Definition

DICER1 syndrome (OMIM *606241, #601200) is based on germline mutations in the DICER1 gene and is a cancer predisposition syndrome predisposing to pleuropulmonary blastoma (PPB), ovarian sex-cord stromal tumors, cystic nephroma, thyroid tumors and numerous other benign and malignant neoplasias.

Key Data

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Synonyms DICER1-Pleuropulmonary blastoma familial tumor predisposition syndrome, DICER1-Related Disorders
Gene DICER1
Gene product Endoribonuclease DICER1
Function Cleavage of precursor double strand microRNA into mature microRNA
Heredity Autosomal dominant, new mutations 20%
Prevalence For carrying a pathogenic or probable pathogenic change about 1:2500-1:10,000 in the total population
Genotype-
phenotype correlation		 Mosaic Missens 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).
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Diagnosis

Diagnostics

Genetic counselling 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, teratom

  • Pineoblastoma: pineocytoma, pineal parenchymal tumor of intermediate differentiation, germ cell tumors, medulloblastoma

Clinical Presentation

Disease Affected (average age at first diagnosis)
Pleuropulmonary Blastoma

  • Type I PPB (cystic)
  • Type II PPB (cystic/solid)
  • Type III PPB (solid)
  • Type Ir PPB (cystic)
 Different – depending on the type:

  • 0-24 months (8 months)
  • 12-60 months (31 months)
  • 18-72 months (44 months)
  • Every age
Ovarian sex-cord stromal tumors

  • Sertoli-Leydig cell tumor
  • Juvenile granulosa cell tumor
  • Gynandroblastoma
 Different – depending on the type:

  • 2-45 years (10-25 years)
  • very young girls or >10 years
  • rarely adolescents, mostly adults
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.

Therapeutic Considerations

The treatment of DICER1 syndrome must always be based on the tumor disease present in the patient. This often consists of an initial surgical therapy followed by radio- and/or chemotherapy. Therapy resistances or increased cytotoxicity are not known.

Surveillance Recommendations

Surveillance Recommendations

A standardised approach for early detection of cancer in DICER1 mutations is not yet available, but the International PPB Registry recommends

  • Annual clinical examination

  • Diagnostic imaging or laboratory chemistry 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 the age of 2.5 to 3 years.

  • 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 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

  • 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 mutation is detected at age >12 years, consider sonography abdomen as baseline diagnosis

Sex-cord Stromal Tumors

  • Clinical examination: Pubertas praecox, amenorrhea, signs of virilisation, 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?

  • Bladder endoscopy or examination of the cervix in case of abnormalities

Ciliary Body Medulloepithelioma

  • Clinical examination: abnormalities in 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 at signs of cortisol excess

Pineoblastoma

  • Clinical examination: neurological abnormalities, Cushing’s syndrome, diabetes insipidus?

  • Cranial MRI when symptoms indicate intracranial pressure (headache, tense fontanel, vomiting, lethargy) or other neurological abnormalities, including paresis, impaired vision or nystagmus