The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 7 3392-3396
Copyright © 2004 by The Endocrine Society
Effect of Multiple Endocrine Neoplasia Type 1 (MEN1) Gene Mutations on Premature Mortality in Familial MEN1 Syndrome with Founder Mutations
T. Ebeling,
O. Vierimaa,
S. Kytölä,
J. Leisti and
P. I. Salmela
Department of Medicine (T.E., P.I.S.), University of Oulu and Oulu University Hospital, and Department of Clinical Genetics (O.V., J.L.), Oulu University Hospital, FIN-90029 Oys, Finland; and Medix Laboratories Ltd. (S.K.), FIN-02630 Espoo, Finland
Address all correspondence and requests for reprints to: Tapani Ebeling, Department of Medicine, Oulu University Hospital, PB 20, FIN-90029 OYS, Finland. E-mail: tapani.ebeling{at}oulu.fi.
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Abstract
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Estimation of mortality and the natural course of a disease is usually based on information of carefully studied individuals with or at risk for a specific disease. Genealogical information has rarely been accurate enough for such studies.
With the help of church records and multiple endocrine neoplasia type 1 (MEN1) family information of the two founder MEN1 mutations in Northern Finland (1466del12 and 1657insC), we could trace back common ancestors born in the beginning of the 1700s (1466del12) and approximately 1850 (1657insC) and find 67 probable gene carriers born between 1728 and 1929, which were identified among their offspring. Information was gathered from 34 obligatory MEN1 gene carriers and 31 spouses. The mean age (± SD) of death of affected males (n = 16) was 61.1 ± 12.0 yr vs. 65.8 ± 15.3 yr for unaffected males (n = 16) and for affected females (n = 16) was 67.2 ± 10.7 yr vs. 67.7 ± 14.7 yr for unaffected females (n = 13). The ages of death of the obligatory heterozygotes did not differ from that of the spouses in sex groups or from the sex-matched life expectancy estimates derived from Finnish national statistics. Causes of death differed significantly between female probands and spouses. In conclusion, obligatory MEN1 gene carrier status did not show a harmful effect on survival in this retrospective analysis tracing back to almost 300 yr.
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Introduction
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MULTIPLE ENDOCRINE NEOPLASIA type 1 (MEN1) is an autosomally dominantly inherited disease with almost 100% penetrance of the MEN1 gene (1). The classical manifestations of MEN1 include primary hyperparathyroidism, pituitary adenomas, and gastroenteropancreatic endocrine tumors (2). Two large retrospective analyses of the natural history of untreated MEN1 have been published: a Tasmanian study (3) and a Mayo Clinic survey (4). The data of these studies included causes of death in MEN1 patients, and in the Tasmanian study, siblings were also included. Mutation analysis was either not possible or not used in these studies, however. Thus, healthy carriers were not noted. The recent identification of the MEN1 gene has made it possible to perform prospective studies of life expectancy and prognosis in gene carriers (5). Using family information and genealogical data from church records it is possible in a historical context to evaluate retrospectively whether the MEN1 gene has had an effect on mortality.
Two clusters of MEN1 subjects and families were found in Northern Finland in the Finnish MEN1 survey. The mutation screening of the MEN1 gene has revealed six different germline mutations in 17 familial cases and one isolated case in Finland. The two prevailing mutations (1466del12 and 1657insC) in Northern Finland accounted for more than 80% of MEN1-positive mutation cases. The detection of the founder couples for both mutations allowed us to trace the probable heterozygotes in their offspring and to make an evaluation of the life expectancy in MEN1.
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Subjects and Methods
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The study was carried out in the Departments of Medicine and Clinical Genetics of the Oulu University Hospital. The study population originates mostly from the Oulu University Hospital District in Northern Finland with approximately 750,000 inhabitants. The two commonest founder mutations were studied (1466del12 and 1657insC mutations), which explain more than 80% of the total MEN1 gene-positive cases in Finland known at present (6, 7, 8). For this study, all the families with one or more MEN1 probands with the two founder mutations (1466del12 mutation and 1657insC mutation) were included. There were altogether 15 probands in 13 families with the MEN1 syndrome. In the families, 40 cases have been documented to have the 1466del12 mutation and 30 the 1657insC mutation. The pedigrees made during initial visits of the probands were further extended by genealogical studies. The names, dates, and places of birth of the ancestors and the dates of death were traced using the Finnish church records, which frequently cover birth and family information back to the years 1650–1700. Practically all the roots up to 1700 were evaluated to find common ancestors and many even further. The lines of inheritance back to the MEN1 patients were studied to evaluate obligatory carriers and their spouses with respect to lifespan, including all individuals born before 1929. A survey of causes of death was also performed, mainly based on church records.
SPSS for Windows (Release 10.0.7) was used for statistical analyses. For comparing mean values of ages in groups, Student’s t test was used, and Levene’s homogeneity-of-variance test was used to ascertain appropriateness of the analysis. Using revised (1881–1990) and abridged (1751–1880) life tables for Finland, an estimate of expected lifetime was applied for each obligatory MEN1 carrier and their spouses (9, 10). These tables give sex and birth-year category specific life expectancy values in years at a certain age. In this survey, life expectancy at the age of 25 yr was used. Birth-year categories in earlier years were in 10-yr periods and later in 5-yr stratification periods. The significance of the differences in causes of death was tested by Pearson 
2 test and Fisher’s exact test.
Informed consent for the mutation screening and genotyping studies was obtained from the participating patients of the MEN1 project of Oulu University Hospital, and the screening procedure was approved by the local ethical committee.
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Results
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Common ancestors, with one exception, for all the MEN1 patients were found. For 1466del12 mutations, the roots of eight families were traced back to a small village (open square on map in Fig. 1
) approximately 45 kilometers east of Oulu, where the founder couple was born in 1705 and 1709, respectively. In the ninth family, the connection has not yet been found. The pedigree consists of approximately 7–10 generations, when counted from the present-day patients. Four families with 1657insC mutation could be traced back to a couple living 200 kilometers northeast of Oulu (open circle in Fig. 1), born in 1844 and 1846, and not farther than only four generations from the youngest. The pedigrees of the founder mutations are illustrated in Figs. 2 and 3.
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FIG. 1. Domiciles of the probands (closed symbols) and founder couples (open symbols) in the families of the two prevailing MEN1 mutations according to the type of mutation in Finland. The 1466del12 mutation is illustrated with squares, the 1657insC mutation with circles. The northernmost proband could not be traced back to the corresponding founder couple and was excluded from this study.
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FIG. 2. Pedigree of 1466del12 mutation-positive families with MEN1 case(s) originating from common ancestors. Only obligatory gene carriers (affected, closed symbols) and their spouses are illustrated in descending generations. Subjects born 1930 or later are excluded. Birth years of ancestors are shown. Subjects are numbered by generation (Roman numbers) and by order in the generation (Arabic numbers). Subjects IX:3, IX:12, and IX:16 were alive as of December 14, 2001. Subject IX:9 was not married.
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FIG. 3. Pedigree of 1657insC mutation-positive families with MEN1 case(s) originating from common ancestors. Only obligatory gene carriers (affected, closed symbols) and their spouses are illustrated in descending generations. Subjects born 1930 or later are excluded. Birth years of ancestors are shown. Subjects are numbered by generation (Roman numbers) and by order in the generation (Arabic numbers). Subject III:8 was alive as of December 14, 2001.
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The initial group consisted of 34 obligatory gene carriers, 16 males and 18 females, (MEN1 positive in later text) and of 33 spouses, 18 males and 15 females, born between 1728 and 1929. Two male spouses were excluded from the analyses because of insufficient information (IX:11, IX:17 in Fig. 2
). Thus, the final study group consisted of 34 heterozygotes and 31 spouses. Four female subjects were still alive, two gene positive (IX:12 born 1927 and IX:16 born 1924 in Fig. 2) and two spouses (IX:3 born 1922 in Fig. 2 and III:8 born 1928 in Fig. 3). The detailed clinical characteristics are shown in Tables 1 and 2. In the 1466del12 mutation (mutation 1) pedigree, there were 28 heterozygotes (15 males and 13 females) and 25 spouses (11 males and 14 females) (Table 1), and in the 1657insC mutation (mutation 2) pedigree, six heterozygotes (one male and five females) and six spouses (five males and one female) (Table 2). The living subjects were excluded from true lifespan analysis, but a subanalysis using their age as lifespan was made.
When comparing the ages of death of the obligatory gene carriers (MEN1 positive) with the spouses in sex groups, there were no significant differences. The mean age of affected males (n = 16) was 61.1 ± 12.0 yr with a range of 39–80 yr and that of unaffected males (n = 16) 65.8 ± 15.3 yr and the range 34–84 yr (not significant; P = 0.342). The corresponding figures for affected females (n = 16) were 67.2 ± 10.7 yr with a range of 42–79 yr and that of unaffected females (n = 13) 67.7 ± 14.7 yr and 46–87 yr (not significant; P = 0.917), respectively.
A nonsignificant difference was found for the age of death of the MEN1-positive men in comparison with expected lifetime derived from life expectancy tables based on the 25-year-olds’ table: 61.1 ± 12.0 yr (n = 16) vs. 61.7 ± 3.1 yr (P = 0.841). A respective comparison in the MEN1-positive women gave analogous results; the mean age of death was 67.2 ± 10.7 yr (n = 16) and life expectancy 66.5 ± 3.3 yr, also a nonsignificant difference (P = 0.806).
In male spouses, the respective values were 65.8 ± 15.3 vs. 62.2 ± 1.7 yr (n = 16) (P = 0.377) and in female spouses, 67.7 ± 14.7 vs. 63.7 ± 3.5 yr (n = 13) (P = 0.272). The figures did not differ significantly.
In linear regression analysis with the age of death as dependent variable and pedigree group, MEN1 trait, and sex as explaining variables and expected lifespan and birth year as covariates, no significant associations explaining death age were encountered.
The causes of death of 55 of 61 subjects were found, and causes of death of six subjects were not attained (one proband and five spouses). Reliability of the causes was classified by the investigator as certain (36%), quite certain (13%), and based on only church records (51%). The main causes of death were cardiovascular disease (41.8%), infection (16.4%, mainly tuberculosis), aging (12.7%), trauma (5.5%), withering (5.5%), malignancy not classically associated with MEN1 (5.5%), MEN1-associated causes of death (9.1%, often classified as cancer in the abdomen), MEN1 causes (3.6%, such as gastroenteropancreatic tumor). Withering (synonyms wilting, fading, and wasting away) as a cause of death is a descriptive term and could imply a chronic disease, often malignancy, causing death. When the four last ones (withering, malignancy, MEN1-associated cause of death, and MEN1 cause) were classified as possible MEN1 causes and others as not MEN1 causes, a statistically significant difference was found between probands and spouses in females (Fisher’s exact test, P = 0.003) but not in males (Fisher’s exact test, P = 0.355). In female subjects, of 15 probands, eight (53%) died of possible MEN1 cause, whereas of the 12 female spouses, none died of possible MEN1 cause. Excluding 1657insC mutation from the analyses did not abolish significance, but in the subgroup of 1657insC mutation families, statistical significance could not be estimated because of small numbers.
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Discussion
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The main result of our genetically established genealogical survey was that the lifespan of the subjects considered as MEN1 heterozygotes did not show significant differences in comparison with the group of their spouses in sex groups or to general life expectancy estimates. The small population, the geographical isolation, and the internal migration movement in the 1500s led to formation of numerous founder (11) populations in Finland, and by combining genetic and clinical investigations with careful genealogical studies, several founder chromosomes for various genetic diseases have been established (12, 13, 14).
In 1993, Wilkinson et al. (3) published a retrospective analysis of the natural history of untreated MEN1 in a Tasmanian population. They determined the causes of death in a large MEN1 kindred with data available over a period of 130 yr. Most cases were unrecognized as MEN1 at the time of the patient’s death. They concluded that MEN1 leads to premature death and that neoplasia rather than peptic ulcer disease is the main cause of death. A retrospective review of all MEN1 patients treated at the Mayo Clinic during the period 1951–1997 has recently been published (4). The overall 20-yr survival of MEN1 patients was 64% (95% confidence interval was 56–72%) and that of an age- and gender-matched upper Midwest population was 81% (P < 0.001). Thus, the patients with MEN1 appeared to be at increased risk of premature death. Patients with MEN1 have been reported to die prematurely more likely from MEN1-related causes than nonendocrine causes (15).
The family trees with founder mutations in the MEN1 gene have been reported only from Tasmania (3), Canada (16), and Finland. Such families are unique study populations to evaluate the possible effect of MEN1 mutations on the lifespan of carriers. We have had an opportunity to observe two family trees with such a founder mutation. To ascertain that the true common ancestors are found, practically all the pedigree roots up to 1700 were evaluated, and many were evaluated even further. Nonpaternity is a possibility always worth remembering, and this is the case probably in the 1466del12 mutation-positive family, which could not be connected to ancestors despite the same mutation. Haplotype analysis around the mutant MEN1 allele in our families has shown that the area is quite conserved, and thus recent common ancestors within 10 generations could be expected to be found (Kytölä, S, unpublished data). One of the advantages in our retrospective survey of MEN1 heterozygotes and their spouses is that gene carriers can also be included, thus completing the picture. The evaluation period is also almost 300 yr, a feature unsurpassed by modern prospective studies for centuries. One of the drawbacks in the present genealogical survey is the assumption that the MEN1 gene doesn’t cause mortality before the age of 25 yr. According to the literature, this is quite rare (1), also according to our own unpublished data. Thus, the use of life expectancy tables for 25-yr-olds can be regarded as acceptable. Another selection bias in our study is that these persons were practically all ancestors in the study group, and fertility is obligatory to be an ancestor. MEN1 positivity can cause infertility, for example through hyperprolactinemia, and thus omit subjects from this survey (17). Pituitary adenomas, most of them prolactinomas, are present in 15–20% of patients with MEN1 (18). The family trees of the two MEN1 pedigrees imply that heterozygosity has not, at least markedly, reduced fertility and child number. Heterozygote advantage cannot be excluded when family trees of expanding MEN1 families are looked at. The genetic fitness is close to 100%. Including siblings was not generally possible because MEN1 status could not be judged in them.
The birth and death dates are reliable, grounded on a sound tradition of church records kept by churchmen and initially legislated by the king of Sweden. The causes of death have also often been recorded by the priests, but up to the 20th century they were quite descriptive because of unprofessional classification and lack of autopsies.
When evaluating whether excess mortality exists, the death rate of the whole population to be compared with is a crucially important factor. In the years 1700–1880, death rates of the population of Finland were remarkably high, resembling those of present underdeveloped countries (19), until a sustained decline in mortality began in the decade 1870–1880 (9). Life expectancy of 25-yr-old citizens of Finland by birth-year group and sex is illustrated in Fig. 4. Life expectancy was much higher at age 15 than at birth, demonstrating a high mortality in childhood. This is why the life expectancy value changes in adults were minor or moderate compared with large changes in children’s life expectancy when approaching the year 1900 (9). Birth year and life expectancy showed a strong positive mutual correlation in the whole group and subgroups of men and women as can be expected, because they represent population value estimates. Figure 4 illustrates total life expectancy in years of 25-yr-old citizens of Finland at a certain year in birth-year and sex groups. Between the years of 1750 and 1885, life expectancy of 25-yr-olds was very variable and did not show any consistent trends but rather was a plateau. During that period, the life expectancy mean of 25-yr-old males was 59.5 yr (range, 55.2–62.7) and 61.0 yr (range, 57.2–64.5) for females. After 1885, there was a clear, strong positive linear correlation between life expectancy and birth year. During that phase, life expectancy reached modern lifespan levels, and the rise from 1885 was 13 yr in males and 18 yr in females.
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FIG. 4. Life expectancy of 25-yr-old citizens of Finland at a certain year by birth-year groups and sex. Birth-year group stratification was 10-yr intervals earlier and 5-yr intervals between 1941 and 1990.
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When comparing the lifespan of the obligatory gene carriers to the lifespan of imaginary reference subjects with the same sex and birth year in the same 5- to 10-yr period, the results confirmed the data obtained from the comparison of gene carrier group to spouse group. Assumptions that genetic screening will reduce morbidity and also mortality in MEN1 in the future have been postulated in scientific literature (20). The findings here, which are in contrast with previous studies, could be related to differences in genotypes or in gene-environment interactions. Still, the most probable reason that our genealogical survey did not show excess premature mortality in MEN1 patients can be mainly explained by high mortality in the whole population because of periods of famine, infectious diseases, and wars. Presymptomatic diagnosis has not been shown to yield clear clinical benefit in patients with MEN1 (21). Our retrospective view did not show a harmful effect of MEN1 gene trait positivity to life expectancy, but it can be speculated whether the situation is the same nowadays, when life expectancy is from 13 yr (in men) to 18 yr (in women) higher. The historical study population did not show any significant associations to the age of death when pedigree group, MEN1 trait, and sex were used as explaining variables and as covariates expected lifespan and birth year. The trend of increasing lifespan did not come up, when subjects born 1860 or after were analyzed in subgroups of sex and probands and spouses separately, perhaps because of the small number of subjects. Those four who were excluded from the main analysis because they were still living had all already exceeded the expected life-span [two MEN1 subjects (+1.1 and 6.1 yr) and two spouses (+8.2 and 0.8 yr)], and including them in the analyses with age as lifespan did not change results.
There was a significant difference in causes of death between female probands and female spouses (P = 0.003), but the same was not true in males. In female subjects, of 15 probands, eight (53%) died of possible MEN1 cause, whereas of the 12 female spouses, none died of possible MEN1 cause. This means that female obligatory gene carriers showed a different pattern of causes of death from female controls. The difference in significance between females and males could partly be explained by lower life expectancy in males, and thus competing death causes could have intervened before MEN1 causes. A retrospective classification of old causes of death into MEN1-related and other causes yields only a crude estimate for the evaluation of the effect of MEN1 gene positivity, as MEN1-related causes of death included mainly causes that could be regarded as resulting from a malignancy. Reliability of the initial causes of death in the documents was classified by the investigator as certain in 36% of cases.
The most prevalent mutation (1466del12) is a unique Finnish mutation, but the other one seems to be at a hotspot, because it has been found in five different MEN1 populations (1657insC) (2).
Conclusion
The MEN1 pedigree study population of subjects born between 1728 and 1929 gives information on survival of gene heterozygotes in a historical context. The lifespan of MEN1-positive subjects was equal to their spouse group in sex groups and also similar to the life expectancy estimates derived from Finnish national statistics. Thus, the MEN1 gene did not show a harmful effect to survival in our analyses, but causes of death were different in female probands compared with causes of death in female spouses. More prospective studies are needed to assess whether the MEN1 gene has a statistically significant negative effect to survival in modern eras, when the life expectancy has generally increased in the population. Genetically established genealogical surveys for life expectancy analyses to obtain information on inherited diseases is a promising but rarely used method suitable for isolated populations.
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Acknowledgments
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We thank genealogists Veikko Väätäinen and Markku Kuorilehto for their skillful assistance. The offices of Evangelical Lutheran Church parishes in Northern Finland have helped to accomplish this survey. Especially, the efforts of Treasurer Jouko Hanhela in Ylikiiminki parish are gratefully noticed. The Provincial Archives of Oulu with microfilms of church records have been of utmost importance. We also thank Mrs. Liisa Ukkola and the personnel at the Department of Clinical Genetics in Oulu University Hospital for collecting blood samples and the DNA laboratory in Oulu University Hospital for extracting DNA. Docent Robert Winqwist has helped in analyzing the tissue specimen for MEN1 mutation.
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Footnotes
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This work was supported by Oulu University Hospital scientific (kevo) program and grants from the Cancer Society of Northern Finland.
Abbreviation: MEN1, Multiple endocrine neoplasia type 1.
Received August 29, 2003.
Accepted March 28, 2004.
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References
|
|---|
- 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 Jr SA, Marx SJ 2001 Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 86:5658–5671[Abstract/Free Full Text]
- Guo SS, Sawicki MP 2001 Molecular and genetic mechanisms of tumorigenesis in multiple endocrine neoplasia type-1. Mol Endocrinol 15:1653–1664[Abstract/Free Full Text]
- Wilkinson S, Teh BT, Davey KR, McArdle JP, Young M, Shepherd JJ 1993 Cause of death in multiple endocrine neoplasia type 1. Arch Surg 128:683–690[Abstract]
- Dean PG, van Heerden JA, Farley DR, Thompson GB, Grant CS, Harmsen WS, Ilstrup DM 2000 Are patients with multiple endocrine neoplasia type I prone to premature death? World J Surg 24:1437–1441[CrossRef][Medline]
- 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 1997 Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 276:404–407[Abstract/Free Full Text]
- Kytölä S, Leisti J, Winqvist R, Salmela P 1995 Improved carrier testing for multiple endocrine neoplasia, type 1, using new microsatellite-type DNA markers. Hum Genet 96:449–453[Medline]
- Teh BT, Kytölä S, Farnebo F, Bergman L, Wong FK, Weber G, Hayward N, Larsson C, Skogseid B, Beckers A, Phelan C, Edwards M, Epstein M, Alford F, Hurley D, Grimmond S, Silins G, Walters M, Stewart C, Cardinal J, Khodaei S, Parente F, Tranebjærg L, Jorde R, Menon J, Khir A, Tan TT, Chan SP, Zaini A, Khalid BAK, Sandelin K, Thompson N, Brandi M-L, Warth M, Stock J, Leisti J, Cameron D, Shepherd JJ, Öberg K, Nordenskjöld M, Salmela P 1998 Mutation analysis of the MEN1 gene in multiple endocrine neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism. J Clin Endocrinol Metab 83:2621–2626[Abstract/Free Full Text]
- Kytölä S, Villablanca A, Ebeling T, Nord B, Larsson C, Hoog A, Wong FK, Valimaki M, Vierimaa O, Teh BT, Salmela PI, Leisti J 2001 Founder effect in multiple endocrine neoplasia type 1 (MEN 1) in Finland. J Med Genet 38:185–189[Free Full Text]
- Turpeinen O, Kannisto V 1997 Abridged life tables for Finland 1751–1880. Population 5:1–37. Helsinki: Statistics Finland
- Kannisto V, Nieminen M 1996 Revised life tables for Finland 1881–1990. Population 2:1–67. Helsinki: Statistics Finland
- Vahtola J 1980 The origins of settlement in the Tornio and Kemi River valleys. An onomastic and historical study (in Finnish). Rovaniemi, Finland: Societas Historica Finlandiae Septentrionalis
- de la Chapelle A 1993 Disease gene mapping in isolated human populations: the example of Finland. J Med Genet 30:857–865[Medline]
- de la Chapelle A, Wright FA 1998 Linkage disequilibrium mapping in isolated populations: the example of Finland revisited. Proc Natl Acad Sci USA 95:12416–12423[Abstract/Free Full Text]
- Peltonen L, Jalanko A, Varilo T 1999 Molecular genetics of the Finnish disease heritage. Hum Mol Genet 8:1913–1923[Abstract/Free Full Text]
- Doherty GM, Olson JA, Frisella MM, Lairmore TC, Wells Jr SA, Norton JA 1998 Lethality of multiple endocrine neoplasia type I. World J Surg 22:581–586; discussion 586–587[CrossRef][Medline]
- Olufemi SE, Green JS, Manickam P, Guru SC, Agarwal SK, Kester MB, Dong Q, Burns AL, Spiegel AM, Marx SJ, Collins FS, Chandrasekharappa SC 1998 Common ancestral mutation in the MEN1 gene is likely responsible for the prolactinoma variant of MEN1 (MEN1Burin) in four kindreds from Newfoundland. Hum Mutat 11:264–269[CrossRef][Medline]
- Schuppe HC, Neumann NJ, Schock-Skasa G, Hoppner W, Feldkamp J 1999 Secondary infertility as early symptom in a man with multiple endocrine neoplasia-type 1. Hum Reprod 1:252–254
- Arnold A 2003 Clinical manifestations and diagnosis of multiple endocrine neoplasia type 1. In: Rose, BD, ed. Wellesley, MA: UpToDate
- United Nations 1991 Demographic Yearbook 1987, New York
- Clerici T, Schmid C, Komminoth P, Lange J, Spinas GA, Brandle M 2001 10 Swiss kindreds with multiple endocrine neoplasia type 1: assessment of screening methods. Swiss Med Wkly 131:381–386[Medline]
- Arnold A 2003 Classification and pathogenesis of the multiple endocrine neoplasia syndromes. In: Rose, BD, ed. Wellesley, MA: UpToDate
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O Vierimaa, T M L Ebeling, S Kytola, R Bloigu, E Eloranta, J Salmi, E Korpi-Hyovalti, L Niskanen, A Orvola, E Elovaara, et al.
Multiple endocrine neoplasia type 1 in Northern Finland; clinical features and genotype phenotype correlation
Eur. J. Endocrinol.,
September 1, 2007;
157(3):
285 - 294.
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Abstract
Introduction
