DICER1 Syndrome – Definition
DICER1 syndrome (OMIM *606241, #601200) is based on germline mutations in the DICER1 gene and is a cancer predisposition syndrome that predisposes to pleuropulmonary blastoma (PPB), ovarian germline tumours, cystic nephroma, thyroid tumours and numerous other benign and malignant neoplasms.
Synonyms:
DICER1-Pleuropulmonary blastoma familial tumor predisposition syndrome, DICER1-Related Disorders
Gene:
DICER1
Gene product:
Endoribonuclease DICER1
Function:
Cleavage of precursor double-stranded microRNA into mature microRNA
Pattern of inheritance:
Autosomal dominant, de novo mutation 20%
Prevalence:
For carrying a pathogenic or probably pathogenic alteration about 1:2500-1:10,000 in the total population
Genotype-
phenotype correlation:
Mosaic Missense mutations in the RNase IIIb domain of DICER1 cause the GLOW syndrome (Global developmental delay, Lung cysts, Overgrowth, and Wilms tumor)
Penetrance:
Incomplete; while in one family rarely more than one person is diagnosed with PPB, penetrance is higher in other diseases (e.g. nodular thyroid hyperplasia, benign lung cysts).
DICER1 Syndrome – Diagnosis
Diagnostics
Genetic counseling and testing for the presence of DICER1 syndrome should be offered if the following tumors occur:
- Pleuropulmonary Blastoma (PPB)
- Ovarian sex-cord stromal tumors (Sertoli-Leydig cell tumor, juvenile granulosa cell tumor, gynandroblastoma)
- Cystic nephroma
- Neoplasms of the thyroid gland, including multinodular goiter, adenomas, and differentiated thyroid carcinoma
- Ciliary body medulloepithelioma (CBME)
- Embryonal rhabdomyosarcoma (ERMS) of the cervix (Sarcoma botryoides)
- Nasal chondromesenchymal hamartoma (NCMH)
- Pituitary blastoma
- Pineoblastoma
Genetic Diagnostics
To confirm the diagnosis, the detection of a heterozygous pathogenic germline variant in the DICER1 gene is necessary. If the sequence analysis used for this purpose does not show a pathogenic variant, a deletion/duplication analysis should then be performed.
Differential Diagnoses
- PPB: Cystic adenomatoid lung malformation, pulmonary sequestration, bronchogenic cysts, Birt-Hogg-Dubé syndrome, Marfan syndrome, tuberous sclerosis, cystic fibrosis, Ehlers-Danlos syndrome, alpha-1-antitrypsin deficiency, solid lung tumors, synovial sarcoma, rhabdomyosarcoma, Ewing sarcoma, pulmonary blastoma, inflammatory myofibroblastic tumor
- Ovarian sex-cord stromal tumors: small cell ovarian carcinoma of hypercalcemic type, immature teratoma, yolk sac tumor, adult granulosa cell tumor
- Cystic nephroma: cystic kidney tumors, mixed epithelial-stromal tumor of the kidney, isolated kidney cysts, Von-Hippel-Lindau syndrome, autosomal-recessive polycystic kidney disease, autosomal-dominant polycystic kidney disease
- Struma multinodosa: familial non-medullary thyroid carcinoma, papillary thyroid carcinoma, familial struma multinodosa, PTEN hamartoma tumor syndrome, Pendred syndrome, fibrous dysplasia
- CBME: Children: Retinoblastoma, Ciliary Body Cyst, Leiomyoma, Xanthogranuloma
Adults: adenoma or adenocarcinoma of ciliary epithelium, mesoectodermal leiomyoma, neurilemmoma, metastatic carcinoma, granuloma - ERMS: Benign cervical polyp, granulation tissue polyp, squamous epithelial papilloma, Müller papilloma, Müller adenosarcoma
- NCMH: embryonic rhabdomyosarcoma, aneurysmatic bone cyst, fibrous dysplasia
- Pituitary blastoma: pituitary adenoma, hyperplasia, carcinoma, hamartoma, teratoma
- Pineoblastoma: pineocytoma, pineal parenchymal tumor of intermediate differentiation, germ cell tumors, medulloblastoma
Clinical Presentation
| Disease | Affected patients (average age at first diagnosis) |
|---|---|
Pleuropulmonary blastoma
|
Varies – depending on type:
|
Germline tumors of the ovary
|
Varies – depending on type:
|
| Cystic nephroma | 0-48 months |
| Multinodular goiter | 5-40 years (10-20 years) |
| Medulloepithelioma of the ciliary body | 3-10 years |
| Embryonal rhabdomyosarcoma of the cervix | 4-45 years (10-20 years) |
| Nasal chondromesenchymal hamartoma | 6-18 years |
| Pituitary blastoma | 0-24 months |
| Pineoblastoma | 2-25 years |
Other diseases described in connection with sex-cord stromal variants in the DICER1 gene: Differentiated thyroid carcinoma (5-40 years (10-20 years)), Wilms tumor (3-13 years), juvenile hamartomatous intestinal polyps (0-4 years), anaplastic sarcoma of the kidney (2-20 years), medulloblastoma, embryonal rhabdomyosarcoma of the bladder (<5 years), embryonal rhabdomyosarcoma of the ovary, neuroblastoma (<5 years), congenital phthisis bulbi (birth), primitive neuroectodermal tumor of the cervix.
Special Features of Treatment
The treatment of DICER1 syndrome must always be based on the tumor disease present in the patient. This often consists of initial surgical treatment followed by radio and/or chemotherapy. Resistance to therapy or increased cytotoxicity is not known.
Diagnosis of DICER1 Syndrome- What's Next?
Once diagnosed, it is recommended that the patient be managed by a cancer predisposition specialist. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. There is also some additional information at the end of this page, including links to support groups.
Diagnosis of DICER1 Syndrome - What's next?
Once diagnosed, it is recommended that the patient be managed by a cancer predisposition specialist. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. There is also some additional information at the end of this page, including links to support groups.
Recommendations for Early Detection in Your Patients
The recommendations below were adapted by the American Association of Cancer Research (AACR) in 2024.
Pleuropulmonary Blastoma
- Clinical examination: shortness of breath, chest pain, fever, weight loss?
- Chest x-ray every 6 months from birth to age 8, then annually until age 12
- Consider low-dose lung CT at the age of 3 months. If the first lung CT is normal, a repeat scan at 2.5 years of age may be considered.
- If DICER1 is diagnosed after the age of 12, baseline lung imaging may be considered.
Tumors of the Thyroid Gland
- Annual clinical examination from 8 years of age
- Thyroid sonography:
- From the age of 8 years; if the findings are normal, the ultrasound examination should be repeated after 3 years
- For new asymmetries and/or thyroid nodules
- Consider annual ultrasound every 5 years after completion of chemotherapy or radiotherapy
- Functional tests for clinical indications of hypo- or hyperthyroidism
- Benign thyroid nodules are common and most DICER1-associated thyroid cancers are indolent with a low incidence of extrathyroidal metastases
- Thyroblastoma or poorly differentiated thyroid cancer should be considered in the presence of a rapidly growing mass or other worrying clinical features.
Cystic Nephroma
- Clinical examination: abdominal pain, swelling, haematuria?
- Abdominal ultrasound every 6 months from birth or diagnosis until 8 years of age, then annually until 12 years of age
- Baseline ultrasound at diagnosis after 12 years
Germline Stromal Tumors
- Clinical examination: Pubertas praecox, amenorrhea, signs of virilization, abdominal or pelvic space requirements?
- If abnormal, appropriate imaging or laboratory chemistry (AFP, β-HCG, LDH, inhibin A and B, oestradiol, testosterone, CA125, serum electrolytes including calcium).
- Pelvic ultrasound every 6 months from birth or diagnosis until at least age 40, transabdominal in children and adolescents, transvaginal in adults
Embryonal Rhabdomyosarcoma of the Cervix (Sarcoma Botryoides)
- Clinical examination: hematuria, abnormal vaginal bleeding?
- Cystoscopy or examination of the cervix in case of abnormalities
Medulloepithelioma of the ciliary body
- Educate patients and parents about clinical signs: Abnormalities of the eye or orbit? Visual impairment?
- Visual acuity test and dilated eye exam yearly at 3-10 years of age
Nasal chondromesenchymal hamartoma
- ENT examination for symptoms: breathing or eating difficulties, rhinorrhoea, epistaxis, visual disturbances, otitis media
- Nasal endoscopy for ophthalmological signs (e.g. ophthalmoplegia, ptosis, hypotropia, enophthalmos) of orbital involvement
Pituitary blastoma, pineoblastoma, primary intracranial sarcoma and rare tumours
- Clinic: neurological abnormalities, Cushing’s syndrome, diabetes insipidus?
- Cranial MRI if clinical symptoms suggesting intracranial pressure occur (headache, tense fontanel, vomiting, lethargy) or other neurological abnormalities including gaze palsy, visual disturbances or nystagmus
- Cranial MRI for signs of excess cortisol
