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• Defining clinical criteria for diagnostic molecular genetic testing in multiple endocrine neoplasia
  Bijay Vaidya
  Published on: 27 April 2016

• Published on: 27 April 2016

  Defining clinical criteria for diagnostic molecular genetic testing in multiple endocrine neoplasia

  • Bijay Vaidya, Physician
  • Other Contributors:
    • Andrew T. Hattersley, and Sian Ellard.

  Dear Editor,

  We read with great interest the paper of Cardinal and colleagues reporting findings of an Australian diagnostic MEN1 genetic testing service.¹ Molecular genetic diagnosis of MEN1 has been possible since the identification of the MEN1 gene in 1997.² In 2001, consensus guidelines outlining clinical criteria for MEN1 mutation testing were published.³ The gu...

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  Dear Editor,

  We read with great interest the paper of Cardinal and colleagues reporting findings of an Australian diagnostic MEN1 genetic testing service.¹ Molecular genetic diagnosis of MEN1 has been possible since the identification of the MEN1 gene in 1997.² In 2001, consensus guidelines outlining clinical criteria for MEN1 mutation testing were published.³ The guidelines recommend genetic testing in a patient meeting clinical criteria for sporadic MEN1 (the presence of at least 2 out of 3 main MEN1-related tumours, i.e. parathyroid, pancreatic and pituitary) or familial MEN1 (as in sporadic MEN1 plus at least one first-degree relative with one or more main MEN1-related tumours), and in a patient suspicious of MEN1 (multiple parathyroid tumours before age 30, recurrent hyperparathyroidism, gastrinoma or multiple islet cell tumours at any age, and familial isolated hyperparathyroidism). These clinical criteria were defined on the basis of initial research findings, and therefore reports of how the criteria apply in routine clinical practice are important. Similar to the study of Cardinal and colleagues, we have also recently reported a large cohort of patients from the UK, who underwent MEN1 genetic testing at our diagnostic molecular genetics laboratory.⁴ Likewise, Klein and colleagues have analysed a large diagnostic laboratory series from the USA.⁵

  The MEN1 mutation detection rates in the three diagnostic series are very similar with an overall mutation detection rate of 34% (Table 1). In patients with 2 or more main MEN1-related tumours (i.e., fulfilling clinical criteria for MEN1), the pick up rates were 26% and 68% for sporadic and familial cases, respectively (Table 1). These compare to the pick up rates in research cohorts of 52% in sporadic MEN1 and 87% in familial MEN1.⁴ These findings from the diagnostic laboratory series firmly support the guideline recommendation of MEN1 genetic testing in patients fulfilling the clinical criteria of sporadic or familial MEN1. These series also show that the likelihood of finding a MEN1 mutation increases in the presence of a family history, and also depends upon the clinical features. Patients with 3 main MEN1-related tumours (as compared to those with 2 tumours)⁴ and patients with a combination of parathyroid & pancreatic tumours (as compared to those with parathyroid and pituitary tumours)^4,5 are more likely to yield a positive mutation result.

  Whilst the importance of genetic testing in patients fulfilling clinical criteria for sporadic or familial MEN1 is generally accepted, it remains uncertain as to which of the patients with isolated MEN1-related tumours should be screened for an MEN1 mutation. Sporadic isolated MEN1-related tumours (such as parathyroid and pituitary) are fairly common in the general population, and it is not feasible to perform expensive and laborious MEN1 genetic testing in all such cases. Although we did not find MEN1 mutations in the 10 patients with sporadic hyperparathyroidism in our series, Cardinal and colleagues found a MEN1 mutation in one (out of 11) patient with sporadic hyperparathyroidism, suggesting that MEN1 genetic testing should be carried out in patients with early onset, multiglandular parathyroid tumours. Clearly, further studies with much larger cohorts of patients are necessary to establish clinical criteria for MEN1 genetic testing in patients with various sporadic isolated MEN1-related tumours or rarer combinations of different MEN1-related tumours. In many countries molecular genetic testing for MEN1 is carried out by a single national laboratory or a small number of nominated regional centres. This should allow the collection of clinical information from large cohorts of patients undergoing MEN1 mutation analysis, which is likely to facilitate the further definition of clinical criteria for MEN1 genetic testing.

  B Vaidya¹, AT Hattersley¹ & S Ellard²

  Departments of ¹Endocrinology and ²Molecular Genetics, Royal Devon & Exeter NHS Foundation Trust, Peninsula Medical School, Exeter, UK

  References:

  1. Cardinal JW, Bergman L, Hayward N, Sweet A, Warner J, Marks L, Learoyd D, Dwight T, Robinson B, Epstein M, Smith M, Teh BT, Cameron DP, Prins JB. A report of a national mutation testing service for the MEN1 gene: clinical resentations and implications for mutation testing. J Med Genet 2005;42:69-74.

  2. Chandrasekharappa SC, Guru SC, Manickam P, Olufemi SE, Collins FS, Emmert-Buck MR, Debelenko LV, Zhuang Z, Lubensky IA, Liotta LA, Crabtree JS, Wang Y, Roe BA, Weisemann J, Boguski MS, Agarwal SK, Kester MB, Kim YS, Heppner C, Dong Q, Spiegel AM, Burns AL, Marx SJ. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 1997;276:404-7.

  3. Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, Conte-Devolx B, Falchetti A, Gheri RG, Libroia A, Lips CJ, Lombardi G, Mannelli M, Pacini F, Ponder BA, Raue F, Skogseid B, Tamburrano G, Thakker RV, Thompson NW, Tomassetti P, Tonelli F, Wells SA, Marx SJ. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001;86:5658-71.

  4. Ellard S, Hattersley AT, Brewer CM, Vaidya, B. Detection of an MEN1 gene mutation depends on clinical features and supports current referral criteria for diagnostic molecular genetic testing. Clin Endocrinol 2005; 62:169-175.

  5. Klein RD, Salih S, Bessoni J, Bale AE. Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory. Genet Med 2005;7:131-8.

  Table 1. MEN1 mutation detection rates in large diagnostic laboratory series
  
  

  	Cardinal et al.1	Ellard et al.4	Klein et al.5	Total
  All probands	55/150 (37%)	68/186 (37%)	89/288 (31%)	212/624 (34%)
  Two or more main MEN1-related tumours: Sporadic Familial	8/50 (16%) 41/56 (73%)	22/70 (31%) 28/37 (76%)	6/20 (30%) 44/73 (60%)	36/140 (26%) 113/166 (68%)
  Isolated parathyroid tumours: Sporadic Familial	1/11 (9%) 5/23 (22%)	0/10 6/17 (35%)	- 4/24 (17%)	1/21 (5%) 15/64 (23%)
  Isolated pancreatic tumours: Sporadic Familial	- -	0/4 1/3 (33%)	- 2/10 (20%)	0/4 3/13 (23%)
  Isolated pituitary tumours: Sporadic Familial	- 0/6	0/9 0/9	- 3/10 (30%)	0/9 3/25 (12%)

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  Conflict of Interest:
  None declared.

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