DICER1 syndrome: an inherited tumour predisposition explained

The DICER1 gene carries instructions for an enzyme involved in regulating other genes through small molecules called microRNAs. A published review explains that DICER1 syndrome was first described in 2009, when it was linked to a familial form of pleuropulmonary blastoma, a rare lung cancer of childhood, and that it is the first cancer predisposition syndrome linked to a defect in microRNA processing.

In DICER1 syndrome a person is born with one altered copy of the gene in every cell. That alone is not usually enough to cause a tumour. The review says DICER1-related tumours are characterised by a second, acquired change in the other copy of the gene, within the tumour itself, which is why most carriers never develop a tumour. The condition is therefore described as a predisposition, meaning a raised chance, not a certainty.

It can affect many organs, usually at a young age. Tumours associated with DICER1 syndrome are rare in the general population, which is why the syndrome is sometimes recognised only after a child or young adult develops one of them.

The review lists the most common tumour manifestations as pleuropulmonary blastoma, Sertoli-Leydig cell tumour of the ovary, cystic nephroma of the kidney and cervical embryonal rhabdomyosarcoma. Non-neoplastic features include benign cystic lung lesions, thyroid follicular nodular disease, global developmental delay and macrocephaly, with less commonly seen retinal changes and kidney and urinary tract anomalies. It also lists, as moderate-frequency or rarer findings, differentiated thyroid carcinoma, pituitary blastoma, pineoblastoma, Wilms tumour and juvenile hamartomatous intestinal polyps.

Different problems appear at different ages. The review notes that pleuropulmonary blastoma peaks at around 8 months of age, whereas thyroid follicular nodular disease peaks between 10 and 20 years. It adds that subclinical disease is not uncommon: small lung and kidney cysts and tiny thyroid nodules can easily remain undetected, and that in one study 87% of asymptomatic DICER1-mutated patients had thyroid nodules on ultrasound and 43% had lung cysts on CT.

A case series from a UK centre, published in 2024, describes children who presented with a thyroid cancer, a pineoblastoma, a pleuropulmonary blastoma and a urethral rhabdomyosarcoma, and a child identified through sibling testing. The authors conclude that DICER1 is a heterogeneous condition and that two of the children presented with characteristic tumours before the ages at which routine screening is recommended to start.

Early reports of DICER1 families focused on those with many tumours, which made the condition appear more dangerous than it is for most carriers. The review reports a more balanced picture: by age 10, 5.3% of non-proband carriers (relatives found through testing, not the first person in a family to be diagnosed) had developed a neoplasm, rising to 19.3% by age 50. It also reports a sex difference, with females having a 50% lifetime chance of showing no neoplasm formation and males 80%, because of thyroid, cervical and ovarian manifestations.

These figures are averages from published series and vary between studies and families, so they should not be read as a personal prediction. What they show is that most carriers do not develop a cancer, that risk is concentrated in childhood and young adulthood for some tumour types, and that surveillance is designed to find problems early, when they are most treatable.

DICER1 syndrome is inherited in an autosomal pattern. A person with a pathogenic DICER1 variant has a 50% chance of passing it to each child. The review reports that about 87% of people with the syndrome inherited the variant from a parent, while 13% had a new variant that arose for the first time in them, so a family history is often, though not always, present. It also notes that the geographical distribution shows no evidence of higher prevalence in any region and that the syndrome is not known to affect a specific ethnic group.

Because the penetrance is incomplete, a parent who carries the variant may never have had a tumour and may only discover it when a child is diagnosed. The Glasgow case series authors say there is a need for cascade testing of family members, meaning offering testing to relatives in turn, alongside regular screening for tumour development in affected children.

Genetic counselling is the usual starting point. A genetics team can explain what a result means for you, your children and other relatives, and the pros and cons of testing a child before they can decide for themselves.

Genomics England PanelApp, which supports the NHS Genomic Medicine Service, lists a DICER1-related cancer predisposition panel used for the clinical indication R364 in the service. It notes that the testing criteria are in the national genomic test directory and that queries should be directed to your regional Genomic Laboratory Hub. In practice, a GP or specialist refers to a clinical genetics service, which decides whether you meet the criteria, for example a personal or family history of the characteristic tumours.

The review explains that the diagnosis is established when a heterozygous germline loss-of-function variant is found by sequence analysis, which detects more than 90% of pathogenic variants, and that when no variant is found by sequencing, deletion and duplication analysis are the next step. A test result may also come back showing a variant of uncertain significance, which the genetics team will explain.

There is no way to prevent the gene change, so management centres on surveillance and prompt treatment of any tumour found. The review summarises a European surveillance protocol, produced by a European paediatric oncology working group together with a clinical guideline working group, as an annual clinical examination from birth to 20 years with thyroid surveillance, a six-monthly chest X-ray from birth until 8 years, a renal ultrasound from birth to 6 years and a thyroid ultrasound every 3 years from 8 to 40 years. It also describes newer US guidance advising six-monthly pelvic ultrasound in girls from birth, because 15% of ovarian tumours in carriers were diagnosed before age 8.

Protocols are updated as evidence grows, and services may differ in details, so follow the schedule from your own genetics or paediatric oncology team. The same review notes that an information leaflet was produced to raise awareness of possible signs and symptoms of DICER1-associated tumours, which is useful for families and clinicians.

Treatment depends on the tumour found, and is delivered by the relevant specialist team, for example surgery for thyroid nodules or cancers, and paediatric oncology for childhood tumours. Management of lung cysts and kidney lesions follows the same principles.

Receiving a result can be unsettling, particularly for parents. It helps to remember that most carriers remain well, and that the purpose of surveillance is to turn an uncertain risk into a managed one. Ask your genetics team for a named contact and a written plan.

Seek prompt medical advice for persistent cough, breathlessness or chest pain, a neck lump, abdominal swelling or pain, blood in the urine, unexplained pain or abnormal bleeding or a pelvic mass, as in any family with a tumour predisposition. Call 999 for severe breathlessness or sudden collapse. Support for rare genetic conditions is available through genetic counselling services and through general cancer and rare disease charities.