Presentation: Patient with multiple benign skin tumours with a suspected genetic cause

A middle-aged male presents to the clinic concerned about his risk of cancer development, reporting that his sister was recently diagnosed with renal cell carcinoma. On examination, you notice multiple small, skin-coloured papules on his nose, cheeks and chest.

• Three or more benign skin tumours suggestive of any of the following conditions, with at least two histologically confirmed, should prompt genomic testing:

1. 1. Birt-Hogg-Dubé syndrome;
   2. familial cylindromatosis, or subtypes Brooke-Spiegler syndrome or multiple familial trichoepithelioma (CYLD cutaneous syndrome);
   3. Muir-Torre syndrome; or
   4. Buschke-Ollendorff syndrome (one skin biopsy may be sufficient to make a diagnosis of this particular condition).

• If one of these conditions is suspected, genomic testing is important due to the associated risk of cancer development. Specific surveillance and/or management may be required. All four conditions are covered in the panel test R230 Multiple monogenic benign skin tumours.
• The following conditions may also present with multiple benign skin tumours and, if suspected, will require specific tests where available:

1. 5. Gorlin syndrome (also known as naevoid basal cell carcinoma syndrome)
   6. PTEN syndrome;
   7. Gardner syndrome (a subtype of familial adenomatous polyposis);
   8. tuberous sclerosis complex types 1 and 2;
   9. hereditary leiomyomatosis and renal cell carcinoma syndrome; and
   10. Bazex-Dupré-Christol syndrome.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria, which provides information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.
• To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• Decide which of the tests best suits the needs of your patient and/or family.
• If a patient develops three or more benign skin tumours aligning with conditions 1–4 listed above, the correct test to order is:
  • R230.1 Multiple monogenic benign skin tumours: this includes gene panel sequencing for CYLD, FLCN, LEMD3, MLH1, MSH2 and PDGFRB; and/or
  • R230.2 Birt-Hogg-Dubé syndrome: this includes multiplex ligation-dependent probe amplification (MLPA) for FLCN.
• For conditions 5–10 listed above, specific gene tests or small panels are available.

1. 5. For naevoid basal cell carcinoma syndrome, the clinical indication is R214 Nevoid basal cell carcinoma syndrome or Gorlin syndrome: this is a small gene panel test of PTCH1 and SUFU.
   6. For PTEN hamartoma tumour syndrome, the clinical indication is R213 PTEN hamartoma tumour syndrome: this involves single gene sequencing of PTEN.
   7. For Gardner syndrome, the clinical indication is R414 APC-associated polyposis: this involves single gene sequencing of APC.
   8. For tuberous sclerosis complex, the clinical indication is R228 Tuberous sclerosis: this is a small gene panel test of TSC1 and TSC2.
   9. For hereditary leiomyomatosis and renal cell carcinoma syndrome, the clinical indication is R365 Fumarate hydratase-related tumour syndromes: this involves single gene sequencing of FH.
   10. Bazex-Dupré-Christol syndrome is not currently included in the test directory, so there are no genomic tests available.

• Because none of the tests listed above include whole genome sequencing, you can use your local Genomic Laboratory Hub test order and consent (record of discussion) forms. Parental samples may be needed for interpretation of a child’s result; these can be taken alongside that of the child, and their DNA stored, or can be requested at a later date if needed.
• The majority of tests are DNA-based, and an EDTA sample (typically a purple-topped tube) is required. Exceptions include karyotype testing and DNA repair defect testing (for chromosome breakage), which require lithium heparin (typically a green-topped tube).
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• GeneReviews: Birt-Hogg-Dubé Syndrome
• GeneReviews: CYLD Cutaneous Syndrome

References:

• Horton A, Fostier W, Winship I and others. ‘Facial features of hereditary cancer predisposition‘. Journal of Clinical Oncology 2024: volume 20, issue 9, pages 1,182–1,197. DOI: 10.1200/OP.23.00610

For patients

• British Association of Dermatologists: Birt-Hogg-Dubé syndrome
• British Association of Dermatologists: CYLD cutaneous syndrome