DICER1 Syndrome

DICER1 syndrome is an autosomal dominant disorder caused by germline DICER1 variants, with pleuropulmonary blastoma and a range of rare tumours, notably of the lung, kidney, ovary, thyroid, and brain. Penetrance is low, but early surveillance can detect treatable disease in childhood.

Pathophysiology. DICER1 processes microRNAs. A germline loss-of-function variant plus a somatic hotspot missense variant in the RNase IIIb domain of the second allele disrupts microRNA processing and drives tumours.

Pleuropulmonary blastoma presents under 6 years and progresses from cystic (type I) to solid (type III) disease.

Multinodular goitre and thyroid cancer are common in carriers, and ovarian Sertoli-Leydig cell tumours arise in adolescent girls and young women.

• Pleuropulmonary blastoma: cough, respiratory distress, pneumothorax, a lung cyst
• Cystic nephroma and Wilms tumour
• Ovarian Sertoli-Leydig cell tumour: virilisation or menstrual disturbance
• Multinodular goitre and differentiated thyroid cancer
• Embryonal rhabdomyosarcoma of the cervix or other sites
• Pineoblastoma, pituitary blastoma, ciliary body medulloepithelioma
• Macrocephaly in some, and nasal chondromesenchymal hamartoma

• Genetic testing of DICER1 with deletion and duplication analysis, in children with pleuropulmonary blastoma, cystic nephroma or other characteristic tumours, and in relatives.
• Chest imaging: chest radiograph and chest CT, which differentiate type I from solid disease.
• Abdominal and pelvic ultrasound for kidney and ovary.
• Thyroid ultrasound with fine needle aspiration of suspicious nodules.
• Tumour histology and molecular testing for the RNase IIIb hotspot variant.
• Hormone tests (testosterone, inhibin, AMH) when a Sertoli-Leydig tumour is suspected.

Differential diagnosis.

• Congenital pulmonary airway malformation and other cystic lung lesions
• Pulmonary sequestration and bronchogenic cyst
• Wilms tumour of other cause
• Sporadic ovarian sex cord stromal tumours
• PTEN hamartoma tumour syndrome (thyroid)
• Other cancer predisposition syndromes

• Chest surveillance in childhood: chest radiograph at birth to 8 years every 4 to 6 months, and chest CT at 3 to 6 months of age and again at about 2.5 years, with specialist radiology and minimised radiation dose.
• Abdominal and renal surveillance: abdominal ultrasound every 6 months to 8 years, then yearly to adulthood.
• Ovarian surveillance: pelvic ultrasound every 6 to 12 months from 8 years, with added attention to symptoms.
• Thyroid surveillance: ultrasound from about 8 to 10 years every 1 to 3 years.
• Pleuropulmonary blastoma: type I is treated by lobectomy, with adjuvant chemotherapy depending on pathology. Types II and III need complete resection and intensive chemotherapy (such as ifosfamide, vincristine, actinomycin D and doxorubicin), dosed by body surface area in a paediatric oncology unit.
• Cystic nephroma: nephrectomy or partial nephrectomy, with chemotherapy for anaplastic or sarcomatous change.
• Sertoli-Leydig cell tumour: unilateral oophorectomy with fertility preservation when possible, and chemotherapy for advanced stages.
• Thyroid disease: thyroidectomy for cancer and for goitre needing surgery, with levothyroxine replacement (1.6 microgram/kg daily in adults).
• Genetic counselling: 50% chance of the variant for each child, with reduced penetrance.

Special groups.

• Children with a cystic lung lesion on prenatal scan: genetic testing and early imaging are justified.

Monitoring. Chest radiograph every 4 to 6 months to 8 years, abdominal ultrasound every 6 months to 8 years, and yearly clinical review. Adjust the schedule as children grow.

Referral and escalation. Refer to clinical genetics and paediatric oncology. Urgent for respiratory symptoms with a lung cyst, a spontaneous pneumothorax in a young child, or virilisation.