Presentation: Clinical suspicion of PTEN hamartoma tumour syndrome

A family attends clinic concerned because their five-year-old daughter’s development is delayed and she is displaying some autistic traits. On examination, you note that her head circumference is above the 99th centile. Family history reveals that the mother had follicular thyroid cancer, and you note that she also has macrocephaly and multiple facial papules.

Consider testing for PTEN-HTS when a child presents with macrocephaly (usually over two standard deviations (2SD) above the mean) along with neurodevelopmental difficulties and/or mucocutaneous features.

PTEN-HTS-related mucocutaneous lesions comprise:

• cutaneous facial papules, including trichilemmomas;
• oral mucosal papillomatosis;
• acral (dorsal) keratoses; and/or
• palmoplantar keratoses.

As many of the features develop over time, younger children may not quite meet the eligibility criteria given below. If this is the case and your clinical suspicion remains high (and/or you are not listed as a requesting specialty), you will need to discuss testing with your local clinical genetics service or specialist cancer multidisciplinary team.

Testing criteria are based on clinical features in the proband as well as the wider history. Testing may be considered for living affected individuals (proband) where the individual with or without a family history meets one of the following criteria:

• macrocephaly and mucocutaneous lesions comprising one of the following:
  • ≥6 facial papules, of which ≥3 are trichilemmoma;
  • cutaneous facial papules and oral mucosal papillomatosis;
  • oral mucosal papillomatosis and acral keratosis; or
  • ≥6 palmoplantar keratosis;
• macrocephaly and one or more from Major criteria (see list below);
• macrocephaly and three or more from Minor criteria (see list below);
• cerebellar dysplastic gangliocytoma (adult Lhermitte-Duclos disease); or
• a Cleveland Clinic PTEN score with probability of finding PTEN variant at 10% or higher.

Major criteria

• Breast cancer
• Epithelial thyroid cancer (non-medullary)
• Macrocephaly (occipital frontal circumference ≥97th percentile)
• Endometrial carcinoma

Minor criteria

• Other thyroid lesions (such as adenoma or multinodular goitre)
• Intellectual disability (IQ ≤75)
• Hamartomatous intestinal polyps
• Fibrocystic disease of the breast
• Lipomas
• Fibromas
• Genitourinary tumours (especially renal cell carcinoma)
• Genitourinary malformation
• Uterine fibroids
• Oesophageal glycogenic acanthosis

For a wider guide to approaching genomic testing in a child with macrocephaly, see Presentation: Child with macrocephaly.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see Genomic testing in the devolved nations.
• For information about the genes that are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• Decide which of the panels best suits the needs of your patient or family.
  • If you have a strong clinical suspicion of PTEN-HTS, check the patient’s eligibility for:
    • R213 PTEN hamartoma tumour syndrome: This is a targeted test which uses single gene sequencing.
  • If your differential is wider and the child has a developmental condition, consider:
    • R27 Paediatric disorders: This should be considered if there is at least moderate developmental delay or intellectual disability in association with congenital malformation or overgrowth, and you would like to investigate chromosomal and single-gene causes. R27 is an amalgamation of over 10 panels of genes known to be associated with a broad range of paediatric developmental disorders. It may now be ordered directly by paediatricians, though a discussion with clinical genetics services may be beneficial.
• For tests that are undertaken using WGS, such as R27, you will need to:
  • complete an NHS GMS test order form with details of the affected individual (proband) and their parents where available, including details of the phenotype (using human phenotype ontology (HPO) terms) and the appropriate panel name(s) with associated R number (see How to complete a test order form for WGS for support in completing WGS-specific forms);
  • complete an NHS GMS record of discussion (RoD) form for each person being tested – for example, if you are undertaking trio testing of an affected individual and their parents, you will need three RoD forms (see How to complete a RoD form for support); and
  • submit parental samples alongside the child’s sample to aid interpretation, especially for the larger WGS panels (where this is not possible, for example because the child is in care or the parents are unavailable for testing, the child may be submitted as a singleton).
• For tests that do not include WGS, such as R213:
  • you can use your local Genomic Laboratory Hub (GLH) test order and consent (record of discussion) forms; and
  • parental samples may be needed for interpretation of the child’s result. Parental samples can be taken alongside that of the child, and their DNA stored, or can be requested at a later date if needed.
• Most tests are DNA based, and an EDTA sample (typically a purple-topped tube) is required. There are a few tests for which a different type of tube is used; see Samples for genomic testing in rare disease.
• If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.
• 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: PTEN hamartoma tumor syndrome
• Genetic and Rare Diseases Information Center: PTEN hamartoma tumor syndrome
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory

For patients

• PTEN UK & Ireland
• The PTEN Foundation