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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 10 3487-3492
Copyright © 1997 by The Endocrine Society

Original Studies

A Large Multiple Endocrine Neoplasia Type 1 Family with Clinical Expression Suggestive of Anticipation1

Sophie Giraud, Hélène Choplin, Bin Tean Teh, James Lespinasse, Anne Jouvet, Françoise Labat-Moleur, Gilbert Lenoir, Béatrice Hamon, Patrick Hamon and Alain Calender

Department of Genetics (S.G., G.L., A.C.), Edouard Herriot Hospital, Lyon; Department of Endocrinology (H.C., B.H., P.H.), Chambery General Hospital, Chambery, France; Department of Molecular Medicine (B.T.T.), Karolinska Hospital L6, Stockholm, Sweden; Cytogenetic Laboratory (J.L.), Chambery General Hospital, Chambery; Department of Pathology (A.J.), Neurological Hospital, Lyon; Department of Pathology (F.L.-M.), La Tronche Hospital, Grenoble, France

Address correspondence and reprints to: Dr. Alain Calender, Department of Genetics, Edouard Herriot Hospital, Pavillon E, 69437 Lyon, Cedex 03, France. E-mail: calender{at}cismsun.univ-lyon1.fr


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
We describe a large multigenerational multiple endocrine neoplasia Type 1 (MEN1) family with clinical expression suggestive of anticipation. In the second and third generations, two deceased obligate gene carriers died at the ages of 85 and 76 without the history of MEN1, whereas two other living gene carriers above the age of 65 have had no clinical evidence of MEN1 to date. In the fourth generation, eight members were affected, with four having severe MEN1-related and atypical malignancies: a case of metastatic endocrine pancreatic tumor, two cases of metastatic thymic carcinoids, and a case of spinal ependymoma. In the fifth generation, all five patients were below the age of 22 when the disease was detected. MEN1 was confirmed in the family by linkage analysis using MEN1-linked microsatellite markers and by identification of a nonsense mutation in the MEN1/menin gene. Alleotyping showed loss of heterozygosity (LOH) involving the wild-type alleles in seven tumors in the family including the ependymoma, which is the first MEN1-related case that shows genetic abnormality in chromosome 11q13, suggesting that MEN1 gene might be involved in the tumorigenesis of a subset of ependymomas. In relation to clinical anticipation, repeated expansion studies were carried out but failed to detect any expansion. We conclude that this is a unique MEN1 family and that an unknown genetic mechanism might be contributing to the anticipation phenomenon. We demonstrate in this family that all gene carriers, including the very young members, will need close and careful follow-up.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
MULTIPLE ENDOCRINE Neoplasia Type 1 (MEN1) is characterized by neoplasia of parathyroids, anterior pituitary, duodenum, and endocrine pancreas. The MEN1 gene, a putative tumor suppressor gene, has been mapped to chromosome 11q13 (1) and recently cloned (2, 3). The disease, which is transmitted in an autosomal dominant fashion, has a very high penetrance. For example, in the largest known MEN1 kindred residing in Tasmania, Australia, nonpenetrance has not been found (4). Anticipation is a phenomenon in which severity increases and age of onset decreases in successive generations. It is most commonly found in neuropsychiatric disorders but has been reported in familial cancer syndromes such as familial adenomatous polyposis (FAP) (5), hereditary nonpolyposis colorectal cancer (HNPCC) (6), and familial breast cancer (7), familial testicular cancer (8), and familial leukemia (9). Genetically, this phenomenon has been associated with trinucleotide expansions that occur in a number of neuropsychiatric disorders and can be detected by repeat expansion detection (10). However, an increase in (cytosine adenineguanine)n (CAG)n tract size was observed in families with testicular cancer (11). To date, no reports of anticipation phenomenon in MEN1 have been documented. Here we describe a large MEN1 family with clinical expression suggestive of anticipation. Genetic studies were carried out including cytogenetic studies, linkage analysis, germline mutation analysis in the MEN1 gene, repeat expansions detection, and alleotyping of the tumors.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients and clinical data

The MEN1 kindred (Fig. 1Go) is of Caucasian origin and is currently residing in France. Two branches (A and B in Fig. 1Go) of the family were studied, and their consanguinous relationship was established by geneological studies. The medical records, investigation reports, and death certificates were reviewed. All living members, unless specified, were screened with: a) biochemical investigations: serum calcium, phosphate, parathyroid hormone, prolactin, cortisol, ACTH, growth hormone (GH), insulin-like growth factor 1 (IGF1), thyroid stimulating hormone (TSH), fasting gastrin, glucagon, glucose, insulin C-Peptide, and meal stimulation test with pancreatic polypeptide, somatostatin, vasoactive intestinal polypeptide; and b) radiological investigations: abdominal ultrasonography, abdominal and thoracic computed tomography, medullary and cerebral magnetic resonance imaging.



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  		Figure 1. Phenotypes and haplotypes of MEN1 in the family. The markers are listed in order from centromere to telomere. The haplotypes for each individual are depicted along an illustrated chromosome segment. The inferred disease-bearing chromosome is blackened. The numbers below the individuals are the age when they died. + designates patients with the R415X mutation (exon9) in the MEN1/menin gene. - represents individuals without mutation.

 
Clinically, generations IV and V were severely affected with the disease. In generation IV of the first branch (A in Fig. 1Go), five siblings out of seven were affected. All five patients had primary hyperparathyroidism, with two having additional endocrine pancreatic tumors, one having an ependymoma, and one having elevated prolactin but without radiological evidence of tumor. Individual IV-1 was found to have hyperparathyroidism and endocrine pancreatic tumor at the age of 26 yr. She died at the age of 30 from metastatic endocrine pancreatic tumor. Individual IV-2 was found to have hyperparathyroidism at the age of 26. At the age of 29, she developed hyposthesia and weakness of her left leg, and subsequently a 9 cm spinal cord tumor between the eighth and tenth vertebrae associated with syringomyelia was detected. The tumor was a highly vascularized papillary lesion. The tumor cells were either cubic or polycedric in shape with clear cytoplasm and well-defined membranes. Nuclei were mostly ovoid and peripherally located in the cells with high nucleocytoplasmic ratio. Immunohistochemistry with glial fibrillary acidic protein (GFAP) suggest strongly the diagnosis of papillary ependymoma, although some of the cells were positive with neuroendocrine-specific markers such as S100, neuron specific enolase (NSE), synaptophysin, and chromogranin. Further investigation with electromicroscopy showed the absence of any intracellular dense vesicles as typically seen in neuroendocrine cells. The positivity of chromogranin was therefore explained by the high density of intracellular glycogen-containing particles, such as those seen in epithelial ependymal tissue. The tumor was diagnosed as papillary ependymoma grade II.

Individual IV-4 was diagnosed with an insulinoma at the age of 9 yr and hyperparathyroidism at the age of 13. Individual IV-6 was found to have hyperparathyroidism and prolactinoma at the age of 25, and hyperparathyroidism was established in individual IV-7 at the age of 21. The father (III-1), who is consanguinously related to the other branch (B in Fig. 1Go) was screened repeatedly, but to date, at the age of 67, had no clinical, biochemical, or radiological evidence of other endocrinopathies. His three other siblings who lived overseas were investigated genetically: one of his brothers (III-5), aged 65, who had the mutation had been well, and biochemical and radiological investigations in June, 1996 did not show any lesion or endocrinopathy. The mother (III-2), who was not known to be related to the paternal family, has thyroid goiter but has no evidence of MEN1. Both the grandparents (generation 2) died of old age (85 and 92) and were not known to have any tumor. The children of generation IV were not shown as they are all below the age of 5, thus excluded from screening.

In the second branch (B in Fig. 1Go), three siblings in generation IV had primary hyperparathyroidism, and two were found to have thymic carcinoids after complaining of thoracic pains. The ages of presentation were between 31 and 56 yr. Five of their offspring, in generation 5, were affected at ages between 13 and 22: four patients had primary hyperparathyroidism, and two of them show other endocrine lesions. Individual V-1 presented with pituitary adenoma, and individual V-3 had an extensive pancreatic lesion. Both were treated by surgery. Pancreatic lesions were recently shown in patient V-2 (18 yr old) and will be further investigated. Again, the parents in generation III had no evident clinical manifestations of the disease. The mother (III-8), who was the gene carrier, died at the age of 76. Both she and her mother (II-3) were not known to have any history of MEN1 or malignancy. Individuals IV-7, IV-15, V-5, V-6 (hyperparathyroidism only), and V-2 (hyperparathyroidism and pancreatic lesion) were found through screening to have their disease. The other patients in generations IV and V presented with symptoms of their disease at the ages indicated.

Linkage analysis and loss of heterozygosity (LOH) studies

Informed consent was obtained from members of both families. Genotyping was carried out as previously described (12) using the following markers: D11S480, D11S1883, PYGM, D11S449, D11S1889, and D11S913 (13). To be most conservative, all individuals who had no clinical evidence of disease were scored as "unknown" for linkage analysis. Conventional logarithm-of-odds (lod) score cut-offs were used, i.e. lod >= 3.0 signifies linkage to a given marker, and lod < -2 excludes linkage.

LOH studies were performed as previously described (14) on the following tumors: one ependymoma and two hyperplastic parathyroid glands from individual IV-2, one endocrine pancreatic and one hyperplastic parathyroid gland from individual V-3, two hyperplastic parathyroid tumors from individual V-2.

Repeat Expansion Detection (RED)

The method permits the direct identification of expanded repeat sequences larger than 30 copies in genomic DNA. It was carried out as previously described (15, 16).

Germline mutation analysis in the MEN1/menin gene

The sequencing reaction was performed directly from PCR amplified DNA with the AB1 PRISM 377 ready reaction dye deoxyterminator cycle sequencing kit (Perkin Elmer) and run on the automated sequencer ABI 377 (Applied Biosystems, The Perkin Elmer Corp., Foster City, CA). Primers used for exons 2 to 10 were derived from the SCG2 gene (Suppressor Candidate Gene 2) recently characterized in a European collaborative work (3) and shown to be similar to the MEN1/menin gene cloned by the Nationals Institutes of Health group (2). Specifically for exon 9, primers referenced 12F (forward) and 12R (reverse) produce a 246 bp fragment, as described in reference 3.

Cytogenetic studies

Peripheral blood cells from seven affected patients were cultured and R-banding heat Giemsa (RHG), G-banding trypsin Giesma (GTG), Q-banding fluorescent Quinacrine (QFQ), and R-banding thymidine Buder Giemsa (RTBG) high resolution staining were carried out.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The clinical features of this family are consistent with those of MEN1. Markers D11S1883, PYGM, D11S449, D11S1889, and D11S913 gave positive lod scores at zero recombination fraction with a maximum lod score of 3.75 at PYGM locus, thus confirming its linkage to MEN1. A nonsense mutation (R415X; Fig. 2Go), located in exon 9 of the recently cloned MEN1 gene, was found in 15 members (Fig. 1Go) cosegregating with the 11q13 disease haplotypes. The mutation and haplotypes showed that all clinically affected cases shared the same haplotypes, establishing that the two branches inherited the same disease genotype from the same ancestor (Fig. 1Go). The mutation was found in 2 healthy obligate gene carriers (III-1 and III-5). Cytogenetically, no abnormality can be detected in the affected cases. We were not able to observe any fragile sites (FRA11H and FRA11A) with common culture conditions (RHG, RTBG, GBTG) and with folate-deficient medium. CAG repeat expansions were not detected in the family but were present in positive controls with spinocerebellar ataxia type 3 (SCA3). In the LOH studies, all tumors studied including the spinal ependymoma showed LOH in the MEN1 region involving the loss of the wild type alleles, which was in agreement with inactivation of a tumor suppressor gene (Fig. 3Go). In patients IV-2 and V-2, two hyperplastic parathyroid glands from each patient showed different patterns of LOH, i.e. one gland showed a more extended region of LOH than the other, and both came from the same individual.



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  		Figure 2. Direct sequence analysis showing a nonsense mutation at codon 415, from CGA to TGA (R415X) in exon 9 of the MEN1/menin gene. Top panel: The control sample was prepared from a healthy member of the family carrying an unaffected 11q13 haplotype. Bottom panel: The R415X mutation described in a member of the family affected by the disease. The solid line (—) designs codon 415 (CGA). The star (*) indicates the position of the base change (C to T), which was designated by (N) on the primary sequence.

 


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  		Figure 3. LOH of ependymoma (T1) with PYGM marker using fluorescent method. Size in bp is shown on the X axis at the top of the figure. The peak heights in fluorescence units are shown on the Y axis on the right. Upper trace shows amplification from blood DNA, lower trace from tumor tissue. Each peak has two labels (boxes): the upper one shows the size in bp, the lower one shows the peak area, which is included in the following calculation: if (T2 x N1)/(T1 x N2) <0.6, there is loss of the larger allele and in this case is (871 x 2602)/(13243 x 1852) = 0.09, indicating a clear loss of the larger allele.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Undoubtedly the clinical features expressed in the family are characteristics of MEN1. The diagnosis is further confirmed by linkage analysis, haplotyping, and evidence of a nonsense mutation (R415X in exon 9) in the recently cloned MEN1 gene. Based on the latter, it can be stipulated that the mutation has occurred as far back as the first generation in the pedigree (Fig. 1Go). By comparing the age of presentation and the severity of the disease through each generation, there is evidence of anticipation phenomenon. In the first generation, no information was available. In the second generation, one obligate gene carrier (II-2) died at the age of 85 without any history of malignancy. His spouse (II-1) died at the age of 92. In the third generation, two living gene carriers (III-1 and III-5) are over the age of 65 and have no clinical evidence of MEN1 to date. Subject III-1 was recently further investigated to exclude the Zollinger-Ellison syndrome because of atypical gastric pain. Gastrin levels remain normal both before and after secretin test. One gene carrier (III.8) died at the age of 76 without any history of MEN1-related illness. MEN1 is known to have very high penetrance, with 98.8% penetrance by the age of 53 (17). However, we cannot confirm nonpenetrance in the deceased obligate gene carriers because no autopsy was performed. It is known that nonfunctioning or subclinical tumors have been found at autopsy, contributing to the "all or none" observation in MEN1 (18). However, even if all four obligate gene carriers did have subclinical lesions, they must have had very mild disease compared with their progeny. For example, in the fourth generation, eight were affected, with four having severe disease: two with metastatic carcinoids, one died of metastatic endocrine pancreatic cancer, and one with a large ependymoma. In the fifth generation, out of the five affected, four presented with the disease between the ages of 13 and 16. In two patients (V-1 and V-3), extensive lesions of the pituitary and pancreas were identified and surgically removed. In patient V-1, hyperprolactinaemia remains despite surgery, and recent screening shows evidence of high circulating NSE (neuron-specific-enolase), suggesting subclinical neuroendocrine proliferations. Although primary hyperparathyroidism is the most common presentation, occurring in up to 95% of MEN1 patients, it is uncommon among teenagers (2, 15). Here hyperparathyroidism was found in four patients and was confirmed surgically in two (V-2 and V-3) at the ages of 14 and 16. Taken together, these observations in young patients below age 20 indicate an aggressive and precocious disease in the fifth generation.

Anticipation has been observed in familial cancer syndromes (5, 6, 7, 8, 9), although caution has to be taken regarding biases of ascertainment including selection biases and observation of complementary parent-child pairs (19). In this family, the differences in severity of disease occur between generations and involve several individuals across each generation from both branches, thus minimizing the possibility of chance occurrence. To date, among the familial cancer syndromes, only familial testicular families have shown repeat expansion (11), although the significance and implication of these findings regarding tumorigenesis are yet to be established. We also explored the possible involvement of repeat expansions by using RED but failed to detect any CAG repeat expansions. The results, however, do not exclude smaller repeat expansion (< 30 copies) or other unknown mechanisms for anticipation. The fact that the same mutation (R415X) occurs in all affected cases, and in two and presumably three other older gene carriers with no clinical evidence or history of MEN1, suggests the possible involvement of additional factors. Whether the environmental factor plays a role is questionable because none of the family members are known to be exposed to any industrial hazards. In the first branch of the pedigree, there is no smoker. Anticipation is usually observed in a subset of familial cancer families in contrast with repeat-expansion-associated neuropsychiatric disorders, which are characterized universally by anticipation. We believe that this phenomenon is uncommon in MEN1. It is possible that in this and other reported familial cancer families, cosegregation of other modifying genes might be involved, resulting in more severe phenotypes in subsequent generations.

MEN1-related tumors, particularly parathyroid and endocrine pancreas, frequently showed LOH of the wild-type allele supporting the hypothesis that the MEN1 gene is a tumor suppressor gene (20, 21). Our studies also support this theory. The LOH found in the ependymoma is interesting. Ependymomas constitute 5–10% of all primary childhood CNS tumors and occur primarily in the ventricles of the brain. On the other hand, spinal cord ependymoma, as in this case, occurs more commonly in adults. Although chromosome 22q has been implicated in its tumorigenesis (22), two previous reports have demonstrated cytogenetic translocation involving 11q13 in two sporadic ependymomas (23, 24). Clinically, one case of ependymoma has been reported in a MEN1 patient (25), and the other has been found in the largest MEN1 family in Australia (4). Our study is the first to show genetic involvement of the MEN1 gene in a MEN1-related ependymoma. In this family, a nonsense mutation (R415X) occurs in exon 9 of the MEN1 gene, resulting probably in a truncated protein. Further studies will be needed to evaluate genotype-phenotype correlations in MEN1 and the type of mutations that could be associated with an increased risk of thymic carcinoids and other uncommon lesions. Based on previous reports and in our findings, we conclude that ependymoma is a feature of MEN1, although uncommon compared with other MEN1-related tumors. We also propose that the MEN1 gene is involved in the tumorigenesis of a subset of ependymomas.

In conclusion, we present a large, unique MEN1 family, with interesting clinical features suggestive of anticipation, and an unknown genetic mechanism that might contribute to this phenomenon. As pointed out in McInnis’ recent editorial (26) regarding anticipation, the knowledge about the mechanisms associated with anticipation is lacking but the exploration of them is crucial in developing a broader view of the classes of DNA instability and a deeper understanding of the molecular events involved when the effects of a mutation change as it is transmitted between generations. From the management point of view, because of the phenomenon suggestive of anticipation, all gene carriers in this unique family, including those very young members, would require close and careful follow-ups.


   Acknowledgments
 
We are indebted to the patients for participating in the genetic screening program. We kindly thank Dr. C. Larsson and Dr. M. Schalling (Karolinska Hospital, Stockholm, Sweden) and Dr. J. Weissenbach (Genethon, Evry, France) for the gift of RFLP probes and technical advice.


   Footnotes
 
1 This work was supported in part by an INSERM (Institut National de la Sante et de la Recherche Medicale) clinical network and grants from the Hospices Civils de Lyon, referenced PHRC 95-030. Clinical and genetic studies in France were performed in the framework of GENEM 1 (Groupe d’Etude des Néoplasies Endocriniennes Multiples de type 1). Back

Received January 22, 1997.

Revised April 15, 1997.

Revised June 12, 1997.

Accepted June 20, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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  3. The European Consortium on MEN1. 1997 Identification of the Multiple Endocrine Neoplasia (MEN1) gene from a 1,2 Mb sequence-ready contig of chromosome 11q13. Hum Mol Genet. 6:1177–1183.[Abstract/Free Full Text]
  4. Shepherd JJ. 1991 The natural history of multiple endocrine neoplasia type 1. Highly uncommon or highly unrecognized. Arch Surg. 126:935–952.[Abstract/Free Full Text]
  5. Presciuttini S, Varesco L, Sala P, et al. 1994 Age of onset in familial adenomatous polyposis: heterogeneity within families and among APC mutations. Ann Hum Genet. 58:331–342.[Medline]
  6. Rodriguez-Bigas MA, Lee PH, O’Malley L, et al. 1996 Establishment of a hereditary non-polyposis colorectal cancer registry. Dis Colon Rectum. 39:649–653.[CrossRef][Medline]
  7. Lindblom A. 1995 Familial breast cancer and genes involved in breast carcinogenesis. Breast Cancer Res Tr. 34:171–183.
  8. Heimdal K, Olsson H, Tretli S, Flodgren P, Borresen A-L, Fossa SD. 1996 Familial testicular cancer in Norway and southern Sweden. Br J Cancer. 73:964–969.[Medline]
  9. Horwitz M, Goode EL, Jarvik GP. 1996 Anticipation in familial leukemia. Am J Hum Genet. 59:990–998.[Medline]
  10. Schalling M, Hudson TJ, Buetow KH, Housman DE. 1993 Direct detection of novel expanded trinucleotide repeats in the human genome. Nat Genet. 4:135–139.[CrossRef][Medline]
  11. King BL, Peng H-Q, Goss P, et al. 1997 Repeat expansion detection analysis of (CAG)n tracts in tumor cell lines, testicular cancer families. 57:209–214.
  12. Teh BT, Cardinal J, Shepherd J, et al. 1995 Genetic mapping of the multiple endocrine neoplasia type 1 locus at 11q13. J Intern Med. 238:249–253.[Medline]
  13. European Consortium on MEN1. 1996 Definition of the minimal MEN1 can- didate area based on a 5-Mb integrated map of proximal 11q13. Genomics. 37:354–365.[CrossRef][Medline]
  14. Canzian F, Salovaara R, Hemminki A, et al. 1996 Semiautomated assessment of loss of heterozygosity and replication error in tumors. Cancer Res. 56:3331–3337.[Abstract/Free Full Text]
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  20. Thakker RV, Bouloux P, Wooding C, et al. 1989 Association of parathyroid tumors in multiple endocrine neoplasia type 1 with losses of alleles on chromosome 11. N Engl J Med. 312:218–224.
  21. Byström C, Larsson C, Blomberg C, et al. 1990 Localization of the MEN1 gene to a small region within chromosome band 11q13 by deletion mapping in tumors. Proc Natl Acad Sci USA. 87:1968–1972.[Abstract/Free Full Text]
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