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Endocrine Practice (K.F.-R., S.R., F.R.), D-69120 Heidelberg, Germany; Institute of Hormone Research (W.H.), 20251 Hamburg, Germany; Department of Surgery (P.G.), Lukas Krankenhaus, 41464 Neuss, Germany; and Department of Internal Medicine (W.M.), University of Greifswald, 17487 Greifswald, Germany
Address all correspondence and requests for reprints to: Priv. Doz. Dr. Med. Karin Frank-Raue, Endokrinologische Gemeinschaftspraxis, Brückenstrasse 21, D-69120 Heidelberg, Germany. E-mail: karin.frankraue{at}raue-endokrinologie.de.
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Abstract |
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Objective: Here we present a family with coexistence of MEN1 gene mutation and RET mutation.
Results: Six family members carrying MEN1 gene mutation IVS5 + 1G>A only, one family member with RET mutation Y791F, and three family members with both MEN1 gene and RET mutation were studied. The key to diagnosis was recurrent HPT in a young male carrying RET mutation Y791F, a mutation not likely to give rise to recurrent HPT.
Conclusion: MEN1 gene mutation and RET codon 791 mutation in the same patient did not affect the typical phenotype of MEN1 or MEN2, and also the course of diseases seems to be unchanged. The reason may be that both mutations, although contributing to tumor pathogenesis, do not interact and induce a worsening of the cancer syndromes.
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Introduction |
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In patients with MEN1, parathyroid hyperplasia or multiple adenomas occur in approximately 90–95%. HPT is usually the first clinical expression of MEN1, with a typical age of onset of 20–25 yr (1, 4). A strong proliferative drive in parathyroid cells appears to exist in MEN1, as indicated by the high rate of recurrent HPT after apparently successful subtotal parathyroidectomy. One report (5), for example, found a recurrence rate above 50% at 12 yr. The high recurrence rate clearly distinguishes the HPT of MEN1 from that seen in sporadic disease. MEN1 is inherited as an autosomal dominant trait caused by inactivating mutations of the MEN1 gene, a tumor suppressor gene.
MEN2A-related HPT is characterized by a mild hypercalcemia, which is mostly asymptomatic. In MEN2A, parathyroid tumors are found in 20–30% of affected family members. HPT is rarely the first feature recognized in MEN2A. Mean age at diagnosis of HPT in MEN2A is 38 yr. More frequently these patients present with medullary thyroid carcinoma (MTC) and pheochromocytoma. HPT in MEN2A has a relatively low recurrence rate (12%) (6). MEN2 is an autosomal dominant disorder, caused by activating mutations of the RET protooncogene.
Here we present a family with coexistence of MEN1 gene and RET mutation: six family members carrying MEN1 mutation IVS5 + 1G>A only, one family member with RET mutation Y791F, and three family members with both MEN1 gene and RET mutation. The key to diagnosis was recurrent HPT in a young male carrying RET mutation Y791F, a mutation not likely to give rise to recurrent HPT.
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Subjects and Methods |
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Genomic DNA was extracted from peripheral blood leukocytes using the QIAGEN blood minikit (QIAGEN, Hilden, Germany). Five fragments covering the exons 10, 11 and 13–16 of the RET protooncogene and five fragments covering exons 2–10 of the MEN1 gene were amplified with PCR primers (Table 1
) using the Expand high-fidelity PCR system (Roche, Mannheim, Germany) according to the manufacturer’s instructions. The resulting fragments were sequenced with the Thermo sequenase cycle sequencing kit (Amersham, Freiburg, Germany) with IRD-labeled primers (MWG-Biotech, Ebersberg, Germany) and analyzed on the Li-cor IR2-System (Li-COR, Lincoln, NE).
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A 35-yr-old male (Fig. 1, II 8) was referred for family screening in MEN2A (7). Informed consent for the examinations was obtained from all family members.
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, II 7) RET protooncogene showed a Tyr 791 Phe substitution (RET mutation Y791F); molecular analysis was performed because of recurrent HPT; the brother was operated twice for HPT. Thyroidectomy and parathyroidectomy confirmed HPT, but on histological examination no C cell hyperplasia (CCH) or MTC was found. The same RET mutation Y791F (TAT-TTT) was found in our patient. Biochemical workup revealed HPT and borderline elevated basal calcitonin 12 pg/ml (normal range <10 pg/ml) with normal increment after pentagastrin 28 pg/ml (normal range < 79 pg/ml).
Family history disclosed typical manifestations of MEN1 in seven family members (Fig. 1).
Biochemical work-up in our patient revealed that prolactin was clearly elevated (2100 µg/liter, normal range <16 µg/liter) and magnetic resonance imaging identified a 2.8-cm macroprolactinoma. Gastrin was slightly elevated (186 ng/liter basal level, normal range < 100 ng/liter, after secretin stimulation 218 ng/liter, normal range after secretin < 200 ng/liter). Computerized tomography of the pancreas detected four pancreatic tumors, 2.2, 1.5, and two of 0.9 cm in diameter, respectively. Molecular analysis confirmed additionally to the RET mutation a germline mutation in the MEN1 gene: heterozygous substitution G to A at position +1 in intron 5 (MEN1 gene mutation IVS5 + 1G>A, or 934 + 1G>A), an intronic splice site mutation.
Further genetic analysis in the family revealed RET mutation Y791F in the 65-yr-old father but no MEN1 gene mutation. He has no thyroid or parathyroid disease and no pheochromocytoma, and his basal calcitonin level is 5.2 pg/ml with normal increment after pentagastrin stimulation (11.2 pg/ml). In his family history there is neither hereditary MTC nor pheochromocytoma or HPT.
Molecular analysis in the 63-yr-old mother showed the same DNA change in the MEN1 gene as in our patient but no RET mutation. She had been operated twice because of recurrent HPT with persistent hypercalcemia thereafter; her gastrin and prolactin levels are slightly elevated.
Molecular analysis of the other family members showed coincidence of the RET mutation Y791F and MEN1 gene mutation IVS5 + 1G>A in the brother of our patient (Fig. 1, II 7) and one of his daughters (6 yr of age) (Fig. 1, III 2).
In our patient (Fig. 1, II 8), total parathyroidectomy with reimplantation of half of a gland in the forearm and total thyroidectomy was done. Histology confirmed hyperplastic parathyroid tumors with predominant follicular growth and nodular CCH confirmed by immunohistological staining with calcitonin, carcinoembryonic antigen, and chromogranin A.
Postoperative calcium and stimulated calcitonin levels were in the normal range (basal 1.2 pg/ml, 3.5 pg/ml after pentagastrin). Gastrin level decreased after parathyroidectomy in the normal range (109 ng/liter basal level, 128 ng/liter after secretin stimulation).
Surgical treatment of the pancreatic lesions was postponed; during 2-yr follow-up, neither biochemical activity nor growth of the tumors was documented.
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Discussion |
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In MEN2A the relationship between specific mutations and syndromic features has been established (8). In particular, the risk for pheochromocytoma and HPT is clearly associated with the presence of the RET mutation at a specific position, i.e. at codon 634 (9). At this position the overall HPT prevalence was 19%, and it is much lower in the noncystein RET mutations in exons 13–15. Especially in RET mutation Y791F, we are aware of only three patients with HPT, ours with coincident MEN1 and one from Austria (7, 10) (Table 2).
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the phenotype of 63 patients with RET mutation Y791F available in the literature is given (10, 11, 12, 13, 14, 15, 16). The penetrance and aggressiveness of MTC appears to be quite low. The extent of tumor spread is quite variable, but half of the operated patients show CCH even at the age of 54 yr; in six patients normal histology is documented. There is only a minority of three patients with advanced MTC and lymph node involvement. Only two patients died from MTC. In concordance with these data, only CCH was seen in the thyroid histology of our patient and normal C cells in his brother. Current data demonstrate a significant age-related progression from C cell hyperplasia to MTC, and, ultimately, nodal metastasis in patients whose RET mutations were grouped according to the extracellular- and intracellular-domain codons (17). The 1999 consensus statement (4) advocates prophylactic total thyroidectomy before the age of 5 yr in patients with mutations in RET codons 611, 618, 620, or 634. The participants failed to reach agreement on the approach to children with mutations in codons 609, 768, 790, 791, 804, or 891. In these mutations, a more individualized approach to the timing and extent of prophylactic surgery is possible (18). Therefore, in the family members with RET mutation Y791F, we usually do calcitonin measurement and pentagastrin stimulation test every 1–2 yr, and prophylactic thyroidectomy is postponed until calcitonin levels after pentagastrin exceed 100 pg/ml. Others discuss to postpone surgery until the age of 20 yr (12).
MEN1 has no clear syndromic variants (19, 20). Despite extensive studies no relationship between type or location of MEN1 gene mutations and the clinical features of MEN1 has been found. This lack of genotype-phenotype correlation is further confirmed by the observation that families sharing common mutations exhibit heterogeneous clinical expression.
In many recent studies, novel MEN1 gene mutations were reported (21, 22). Novel missense mutations accounted for 15% of the total mutations, and the possibility that a novel splice donor mutation, as in our case, is a rare nonpathogenic event cannot be excluded. But the heterozygous substitution of G to A at position +1 in intron 5 disrupts the consensus sequence in the splice donor site, critical for the splicing reaction (original donor sequence is G/GT that is changed to G/AT in the mutant allele). A G to A substitution at position +1 is frequently described as leading to retention of the according intron (23). This will lead to a nonsense peptide sequence from this position on and a premature termination of protein synthesis. The DNA change in our patients with MEN1, IVS5 + 1G>A or 934 + 1G>A, is located near a reported mutation (934 + 2bp in the splice junction of exon 5) in sporadic parathyroid tumors (24). This also implies a loss of function by this type of mutation.
The family history establishes a clear clinical diagnosis of MEN1, and the history indicates some degree of genetic linkage of the MEN1 trait to the reported DNA change. Recent data show a clear correlation between the frequency of mutations and the number of MEN1-related tumors (21). The highest frequency of mutations was found in index cases with parathyroid, pituitary, and pancreatic tumors (91% in familial cases). Also in our patient, all three manifestations were found.
Clinical manifestation of MEN1 in our family cosegregates with the DNA change in the MEN1 gene: seven of nine gene carriers in generation I and II are also clinically affected, and only the two young girls in generation III showed no clinical manifestation as suspected in this young age. None of the two nongene carriers (II 1 and II 2) showed clinical manifestations of MEN1. The cosegregation of the observed DNA change in the MEN1 gene with the affected phenotype provides support for a possible pathogenetic role of this mutation and remains a valid marker to diagnose mutation carriers in this family.
HPT reaches nearly 95% penetrance at the age of 40 yr and is usually the first clinical expression of MEN1, with a typical age of onset of 25–30 yr. A few cases have been diagnosed as early as 8 yr of age. MEN1 almost never causes parathyroid cancer (1); recently one case with parathyroid cancer who died at the age of 75 yr was reported (23). We therefore assume that HPT in both brothers is not the first manifestation of MEN2, especially in RET mutation Y791F. It might be speculated that HPT in both patients is induced by the MEN1 mutation. Both mutations induce tumor promotion in the parathyroid cells but may not act additively or amplifyingly on tumor growth in the parathyroids. In accordance with this expectation, the 6-yr-old daughter with coincident mutations showed no clinical or biochemical feature of MEN1 or MEN2.
It may be speculated that the RET protooncogene mutation may worsen the course of the potential neoplastic transformation of the pancreatic islet cells found in 40–60% of MEN1 gene carriers. The pancreatic lesions of our patient with MEN1 gene and RET mutation did not manifest earlier and did not grow more aggressively than in other MEN1 patients.
MEN1 often causes simultaneous HPT and Zollinger-Ellison syndrome. Hypercalcemia increases the secretion of gastrin from gastrinomas; conversely, successful parathyroidectomy lowers blood calcium and can thus decrease gastrin release in MEN1 (25). This phenomenon could also be demonstrated in our patient; Zollinger-Ellison syndrome could be excluded after parathyroidectomy by normalization of the basal and stimulated gastrin levels. At the moment we have no indication of a hormone excess from the pancreatic lesions. In balancing the long-term side effects of diabetes caused by total pancreatectomy with the 30–35% probability that a tumor will metastasize, we decided to postpone an operation.
In conclusion, the MEN1 gene mutation IVS5 + 1G>A and RET mutation Y791F in the same patient did not affect the typical phenotype of MEN1 or MEN2, and also the course of diseases seems to be unchanged. The reason for that may be that both mutations, although contributing to tumor pathogenesis, do not interact and induce a worsening of the cancer syndromes.
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Footnotes |
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First Published Online May 3, 2005
Abbreviations: CCH, C cell hyperplasia; HPT, primary hyperparathyroidism; MEN, multiple endocrine neoplasia; MTC, medullary thyroid carcinoma.
Received September 3, 2004.
Accepted April 25, 2005.
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