Genetic testing for endocrine neoplasia (R217)

Background information

Multiple endocrine neoplasia (MEN) describes a dominant familial predisposition to tumours of endocrine organs.

The most common endocrine neoplasia, MEN1 (MEN1), is characterised by hyperparathyroidism due to parathyroid gland hyperplasia or adenoma, functional or non-functional neuroendocrine tumours and anterior pituitary tumours.

MEN2 (RET) is characterised by medullary thyroid carcinoma, pheochromocytoma and hyperparathyroidism, with MEN3 (MEN2B) also associated with ganglioneuromas of the lips, tongue and colon, and a marfanoid habitus.

MEN4 (CDKN1B) has extensive clinical overlap with MEN1, and the most common features are parathyroid and pituitary neoplasias, possibly causing acromegaly. FIPA (also known as 'pituitary adenoma predisposition') is a condition that displays an autosomal dominant inheritance with incomplete penetrance.

15-20% of FIPA families have been identified to have mutations within the AIP gene.

Families with AIP mutations are generally characterised by young onset somatotroph or lactotroph macroadenomas and frequently associated acromegaly.

Hyperparathyroidism Jaw-Tumour syndrome (HPT-JT) is an aggressive autosomal dominant condition caused by mutations in the CDC73 gene, and characterised by primary hyperparathyroidism (HPT) which may develop in late childhood.

Patients with HPT-JT are at risk of developing fibroosseous jaw tumours (~30%), renal lesions and uterine lesions, and approximately 15% of patients also develop parathyroid carcinoma (which is very rare in the general population).

Testing strategy

Clinically affected probands:

R217.1 - analysis for small variants in the gene panel indicated below

R217.2 - dosage analysis for copy number variants in MEN1, AIP, CDKN1B and CDC73

Individual gene analysis is available to non NHSE referrals where clinically indicated

Genes tested:

Genes analysed are in accordance with the 'green' high evidence of clinical association gene list in panel app:

AIP, CDC73, CDKN1B, MEN1, RET (exons 5, 8, 10, 11 and 13-16)

Targeted analysis for known / previously reported familial variants:

• Presymptomatic testing in clinically unaffected family members at risk of inheriting a previously reported familial pathogenic variant (R242)
• Diagnostic confirmation in individuals at risk of inheriting a previously reported familial pathogenic variant and clinically suspected of having the familial condition (R240)
• Segregation studies in affected family members to aid variant interpretation (R375)
• Prenatal diagnosis is not typically requested

Sample requirements and referral information

All referrals should ideally be accompanied by a completed pre-referral form.

Clinical guidance and advice is available to referring consultants from:

Professor Rajesh Thakker, Professor of Medicine
OCDEM, Churchill Hospital

Email: rajesh.thakker@ndm.ox.ac.uk

Requesting specialties:

• Endocrinology
• Clinical Genetics

Specimen requirements and referring samples

Price list for non NHSE referrals (pdf)