DICER1 Syndrome – Definition
Das DICER1-Syndrom (OMIM *606241, #601200) beruht auf Keimbahnmutationen im DICER1-Gen und ist ein Krebsprädispositionssyndrom, welches für Pleuropulmonales Blastom (PPB), Keimstrangtumoren des Ovars, zystisches Nephrom, Tumoren der Schilddrüse und zahlreiche weitere benigne sowie maligne Neoplasien prädisponiert.
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.
Diagnose DICER1 Syndrome. Wie geht es weiter?
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
A standardized procedure for the early detection of cancers with DICER1 mutations is not yet available, but the International PPB Registry recommends
- Annual clinical examination
- Imaging and laboratory diagnostics depending on the type of tumor, patient age, and clinical findings
Pleuropulmonary Blastoma
- Clinical examination: shortness of breath, chest pain, fever, weight loss?
- X-ray thorax every 4-6 months (0-8 years), then annually (8-12 years)
- CT thorax initial between 3 and 6 months. If the findings are inconspicuous, the next CT thorax should be performed at 2.5 to 3 years old.
- If the mutation is detected at age >12 years, consider X-ray thorax or CT thorax as baseline diagnosis
Tumors of the Thyroid Gland
- Sonography of thyroid gland:
- From 8 years; in case of inconspicuous findings, renewed sonography after 3 years
In case of new asymmetries and/or nodes of the thyroid gland
After chemotherapy or before starting chemotherapy
- From 8 years; in case of inconspicuous findings, renewed sonography after 3 years
- Functional tests for clinical signs of hypo- or hyperthyroidism
Cystic Nephroma
- Clinical examination: abdominal pain, swelling, haematuria?
- Sonography abdomen every 6 months (0-8 years), then annually (8-12 years)
- If a mutation is detected at age >12 years, consider sonography abdomen as baseline diagnosis
Germline Stromal Tumors
- Clinical examination: Pubertas praecox, amenorrhea, signs of virilization, abdominal or pelvic space requirements?
- If abnormal findings are found, appropriate imaging or laboratory chemical diagnostics (AFP, β-HCG, LDH, inhibin A and B, estradiol, testosterone, CA125, serum electrolytes incl. calcium)
- Pelvic and abdominal ultrasound every 6-12 months from 8-10 years to at least 40 years of age
Embryonal Rhabdomyosarcoma of the Cervix (Sarcoma Botryoides)
- Clinical examination: hematuria, abnormal vaginal bleeding?
- Cystoscopy or examination of the cervix in case of abnormalities
Ciliary Body Medulloepithelioma
- Clinical examination: abnormalities in the eye or orbit?
- Ophthalmological examination annually from about 3 years of age and at least until the age of 10, including measurement of visual acuity
Nasal Chondromesenchymal Hamartoma
- Clinical examination from infancy to adulthood: respiratory or eating disorders, rhinorrhoea, epistaxis, visual disorders, otitis media?
- Nasal endoscopy for ophthalmological signs (e.g., ophthalmoplegia, ptosis, hypotrophy, enophthalmos) of orbital involvement
Pituitary Blastoma
- Cranial MRI for signs of excess cortisol
Pineoblastoma
- Clinical examination: neurological abnormalities, Cushing’s syndrome, diabetes insipidus?
- Cranial MRI if symptoms suggestive of intracranial pressure occur (headache, tense fontanel, vomiting, lethargy) or other neurological abnormalities, including gaze palsy, visual disturbances, or nystagmus
