DICER1-Related Disorders

Actionability Pediatric Summary Report

Secondary Findings in Pediatric Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Gene: DICER1 (HGNC:17098)
• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 05/29/2019
• Curation Status: Released (1.1.2)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
DICER1	N/A (0017288)	138800	Moderate Actionability
DICER1	N/A (0017288)	180295	Assertion Pending
DICER1	N/A (0017288)	601200	Assertion Pending

Actionability Assertion Rationale

• All experts agreed with the assertion computed according to the rubric.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Morbidity and mortality from pleuropulmonary blastoma / Chest imaging	2	2N	2B	2	8NB
Morbidity and mortality from thyroid carcinoma and other DICER-related cancers / Surveillance	2	2C	2D	2	8CD

Severity of Outcome

Prevalence of the Genetic Condition

The prevalence of DICER1-related disorders is not known. Except for thyroid gland neoplasia, all the conditions associated with a germline DICER1 pathogenic variant are rare. For example, about 25-30 cases of pleuropulmonary blastoma (PPB) from the United States are reported to the International PPB Registry (IPPBR) annually. A systematic review identified DICER1 germline mutations in 67% of tested pleuropulmonary blastomas, 73% of cystic nephromas, and 57% of Sertoli-Leydig cell tumors.

Clinical Features (Signs / symptoms)

DICER1 expression levels are associated with cancer risk and progression by affecting cell proliferation and cell apoptosis. DICER1-related disorders are a familial tumor susceptibility syndrome that confers increased risk most commonly for PPB; ovarian sex cord-stromal tumors (Sertoli-Leydig cell tumor [SLCT], juvenile granulosa cell tumor [JGCT], and gynandroblastoma); cystic nephroma (CN)/Wilms tumor (WT); and thyroid gland neoplasia (multinodular goiter [MNG], adenomas, or differentiated thyroid cancer [DTC]). Less commonly observed tumors are ciliary body medulloepithelioma (CBME); botryoid-type embryonal rhabdomyosarcoma (ERMS) of the cervix or other sites; nasal chondromesenchymal hamartoma (NCMH); renal sarcoma; pituitary blastoma; and pineoblastoma. Juvenile-type gastrointestinal polyps have also been observed in childhood. Novel phenotypes continue to be discovered. DICER1-syndrome is a rare disease having insufficient cases to provide effective understanding of the pathogenic mechanism and clinical characteristics of the disorder.

Natural History (Important subgroups & survival / recovery)

Most individuals with pathogenic variants in DICER1 are healthy or have only minor DICER1-associaited conditions. The most severe manifestations tend to present in early childhood with adulthood characterized by good health. The majority of tumors in individuals with DICER1 pathogenic variants occur in individuals younger than 40. Many of these tumors typically only occur in childhood, including: PPB (before age 7), CN (before age 4), CBME typically occurs in young children, pituitary blastoma (before age 2), and childhood pineoblastoma (only one has been reported associated with a DICER1 mutation). Tumors affecting the female reproductive system may occur during adulthood. The age of onset of ovarian sex cord-stromal tumors varies from 2 to 61 years depending on clinical subtype with most presenting from late childhood to early adulthood with a median of 16.9 years. ERMS of the cervix most commonly occurs in pubertal and post-pubertal adolescent girls and young women. MNGs and DTC typically occur between ages 5 to 40, with peak incidence between 10-20 years. Females are more likely to present with multimorbidity than males (64% versus 25%).

Likelihood of Outcome

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

1-2 in 5000

An estimated 1:2,529 to 1:10,600 individuals in the general population carry a pathogenic or likely pathogenic DICER1 variant.

Tier 3

Penetrance (Includes any high-risk racial or ethnic subgroups)

Unknown

Data from 51 relatives of 17 index patients identified 25 individuals with a DICER1 pathogenic variant. Of these, one mother had a Sertoli-Leydig tumor, one half-sibling had cystic nephroma, and six relatives had thyroid cysts/goiter. The remaining 17 individuals did not have clinical features or symptoms likely to be related to the DICER1 mutation, one relative having muscular dystrophy and another Wegener’s granulomatosis.

Tier 3

5-39 %

A multiple registry study examining neoplasm incidence in a cohort containing 102 non-probands with DICER1 pathogenic variants (3,344 person-years of observation in non-probands) found that by age 10 years, 5.3% (95% CI, 0.6% to 9.7%) of non-probands had developed a neoplasm (females, 4.0%; males, 6.6%). By age 50 years, 19.3% (95% CI, 8.4% to 29.0%) of non-probands had developed a neoplasm (females, 26.5%; males, 10.2%).

Tier 5

>= 40 %

In a US family-based cohort the cumulative incidence of multinodular goiter or thyroidectomy in individuals with a DICER1 pathogenic variant was 32% in females and 13% in males by age 20; by age 40 the incidence was 75% in women and 17% in men. Four cases of DTC were observed among 145 individuals with DICER1 pathogenic variants (mean age at onset, 34 years).

Tier 3

Unknown

In an observational surveillance study of 20 patients with DICER1 pathogenic variants (8 non-probands) at one institution, ranging in age from 1.5 years to 65 years, five patients were diagnosed with PPB (25%). In a multiple registry study containing 207 patients with DICER1 pathogenic variants (102 non-probands) with a total of 4,747 person-years of risk and 370 person-years of follow-up, 47 patients were observed to have a non-type I (malignant) PPB (23%). Additionally, there were 28 type Ir PPB (regressed or non-progressed type I PPB) in 28 of the 102 non-proband DICER1 carriers (27%; female, n = 15; male, n = 13; p < .05).

Tier 5

Relative Risk (Includes any high-risk racial or ethnic subgroups)

>3

In a family-based cohort, individuals with a DICER1 mutation were found to have a 16 to 24-fold increased risk of thyroid cancer compared with SEER rates.

Tier 3

Unknown

In a multiple registry study containing 207 DICER1 carriers (102 non-probands), standardized incidence ratios (SIR) were calculated from SEER data, adjusting for age-, sex-, race-, and birth cohort–specific cancer incidence. For the 102 non-probands with 3,344 person-years of risk, the study calculated an SIR of 2.1 (95% CI: 1.0-3.7) for all malignant neoplasms and an SIR of 19 (95%CI: 5.1-48) for thyroid cancer. In these non-probands, 1 type I PPB was observed, but risk estimates could not be calculated as this tumor type is not tracked by SEER. The SIR for the entire cohort of 207 patients, including 105 probands, (4,747 person-years of risk) for all malignancies was 18 (95% CI: 15-22), for Type II and III PPB was 3.2 x 10e6 (95% CI: 2.4 x 10e6 – 4.3 x 10e6), and for thyroid cancer was 39 (95% CI: 19-72).

Tier 5

Expressivity

There is no hint that the genetic characteristics of patients with multimorbidity are different from patients without multimorbidity.

Tier 3

Intervention Effectiveness

Patient Management

At each visit families should be counseled regarding the potential signs and symptoms of DICER1-associated conditions.

Tier 2

Botryoid-type ERMS presents with vaginal bleeding or spotting or passage of tissue. Therefore, when signs/symptoms of hematuria or abnormal vaginal bleeding are present, endoscopic evaluation of the bladder or direct visualization of the cervix are recommended, respectively. Limited data suggests good prognosis for these tumor types following complete surgical excision and chemotherapy. A case series of 14 cervical cases of ERMS (mean age at diagnosis 12.4 years, range 9 months to 32 years) found that following conservative surgery and chemotherapy, no tumor-related deaths had been recorded. Three patients were found to have recurrent active disease (1 and 7 years following initial diagnosis). The remaining 11 patients remained disease-free with eight patients having 2 years or more of follow-up having remained tumor-free for 2 to 20 years. Only one of these cases had an identified DICER1 pathogenic variant.

Tier 3

Nasal endoscopy is warranted if ophthalmologic signs resulting from orbital involvement of the NCMH are present. NCMH is considered a benign neoplasm.

Tier 2

Surgical removal is curative; however local recurrences can occur. There have been 28 cases of NCMH reported in the literature (4 with a DICER1 pathogenic mutation).

Tier 3

Urgent brain MRI is recommended for persons with a DICER1 pathogenic variant with signs of intracranial pathology or cortisol excess for the detection of pineoblastoma or pituitary blastoma.

Tier 2

With chemotherapy and radiation therapy, overall survival is improved by 60%-75% in some studies. Surgery with or without adjuvant therapy can be curative for pituitary blastoma, although of the six reported cases, two were known to have died of the disease.

Tier 3

Surveillance

Individuals should have an annual physical examination and targeted review of symptoms.

Tier 4

In order to detect pulmonary cysts or PPB (one of the most important causes of DICER1-associated morbidity and mortality), chest x-rays are recommended every 6 months from birth to through age 7 years and then annually from 8-12 years. A chest computed tomography (CT) (with efforts to minimize radiation) should be obtained by 9 months of age, preferably between 3 and 6 months of age and repeated at approximately 2.5 years of age. The utility of routine surveillance beyond age 12 is unknown and thus not recommended; however, if a pathogenic variant is detected at >12 years of age, a baseline CT or chest x ray can be considered. CT offers a higher level of sensitivity for the detection of cystic lung lesions than chest x-ray; however, due to the potential need for sedation and radiation dose chest x-rays are the primary screening modality. The goal of surveillance imaging in DICER1 is to detect PPB in its earliest, cystic and most curable form (Type I PPM). The 5-year disease-free survival (DFS) and overall survival (OS) for Type I PPB is 82% and 91% respectively. For type II and Type III the 5-year DFS are 59% and 37% and the 5-year OS is 71% and 53%. Additional studies are needed to guide decisions regarding resection versus observation in for pulmonary cysts in pediatric patients. Pulmonary cysts identified in adults are assumed to have low malignancy, resection may be considered based on size and location.

Tier 2

Abdominal ultrasound is recommended for the detection in infancy or at the time of the first chest CT then every 6-12 months until at least 8 years of age. Annual ultrasound may be considered until 12 years of age. If the individual is identified after 12 years of age, a baseline abdominal ultrasound should be performed. Additional studies are needed to clarify whether a normal ultrasound and/or resection of CN in early childhood predicts a lower likelihood of later renal malignancy. Detection of WT at an earlier stage of disease is associated with a lower burden of therapy and more favorable prognosis. Thus, early diagnosis may improve outcomes and reduce late effects associated with therapy.

Tier 2

Beginning at ages 8-10 females should receive pelvic ultrasound performed in conjunction with abdominal ultrasound (every 6-12 months) until at least age 40 or as needed for signs and symptoms. The optimal timing of ultrasound and/or pelvic examinations and the relative sensitivity of varying surveillance strategies is not yet known. Tumors detected at stage IA/IB are generally treated with surgery alone, while later stages may require adjuvant therapy.

Tier 2

Individuals should undergo thyroid ultrasound with assessment for regional adenopathy every 2 to 3 years starting at age 8 or as needed for signs and symptoms. There have been no prospective studies on the efficacy or timing of thyroid ultrasound in individuals with DICER1 pathogenic variants. Thyroid cancer is generally indolent but surgery alone is curative when found in its earliest form. There is no indication for prophylactic thyroidectomy in patients with DICER1-associated conditions.

Tier 2

An annual routine dilated ophthalmologic exam with visual acuity screening is recommended from age 3 to at least age 10 for detection of CBME. Most patients present with visual symptoms or abnormalities on ophthalmologic exam.

Tier 2

Within one institution 20 patients (12 probands, 8 family members) ranging in age from 1.5 years to 65 years who carried a DICER1 pathogenic variant were followed. Thirteen presented clinically with manifestations of DICER1 Syndrome with 9 having multiple manifestations. Median age of first manifestation was 3.0 years. Five patients were diagnosed with PPB and 3 with pineoblastoma, with one patient dying as a result of pineoblastoma detected clinically. Ongoing surveillance was conducted for 12 patients for a median of 23 months. Under surveillance 9 asymptomatic lesions were detected in 7 of the 14 patients. Two patients with a PPB underwent lesion resection and remained disease free at 5-19 months. Surveillance also detected one patient with cystic lung lesions, two patients with pineal cysts, and two with thyroid nodules/cysts which continue to be monitored.

Tier 5

A comprehensive surveillance program was conducted within 16 individuals with DICER1 syndrome (mean age 4.2 years, range 14 days to 17 years). Over a mean follow up of 51.5 months these individuals received a total of 663 imaging studies; however, only a minority of these were classified as surveillance (the majority were for diagnosis or follow up of suspected cancers). Imaging classified as surveillance in these patients identified malignant lesions in 25% of patients (i.e., PPB and renal sarcoma) and benign lesions in an additional 25% of patients. Over the course of the follow up four patients had no lesions identified either through surveillance or clinically; however, these were the younger patients in the cohort.

Tier 5

Circumstances to Avoid

No circumstances to avoid were identified.

Nature of Intervention

Nature of Intervention

The proposed interventions include various imaging techniques as well as examination and patient education. Potential risk of screening modalities may include radiation exposure, need for sedation and likelihood of false positives.

Context: Adult Pediatric

Chance to Escape Clinical Detection

Many of the cancers that are associated with the presence of a DICER1 pathogenic variant are not screened for in the general population.

Context: Adult Pediatric

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			DICER1			138800	0017288	0007681
DICER1			180295	0017288	0005212
DICER1			601200	0017288	0011014

References List

Bueno MT, Martinez-Rios C, la Puente Gregorio A, Ahyad RA, Villani A, Druker H, van Engelen K, Gallinger B, Aronoff L, Grant R, Malkin D, Greer MC. (2017) Pediatric imaging in DICER1 syndrome. Pediatric radiology. 47(10):1292-1301.

Cai S, Zhao W, Nie X, Abbas A, Fu L, Bihi S, Feng G, Liu T, Lv Y, Ma X, Peng X. (2017) Multimorbidity and Genetic Characteristics of DICER1 Syndrome Based on Systematic Review. Journal of pediatric hematology/oncology. 39(5):355-361.

L Doros, KA Schultz, DR Stewart, AJ Bauer, G Williams, CT Rossi, A Carr, J Yang, LP Dehner, Y Messinger, DA Hill. DICER1-Related Disorders. (2014) . In: MP Adam, HH Ardinger, RA Pagon, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK196157/

PLEUROPULMONARY BLASTOMA; PPB. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 601200, (2017) World Wide Web URL: http://omim.org/

Schultz KAP, Rednam SP, Kamihara J, Doros L, Achatz MI, Wasserman JD, Diller LR, Brugieres L, Druker H, Schneider KA, McGee RB, Foulkes WD. (2017) PTEN, DICER1, FH, and Their Associated Tumor Susceptibility Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood. Clinical cancer research : an official journal of the American Association for Cancer Research. 23(12):e76-e82.

Schultz KAP, Williams GM, Kamihara J, Stewart DR, Harris AK, Bauer AJ, Turner J, Shah R, Schneider K, Schneider KW, Carr AG, Harney LA, Baldinger S, Frazier AL, Orbach D, Schneider DT, Malkin D, Dehner LP, Messinger YH, Hill DA. (2018) DICER1 and Associated Conditions: Identification of At-risk Individuals and Recommended Surveillance Strategies. Clinical cancer research : an official journal of the American Association for Cancer Research. 24(10):2251-2261.

Stewart DR, Best AF, Williams GM, Harney LA, Carr AG, Harris AK, Kratz CP, Dehner LP, Messinger YH, Rosenberg PS, Hill DA, Schultz KAP. (2019) Neoplasm Risk Among Individuals With a Pathogenic Germline Variant in DICER1. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 37(8):668-676.

van Engelen K, Villani A, Wasserman JD, Aronoff L, Greer MC, Tijerin Bueno M, Gallinger B, Kim RH, Grant R, Meyn MS, Malkin D, Druker H. (2018) DICER1 syndrome: Approach to testing and management at a large pediatric tertiary care center. Pediatric blood & cancer. 65(1).