Clinical characteristics.

DICER1-related tumor predisposition (DICER1) is characterized by an increased risk for a spectrum of malignancies, benign neoplasms, and other clinical findings. The most common features are lung cysts and thyroid nodules. DICER1-related neoplasms include pleuropulmonary blastoma (PPB), Sertoli-Leydig cell tumor (SLCT), including gynandroblastoma, pediatric cystic nephroma (CN), and differentiated thyroid carcinoma. Less commonly observed neoplasms include ciliary body medulloepithelioma, nasal chondromesenchymal hamartoma, pituitary blastoma, pineoblastoma, DICER1-associated central nervous system (CNS) sarcoma, embryonal tumor with multilayered rosettes (without somatic alterations of chromosome 19 microRNA cluster), pulmonary blastoma, well-differentiated fetal lung adenocarcinoma, embryonal rhabdomyosarcoma (primarily of the female reproductive tract), anaplastic sarcoma of the kidney, primary ovarian sarcoma, PPB-like peritoneal sarcoma, extraovarian SLCT, multicystic neoplasms of the liver, and Wilms tumor. Additional clinical features can include macrocephaly, retinal abnormalities, structural anomalies of the urinary collecting system or kidney (including kidney cysts), hamartomatous polyps, and liver cysts. The majority of tumors occur in individuals younger than age 40 years. PPB typically presents in infants and children younger than age seven years. Ovarian sex cord-stromal tumors are most often diagnosed before age 40 years. Pediatric CN generally presents in young children but has also been reported in adolescents.

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 type II or III PPB and certain other malignant tumors may also include radiation, primarily to treat residual disease or recurrence. Thyroid nodules that have concerning features may require biopsy (generally fine-needle aspiration [FNA]) and/or surgical resection. Thyroid carcinoma may require specific treatment in addition to surgery depending on certain characteristics. Ovarian tumors require surgery and may also require chemotherapy depending on stage and histology, with radiation generally reserved for relapsed disease. Ciliary body medulloepithelioma has been treated with resection, cryotherapy, or plaque brachytherapy. Pineoblastoma and DICER1-associated CNS sarcoma are treated with resection, radiotherapy, and chemotherapy.

Surveillance: Family education regarding signs and symptoms of DICER1-related tumors is the cornerstone of surveillance. Clinical evaluation for manifestations of DICER1-related tumors every six months or at each visit; chest radiograph at birth, every six months until age eight years, then annually until age 12 years. Chest CT at age three months and age 30 months. Consider baseline chest radiograph or CT in those diagnosed after age 12 years. Thyroid ultrasounds every three years beginning at age eight years. Consider annual thyroid ultrasound for five years following the completion of chemotherapy for individuals who have received chemotherapy. FNA following age-appropriate guidelines for evaluating thyroid nodules. Pelvic ultrasounds for gynecologic tumors in females every six months until at least age 40 years. Abdominal ultrasounds for pediatric CN and other kidney tumors every six months until age eight years and then annually until age 12 years. Consider baseline abdominal ultrasound in those diagnosed after age 12 years. Monitor for decreased visual acuity and leukocoria at each visit. Assess visual acuity and dilated ophthalmology examination annually from age three to ten years. Urgent evaluation for any concerning ocular symptoms. Monitor for signs and symptoms of CNS malignancy. Urgent brain MRI for any concerning neurologic symptoms. Consider shared decision making about screening brain MRI in the absence of symptoms in late adolescence and early adulthood. Assess for manifestations of intestinal obstruction as needed.

Evaluation of relatives at risk: Clarify the genetic status of first-degree relatives (of all ages) – with cascade testing as indicated (including parents, children, and sibs) – of an individual with DICER1 by molecular genetic testing for the DICER1 pathogenic variant in the family in order to provide recommendations for age-appropriate surveillance and early intervention. As screening recommendations begin in infancy, testing at-risk individuals soon after birth is recommended.

Pregnancy management: Symptom-directed surveillance for DICER1-associated conditions. SLCT has been reported during pregnancy in individuals with DICER1; therefore, up-to-date screening prior to conception is recommended. If concerns arise during pregnancy, prompt consultation with specialists in high-risk obstetrics and fetal medicine is indicated to support pregnancy monitoring and delivery planning.

Genetic counseling.

DICER1 is inherited in an autosomal dominant manner with reduced, age-related penetrance. Approximately 85% of individuals diagnosed with DICER1-associated PPB are thought to have inherited a DICER1 germline pathogenic variant from a parent who may or may not have PPB or other DICER1-associated findings. Each child of an individual with a germline constitutional DICER1 pathogenic variant has a 50% chance of inheriting the pathogenic variant. Because the penetrance of heterozygous germline DICER1 pathogenic variants is reduced, 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, predictive testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

DICER1-related tumor predisposition (DICER1) should be considered in individuals with the following clinical features, laboratory features, and/or family history [Schultz et al 2024].

Clinical features

• Tumor/cyst by location and type
  • Thorax. Pleuropulmonary blastoma (PPB) of all types, embryonal rhabdomyosarcoma of the thorax, pulmonary blastoma, well-differentiated fetal lung adenocarcinoma, and lung cyst(s) in childhood (especially if multiseptated, multiple, and/or bilateral, and/or unexplained by other risk factors such as infection, prematurity, or mechanical ventilation in infancy). A lung cyst during early childhood may be misdiagnosed as a congenital pulmonary airway malformation. Lung cyst(s) in adulthood are suggestive, especially if there is family history to suggest DICER1.
  • Thyroid. Thyroid adenoma/nodule (especially in those age <10 years), multinodular goiter, differentiated thyroid carcinoma (especially childhood-onset follicular thyroid carcinoma), poorly differentiated thyroid carcinoma, thyroblastoma
  • Female reproductive tract. Ovarian sex cord-stromal tumors (e.g., Sertoli-Leydig cell tumor [moderately and poorly differentiated], gynandroblastoma, juvenile granulosa cell tumor [especially if anaplasia and/or high mitotic index]), primary ovarian sarcoma, embryonal rhabdomyosarcoma of the uterus, cervix, or vagina, uterine adenosarcoma
  • Kidney. Pediatric cystic nephroma, anaplastic sarcoma of kidney, Wilms tumor, and/or kidney cysts (especially in those with a family history of DICER1-related tumors)
  • Ciliary body medulloepithelioma
  • Nasal chondromesenchymal hamartoma
  • Central nervous system. Pituitary blastoma, pineoblastoma, primary intracranial sarcoma, embryonal tumor with multilayered rosettes (without somatic alterations of chromosome 19 microRNA cluster)
• Other tumors
  • Presacral malignant teratoid neoplasm of infancy
  • PPB-like peritoneal sarcoma
  • Multicystic liver lesions with PPB-like features
  • Extraovarian Sertoli-Leydig cell tumor
  • Testicular Sertoli cell tumor and Leydig cell tumor
• Other clinical features
  • Macrocephaly
  • Juvenile-like hamartomatous intestinal polyp (non-Peutz-Jeghers syndrome type)
  • Childhood nonparasitic liver cysts

Laboratory findings 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, Somatic mosaicism for a DICER1 pathogenic variant).

Family history may be consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of DICER1 is established in a proband by identification of a heterozygous germline pathogenic (or likely pathogenic) variant in DICER1 per DICER1-specific American College of Medical Genetics (ACMG) / Association for Molecular Pathology (AMP) variant classification guidelines (see Table 1) [Hatton et al 2023].

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous DICER1 variant of uncertain significance does not establish or rule out the diagnosis (see Molecular Pathogenesis, DICER1-specific laboratory technical considerations).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

DICER1-related tumor predisposition (DICER1) is characterized by an increased risk for a spectrum of malignancies, benign cysts and tumors, and other clinical findings. The most common features include macrocephaly, lung cysts, and thyroid nodules. DICER1-related neoplasms include pleuropulmonary blastoma (PPB), ovarian sex-cord stromal tumors (e.g., Sertoli-Leydig cell tumor [SLCT]), pediatric cystic nephroma, and differentiated thyroid carcinoma. Less common neoplasms include ciliary body medulloepithelioma, nasal chondromesenchymal hamartoma, central nervous system (CNS) tumors (pituitary blastoma, pineoblastoma, primary intracranial sarcoma, embryonal tumor with multilayer rosettes [without somatic alterations of chromosome 19 microRNA cluster]), pulmonary blastoma, well-differentiated fetal lung adenocarcinoma, embryonal rhabdomyosarcoma (primarily of the female reproductive tract), anaplastic sarcoma of the kidney, ovarian sarcoma, other sarcomas, extraovarian SLCT, multicystic neoplasms of the liver, Wilms tumor, and presacral malignant teratoid tumor. Additional clinical features may include retinal abnormalities, structural anomalies of the urinary collecting system or kidney (including kidney cysts), liver cysts, and dental anomalies. To date, more than 1,500 individuals have been identified with a germline pathogenic variant in DICER1, based on literature reports and unpublished data from the International PPB/DICER1 Registry and the NIH Natural History Study. The following description of the phenotypic features associated with this condition is based on these reports.

Onset. The majority of tumors reported in individuals with DICER1 are identified prior to age 40 years.

Pleuropulmonary blastoma (PPB). The natural history of PPB suggests that many tumors have a precancerous / early cancerous stage in the form of lung cysts or type I PPB. Progression from type I to type II or type III PPB can occur quickly and is thought to result from the accumulation of pathogenic variants in TP53 and other genes [Pugh et al 2014, González et al 2021]. When progression occurs, the mesenchymal cells of a type I PPB expand and overgrow the cyst septa, replacing the cyst with a cystic and solid (type II) or purely solid (type III) multipatterned sarcoma. Nearly all type I, II, and III PPBs occur in children younger than age seven years, although they have rarely been reported in older children and exceedingly rarely in adults. Type I PPB can regress to a benign multiseptated cyst, type Ir (regressed), that has little to no neoplastic potential [Hill et al 2008]. Type II or III PPB can metastasize to the brain, bone, local thoracic lymph nodes, and/or liver.

PPB occurs in four main types:

• Type I PPB is a purely cystic lesion containing a layer of primitive small cells with or without rhabdomyoblastic features. If left in situ, the malignant component of type I PPB may proliferate further, leading to type II or type III PPB. Typically, type I PPB becomes evident in infants and young children, primarily in those younger than age three years (median age at diagnosis: 8 months), with respiratory distress due to a large space-occupying cyst in the lung or pneumothorax secondary to rupture of the air-filled cyst. Occasionally, lung cysts are identified in asymptomatic children during radiographic studies performed for surveillance or other indications. Type I PPB has no metastatic potential. Five- and ten-year overall survival (OS) for type I PPB is 98% and 95.5%, respectively [Nelson et al 2023].
• Type Ir PPB (regressed or non-progressed) presents in individuals of any age (median age: 2.6 years, range: 0.2–45.4 years) and lacks a malignant component [Hill et al 2008, Nelson et al 2023]. Type Ir PPB is frequently detected in asymptomatic individuals during surveillance or as an incidental finding. Cysts are generally smaller than type I and may appear unilocular on cross-sectional imaging compared to the predominantly multiseptated type I PPB. A model incorporating age and largest cyst dimension has been developed to assist in differentiation between type I and Ir PPB [Nelson et al 2023]. Type Ir PPBs are frequently misclassified as type I PPBs or as alternative cystic lesions. Careful evaluation of the entirety of the cystic lesion is recommended, as well as central pathology review by the International PPB/DICER1 Registry. Five- and ten-year OS for type Ir PPB is 100% [Nelson et al 2023]. Type Ir has no metastatic potential. Notably, two instances of progression to type II/III PBB have been reported, and it remains unclear if these represent true progressions, metachronous tumors, or misdiagnosis of a type I PPB due to inadequate sampling of the entire cyst.
• Type II PPB is a mixed cystic and solid tumor that presents at a median age of 35 months [Schultz et al 2023]. Children with type II PPB typically present with weight loss, fever, shortness of breath, and opacity or pneumothorax on chest radiograph. Five-year OS for individuals with type II PPB ranges from 79% to 89% but is exceedingly poor in those with metastatic disease (40%) [Schultz et al 2023]. Less than gross total resection is associated with worse outcomes, but metastatic disease is the predominant poor prognostic factor.
• Type III PPB is a purely solid, multipatterned sarcoma with anaplasia that presents at a median age of 39 months [Schultz et al 2023]. Clinical manifestations typically include respiratory distress, weight loss, fever, and a large, solid opacity on radiograph, often with mediastinal shift. Survival for type III PPB is significantly lower than type II, with a five-year OS of 56%-61%, but is almost uniformly fatal if metastatic disease is present at diagnosis. Type III PPB is also associated with worse outcomes if less than gross total resection is accomplished.

Children with type II or III PPB 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 metastases.

Multinodular goiter (MNG) and thyroid carcinoma. DICER1 plays a significant role in thyroid tumorigenesis from benign neoplasms to dedifferentiated thyroid tumors [Ghossein et al 2022, Riascos et al 2024, Rodrigues et al 2025]. DICER1 is associated with an increased risk of developing thyroid nodules and/or MNG. By age 20 years, 32% of women and 13% of men with DICER1 have been diagnosed with MNG and/or have undergone a thyroidectomy [Khan et al 2017b, Oliver-Petit et al 2019].

Individuals with DICER1 are also at increased risk for developing differentiated thyroid carcinoma (DTC), including papillary and follicular thyroid carcinoma [Rutter et al 2016, Wasserman et al 2018, Hellgren et al 2021, Cameselle-Teijeiro et al 2025], poorly differentiated or high-grade thyroid carcinoma [Chernock et al 2020, Yegen et al 2023, Ver Berne et al 2024, Whaley et al 2024, Schiavo Lena et al 2025], and, rarely, thyroblastoma [Erickson et al 2023, Jitpasutham et al 2023, Yin et al 2026]. DICER1-associated DTC is often encapsulated and is typically not associated with lymphatic or vascular invasion, extrathyroidal extension, or regional lymph node metastasis [van der Tuin et al 2019, Onder et al 2022, Mastnikova et al 2024]. DICER1 pathogenic variants appear to be the most common alteration found in follicular thyroid carcinoma in children, and DICER1 may be the most common cause of hereditary predisposition to follicular thyroid cancer in children [Bongiovanni et al 2020, Lee et al 2020, Hellgren et al 2021, Juhlin et al 2021].

A history of PPB is associated with an increased risk of DICER1-associated DTC with a shorter latency, with the potential for diagnosis within five years of PPB therapy [de Kock et al 2014c]. The etiology for this increased risk may be secondary to exposure to chemotherapy and/or repeated radiologic imaging. The outcome of thyroid tumors in DICER1-associated DTC is generally favorable, as the majority of tumors are intrathyroidal. However, poor prognosis may be associated with DICER1-associated poorly differentiated thyroid carcinoma [Chernock et al 2020, Yegen et al 2023, Ver Berne et al 2024] and thyroblastoma [Chen et al 2025].

Ovarian tumors. Sex cord-stromal tumors are the most common ovarian tumors in individuals with DICER1, although other ovarian tumors have been reported. Among 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). For all ovarian malignancies, stage at diagnosis affects both treatment and prognosis. Most ovarian sex cord-stromal tumors present at an early stage. DICER1-related ovarian 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 be seen in about 35% of individuals and warrant measurement of testosterone levels [Nelson et al 2024a]. While SLCT can occur at any age, it occurs most often in adolescents and young adults [Merideth et al 2020].
  SLCT is classified as well, moderately, or poorly differentiated based on histology. Retiform pattern has also been described. Heterologous elements are common and most commonly include intestinal-type mucinous epithelium and mesenchymal elements in the form of rhabdomyosarcomatous and cartilaginous differentiation. Less commonly, carcinoid and hepatoid elements have been described. Nearly all moderately and poorly differentiated SLCT have a somatic pathogenic variant in DICER1, and 60% of individuals with SLCT have DICER1 [Nelson et al 2024a]. Molecular studies of well-differentiated SLCT suggest that they are genetically distinct from moderately and poorly differentiated SLCT and lack somatic DICER1 (and FOXL2) pathogenic variants [Karnezis et al 2019, McCluggage et al 2023, Lyu et al 2025, Němejcová et al 2025]. Mesenchymal heterologous elements, poorly differentiated tumors, and higher-stage disease are associated with worse prognosis [Nelson et al 2024a]. DICER1-related SLCT is associated with a better prognosis compared to sporadic SLCT and SLCT with biallelic DICER1 pathogenic variants confined to tumor tissue, even when adjusting for other prognostic factors [Nelson et al 2025].
• Gynandroblastoma is characterized as a sex cord-stromal tumor of mixed forms and generally includes both SLCT and juvenile granulosa cell tumor (juvGCT) components. Girls and young women with this tumor may present with or without signs of excess hormonal production. As with most other sex cord-stromal tumors, gynandroblastoma is associated with a favorable prognosis if found as early stage (stage IA). Gynandroblastoma with SLCT and follicular differentiation mimicking juvGCT is felt to be more appropriately categorized as SLCT [Ordulu & Young 2021] and such tumors are associated with DICER1 [Schultz et al 2017].
• JuvGCT, especially anaplastic juvGCT, may be associated with DICER1 [Baillard et al 2021, Onder et al 2021, Boyraz et al 2026]. JuvGCT may present with typical signs of an ovarian tumor including abdominal pain, abdominal distention, or mass. Precocious puberty, secondary amenorrhea, or virilization may be noted. Biochemical markers are variable and may include increased blood concentrations of inhibin A, inhibin B, CA125, and testosterone. Individuals may present with elevated inhibin B levels at diagnosis and with recurrence. JuvGCT generally have a favorable prognosis if identified at stage 1A or 1C1, though high mitotic index, anaplastic features, or higher-stage tumors are associated with a worse prognosis [Harris et al 2025, Schneider et al 2025, Boyraz et al 2026].
• Other ovarian tumors. DICER1-related primary ovarian sarcoma has been reported and is characterized by childhood presentation and high-grade sarcoma-like features [de Kock et al 2015, Schultz et al 2016, Melendez-Zajgla et al 2018, McCluggage et al 2020, Warren et al 2020, Lethongsavarn et al 2023]. Less common ovarian tumors have been reported among individuals with DICER1 including yolk sac tumor, highly differentiated follicular carcinoma, Sertoli cell tumor, mucinous adenocarcinoma, and carcinoid tumor [McCluggage et al 2022, Schultz et al 2024, Seav et al 2024].

Kidney tumors/cysts

• Pediatric cystic nephroma (CN) is the most common kidney manifestation in individuals with DICER1 [Schultz et al 2024]. Pediatric CN is considered a benign neoplasm that presents as a multicystic parenchymal kidney tumor (most commonly as a painless, enlarging abdominal or flank mass). Pediatric CN is most common in children younger than age four years, although DICER1-associated pediatric CN has also been reported in older children and adolescents. Hematuria, hypertension, and urinary tract infection are uncommon presentations. Pediatric CN may grow rapidly and cause concern for mass effect on normal-functioning kidneys, a particular concern in bilateral tumors.
• Anaplastic sarcoma of the kidney (DICER1-related sarcoma of the kidney). A small number of children with DICER1-associated pediatric CN have later developed high-grade kidney sarcomas resembling types II or III PPB [Doros et al 2014] known as anaplastic sarcomas of the kidney [Wu et al 2018, Kroll-Wheeler & Heider 2022, Schoettler et al 2024]. This sarcomatous transformation in the kidney is similar to the transformation observed in the lung from type I to III PPB [Wu et al 2016a, Wu et al 2016b].
• Wilms tumor has been noted in individuals with DICER1; however, other types of kidney tumors are more common [Wu et al 2013].
• Simple kidney cysts. Dicer1 knockout mice demonstrate a spectrum of kidney abnormalities, including renal parenchymal cysts [Nagalakshmi et al 2011]. In a family-based cohort study, a nonsignificant excess in kidney cysts was reported in children with DICER1, and in adults with DICER1, no excess in kidney cysts was observed [Khan et al 2018]. In a larger observational cohort of more than 700 individuals with DICER1 with available imaging, 11% were reported to have a simple kidney cyst (median age at first imaging: 27 years); however, the absence of familial controls limits the interpretation [Schultz et al 2024]. Further study is needed to elucidate the prevalence and clinical significance of simple kidney cysts in individuals with DICER1.

Ciliary body medulloepithelioma (CBME) is a primitive neuroepithelial neoplasm arising from the nonpigmented ciliary epithelium. CBME is typically identified in young children with a mean age at diagnosis of six years. Individuals may be asymptomatic when the tumor is small; however, decreased visual acuity, leukocoria, or new-onset strabismus is often noted. On examination, a visible retrolental ciliary body mass or cataract with subluxation and possible secondary glaucoma may be identified. Although CBME is considered a malignant neoplasm based on 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 DICER1, three had CBME; two of the children presented with vision loss of unknown duration, with a normal dilated eye exam noted one year prior to CBME diagnosis [Huryn et al 2019]. In a study of six individuals with CBME, two had DICER1; one individual had a history of strabismus for one year, and the other had a history of leukocoria for one month [August et al 2025]. Bilateral CBME was reported in one individual with DICER1 [Danowska et al 2025].

Nasal chondromesenchymal hamartoma (NCMH) typically presents in childhood with chronic sinusitis, congestion, or other sinonasal symptoms. In a review of 99 tumors from 64 individuals, the ethmoid and orbital sinuses were the most frequent locations for NCMH [Vasta et al 2020b, Hu et al 2024]. Common CT findings include bony remodeling, erosions, and calcifications. MRI typically shows a heterogeneous expansile lesion with predominantly hyperintense T₂ signal and heterogenous post contrast enhancement [Avsenik et al 2024]. NCMH is considered a benign neoplasm. Surgical removal is generally curative; however, local recurrences can occur (see Management). A study of 102 individuals with DICER1 not ascertained for known tumors (non-probands) found that approximately 1% had NCMH [Stewart et al 2019].

CNS tumors

• Pituitary blastoma is a rare tumor most often described in children age two years and younger, with rare case reports of older presentations [de Kock et al 2020a, Chong et al 2021, Das et al 2025]. Individuals may present with Cushing syndrome, ophthalmoplegia, and/or diabetes insipidus. Adrenocorticotropic hormone levels are elevated in the majority of individuals [de Kock et al 2014b].
• Pineoblastoma is a rare primitive neuroectodermal tumor of the pineal gland that typically occurs in the first two decades of life [de Kock et al 2020a]. Pineoblastomas are generally large and associated with obstructive hydrocephalus at diagnosis, and may present with vomiting, headache, and change in mental status [Tate et al 2011]. DNA methylation profiling is recommended to confirm the molecular subtype [Li et al 2020]. While somatic DICER1 RNase IIIb hot spot pathogenic variants have been identified in some pineoblastomas, biallelic loss-of-function variants (germline and somatic) have been more commonly described in DICER1-related pineoblastomas, distinct from the typical somatic molecular findings seen in other DICER1-related tumors [de Kock et al 2014a].
• Primary intracranial sarcoma is a rare primary CNS tumor with spindle cell, rhabdomyosarcomatous, and chondroid patterns. This entity has histologic features similar to CNS metastases from PPB; thus, when this histologic pattern is seen in an 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 sarcoma [de Kock et al 2018, Koelsche et al 2018, Das et al 2019, Kamihara et al 2020, Diaz Coronado et al 2022].
• Embryonal tumor with multilayered rosettes (ETMR) is a rare, high-grade embryonal CNS tumor that occurs almost exclusively in children younger than age four years. These tumors arise either in the cerebral hemispheres or posterior fossa. ETMR is rarely reported in individuals with DICER1; rather, most ETMR is due to somatic alterations of chromosome 19 microRNA cluster, which is histologically similar to DICER1-related ETMR [Gojo et al 2023].

Embryonal rhabdomyosarcoma (ERMS) of the uterus, cervix, or vagina has been described in individuals with DICER1 and most commonly occurs in pubertal and postpubertal adolescent girls and young women [Apellaniz-Ruiz et al 2021, Bennett et al 2021, Kebudi et al 2021, Devins et al 2022]. ERMS may present with vaginal bleeding, polypoid mass, and/or abdominal pain. Autoamputation has been reported in infants [Nashed et al 2021, Wilson et al 2022]. Genitourinary ERMS with DICER1 pathogenic variants have distinct methylation profiles compared to DICER1 wild-type tumors, implying a distinct subtype [Kommoss et al 2021].

Other tumors of the cervix/uterus. Primary primitive neuroectodermal tumors of the cervix have been reported in individuals with DICER1 [Foulkes et al 2011, Schultz et al 2024]. Other sarcomas of the cervix and uterus have been reported, including those sharing histologic similarities to PPB [Stolnicu et al 2023, Dashti et al 2024].

Presacral malignant teratoid tumor is a rare DICER1-associated neoplasm recognized in infancy whose mixed primitive pathology can be mistaken for immature teratomas [Nakano et al 2019b]. Rhabdomyosarcoma in the absence of teratomatous elements or endodermal sinus tumor distinguishes this tumor type from immature teratoma [Nakano et al 2019b].

PPB-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 ERMS with overlapping features of adenosarcoma [Schultz et al 2020].

Multicystic liver lesions have been reported as so-called mesenchymal hamartoma of the liver very rarely in individuals with DICER1 [Apellaniz-Ruiz et al 2019, Vargas & Perez-Atayde 2019] resembling solitary (nonparasitic) bile duct cysts. These lesions appear analogous to pediatric CN and type I PPB and may have the potential to progress to a primitive sarcoma [Mitchell et al 2022].

Testicular neoplasms are rare in individuals with DICER1. To date, two individuals with DICER1-related testicular neoplasms have been reported, one with a Sertoli cell tumor and somatic DICER1 hot spot pathogenic variant, and one with a Leydig cell tumor without tumor testing available [Golmard et al 2022]. There is no evidence that DICER1 is associated with an increased risk of testicular germ cell tumors [Vasta et al 2020a].

Hamartomatous polyps. Juvenile-like hamartomatous polyps in the small intestine have been described in individuals with DICER1 [González et al 2022]. Generally, these have been identified from birth to age ten years. Polyps can rarely result in intestinal obstruction and surgery may be required. The true prevalence of hamartomatous polyps in individuals with DICER1 remains unknown. Because routine gastrointestinal screening is not currently recommended, it is likely that polyps in some individuals remain undiagnosed.

Additional clinical features

• Macrocephaly has been reported in 42% of individuals with DICER1. Macrocephaly, defined as a head circumference greater than the 97th centile in published reference populations, may be observed in early childhood (age <5 years). Data are lacking on the frequency of congenital macrocephaly in infants with DICER1. There are no published data on brain imaging findings in those with DICER1-related macrocephaly [Khan et al 2017a].
• Retinal abnormalities. In a family-based cohort study, a significant difference in the incidence of retinal abnormalities in individuals with DICER1 (11/103; 11%) was observed when compared to family controls (1/69; 1.4%). Retinal abnormalities included pigmentary abnormalities, epiretinal membranes, drusen, and retinitis pigmentosa [Huryn et al 2019]. To date, there is no evidence to suggest increased risk for visual impairment in those with DICER1-related retinal abnormalities.
• Structural abnormalities of the urinary collecting system or kidney. In a family-based cohort study, 8/89 individuals (9%) with DICER1 had ultrasound-detected structural abnormalities of varying severity within the urinary collecting system or kidney, nephrolithiasis, or nephrocalcinosis; none of the family controls (0/61) had similar findings on ultrasound [Khan et al 2018].
• Dental anomalies. In a family-based cohort study of 57 individuals with DICER1 and 55 family controls, bulbous crown and periodontitis were associated with DICER1 [Choi et al 2019]. There is no evidence to suggest clinically significant impairment of dental function.
• Other
  • Pierre-Robin sequence, left arm and leg shortening, and bilateral hip dysplasia (1 individual) [Venger et al 2023]
  • Macroglossia, developmental delay, bilateral varus forefoot (1 individual) [Venger et al 2023]
  • Two-vessel umbilical cord, undescended testis, inguinal hernia, postaxial polydactyly, ear pits, rocker bottom feet, intellectual disability, dysmorphic features, and autism (1 individual) [Pontén et al 2022]
  • Macrosomia, dysmorphic facial features (prominent forehead, low-set ears, hypertelorism, ptosis), Chiari type I malformation, and developmental delay (1 individual) [Venger et al 2023]

Prognosis. To date, there is no data regarding life expectancy. Apart from cancer-related risk, life expectancy is normal.

Somatic mosaicism for a DICER1 pathogenic variant has been described, including loss-of-function and RNase IIIb missense variants. The presence of biallelic DICER1 somatic pathogenic variants identified in tumor tissue in the absence of a germline pathogenic variant may indicate sporadic tumorigenesis with no increased risk of additional DICER1-related features; however, the possibility of mosaicism should be considered, especially in individuals with multiple manifestations of DICER1. Individuals with a mosaic loss-of-function variant tend to have a similar to less severe phenotype compared to individuals with a germline heterozygous loss-of-function variant, while individuals with a mosaic RNase IIIb missense variant may have more sites of disease [Brenneman et al 2015, de Kock et al 2016].

Initial study of individuals with mosaic RNase IIIb missense variants suggested a specific phenotype termed GLOW syndrome (global developmental delay, lung cysts, overgrowth, Wilms tumor), hypothesized to arise from activation of the PI3K/AKT/mTOR pathway [Klein et al 2014, Klein & Martinez-Agosto 2020]. Further study of individuals with mosaic RNase IIIb missense variants suggest that manifestations extend beyond GLOW syndrome and include other known DICER1-related manifestations [Brenneman et al 2015, de Kock et al 2016]. Overall, individuals with mosaic RNase IIIb missense variants are characterized by more disease foci and earlier onset. Not all individuals exhibit developmental differences. Further research is needed to better understand phenotypes related to RNase IIIb mosaicism. Note: Postzygotic pathogenic RNase IIIb missense variants (e.g., affecting NM_177438.3:p.Asp1709) in older adults without any evidence of GLOW syndrome have been reported [Mirshahi et al 2021, Salvador et al 2025].

Genotype-Phenotype Correlations

A higher number of disease foci and overgrowth have been observed in individuals with mosaicism for DICER1 pathogenic variants in the RNase IIIb domain [Brenneman et al 2015, de Kock et al 2016]. No other genotype-phenotype correlations have been identified.

Penetrance

The penetrance is reduced and age dependent. The risk of cancers associated with DICER1 varies by 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%-9.7%) had developed a neoplasm (females: 4.0%; males: 6.6%). By age 50 years 19.3% (95% CI; 8.4%-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].

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].

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 PPB.

Nodular hyperplasia of the thyroid is commonly called goiter.

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

Prevalence

The prevalence of DICER1 is estimated at one in 6,099 to 8,416 individuals based on exome sequencing of two population cohorts [Kim et al 2024].

Pleuropulmonary Blastoma (PPB)

Cystic lesions of childhood

• Congenital pulmonary airway malformation (CPAM) (previously known as congenital cystic adenomatoid malformation [CCAM]). Type I PPB cannot be reliably distinguished radiographically from benign congenital cystic lung malformations [Oliveira et al 2011, Engwall-Gill et al 2022]. CPAMs are more likely to be identified prenatally, although cystic PPB has been reported prenatally [Messinger et al 2015, Feinberg et al 2016, Catán Valenzuela et al 2023]. Pneumothoraxes and the presence of multifocal or bilateral cysts are more common in PPB than in other conditions. In a study of postnatally diagnosed lung lesions, the incidence of malignant lesions was nearly 10% [Kunisaki et al 2021]. Given the radiographic challenges of distinguishing benign cystic lung lesions from PPB, indeterminate cystic lung lesions should be treated as possibly malignant until pathologically proven otherwise [Priest et al 2009, Oliveira et al 2011].
• Pulmonary sequestrations and peripheral bronchogenic cysts are more complex lesions that are commonly diagnosed prenatally. Both intra- and extralobar sequestration have features of CPAM type II. Bronchogenic cysts are foregut-derived malformations located within the mediastinum or lung, depending on the stage of gestation. Bronchogenic cysts generally present as fluid-filled unilocular cysts [Kosar et al 2009]. Identification of a systemic feeding vessel on CT scan is diagnostic of pulmonary sequestration and effectively rules out type I or Ir PPB. 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-related tumor predisposition (DICER1) [Foulkes et al 2011].
• Lung cysts and pneumothoraxes. Cysts associated with heritable syndromes (see Table 3) including Birt-Hogg-Dubé syndrome, Cowden syndrome (see PTEN Hamartoma Tumor Syndrome), and tuberous sclerosis complex can be distinguished from PPB on the basis of medical history and physical examination. Pulmonary Langerhans cell histiocytosis can have radiologic similarity to PPB and requires tissue diagnosis to differentiate.
• Synovial sarcoma is among the differential diagnoses for PPB in adolescents and young adults. Synovial sarcomas can be pleural based and cystic [Panigrahi et al 2018, Khalili et al 2022]. 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 SS18 (SYT) is helpful for making a diagnosis of synovial sarcoma.

Solid lung tumors of childhood. The morphologic heterogeneity of type II and III PPB – which includes primitive blastemal-like cells, rhabdomyosarcoma with embryonal-like features, spindle cell sarcoma resembling infantile fibrosarcoma, cartilaginous nodules with fetal or sarcomatous morphology, and scattered, bizarre-appearing, anaplastic cells – presents a diagnostic challenge and contributes to the broad differential diagnosis of type II and III PPB. Other thoracic tumors are rare in children younger than age seven years (the age at which PPB most commonly occurs).

• Benign, solid non-PPB tumors presenting in the newborn period include fetal lung interstitial tumor [Dishop et al 2010], congenital peribronchial myofibroblastic tumor, and solid type III CPAM. There are no known genetic associations with these three conditions. To date, solid PPB has been observed only rarely in newborns.
• 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 that resemble PPB.
• Pulmonary blastoma (PB) is a distinct entity from PPB and is primarily an adult tumor, although 10% of PBs have been reported in persons less than age 20 years. PB (encompassing classic biphasic subtype, CBPB) was reclassified as a sarcomatoid carcinoma in the 2021 World Health Organization (WHO) classification. The five-year overall survival rate is 52%, with age, histologic grade, and surgical status as independent prognostic factors [Yang et al 2025].
• 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 [Tanaka et al 2017].

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 percentage 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 to be between 4% and 10% of the population, with higher prevalence associated with advancing age [Unlu et al 2022].
• Familial MNG is suggested by early-onset MNG without iodine deficiency and most frequently described with an autosomal dominant pattern of inheritance [Paschke 2011].
• Familial MNG and MNG associated with other non-thyroid tumors should prompt consideration of familial non-medullary thyroid carcinoma and familial MNG (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 help distinguish 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. Inhibin A, inhibin B, and CA125 have been reported to be elevated in some individuals with juvenile granulosa cell tumor [Harris et al 2025]. Given the association with virilization, preoperative testosterone measurement may be helpful. Tumor markers may or may not be elevated at recurrence even when elevated at diagnosis [Nelson et al 2024a, Harris et al 2025].

Kidney cysts and tumors

• Pediatric cystic nephroma is a benign, well-circumscribed, multiloculated cystic kidney tumor predominantly seen in infants and young children. In this age group, the differential diagnosis of a cystic kidney mass includes segmental multicystic dysplastic kidney, cystic partially differentiated nephroblastoma, and Wilms tumor with cystic change [Wood et al 2015, Chung et al 2016]. These entities may share overlapping imaging features; however, the presence of blastemal elements or solid components favors a nephroblastomatous process over cystic nephroma [van Peer et al 2021].
• Wilms tumor is more commonly non-DICER1-related (see Wilms Tumor Predisposition).
• Birt-Hogg-Dubé syndrome is associated with kidney cysts, oncocytoma, and chromophobe renal cell carcinoma. (Note: Oncocytoma and chromophobe renal cell carcinoma are not known to be associated with DICER1.)
• Multiple kidney cysts may also be seen in von Hippel-Lindau syndrome, autosomal recessive polycystic kidney disease, and autosomal dominant polycystic kidney disease (see Table 4).

Ciliary body medulloepithelioma

• In children, the clinical differential diagnosis may include retinoblastoma, Coats disease, persistent hyperplastic primary vitreous, and juvenile xanthogranuloma [Tadepalli et al 2019].
• In adults, the clinical differential diagnosis may include adenoma or carcinoma of the ciliary epithelium. Metastatic carcinoma to the ciliary body and ciliochoroidal melanoma may also be considered [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 that may cause bleeding in children.
• Adenosarcoma is a polypoid neoplasm of the cervix/uterus with a pattern of benign endocervical glands and a spindle cell sarcomatous stroma without rhabdomyoblastic differentiation. There is histologic overlap with embryonal rhabdomyosarcoma.

Pituitary blastoma

• Clinically, a pituitary mass in a young child should prompt consideration of adenoma, germ cell tumors, Langerhans cell histiocytosis, craniopharyngioma, and much rarer entities including pituitary carcinoma or hamartoma.
• 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. The pineal gland is also a common location for germ cell tumors. Complicated pineal cysts may also occur.
• Other embryonal tumors such as medulloblastoma should be considered if the tumor does not originate from the pineal region.
• Pineoblastomas may also be caused by pathogenic variants in other genes involved in microRNA biogenesis pathways including DROSHA and DGCR8 [Fiorica et al 2025] or may be associated with pathogenic variants in RB1, MYC, or FOXR2 [Li et al 2020].

Hereditary Disorders

Evaluations Following Initial Diagnosis

To establish the presence of DICER1-related features in an individual diagnosed with DICER1, the evaluations summarized in Table 4 and described in the following text (if not performed as part of the evaluation that led to the diagnosis) are recommended. These recommendations are not intended to address tumor staging, evaluation of a known tumor, or ongoing surveillance recommendations.

Treatment of Manifestations

Surveillance

Surveillance guidelines for individuals with a germline DICER1 pathogenic variant have been established by the International PPB/DICER1 Registry, the Host Genome Working Group of the European branch of the International Society of Pediatric Oncology (SIOP-E), and the CanGene-CanVar project [Bakhuizen et al 2021, Schultz et al 2024]. 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 a tumor are detected, additional evaluation will be needed. Table 5 is not intended to address tumor staging, evaluation for a known tumor, or post-tumor surveillance.

Individuals with somatic mosaicism for a loss-of-function variant should follow standard DICER1 surveillance. Individuals with known or suspected mosaicism for an RNase IIIb missense variant should, at a minimum, be offered DICER1 surveillance, although expert consultation and individualized decision making are advised given the early onset of disease and the higher frequency of multisite disease in individuals with a DICER1 pathogenic variant in the RNase IIIb domain.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of first-degree relatives (of all ages) – with cascade testing as indicated (including parents, children, and sibs) – of an individual with DICER1 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 four months) for the family-specific DICER1 pathogenic variant is recommended. Pulmonary screening can then be initiated for those with a known DICER1 pathogenic variant.
• 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/adolescence and young adulthood).

Note: First-degree relatives at risk for a known familial DICER1 pathogenic variant who are unable to or choose not to undergo molecular genetic testing should follow the recommended DICER1 surveillance. Surveillance should be based on the recommendations detailed in Table 5 unless/until genetic testing confirms that they did not inherit the familial pathogenic 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 then, 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 DICER1. If a DICER1 pathogenic variant is not identified, the family member's prior tumor susceptibility risk remains unchanged.

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

Pregnancy Management

To date, studies have not demonstrated pregnancy-specific risks for individuals with DICER1. Management should include symptom-directed surveillance for DICER1-associated conditions. SLCT has been reported during pregnancy in individuals with DICER1; therefore, up-to-date screening prior to conception is recommended. If concerns arise during pregnancy, prompt consultation with specialists in high-risk obstetrics and fetal medicine is indicated to support pregnancy monitoring and delivery planning.

Therapies Under Investigation

The first-ever fully prospective study of PPB, Children's Oncology Group (COG) ARAR2331 (NCT06647953), began enrollment in 2025. COG ARAR2331 seeks to standardize the administration of chemotherapy in individuals diagnosed with type I PPB based on published risk factors. Children less than age five years with type I PPB with positive margins and/or unresectable cysts ≥1 cm in size despite best surgery will receive adjuvant chemotherapy. For type II and III PPB, COG ARAR2331 will test the addition of camptothecins in a window therapy approach. COG ARAR2331 also includes the collection of tumor tissue and serial blood samples for tumor profiling, liquid biopsies, and future correlative biology studies.

Multiple research efforts are under way to refine surveillance guidelines and improve outcomes for children and adults with DICER1. For more information, see 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-related tumor predisposition (DICER1) is inherited in an autosomal dominant manner with reduced, age-related penetrance.

Risk to Family Members

Parents of a proband

• Approximately 85% of individuals diagnosed with DICER1-associated pleuropulmonary blastoma (PPB) are thought to have inherited a DICER1 germline pathogenic variant from a parent who may or may not have PPB or other DICER1-associated findings [Brenneman et al 2015].
• Approximately 15% of individuals with a DICER1-associated PPB have DICER1 as the result of a de novo germline pathogenic variant [Schultz et al 2018]. (Note: Approximately 10% of individuals with a de novo DICER1 pathogenic variant have somatic mosaicism for the variant [Brenneman et al 2015, de Kock et al 2016].)
• If the proband appears to be the only family member with DICER1, molecular genetic testing is still recommended for the parents of the proband to evaluate their genetic status, determine their need for surveillance, and inform reproductive counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant present in the germ (gonadal) cells only.
• Some individuals with a single or multiple DICER1-associated tumors may appear to be the only affected family member because of failure to recognize the disorder in relatives, reduced penetrance, or lack of information about the family. Therefore, de novo occurrence of a DICER1 pathogenic variant cannot be confirmed unless molecular genetic testing has demonstrated that neither parent has the DICER1 pathogenic variant identified in the proband.

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 constitutional germline DICER1 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. If a parent has somatic mosaicism for a DICER1 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is ≤50%.
• Sibs who inherit a DICER1 pathogenic variant are at increased risk for PPB, pulmonary cysts, thyroid gland neoplasia, ovarian tumors, cystic nephroma, and other DICER1-related features. The penetrance of heterozygous germline DICER1 pathogenic variants is reduced, age dependent, and varies by sex (see Penetrance). Many individuals with a germline DICER1 pathogenic variant remain clinically unaffected.
• If the germline pathogenic variant identified 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 possibility of parental gonadal 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 because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism.

Offspring of a proband

• Each child of an individual with a germline constitutional DICER1 pathogenic variant has a 50% chance of inheriting the pathogenic variant.
• Each child of an individual with DICER1 caused by a somatic mosaic pathogenic variant has up to 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, the parent's family members may be at risk for PPB and/or other 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.

Predictive testing for at-risk asymptomatic family members requires prior identification of the germline loss-of-function DICER1 pathogenic variant in the family. Note: As DICER1 screening recommendations begin in infancy, testing at-risk individuals soon after birth is recommended.

Genetic cancer risk assessment and counseling. For a comprehensive description of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see Cancer Genetics Risk Assessment and Counseling – for health professionals (part of PDQ®, National Cancer Institute).

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 and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

DICER1 encodes endoribonuclease Dicer, an RNase III that functions in the microRNA (miRNA) and small interfering (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 Mechanism of disease causation) 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 enzyme expression from the wild-type allele can be upregulated.

DICER1-related tumor predisposition (DICER1)-associated sarcomas in many anatomic locations exhibit morphologic similarities to pleuropulmonary blastoma (PPB) [Warren et al 2020]. Methylation profiling among mesenchymal tumors identified in individuals with DICER1 identified three distinct molecular subclasses termed low-grade mesenchymal tumor with DICER1 alteration (LGMT DICER1), sarcoma with DICER1 alteration (SARC DICER1), and primary intracranial sarcoma with DICER1 alteration (PIS DICER1) [Kommoss et al 2023].

Mechanism of disease causation. DICER1 generally occurs due to a germline loss-of-function pathogenic variant and an acquired somatic pathogenic variant. The acquired somatic pathogenic variant in DICER1-associated tumors is not typically a loss-of-function variant; instead, it affects a hot spot missense variant in the RNase IIIb domain with altered miRNA production. The presence of biallelic loss-of-function DICER1 pathogenic variants is rare among DICER1-related tumors with the exception of pineoblastoma.

Somatic missense pathogenic variants appear to preferentially affect amino acids in the RNase IIIb domain (codons 1705, 1709, 1713, 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].

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

Variants of uncertain significance present a challenge. The ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel (https://clinicalgenome.org/affiliation/50050) has developed individualized germline sequence variant curation guidelines that have helped reduce the number of variants of uncertain significance [Hatton et al 2023]. Variant of uncertain significance status should be revisited intermittently. RNA sequencing, tumor tissue testing, and testing of informative family members can be considered to aid in determining variant pathogenicity.

Author Notes

Websites with additional information about DICER1-related tumor predisposition (DICER1):

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

About the authors' research. The authors represent a multidisciplinary collaborative group that seeks to understand the etiology and best treatments for 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 developing novel diagnostics and therapeutics. The International PPB/DICER1 Registry shares available information with individuals, families, and treating physicians. Together with the registry, Dr Hill identified heterozygous germline DICER1 pathogenic variants as the genetic basis of pleuropulmonary blastoma (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 microRNAs 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 microRNAs important in controlling proliferation and differentiation in development. 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, gynandroblastoma, and juvenile granulosa cell tumor. Interested individuals are encouraged to contact Dr Schultz and the International PPB/DICER1 Registry team (gro.nmsnerdlihc@1RECID) with any questions regarding DICER1-related conditions or for further information regarding participation in DICER1-related research efforts.

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.

Dr Schultz, Dr Stewart, and Ms Hatton are volunteer members of the ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel (VCEP; https://clinicalgenome.org/affiliation/50050/). The NIH-funded ClinGen VCEP has developed and published DICER1-specific variant curation guidelines based on the ACMG/AMP sequence variant interpretation guidelines. The VCEP uses these guidelines to curate and publish variants to ClinVar with 3-star Expert Panel review status and to the ClinGen Evidence Repository. The curation guidelines are periodically reviewed with plans to develop and publish subsequent revisions. For the most recent guidelines, visit the ClinGen criteria specification registry at https://cspec.genome.network/cspec/ui/svi/doc/GN024.

Acknowledgments

The authors thank Dr John R Priest and Gretchen M Williams for their contributions to data collection used in this review. The authors also thank Dr Tom Rosenberg for his expertise and for critically reviewing the central nervous system sections.

This work was supported in part by Children's Minnesota Foundation and the Pine Tree Apple Classic Fund, National Cancer Institute (NCI), and the Intramural Research Program of the NIH.

Author History

Andrew J Bauer, MD (2014-present)
Ann G Carr, MS, CGC; Westat (2014-2026)
Louis P Dehner, MD (2014-present)
Leslie Doros, MD; Children's National Medical Center (2014-2026)
Amanda Field, MPH (2020-present)
Anne K Harris, MPH (2020-present)
Jessica Hatton, MS, CGC (2026-present)
D Ashley Hill, MD (2014-present)
Laryssa A Huryn, MD; National Institutes of Health (2020-2026)
Junne Kamihara, MD, PhD (2020-present)
Melissa A Merideth, MD, MPH (2020-present)
Yoav Messinger, MD (2014-present)
Alexander T Nelson, MD (2026-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

• 25 March 2026 (sw) Comprehensive update posted live
• 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. Available online. Accessed 1-13-22.

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