Presentation: Patient with familial pituitary adenoma

A 24-year-old female presents with amenorrhoea following cessation of the oral contraceptive pill, with headaches, visual problems and grade two galactorrhoea. Her prolactin level is 36,000mU/l. She has a distant cousin with acromegaly who is 196cm tall.

• Genes associated with isolated pituitary adenomas (pituitary neuroendocrine tumours) should be tested if a patient presents with:
  • any pituitary adenoma or insulinoma (under the age of 20);
  • pituitary macroadenoma (under the age of 30); or
  • isolated pituitary adenoma (under the age of 35), with at least one first-degree relative who also has an isolated pituitary adenoma.
• Genomic testing for X-linked acrogigantism should be considered if a patient presents with onset of excess of growth hormone and insulin-like growth factor 1 (IGF-1) levels before the age of five, with increased growth velocity and/or tall stature (height over two standard deviations (2SD) above the mean or over 3SD over mid-parental height).
• Please note that the above guidance differs from the current National Genomic Test Directory eligibility criteria. The relevant panel (R217 Endocrine neoplasia) criteria does not recognise the full breadth of the phenotype nor affected females, and a request for revision of this criteria is underway.
• The current version of the test directory lists the following indications for testing:
  • onset of excess of growth hormone diagnosed by the age of 20 in male patients; and
  • increased growth velocity and/or tall stature (height over 2SD above the mean or over 3SD over mid-parental height).
• If testing on blood samples returns negative results and clinical suspicion of X-linked acrogigantism is strong, please contact the testing laboratory to discuss sending a fresh frozen tissue or skin biopsy sample to identify a mosaic form of the condition.
• Note that syndromic causes of pituitary adenomas could present first with pituitary adenoma (this accounts for 15% of multiple endocrine neoplasia type 1 (MEN1) patients). This combined with de novo variants could mimic isolated pituitary adenoma. Low penetrance may mask family history.

• 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 containing details 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 panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• For patients presenting with isolated young-onset pituitary adenoma, the panel R217.1 Endocrine neoplasia is appropriate.
  • The R217.1 panel contains 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.
  • This panel is also used to investigate other endocrine neoplasia disorders, such as familial isolated pituitary adenoma and MEN1.
• Genomic testing for patients with suspected X-linked acrogigantism (for example, those with duplications of the GPR101 gene) or McCune-Albright syndrome, which would be conducted via R327 Mosaic skin disorders (deep sequencing), should be discussed at a multi-disciplinary team meeting.
• Rarely, young-onset or familial pituitary tumours have been identified in patients with variants in genes not included in R217, such as SDHx and MAX.
• If a genetic diagnosis in a pituitary tumour predisposition gene has been established in another family member, single gene testing for that specific familial variant can be considered. R240 Diagnostic testing for known mutation(s) can be selected if the pathogenic variant report about the close family member is available and testing was performed in an accredited laboratory.
• None of the tests outlined 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 these tests are DNA based, and an EDTA sample (purple-topped tube) is required. The sample is best stored at 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)
• Queen Mary University of London: Familial isolated pituitary adenoma patients