1. DISEASE CHARACTERISTICS 1.1 NAME OF THE DISEASE (SYNONYMS) Multiple endocrine neoplasia 2A (MEN 2A), multiple endocrine neoplasia 2B (MEN 2B), familial medullary thyroid carcinoma (FMTC).

1.2 OMIM# OF THE DISEASE MEN 2A: 171400; MEN 2B: 162300; FMTC: 155240. 1.3 NAME OF THE ANALYSED GENES OR DNA/CHROMOSOME SEGMENTS _RET_ proto-oncogene/10q11.2. 1.4 OMIM# OF THE GENE(S)

164761. 1.5 MUTATIONAL SPECTRUM Mostly point mutations, insertions of few nucleotides, small indels. Presently mutations are described in exons 5, 8, 10, 11, 13, 14, 15 and 16.1, 2, 3, 4 1.6

ANALYTICAL METHODS Bidirectional sequencing of coding regions. 1.7 ANALYTICAL VALIDATION Direct sequencing of both strands, verification of sequence results with genomic DNA from the second

diagnostics is rarely done because adequate prevention/therapy of the associated diseases is available. Theoretically, we would recommend pre-implantation diagnosis in MEN 2B families, but

these cases are very rare. 2. TEST CHARACTERISTICS 2.1 ANALYTICAL SENSITIVITY (PROPORTION OF POSITIVE TESTS IF THE GENOTYPE IS PRESENT) About 98%. 2.2 ANALYTICAL SPECIFICITY (PROPORTION OF

NEGATIVE TESTS IF THE GENOTYPE IS NOT PRESENT) About 98%. 2.3 CLINICAL SENSITIVITY (PROPORTION OF POSITIVE TESTS IF THE DISEASE IS PRESENT) The clinical sensitivity can be dependent on

variable factors such as age or family history. In such cases a general statement should be given, even if a quantification can only be made case by case. About 97%.5 2.4 CLINICAL

SPECIFICITY (PROPORTION OF NEGATIVE TESTS IF THE DISEASE IS NOT PRESENT) The clinical specificity can be dependent on variable factors such as age or family history. In such cases a general

statement should be given, even if a quantification can only be made case by case. About 98%. 2.5 POSITIVE CLINICAL PREDICTIVE VALUE (LIFETIME RISK OF DEVELOPING THE DISEASE IF THE TEST IS

POSITIVE) Depending on the specific codon mutated: _MEN 2A_: frequency of MTC 90–95%, pheochromocytoma 40–50%, hyperparathyroidism 10–20%. _MEN 2B_: frequency of MTC 100%, pheochromocytoma

50%, hyperparathyroidism 0%. _FMTC_: frequency of MTC 80%, rarely pheochromocytoma/parathyroid disease (below 5%).6, 7, 8 2.6 NEGATIVE CLINICAL PREDICTIVE VALUE (PROBABILITY OF NOT

DEVELOPING THE DISEASE IF THE TEST IS NEGATIVE) Assume an increased risk based on family history for a non-affected person. Allelic and locus heterogeneity may need to be considered. Index

case in that family had been tested: About 98%. Index case in that family had not been tested: Depending on age, phenotype and number of family members under investigation. 3. CLINICAL

UTILITY In MEN 2, DNA analysis has obtained a central role in diagnosis and management. For this reason it is inconceivable that in MEN 2 families patients may refuse early DNA analysis for

their children at risk. Delay in treatment may have serious consequences for survival and quality of life. 3.1 (DIFFERENTIAL) DIAGNOSIS: THE TESTED PERSON IS CLINICALLY AFFECTED (To be

answered if in 1.10 ‘A’ was marked) If a person is clinically affected with MTC, about 70–75% of cases are sporadic, the remaining 25–30% belong to the hereditary variety (MEN 2/FMTC). In

all cases of MTC genetic testing for mutations in the _RET_ proto-oncogene is recommended.1 The probability that an individual with apparent sporadic MTC will be found to have a _RET_

mutation is 1–7%.1, 9, 10 In rare families, both HSCR and MEN 2 appear to segregate with germline _RET_ mutations in codon 609, 611, 618, or 620.11, 12 3.1.1 CAN A DIAGNOSIS BE MADE OTHER

THAN THROUGH A GENETIC TEST? 3.1.2 DESCRIBE THE BURDEN OF ALTERNATIVE DIAGNOSTIC METHODS TO THE PATIENT? In the past, pentagastrin and calcium infusion tests were used to stimulate

calcitonin secretion by thyroid C-cells, but nowadays _RET_-mutation screening is available for familial MTC and thus these tests have lost their clinical significance with respect to

diagnosis. The widespread availability of _RET_ gene mutation analysis and prophylactic thyroidectomy in MEN 2 disease-gene carriers has made periodical C-cell stimulation tests largely

obsolete for detection of MTC in MEN 2 families. For detection of MTC, C-cell stimulation tests are useful for family members who refuse DNA analysis. In addition, preoperatively it may

facilitate a decision with regard to the extensiveness of the surgical procedure. Occasionally, MTCs do not secrete calcitonin,13, 14 but this has not been observed in MEN 2 gene carriers.

Tests for pheochromocytoma and HPT significantly add to the burden. 3.1.3 HOW IS THE COST EFFECTIVENESS OF ALTERNATIVE DIAGNOSTIC METHODS TO BE JUDGED? After 3–4 appointments with calcitonin

stimulation test the costs are equal to the molecular diagnostic test. Savings through unnecessary testing for pheochromocytoma and HPT further increase the cost effectiveness. 3.1.4 WILL

DISEASE MANAGEMENT BE INFLUENCED BY THE RESULT OF A GENETIC TEST? 3.2 PREDICTIVE SETTING: THE TESTED PERSON IS CLINICALLY UNAFFECTED BUT CARRIES AN INCREASED RISK BASED ON FAMILY HISTORY (To

be answered if in 1.10 ‘B’ was marked) 3.2.1 WILL THE RESULT OF A GENETIC TEST INFLUENCE LIFESTYLE AND PREVENTION? If the test result is positive (please describe): _Positive test result_:

Depending on the detected mutation the patient should undergo prophylactic thyroidectomy or yearly calcitonin measurement. Likewise, also depending on the detected mutation the patient

should undergo biochemical testing for pheochromocytoma and HPT. If the test result is negative (please describe): _Negative test result_: Person can be excluded from further evaluations.

3.2.2 WHICH OPTIONS IN VIEW OF LIFESTYLE AND PREVENTION DOES A PERSON AT RISK HAVE IF NO GENETIC TEST HAS BEEN DONE (PLEASE DESCRIBE)? Calcitonin test and clinical evaluation are necessary

every year, with an increasing risk of MTC development and development of lymph node and distant metastases. There is an increasing risk of developing pheochromocytoma or hyperparathyroidism

during one's lifetime. 3.3 GENETIC RISK ASSESSMENT IN FAMILY MEMBERS OF A DISEASED PERSON (To be answered if in 1.10 ‘C’ was marked) 3.3.1 DOES THE RESULT OF A GENETIC TEST RESOLVE THE

GENETIC SITUATION IN THAT FAMILY? Yes, autosomal dominant inheritance. 3.3.2 CAN A GENETIC TEST IN THE INDEX PATIENT SAVE GENETIC OR OTHER TESTS IN FAMILY MEMBERS? Early DNA analysis

(already at birth) may be considered as a safe clinical test with clinical consequences and makes periodical measurement of calcitonin levels and ultrasound redundant in non-carriers. 3.3.3

DOES A POSITIVE GENETIC TEST RESULT IN THE INDEX PATIENT ENABLE A PREDICTIVE TEST IN A FAMILY MEMBER? Yes. 3.4 PRENATAL DIAGNOSIS (To be answered if in 2.10 ‘D’ was marked) This is rarely

necessary, because the disease can be managed properly (prophylactic thyroidectomy at an adequate age determined by the respective _RET_ mutation, adrenalectomy in pre-symptomatic stage of

pheochromocytoma, parathyroidectomy in asymptomatic stage of hyperparathyroidism). 3.4.1 DOES A POSITIVE GENETIC TEST RESULT IN THE INDEX PATIENT ENABLE A PRENATAL DIAGNOSTIC? Yes, but this

is rarely done, because postnatal therapy is available. 4. IF APPLICABLE, FURTHER CONSEQUENCES OF TESTING Please assume that the result of a genetic test has no immediate medical

consequences. Is there any evidence that a genetic test is nevertheless useful for the patient or his/her relatives? (Please describe) Molecular diagnosis of the proband allows for a precise

recommendation of further therapy (prophylactic thyroidectomy at the appropriate age, depending on the respective _RET_ mutation) and also for recommendation concerning the commencement and

frequency of biochemical testing for pheochromocytoma and hyperparathyroidism. Cure of MTC is only possible as long as MTC is limited to the thyroid gland; therefore diagnosis at an early

stage is the prerequisite for cure. Genetic test allows for regular biochemical screening using epinephrine and nor-epinephrine analysis to prevent hypertensive crisis induced by

pheochromocytoma,16 and regular serum calcium and parathyroid hormone measurement to diagnose hyperparathyroidism at an early stage.15 Molecular diagnosis of the proband allows for an

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111–116. Article  Google Scholar  Download references ACKNOWLEDGEMENTS This work was supported by EuroGentest, an EU-FP6-supported NoE, contract number 512148 (EuroGentest Unit 3: ‘Clinical

genetics, community genetics and public health’, Workpackage 3.2). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Endocrine Practice and Molecular Laboratory, Heidelberg, Germany Friedhelm

Raue, Susanne Rondot, Egbert Schulze & Karin Frank-Raue * Maria Sklodowska Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland Sylwia Szpak-Ulczok & Barbara

Jarzab Authors * Friedhelm Raue View author publications You can also search for this author inPubMed Google Scholar * Susanne Rondot View author publications You can also search for this

author inPubMed Google Scholar * Egbert Schulze View author publications You can also search for this author inPubMed Google Scholar * Sylwia Szpak-Ulczok View author publications You can

also search for this author inPubMed Google Scholar * Barbara Jarzab View author publications You can also search for this author inPubMed Google Scholar * Karin Frank-Raue View author

publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Friedhelm Raue. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no

conflict of interest. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Raue, F., Rondot, S., Schulze, E. _et al._ Clinical utility gene card for:

multiple endocrine neoplasia type 2. _Eur J Hum Genet_ 20, 3 (2012). https://doi.org/10.1038/ejhg.2011.142 Download citation * Published: 24 August 2011 * Issue Date: January 2012 * DOI:

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