Clinical characteristics.

DICER1 tumor predisposition (DICER1) is characterized by an increased risk for pleuropulmonary blastoma (PPB), pulmonary cysts, thyroid gland neoplasia (multinodular goiter, adenomas, and/or thyroid cancer), ovarian tumors (Sertoli-Leydig cell tumor, gynandroblastoma, and sarcoma), and cystic nephroma. Less commonly observed tumors include ciliary body medulloepithelioma, nasal chondromesenchymal hamartoma, embryonal rhabdomyosarcoma, pituitary blastoma, pineoblastoma, central nervous system (CNS) sarcoma, other CNS tumors, and presacral malignant teratoid tumor. The majority of tumors occur in individuals younger than age 40 years. PPB typically presents in infants and children younger than age six years. Ovarian sex cord-stromal tumors are most often diagnosed before age 40 years. Cystic nephroma generally presents in young children but has also been reported in adolescents. Additional clinical features that may be seen include macrocephaly, ocular abnormalities, structural anomalies of the kidney and collecting system, and dental anomalies (bulbous crowns).

Diagnosis/testing.

The diagnosis of DICER1 is established by identification of a heterozygous germline DICER1 pathogenic variant that is known or suspected to cause loss of function.

Management.

Treatment of manifestations: Treatment for DICER1-associated malignant tumors is dependent on tumor type and stage. Most often treatment involves surgical resection with or without chemotherapy. The treatment of PPB may also include radiation, primarily to treat residual disease or recurrence. Thyroid nodules that have concerning features may require biopsy and/or surgical resection. Ovarian tumors require surgery and may also require chemotherapy. Ciliary body medulloepithelioma has been treated with resection or plaque brachytherapy.

Surveillance: Chest radiograph shortly after birth is recommended for infants at risk for a germline DICER1 pathogenic variant. In individuals with confirmed DICER1, clinical examination and imaging-based surveillance for signs and symptoms of PPB, thyroid gland neoplasia, ovarian sex cord-stromal tumors, and other DICER1-associated tumors is recommended. Current imaging guidelines include chest radiograph every four to six months until age eight years, and every 12 months from age eight to 12 years. Chest CT at age three to six months with repeat chest CT at age 30 months to three years should be considered. Baseline chest radiograph or chest CT should be considered in those diagnosed after age 12 years. Thyroid ultrasound is recommended beginning at age eight years with subsequent ultrasounds every three to five years. Individuals with a history of chemotherapy exposure should begin thyroid ultrasound within three to five years of treatment. Thyroid function testing is recommended for individuals with symptoms of thyroid dysfunction. Pelvic ultrasounds for surveillance for gynecologic tumors in females are recommended every six to 12 months beginning at age eight years and extending until at least age 40 years. Screening for cystic nephroma and other renal tumors includes abdominal ultrasounds every six months until age eight years and then annually until age 12 years. Visual acuity measurement and dilated ophthalmology examination for ciliary body medulloepithelioma is recommended annually from age three years until at least age ten years. Annual physical examination should include assessment of extraocular movements, assessment of red reflex, neurologic examination, and thyroid palpation. Family education is the cornerstone of surveillance.

Evaluation of relatives at risk: If a germline DICER1 pathogenic variant has been identified in an affected family member, it is reasonable to offer molecular genetic testing to at-risk relatives of all ages to clarify their genetic status and to provide recommendations for age-appropriate surveillance and early intervention.

Pregnancy management: In rare instances large lung cysts may cause respiratory distress in newborns, and thus a third-trimester ultrasound is recommended for pregnancies in which the fetus is at risk for a DICER1 pathogenic variant. If lung cysts are identified, consultation with specialists in high-risk obstetrics and fetal medicine is recommended.

Genetic counseling.

DICER1 is inherited in an autosomal dominant manner with reduced penetrance. In individuals with PPB with a detectable germline DICER1 pathogenic variant, approximately 80% of the germline pathogenic variants were inherited from a parent and approximately 20% were de novo. Each child of an individual with a DICER1 germline pathogenic variant has a 50% chance of inheriting the variant. Given the reduced penetrance, many individuals with a germline DICER1 pathogenic variant remain clinically unaffected. Once a germline DICER1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

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

• Pleuropulmonary blastoma (PPB)
• Single or multiple pulmonary cysts and/or pneumothorax identified in a newborn or young child
• Thyroid adenomas, multinodular goiter, and/or well-differentiated thyroid cancer, especially in individuals with a family history of additional features of DICER1. Poorly differentiated thyroid cancer has also been described.
• Ovarian tumors including sex cord-stromal tumors (e.g., Sertoli-Leydig cell tumor, gynandroblastoma, embryonal rhabdomyosarcoma, undifferentiated sarcomas)
• Cystic nephroma with or without progression to anaplastic sarcoma of kidney
• Ciliary body medulloepithelioma
• Nasal chondromesenchymal hamartoma
• Embryonal rhabdomyosarcoma of the cervix or other sites with features of adenosarcoma
• Pituitary blastoma
• Pineoblastoma
• DICER1-associated central nervous system (CNS) sarcoma
• Other CNS embryonal tumors / ETMR-like (embryonal tumor with multilayer rosettes)
• Presacral malignant teratoid neoplasm of infancy
• Multicystic hepatic lesions
• Pleuropulmonary blastoma-like peritoneal sarcoma (peritoneal "PPB")
• Macrocephaly

Laboratory finding on tumor tissue testing. Identification of a somatic DICER1 pathogenic variant by molecular genetic testing of tumor tissue may suggest the presence of a germline DICER1 pathogenic variant. Note: (1) Fresh-frozen tumor is preferable for molecular testing; formalin-fixed, paraffin-embedded samples may also be suitable. (2) Identification of a DICER1 pathogenic variant in tumor tissue has been described in the absence of a germline DICER1 pathogenic variant.

Note: Somatic mosaicism for a DICER1 pathogenic variant should be suspected in individuals with features of DICER1 – for example, one of the tumors described above with or without somatic overgrowth (see Clinical Description, GLOW syndrome).

Establishing the Diagnosis

The diagnosis DICER1 is established in a proband by identification of a heterozygous germline pathogenic variant in DICER1 that is known or suspected to cause loss of function (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing and multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of DICER1 is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with increased tumor susceptibility are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

To date, more than 1,000 individuals have been identified with a germline pathogenic variant in DICER1 including literature reports and unpublished International PPB/DICER1 Registry and NIH Natural History Study data. The following description of the phenotypic features associated with this condition is based on these reports.

Studies to date have focused on germline DICER1 pathogenic variants occurring in children with pleuropulmonary blastoma (PPB), in girls and women with ovarian sex cord-stromal tumors, children with cystic nephroma, and families with thyroid hyperplasia as well as other tumor types. The majority of tumors reported in individuals with a germline DICER1 pathogenic variant occur in individuals younger than age 40 years. Less is known about the risk for malignancies or other conditions in older adults with a germline DICER1 pathogenic variant.

Pleuropulmonary blastoma (PPB) occurs primarily in very young children. Clinically significant PPB typically presents in infants and in children younger than age seven years; however, rare occurrences have been reported in older children and one adult [Hill et al 1999].

PPB occurs in four main types:

• Type I PPB is a purely cystic lesion containing a layer of malignant cells. If left in situ, the malignant component of type I PPB may proliferate further, leading to type II PPB. Typically, type I PPB becomes evident in infants and young children (median age at diagnosis: 8 months) with difficulty breathing due to a large space-occupying cyst in the lung or pneumothorax secondary to a rupture of the air-filled cyst. Occasionally lung cysts are identified in asymptomatic children when radiographic studies are performed for nonrespiratory symptoms or surveillance. Five-year survival for type I PPB is 89% [Messinger et al 2015].
• Type II PPB is a mixed cystic and solid tumor that presents at a median age of 35 months. A child with type II PPB typically presents with weight loss, fever, shortness of breath, and opacity or pneumothorax on chest radiograph. Five-year survival for type II PPB is 71% [Messinger et al 2015].
• Type III PPB is a purely solid, aggressive sarcoma which may present with respiratory distress and mediastinal shift. Type III PPB presents at a median age of 41 months. Children with type III PPB typically present with weight loss, fever, shortness of breath, and opacity on chest radiograph. Five-year survival for type III PPB is 53% [Messinger et al 2015].
• Type Ir (regressed or nonprogressed) PPB presents in individuals of any age and lacks a malignant component. Five-year survival for type Ir PPB is 100% [Messinger et al 2015].

The natural history of PPB suggests that many tumors have a precancerous / early cancerous stage in the form of lung cysts. Although not all PPB lung cysts transform into high-grade sarcoma, no radiographic characteristics can yet identify which cysts will progress to sarcoma. Progression from cyst to sarcoma can occur quickly. When progression occurs, the mesenchymal cells of a type I PPB expand and overgrow the cyst septa and replace the cyst with a cystic and solid (type II) or purely solid (type III) sarcoma. Type I PPB has no metastatic potential, but individuals with type II or III PPB can present with or develop metastasis to the brain, bone, local thoracic lymph nodes, and liver.

Children with PPB type II or III may have tumor recurrence locally in the thorax and/or distant metastatic disease. The brain, followed by bone, is the most common site of distant metastasis in PPB. The outcome for these individuals is poor, although some have survived long-term [Priest et al 2007, Nakano et al 2019a].

Multinodular goiter (MNG) and thyroid cancer. Germline DICER1 pathogenic variants are associated with an increased risk of developing thyroid nodules and/or MNG. By age 20 years, 32% of women and 13% of men with a DICER1 pathogenic variant will be diagnosed with MNG and/or have undergone a thyroidectomy [Khan et al 2017b].

However, data also suggest a risk for DICER1-associated differentiated thyroid cancer (DTC) including papillary and follicular thyroid cancer [Hill et al 2009, Rio Frio et al 2011, Slade et al 2011, Rutter et al 2016]. DICER1-associated DTC is often encapsulated and is typically not associated with lymphovascular invasion, extrathyroidal extension, or regional lymph node metastasis [Rutter et al 2016, van der Tuin et al 2019].

A history of PPB is associated with an increased risk of DICER1-associated DTC with a shorter latency, within five years of PPB therapy [de Kock et al 2014b]. The etiology for this increased risk may be secondary to DICER1-associated DTC confounded by exposure to the chemotherapy and/or repeated radiologic imaging. Outcome of thyroid tumors in DICER1-associated DTC is favorable with a high likelihood of achieving remission.

Poorly differentiated thyroid cancer has rarely been reported [Chernock et al 2020].

Ovarian sex cord-stromal tumors. Age of onset varies widely from early childhood to late adulthood, although most individuals are diagnosed within the reproductive years (95% before age 40 years). Most ovarian sex cord-stromal tumors present at an early stage. Types of ovarian sex cord-stromal tumors include the following:

• Sertoli-Leydig cell tumor (SLCT) may present with typical signs of an ovarian tumor including abdominal distention, abdominal pain, or mass. Menstrual cycle irregularity, amenorrhea, and precocious puberty may be noted. Signs of virilization such as hirsutism, voice changes, or acne may also be seen and warrant measurement of testosterone levels. While the tumor can occur at any age, it occurs most often in adolescents and young adults.
  Ovarian sex cord-stromal tumors are staged using the International Federation of Gynecology and Obstetrics (FIGO) staging system. Well-differentiated, stage Ia tumors generally behave in a benign fashion. Poorly differentiated or higher-stage tumors are associated with a poorer prognosis. Most DICER1-associated SLCTs have moderately differentiated features although well differentiated and poorly differentiated forms have been described.
• Gynandroblastoma. Girls and young women with this tumor may present with or without signs of excess hormonal production. Gynandroblastoma is associated with a favorable prognosis if found as stage Ia. Individuals with higher risk histologic features (e.g., poorly differentiated, sarcomatous elements) or higher-stage disease may require adjuvant therapy.

Cystic nephroma (CN) is the most common renal manifestation in individuals with DICER1. CN is considered a benign neoplasm that presents as a cystic parenchymal renal tumor (most commonly as a painless, enlarging abdominal or flank mass). CN is most common in children younger than age four years, although DICER1-associated CN has also occurred in adolescents. Hematuria, hypertension, and urinary tract infection are uncommon presentations. CN may grow rapidly and cause concern for mass effect on normal-functioning kidneys, a particular concern in bilateral tumors.

A small number of children with DICER1-associated CN have later developed high-grade renal sarcomas resembling PPB [Doros et al 2014]. This sarcomatous transformation in the kidney is similar to the transformation observed in the lung from type I to III PPB. These tumors are known as anaplastic sarcomas of the kidney [Wu et al 2018].

Ciliary body medulloepithelioma (CBME) is a primitive neuroepithelial neoplasm arising from the nonpigmented ciliary epithelium. CBMEs are typically identified in young children with an average age at diagnosis of six years. Individuals may be asymptomatic when the tumor is small; however, decreased visual acuity, leukocoria, or new strabismus is often noted. On examination, a visible retrolental ciliary body mass or cataract with subluxation and possible secondary glaucoma may be identified.

Although CBMEs are considered malignant neoplasms based on their histology, distant metastasis and mortality are rare. Mortality from CBME usually results from intracranial spread rather than systemic metastases. In a study of 103 individuals with a germline DICER1 pathogenic variant, three individuals with CBME were identified; two of the children presented with vision loss of unknown duration, with a normal dilated eye exam noted within one year prior to CBME diagnosis [Huryn et al 2019].

Nasal chondromesenchymal hamartoma (NCMH) typically presents in children with chronic sinusitis, congestion, or other sinonasal symptoms. NCMH is considered a benign neoplasm. Surgical removal is generally curative; however, local recurrences can occur (see Management). A study of 102 individuals with a germline DICER1 pathogenic variant, not ascertained for a tumor (non-probands), found that approximately 1% had NCMH [Stewart et al 2019].

Embryonal rhabdomyosarcoma (ERMS) of the cervix in individuals with a DICER1 germline pathogenic variant most commonly occurs in pubertal and postpubertal adolescent girls and young women. ERMS may present with vaginal bleeding or passage of tissue.

Pituitary blastoma is a rare tumor described in children age two years and younger who may present with Cushing syndrome, ophthalmoplegia, and diabetes insipidus; ACTH levels are elevated in the majority of individuals [de Kock et al 2014a]. Treatment has included resection with or without adjuvant therapy, which can be curative, although in one series, five of thirteen individuals died after resection [de Kock et al 2014a].

Pineoblastoma is a type of primitive neuroectodermal tumor of the pineal gland that typically occurs in children. To date, fewer than ten instances have been associated with a DICER1 germline pathogenic variant [de Kock et al 2020]. Pineoblastomas are generally large and associated with obstructive hydrocephalus at diagnosis [Tate et al 2011]. Treatment includes surgical resection with craniospinal irradiation and chemotherapy [Mynarek et al 2017]. Pineoblastoma has been described to have a short clinical course and poor prognosis.

Central nervous system (CNS) sarcoma is a more recently identified DICER1-associated tumor type. DICER1-associated CNS sarcoma has histologic features similar to CNS metastases from PPB including spindle cell, rhabdomyosarcomatous, and chondroid patterns. When this histologic pattern is seen in a primary intracranial neoplasm, especially in a child, further workup is indicated (including chest and abdominal imaging) to confirm that the CNS sarcoma is primary and not due to metastatic PPB or other metastatic DICER1-associated sarcomas [de Kock et al 2018, Koelsche et al 2018, Das et al 2019, Kamihara et al 2020].

Other CNS embryonal tumors/ETMR-like (embryonal tumor with multilayer rosettes) occurring in the posterior fossa and thalamus and sparing the pineal gland have been described in two individuals with a germline DICER1 pathogenic variant [Uro-Coste et al 2019, de Kock et al 2020].

Presacral malignant teratoid tumor is a DICER1-associated neoplasm recognized in infancy whose mixed primitive pathology can be mistaken for sacrococcygeal teratoma, [Nakano et al 2019b]. Rhabdomyosarcoma in the absence of yolk sac tumor is the clue to this tumor type.

Wilms tumor may rarely be associated with a germline DICER1 pathogenic variant.

Multicystic hepatic lesions have been reported as mesenchymal hamartoma of the liver in individuals with DICER1 [Apellaniz-Ruiz et al 2019]. This lesion resembles solitary (non-parasitic) bile-ducts cysts [Vargas & Perez-Atayde 2019]. These hepatic lesions appear analogous to cystic nephroma and PPB type I and may have the potential to progress to a primitive sarcoma.

Pleuropulmonary blastoma-like peritoneal sarcoma may present as one or several masses or diffuse pelvic and peritoneal thickening. Histopathology may show diffuse, but discontinuous foci of a cambium layer-like proliferation of a primitive sarcoma with and without rhabdomyosarcomatous features and scattered chondroid nodules. The histopathology is similar to cervical embryonal rhabdomyosarcoma with overlapping features of adenosarcoma [Bean et al 2019].

Other clinical features [Choi et al 2019, Huryn et al 2019, Khan et al 2018]

• Macrocephaly has been reported in 42% of individuals with DICER1. Macrocephaly, defined as a head circumference greater than the 97th percentile in published reference populations, may be observed in early childhood (age <5 years); data are lacking on the frequency of a congenital presentation of this phenotype. There are no published data on brain imaging findings in DICER1-associated macrocephaly [Khan et al 2017a].
• Structural abnormalities of the collecting system or kidney. In a family-based cohort study, eight (9%) of 89 individuals with a pathogenic germline variant in DICER1 harbored ultrasound-detected structural abnormalities of varying severity within the collecting system or kidney, nephrolithiasis, or nephrocalcinosis; none of the family controls (0/61) had similar findings on ultrasound [Khan et al 2018].
• Retinal abnormalities. In a family-based cohort study, a significant difference in the rate (11/103; 11%) of retinal abnormalities in individuals with a pathogenic germline variant in DICER1 was observed versus family controls (1/69; 1.5%). Retinal abnormalities included pigmentary abnormalities, epiretinal membranes, drusen, and retinitis pigmentosa [Huryn et al 2019].
• Dental anomalies (e.g., bulbous crowns)

Somatic mosaicism for a DICER1 pathogenic variant has been described in individuals with:

• Thyroid nodules, including benign follicular adenomas and nodules of indeterminate cytology;
• Differentiated thyroid cancer, often low-invasive, encapsulated, follicular variant of papillary thyroid cancer or minimally invasive follicular thyroid cancer, to solid-variant and poorly differentiated follicular thyroid carcinoma associated with spindle cell sarcoma with rhabdomyosarcoma differentiation [Ravella et al 2018, Wasserman et al 2018, Yang et al 2018];
• Wilms tumor.

GLOW syndrome (global developmental delay, lung cysts, overgrowth, Wilms tumor). Two children with somatic mosaicism for a DICER1 pathogenic variant in the RNase IIIb domain were described with developmental delay, very large, multiple lung cysts, overgrowth, macrocephaly, and bilateral Wilms tumor [Klein et al 2014]. The phenotype was hypothesized to arise from activation of the PI3K/AKT/mTOR pathway [Klein & Martinez-Agosto 2020]. Five children with mosaic RNase IIIb domain pathogenic variants harbored significantly more disease foci than children with DICER1 germline loss-of-function variants [Brenneman et al 2015] and had a significantly earlier mean age of diagnosis. A detailed study of four children with somatic mosaicism for a DICER1 pathogenic variant in RNase IIIb domain showed it to be an important cause of more severe DICER1-associated phenotypes, including higher tumor burden [de Kock et al 2016].

Genotype-Phenotype Correlations

A higher number of disease foci and overgrowth have been observed in individuals with mosaicism for DICER1 pathogenic variant in the RNase IIIb domain. No other genotype-phenotype correlations have been identified.

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 [Khan et al 2017b].

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%). After age ten years, female risk was greater than male risk [Stewart et al 2019].

Nomenclature

Pleuropulmonary blastoma (PPB) has been referred to as "rhabdomyosarcoma arising in congenital cyst."

Pulmonary blastomas, biphasic epithelial and mesenchymal malignancies of the lung occurring in a broader age group, are not generally related to pleuropulmonary blastoma.

Nodular hyperplasia of the thyroid is commonly called goiter.

Ciliary body (or ocular) medulloepithelioma has also been called diktyoma or a teratoneuroma.

Prevalence

In an analysis of 53,105 non-cancer exomes from the Exome Aggregation Consortium, the prevalence of a germline loss-of-function and/or previously published DICER1 pathogenic variant was between 1:2,529 and 1:10,600 [Kim et al 2017]. A similar analysis in the Cancer Genome Atlas calculated the prevalence of DICER1 pathogenic variants to be 1:4,600 [Kim et al 2019].

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 [Priest et al 2009, Oliveira et al 2011].

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 [Shanti & Klein 2008], there is one report of a pulmonary sequestration in an individual with DICER1 [Foulkes et al 2011].

Lung cysts and pneumothoraces. Multiple inherited (see Table 3) and noninherited disorders can present with lung cysts and/or pneumothorax. However, many of these can be distinguished from PPB on the basis of medical history and physical examination.

Solid lung tumors of childhood. Other thoracic tumors are rare in children younger than age seven years, the age at which PPB most commonly occurs.

• Most non-PPB tumors presenting in the newborn period are solid lung tumors; they include fetal lung interstitial tumor [Dishop et al 2010], congenital peribronchial myofibroblastic tumor, and solid type 3 CPAM. There are no known genetic associations with these three conditions. To date, solid PPB has only rarely been observed in newborns.
• Synovial sarcoma is the main differential diagnosis for PPB in adolescents and young adults. Synovial sarcomas can be pleural-based and cystic [Cummings et al 2010]. PPBs are typically more heterogeneous than synovial sarcomas, but the spindle cell components of PPB and synovial sarcoma can be remarkably similar. Immunohistochemistry demonstrating epithelial markers or identification of a fusion protein involving the SS18 (SYT) is helpful for making a diagnosis of synovial sarcoma.
• Rhabdomyosarcoma and Ewing sarcoma tend to originate in the chest wall or soft tissue of the diaphragm rather than the lung parenchyma. Rarely, malignant peripheral nerve sheath tumors may have sarcomatous elements which resemble PPB.
• Pulmonary blastoma is a biphasic tumor with malignant epithelial elements and mesenchyme with a median age range at presentation of 43 years [Van Loo et al 2011].
• Inflammatory myofibroblastic tumor (IMT) originates in the lung (typically in children age >3-4 years) as a well-circumscribed, lobar-based mass. These tumors comprise myofibroblasts that can be demonstrated by immunostain for smooth muscle actin; 40%-50% of IMTs have translocations involving ALK (encoding ALK tyrosine kinase receptor) and show immunostaining for the ALK protein.

Other Tumors

Multinodular goiter (MNG)

• Nonsyndromic MNG is associated with iodine deficiency, female sex, and advancing age. Elevated thyroid stimulating hormone from iodine deficiency, goitrogens, and inborn errors of thyroid hormone biosynthesis are also associated with an increased risk of developing MNG.
• The method of detection correlates with disease prevalence: a higher percent of disease is found by ultrasound examination or autopsy compared to physical examination. In general, in iodine-sufficient countries the prevalence of MNG is estimated at 4% of the population [Pinchera et al 1996]. Familial MNG is suggested by early-onset MNG without iodine deficiency and most frequently described with an autosomal dominant pattern of inheritance [Paschke 2011].
• MNG is common in adults, even outside of iodine-deficient regions [Colamaio et al 2012]. Familial MNG and MNG associated with other non-thyroid tumors should prompt consideration of familial nonmedullary thyroid carcinoma and familial multinodular goiter (see Phenotypic Series: Goiter, multinodular). See Table 3 for additional hereditary disorders associated with MNG.

Ovarian sex cord-stromal tumors

• Ovarian germ cell tumors are seen more commonly in young children and adolescent girls whereas epithelial ovarian tumors are seen more often in older women.
• Ovarian small cell carcinoma of the hypercalcemic type may histologically mimic an ovarian sex cord-stromal tumor. Preoperative measurement of calcium levels may be helpful in distinguishing this unique tumor.
• Sertoli-Leydig cell tumor and (rarely) juvenile granulosa cell tumor may also secrete alpha-fetoprotein (AFP), thus leading to consideration of immature teratoma or yolk sac tumor. Typically, the elevation in AFP is <500 ng/mL with sex cord-stromal tumors, and pathologic examination generally confirms the correct diagnosis.

Renal cysts and cystic tumors

• Cystic renal tumors or lesions include congenital mesoblastic nephroma (solid and cystic), cystic partially differentiated nephroblastoma, cystic Wilms tumor, renal cell carcinoma, clear cell sarcoma, and multicystic dysplastic kidney.
• Mixed epithelial and stromal tumor (MEST) of the kidney, which includes adult cystic nephroma (CN), occurs in women older than age 50 years. Unlike pediatric CN, MEST is not associated with germline DICER1 pathogenic variants [Vanecek et al 2017].
• Although also seen in individuals with DICER1, isolated renal cysts are common in the general population, and the prevalence rises with age. Simple renal cysts (Bosniak category I) and cystic renal dysplasia are most commonly seen in children. Birt-Hogg-Dubé syndrome [Toro et al 2007] is also associated with renal cysts, oncocytoma, and chromophobe renal cell carcinoma. None of these latter lesions are known to be associated with DICER1 germline pathogenic variants.
• Multiple renal cysts may also be seen in von Hippel-Lindau syndrome, autosomal recessive polycystic kidney disease, and autosomal dominant polycystic kidney disease (see Table 3).

Ciliary body medulloepithelioma

• In children, the clinical differential diagnosis of a mass in the ciliary body includes an anteriorly located retinoblastoma, ciliary body cyst, leiomyoma, and juvenile xanthogranuloma of the ciliary body. Anteriorly located retinoblastoma occurs in older children and is frequently calcified [Vajaranant et al 2005].
• In adults, the clinical differential diagnosis of a mass in the ciliary body includes adenoma or adenocarcinoma of the ciliary epithelium (pigmented or nonpigmented), mesoectodermal leiomyoma, neurilemmoma, metastatic carcinoma, ciliochoroidal melanoma, intraocular toxocariasis, and granuloma [Tadepalli et al 2019].

Nasal chondromesenchymal hamartoma (NCMH)

• The cartilaginous nodules surrounded by a compact, hypercellular zone of immature stromal cells of NCMH can be confused with embryonal rhabdomyosarcoma. However, the stromal cells of NCMH lack a myogenic phenotype.
• Other patterns in NCMH may mimic aneurysmal bone cyst or fibrous dysplasia.

Embryonal rhabdomyosarcoma (ERMS) of the cervix or other genitourinary sites

• Because cervical ERMS is a pedunculated polyp presenting at the cervical os, a benign cervical polyp composed in part of endocervical glands and a squamous mucosa is a common clinical impression.
• Other non-neoplastic polypoid lesions of the cervix are granulation tissue polyp, decidua, and squamous papilloma.
• Mesodermal stromal polyp is composed of enlarged stellate and spindle cells in a pale staining myxoid stroma without any glandular structures. These stromal cells lack the features of rhabdomyoblasts.
• Müllerian papilloma is a purely epithelial lesion with a complex papillary pattern which may cause bleeding in children.
• Müllerian adenosarcoma is a malignant polypoid lesion of the cervix with a pattern of benign endocervical glands and a spindle cell sarcomatous stroma without rhabdomyoblastic differentiation. There is overlap with cervical embryonal rhabdomyosarcoma.

Pituitary blastoma

• Clinically, a pituitary mass in a young child should prompt consideration of craniopharyngioma, adenoma, pituitary hyperplasia, germinoma, Langerhans cell histiocytosis, and much rarer entities including pituitary carcinoma, hamartoma, or teratoma.
• Non-neoplastic inflammatory and granulomatous entities may also affect this region.

Pineoblastoma

• Pineoblastomas must be distinguished from better-differentiated pineal parenchymal tumors like pineocytoma and pineal parenchymal tumor of intermediate differentiation. Pineal cysts may also occur. The pineal gland is also a common location for germ cell tumors.
• Other embryonal tumors such as medulloblastoma should be considered if the tumor is not localized to the pineal region but rather extends into the infratentorial region.

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 (see Surveillance).

Treatment of Manifestations

Surveillance

Surveillance guidelines for individuals with a germline DICER1 pathogenic variant have been established [Schultz et al 2018]. 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.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives of an affected individual by molecular genetic testing for the DICER1 pathogenic variant in the family in order to provide recommendations for age-appropriate surveillance and early intervention.

• Testing of at-risk newborns (before age 4 months) for the family-specific pathogenic variant is recommended. Pulmonary screening by CT scan can then be initiated for those with a known DICER1 pathogenic variant [Schultz et al 2018].
• If not already performed, molecular genetic testing should be prioritized for children younger than age seven years (because they are at greatest risk for PPB tumors that may need intervention) and young girls/women (because of the risk of ovarian tumors during late childhood/early adolescence and young adult years).

Note: If at-risk first-degree relatives are not able to or choose not to undergo molecular genetic testing for a known familial DICER1 pathogenic variant, surveillance should be based on the recommendations detailed in Surveillance unless/until genetic testing confirms that they did not inherit the familial variant.

Relatives of a proband with a suspected DICER1 pathogenic variant. If confirmatory DICER1 molecular genetic testing of an affected family member is not possible, at-risk relatives can undergo molecular genetic testing first by sequence analysis, and if no pathogenic variant is identified, by gene-targeted deletion/duplication analysis. If a DICER1 pathogenic variant is identified, the family member is considered to have tumor susceptibility. If a DICER1 pathogenic variant is not identified, the family member's a priori tumor susceptibility risk remains unchanged.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Based on data from the International PPB/DICER1 Registry (www.PPBregistry.org), prenatal ultrasound examination has detected lung cysts as early as 31-35 weeks' gestational age. Based on this finding, a third-trimester ultrasound is recommended.

Because large lung cysts can in rare cases cause respiratory distress in newborns, it is recommended that prenatal identification of lung cysts prompt consultation with specialists in high-risk obstetrics and fetal medicine to monitor the pregnancy and manage delivery.

Therapies Under Investigation

Multiple research efforts are underway to refine surveillance guidelines and improve outcomes for children and adults with DICER1-associated cancers. For more information, please visit www.PPBregistry.org.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

DICER1 tumor predisposition (DICER1) is inherited in an autosomal dominant manner with reduced penetrance.

Risk to Family Members

Parents of a proband

• Approximately 80% of individuals diagnosed with DICER1-associated pleuropulmonary blastoma (PPB) inherited the DICER1 germline pathogenic variant from a parent who may or may not have PPB or other DICER1-associated findings.
• Approximately 20% of individuals with a DICER1-associated PPB have DICER1 as the result of a de novo germline pathogenic variant [Hill et al 2010].
• Molecular genetic testing is recommended for the parents of a proband to clarify the genetic status of the parents and to determine if the proband inherited a pathogenic variant from a heterozygous parent, or if the DICER1 pathogenic variant occurred de novo in the proband.
• If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or, theoretically, germline mosaicism in a parent.
  Misattributed parentage can also be explored as an alternative explanation for an apparent de novo pathogenic variant.
• The family history of some individuals with a single or multiple DICER1-associated tumors may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, or lack of information about the family. Therefore, an apparently negative clinical family history cannot confirm absence of familial pathogenic variation. Note: Although multiple PPBs within a family with DICER1 are rare, approximately 35% of index cases with DICER1-associated PPB have a close relative with one or more lung cysts or another DICER1-associated tumor and/or clinical feature.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband has a germline DICER1 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant and associated tumor predisposition is 50%.
• If the germline pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the DICER1 pathogenic variant but are clinically unaffected, sibs of a proband are still presumed to be at increased risk for DICER1-associated tumors and clinical features because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with a germline DICER1 pathogenic variant has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent has a germline DICER1 pathogenic variant, his or her family members may be at risk for PPB and/or associated tumors and clinical features.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once a germline DICER1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Note: Although prenatal molecular genetic testing can be used to identify the presence of a germline DICER1 pathogenic variant, prenatal testing cannot be used to predict whether a DICER1-associated tumor(s) will develop (see Penetrance).

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

DICER1 encodes an RNase III that functions in the microRNA (miRNA) and siRNA biogenesis pathways, cleaving precursor double-stranded RNAs into their active forms. Loss-of-function germline pathogenic variants in DICER1 coupled with somatic missense pathogenic variants in particular amino acids (see below) lead to defective production of mature miRNAs from the 5' (5p) end of the miRNA hairpin [Pugh et al 2014]. Most individuals who are heterozygous for a germline DICER1 loss-of-function pathogenic variant are healthy, presumably because DICER1 enzyme expression from the wild type allele can be upregulated.

Mechanism of disease causation. DICER1 tumor predisposition (DICER1) occurs through a loss-of-function mechanism that requires a somatic "second hit" for disease manifestation (see below).

DICER1-specific laboratory technical considerations. Somatic mosaicism has been reported in this disorder; therefore, either primary or follow-up sequencing assays should be designed to detect expected levels of mosaicism.

Cancers and Benign Tumors with Somatic DICER1 Pathogenic Variants

Somatic DICER1 pathogenic variants have been described [Slade et al 2011, de Boer et al 2012, Heravi-Moussavi et al 2012, de Kock et al 2013a, Wu et al 2013, Doros et al 2014, Pugh et al 2014] in many tumor types.

Somatic missense pathogenic variants appear to preferentially affect amino acids in the RNase IIIb domain (codons 1705, 1709, 1809, 1810, or 1813) and are characterized as "missense hot spots." These somatic pathogenic variants lead to defective production of mature miRNAs from the 5' (5p) end of the miRNA hairpin but preserve the cleavage of the 3' (3p) end of the hairpin [Gurtan et al 2012, Anglesio et al 2013, Pugh et al 2014].

Examples of somatic DICER1 variants identified in other tumors:

• Nearly all Sertoli-Leydig cell tumors and gynandroblastoma (based on tumor testing) [Schultz et al 2017], half of which are associated with a germline or mosaic DICER1 pathogenic variant
• Three out of 15 (20%) PPBs with tumor-specific loss-of-function and missense pathogenic variants in DICER1 with normal germline [Pugh et al 2014]
• Eighteen out of 20 (90%) CNs with loss-of-function pathogenic variants in 70% (14/20); however, germline DNA was not examined [Doros et al 2014].
• Two out of 52 (4%) ERMS tumors with loss-of-function pathogenic variants; however, germline DNA was not examined [Doros et al 2012].
• Two pineoblastomas from children with a germline DICER1 pathogenic variant did not have a tumor-specific somatic missense pathogenic variant, suggesting an alternate tumorigenesis pathway [Sabbaghian et al 2012].
• Ninety-five percent of primary intracranial sarcomas in children [Koelsche et al 2018]
• Multiple cases of nasal chondromesenchymal hamartoma. A systematic review of the literature identified 48 cases of NCMH [Mason et al 2015].
• Thyroid nodules with indeterminate cytology and a spectrum of disease that spans the range from benign follicular adenomas to differentiated thyroid cancer and rarely poorly differentiated thyroid cancer [Ravella et al 2018, Wasserman et al 2018, Yang et al 2018, Chernock et al 2020]

Author Notes

Websites with additional information about DICER1 tumor predisposition:

• www.PPBregistry.org
• ppb.cancer.gov
• www.OTSTregistry.org

About the authors' research. The authors of this study represent a multidisciplinary collaborative group that seeks to understand the clinical, pathologic, and genetic basis of DICER1-related cancers and associated conditions. The International PPB/DICER1 Registry's mission is to improve outcomes for children and adults with DICER1-related cancers by defining optimal therapy, validating testing and surveillance guidelines, and development of novel diagnostics and therapeutics. The PPB/DICER1 Registry has recently established the first cohort of uniformly treated individuals with PPB and shares available information with individuals, families, and treating physicians. Together with the Registry, Dr Hill identified heterozygous germline mutation of DICER1 as the genetic basis of PPB. Preliminary data from PPB mouse models and study of human tumors suggests that DICER1 protein is diminished in lung epithelium overlying the mesenchymal tumor, suggesting that loss of miRNAs in developing lung epithelium may affect regulation of secreted growth factors driving mesenchymal proliferation and setting the stage for cancerous transformation. Further work of the Hill group and others has identified recurrent, somatic missense DICER1 pathogenic variants in tumor cells, confirming that DICER1 functions as a two-hit tumor suppressor and loss of DICER1 protein leads to loss of miRNAs important in controlling proliferation and differentiation in development. A better understanding of this syndrome is essential to the development of clinical criteria for identifying affected families and for guiding their medical care. The International PPB/DICER1 Registry is closely affiliated with the International Ovarian and Testicular Stromal Tumor (OTST) Registry, which is devoted to understanding these rare tumors including Sertoli-Leydig cell tumor and gynandroblastoma.

Dr Stewart's group at the National Cancer Institute is focused on the determination of DICER1 pathogenic variant prevalence, penetrance, and phenotype to enable evidence-based early detection of PPB (and other DICER1-associated neoplasms) through identification of individuals with DICER1 pathogenic variants. His work focuses primarily on the recognition of pathogenic germline DICER1 variants and their associated phenotype, risk, and outcomes.

Acknowledgments

The authors thank Dr John R Priest and Gretchen M Williams for their contributions to data collection used in this review.

This work was supported in part by National Cancer Institute (NCI), NIH/NCI R01CA143167 (PI Hill), the Intramural Research Program of the NIH, Hyundai Hope on Wheels, Pine Tree Apple Tennis Classic, MF Schutt Foundation and Children's Minnesota Foundation, and St Baldrick's Foundation.

Author History

Andrew J Bauer, MD (2014-present)
Ann G Carr, MS, CGC (2014-present)
Louis P Dehner, MD (2014-present)
Leslie Doros, MD (2014-present)
Amanda Field, MPH (2020-present)
Anne K Harris, MPH (2020-present)
D Ashley Hill, MD (2014-present)
Laryssa A Huryn, MD (2020-present)
Junne Kamihara, MD, PhD (2020-present)
Melissa A Merideth, MD, MPH (2020-present)
Yoav Messinger, MD (2014-present)
Christopher T Rossi, MD; Children's National Medical Center (2014-2020)
Kris Ann P Schultz, MD (2014-present)
Douglas R Stewart, MD (2014-present)
Pamela Stratton, MD (2020-present)
Gretchen Williams, BS; Children's Hospitals and Clinics of Minnesota (2014-2020)
Jiandong Yang, PhD; Children's National Medical Center (2014-2020)

Revision History

• 30 April 2020 (sw) Comprehensive update posted live
• 24 April 2014 (me) Review posted live
• 23 July 2012 (dh/ym) Original submission

Published Guidelines / Consensus Statements

• American Thyroid Association. Thyroid Nodules and Differentiated Thyroid Cancer Guidelines Pocket Card. (Available online for purchase). Accessed 1-13-22.
• Gharib H, Papini E, Garber JR, Duick DS, Harrell RM, Hegedüs L, Paschke R, Valcavi R, Vitti P. American Association of Clinical Endocrinologists, American College of Endocrinology, and Associazione Medici Endocrinologi Medical Guidelines for Clinical Practice for the Diagnosis and Management of Thyroid Nodules – 2016 Update. Endocr Pract. 2016;22:622–39. online Available. Accessed 1-13-22. [PubMed: 27167915]

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