms of pineal or pituitary mass and ophthalmologic changes. PinB is a rare, yet characteristic manifestation of DICER1 syndrome. It tends to occur at younger ages if a germline DICER1 mutation is present. PMID: 25022261.

Embryonal Rhabdomyosarcomas (ERMS)

ERMS is a frequent pathological finding in tumors related to DICER1 mutation. It is the most prevalent sarcomatous subtype in the mixed-pattern-sarcoma of PPB. ERMS of certain other anatomic sites are highly characteristic in DICER1 syndrome:

ERMS of the uterine cervix (cERMS), also known as “cervical sarcoma botryoides”, is very rare but appears to be highly characteristic of DICER1 mutation. cERMS typically presents between ages 10 to 25 years with abnormal spotting or a polypoid vaginal mass. PMID: 22180160, 24151152, 22157934, 27896549.

Ovarian ERMS (oERMS) has been observed very rarely and may be characteristic of DICER1 mutation. (It is possible that oERMS is not a separate entity but is a subcategory of ovarian SLCT in which ERMS predominates among the heterologous elements found in DICER1-related SLCTs). PMID: 25844550, 25836323.

Bladder ERMS is among the more common ERMS sites in young children, but it appears as if most cases are not related to DICER1 mutation. There are several case reports, with or without germline DICER1 mutations that suggest that bladder ERMS is part of DICER1 syndrome but no cases with somatic “second hit” mutations in DICER1 have been published. PMID: 22180160, 18000857, 20981696.

Vaginal/vulvar ERMS and orbit ERMS (other characteristic early childhood ERMS sites) have not been observed. The alveolar RMS pattern has also not been associated with DICER1 mutations.

Ciliary body medulloepithelioma (CBME)

CBME is a very rare embryonal ocular tumor that may be benign or malignant. Presenting features include leukocoria or decreased visual acuity. CBME is a rare, but somewhat characteristic manifestation of DICER1 syndrome. PMID: 21156700,  27896549.

Nasal chondromesenchymal hamartoma (NCMH)

NCMH is a very rare benign tumor of the nasal cavities and sinus, often presenting with nasal congestion in childhood or adolescence. NCMH is a rare, but somewhat characteristic manifestation of DICER1 syndrome. PMID: 25118636.

Anaplastic sarcoma of the kidney (ASK)

ASK is a rare and aggressive tumor of the kidney. It has been observed in very few patients with DICER1 mutations, and may arise from previously existing cystic nephroma. PMID: 2692897124481001, 27036314.

Other tumors

Other tumors/dysplasias that may occur in individuals with germline DICER1 mutations include Wilms tumor, neuroblastoma, medulloblastoma, and intestinal juvenile hamatomatous polyps. The vast majority of cases are not caused by DICER1 mutations, and observing any of these features alone in a patient is not sufficient to suggest DICER1 syndrome. However, the risk of these conditions appears to be increased in DICER1 mutation carriers, and genetic testing for DICER1 mutations may be indicated if these are present in the context of additional DICER1-related tumors in the family.