Presentation: Patient with endocrine neoplasia

A 17-year-old man presents complaining of sweating, confusion and disorientation, which is worse in the morning or after exercise but is relieved by eating. A supervised fast confirms hyperinsulinaemic hypoglycaemia, and an endoscopic ultrasound reveals a 1.5cm hypervascular nodule in the tail of the pancreas. Cytology from a biopsy confirms a grade-one well-differentiated neuroendocrine tumour. There is a significant family history of hyperparathyroidism, as well as a macroprolactinoma in the patient’s 20-year-old sister.

Consider genomic testing in an individual (proband) affected by endocrine anomalies, with or without a family history, if the individual meets one of the criteria listed below.

• Proband presenting with multiple endocrine neoplasia type 1 (MEN1), including:
  • parathyroid multiglandular disease (hyperplasia or adenomas) before 35 years of age;
  • any pituitary adenoma or insulinoma before 20 years of age;
  • pituitary macroadenoma before 30 years of age;
  • more than two MEN1-related endocrine anomalies at any age;
  • more than one MEN1-related endocrine anomaly and more than one MEN1-related non-endocrine tumour at any age; or
  • more than one MEN1-related endocrine anomaly and a first-degree relative with more than one MEN1-related endocrine anomaly.
• Proband presenting with a pancreatic neuroendocrine tumour as well as clinical features and/or a family history of Von Hippel-Lindau (VHL) syndrome:
  • retinal angioma and spinal or endolymphatic sac tumour before 40 years of age;
  • cerebellar haemangioblastoma before 60 years of age;
  • more than two VHL-related tumours at any age; or
  • more than one VHL-related tumour and a first-degree relative with more than one VHL-related tumour, where one of the tumours is retinal angioma or haemangioblastoma.
• To find out more about the endocrine anomalies found in MEN1 and Von Hippel-Lindau syndrome, see Endocrine neoplasia.

• 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 those working within NHS Wales, please consult the All Wales Medical Genomics Service website for information on how to arrange testing.
• To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels resource.
• For patients who meet the test directory eligibility criteria for endocrine neoplasia (that is, the presence of clinical features pointing to a wider multiple endocrine neoplasia syndrome, such as hypercalcaemia, neuroendocrine tumours, pituitary tumours or VHL) and do not have a personal or family history of a genetic variant in a specific endocrine neoplasia gene, select the panels outlined below.
  • R217 Endocrine neoplasia and R218 Multiple endocrine neoplasia type 2.
    • R217 currently comprises the following genes: AIP, CDC73, CDKN1B, MEN1, PRKAR1A, RET and VHL. It involves small gene panel sequencing and multiplex ligation-dependent probe amplification (MLPA) or equivalent.
    • R218 is a single gene test involving the RET gene.
  • Overlapping clinical indications are listed below.
    • R226 Inherited parathyroid cancer. This includes CDC73 single gene testing, and should be requested for patients with parathyroid carcinoma.
    • R225 Von Hippel Lindau syndrome. This includes VHL single gene testing and MLPA or equivalent.
    • R218 Multiple endocrine neoplasia type 2. This includes RET single gene testing, and should be requested for patients with medullary thyroid carcinoma.
    • R223 Inherited phaeochromocytoma and paraganglioma excluding NF1. Tests within this clinical indication should be used for patients with phaeochromocytoma and paraganglioma. The genes included in this panel are DLST, FH, MAX, MDH2, MEN1, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, SLC25A11, TMEM127 and VHL. It involves small panel sequencing and MLPA or equivalent.
    • R156 Carney complex. This includes PRKAR1A single gene testing and should be requested for patients with syndromic features.
• For patients presenting with endocrine neoplasia where a genetic diagnosis in a relevant predisposition gene has been established in another family member, single gene testing for that specific variant should be considered. For example, R240 Diagnostic testing for known mutation(s) could be selected if the pathogenic variant report about a close family member is available and testing was performed in an accredited laboratory.
• None of the tests listed above include whole genome sequencing, so you should use your local Genomic Laboratory Hub test order and consent (record of discussion) forms.
• The majority of tests are DNA based, and an EDTA sample (purple-topped tube) is required. The sample is best stored at a temperature of four degrees Celsius until it can be posted to the genomic laboratory.
• 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

• NHS England: National Genomic Test Directory

For patients

• Association for Multiple Endocrine Neoplasia (AMEND)
• Neuroendocrine Cancer UK
• Parathyroid UK
• Queen Mary University of London: Familial isolated pituitary adenoma (FIPA)
• The Pituitary Foundation