- Email: [email protected]
Ileorectal anastomosis is appropriate for a subset of patients with familial adenomatous polyposis
August 2001
a median follow-up of 81 months. In 200 patients, the APC mutation was known. They reported that a location of the mutation within the region of codon 1250 –1464 and the presence of colon cancer at the primary IRA were independent predictive factors for the development of rectal cancer.2 The small discrepancy between the 2 studies with respect to location of mutation may be caused by the fact that the Italian series included substantially more patients with a mutation at codon 1309 (n ⫽ 23, of whom 7 developed rectal cancer), compared with the Scandinavian-Dutch series (n ⫽ 8, of whom none developed rectal cancer). Another difference is the follow-up. According to the authors, regular follow-up has only been available in Italy for the last 15–20 years, whereas in Scandinavia and the Netherlands regular follow-up has been used since the 1940s, and one of our inclusion criteria was in fact regular follow-up. In our series, the cumulative risk of secondary rectal cancer was 12% after 20 years and 18% after 30 years, compared with 23% after 20 years in the Italian study. An important finding in our study was the high risk of secondary proctectomy (47%) at 30 years after colectomy. This risk was highest in patients with a mutation in the region of codon 1250 –1500. This finding and the good quality of life after restorative proctocolectomy3 was the basis for our recommendation to offer IRA only to young patients with a few rectal adenomas and a mild polyposis phenotype in the family and to patients with attenuated polyposis. STEFFEN BU¨LOW HANS VASEN CHARLOTTE BU¨LOW MARIE LUISE BISGAARD HEIKKI JA¨RVINEN ¨ RK JAN BJO 1. Bu¨low C, Vasen H, Ja¨rvinen H, et al. Ileorectal anastomosis is appropriate for a subset of patients with familial adenomatous polyposis. Gastroenterology 2000;119:1454 –1460. 2. Bertario L, Russo A, Radice P, et al. Genotype and phenotype as determinants for rectal stump cancer in patients with familial adenomatous polyposis. Ann Surg 2000;231:538 –543. 3. van Duijvendijk P, Slors JF, Taat CW, et al. Quality of life after total colectomy with ileorectal anastomosis or proctocolectomy with an ileal pouch-anal anastomosis for familial adenomatous polyposis. Br J Surg 2000;87:590 –596.
Ileorectal Anastomosis Is Appropriate for a Subset of Patients With Familial Adenomatous Polyposis Dear Sir: The report by Bu¨low et al.1 evaluates the risk of rectal cancer and the frequency of subsequent proctectomy for nonmalignant causes in patients with familial adenomatous polyposis (FAP) who had previously undergone colectomy with ileorectal anastomosis (IRA). The investigators conclude that IRA is appropriate for a subset of FAP patients. They recommend IRA for (young) patients with few rectal adenomas and a family history of a mild phenotype and for patients with attenuated FAP (AAPC), and ileal pouch-anal anastomosis (IPAA) for patients with many rectal polyps. We agree with this recommendation of Bu¨low et al. However, we raise an objection to the additional statement defining AAPC and typical FAP by the site of mutation in the APC gene. This would imply to use the site of mutation as an alternative indicator to recommend either IRA or IPAA. Our reservations are based on the following considerations.
CORRESPONDENCE
503
There is a statistical correlation between site of mutation and phenotype. Nevertheless, the definition of AAPC should be based on clinical evidence and not on the “site of mutation before codon 200 or after 1500” (or whatever exact boundaries will be given). Nasioulos et al.2 reported a family with typical FAP and a mutation encompassing codons 116 –118. Additionally, late onset FAP with distribution of adenomas characteristic of AAPC has been described in most, but not all, affected members of a large FAP family with a nonsense mutation at codon 233.3 Thus, there is obviously no clear boundary in the APC gene that separates AAPC from typical FAP. Furthermore, mutations in the alternatively spliced sequence of exon 9 are known to be associated with AAPC.4,5 Mutations in different introns located at splice site sequences may result in a variable reduction of splicing efficiency with a different residual APC expression and thus, in a hardly predictable phenotype. For example, it has been shown that a base exchange in the splice-donor site of exon 9 (IVS9 ⫹ 5g 3 t) results in a partial deletion of the entire exon 9 leading to a mild, although variable, polyposis phenotype in an extended FAP kindred.6 In a patient with typical FAP, we observed a similar mutation in the splice acceptor site of exon 11 (IVS10 ⫺ 5a 3 g) that creates a new splice site leading to a frameshift and complete loss of normal APC product. These are only few examples showing that the AAPC phenotype is not limited to (and cannot be predicted by) mutations at defined sites of the APC gene. About 60% of published germline APC mutations are frameshift mutations caused by small insertions/deletions that are predicted to lead to truncated proteins. However, the premature stop codon generated by these mutations may arise shortly after the frameshift, but also after more than 60 “false” codons.7 Such “false” proteins of different length may lead to unstable APC proteins, or may induce variable immunogenic or other effects. Their influence on residual function of the mutant APC protein can be variable, and so can be the patient’s phenotype. Many FAP patients carry a unique mutation. We identified diseaserelevant APC mutations in 327 of 680 unrelated patients. In 88 of them, we found the 2 most common mutations, but in the remaining 247 patients, we identified 168 different mutations, of which 86 have not been reported before.8 The clinical relevance in terms of phenotype and recommended surgical procedure of these “private” mutations detected in 1 patient (or 1 family) only can hardly be predicted. When FAP patients have to undergo colectomy, it is the clinician’s difficult task to decide on the extent of surgical intervention. It would be of great help if mutation analysis could indeed be of use in each individual decision, but in fact it is not. From our long-term experience in the field, we feel that clinicians frequently overestimate the value of mutation data. It might even be confusing to draw conclusions from the mutation analysis for the surgical procedure when the observed phenotype of the patient does not coincide with the phenotype “predicted” by the site of the APC mutation. Therapeutic decisions regarding timing and degree of surgical intervention should be based on the present colonic manifestation, e.g., number, size, and site of adenomas, considering age and family history and the clinical situation of the patient, rather than on mutation data. WALTRAUT FRIEDL ELISABETH MANGOLD Institute of Human Genetics REINER CASPARI CHRISTOF LAMBERTI Department of Medicine I
504
CORRESPONDENCE
PETER PROPPING Institute of Human Genetics University of Bonn Bonn, Germany 1. Bu¨low C, Vasen H, Ja¨rvinen H, et al. Ileorectal anastomosis is appropriate for a subset of patients with familial adenomatous polyposis. Gastroenterology 2000;119:1454 –1460. 2. Nasioulos S, Jones I, St John DJB, et al. Does there really exist an APC gene “5⬘ boundary,” separating attenuated from typical FAP? In: 2nd Joint Meeting Leeds Castle Polyposis Group and International Collaborative Group for Hereditary Non-Polyposis Colorectal Cancer; 1999. Melbourne&Lorne, Australia, 1999:49. 3. Smith Ravin J, Pack K, Hodgson S, et al. APC mutation associated with late onset of familial adenomatous polyposis. J Med Genet 1994;31:888 – 890. 4. Soravia C, Berk T, Madlensky L, et al. Genotype-phenotype correlations in attenuated adenomatous polyposis coli. Am J Hum Genet 1998;62:1290 –1301. 5. Van der Luijt RB, Vasen HFA, Tops CMJ, et al. APC mutation in the alternatively spliced region of exon 9 associated with late onset familial adenomatous polyposis. Hum Genet 1995;96:705–710. 6. Varesco L, Gismondi V, Presciuttini S, et al. Mutation in a splicedonor site of the APC gene in a family with polyposis and late age of colonic cancer death. Hum Genet 1994;93:281–286. 7. Scott RJ, van der Luijt R, Spycher M, et al. Novel germline APC gene mutation in a large familial adenomatous polyposis kindred displaying variable phenotypes. Gut 1995;36:731–736. 8. Friedl W, Caspari R, Sengteller M, et al. Can APC mutation analysis contribute to therapeutic decisions in familial adenomatous polyposis? Experience from 680 FAP families. Gut 2001 (in press). doi:10.1053/gast.2001.26939
Reply. We agree with Friedl et al. that attenuated familial adenomatous polyposis (AFAP) is mainly a clinical diagnosis, which may be difficult. When in a given family the numbers of adenomas in the relatives vary from ⬍100 to ⬎100, the diagnosis of polyposis and colorectal cancer is made at a higher age than usual in FAP, and most of the adenomas are right-sided, the diagnosis of AFAP should be suspected. When considering these criteria, the age of the patients and the mode of diagnosis (symptomatic or screen-detected) should be taken into account as well. Because of the diagnostic difficulties, most investigators also add information on the genotype. When polyposis families are reported in the literature with features of AFAP in association with a specific mutation, the identification of this mutation in a family with a similar expression of the disease might support the diagnosis of AFAP. Many investigators have tried to establish correlation between mutations in specific regions within the APC gene and certain manifestations of the disease, e.g., desmoid tumors, the finding of CHRPE, and AFAP. The Friedl group has suggested that mutations in certain regions are associated with specific manifestations of the disease. In a recent study by the group, presented at the AGA 2000 in San Diego, FAP patients were subdivided according to the site of the mutation, and a variation of the average age of onset of the disease was found in subgroups of the patients. We agree with Friedl et al. that it is difficult and often not possible to define exact boundaries. On the other hand, our present study showed a very low risk of secondary proctectomy in polyposis patients with a mutation in codon 0 –200 or ⬎1500, which we used as our definition of AFAP. Based on this, we recommended IRA in AFAP, which corresponds to the international attitude. Apart from this subset of polyposis patients,
GASTROENTEROLOGY Vol. 121, No. 2
we agree that knowledge about genotype-phenotype correlation is still too limited to justify strict recommendations about therapy. We agree that the reported associations are not absolute. For example, patients with mutations in codon 1309 on average have a higher risk of developing profuse polyposis at an early age, but not all patients with this mutation will develop this aggressive form of polyposis.1 We believe that no surgeons will make decisions about surgical method solely on the basis of the genotype. We would like to emphasize that decisions about the type of surgery should be made on the basis of the age of the patient, the endoscopic findings, the phenotype of the disease in the family, the genotype, and, most importantly, the opinion of the patient after a detailed analysis about the natural history of the disease and the pros and cons of the available surgical options. ¨ LOW STEFFEN BU HANS VASEN ¨ LOW CHARLOTTE BU MARIE LUISE BISGAARD HEIKKI JA¨RVINEN JAN BJO¨RK 1. Giardiello FM, Krush AJ, Petersen GM, et al. Phenotypic variability of familial adenomatous polyposis in 11 unrelated families with identical APC mutation. Gastroenterology 1994;106:1542–1547.
Osteoporosis in Newly Diagnosed Inflammatory Bowel Disease Dear Sir: We read with interest the recent article by Erik et al.1 They compared bone mineral density in newly diagnosed patients with inflammatory bowel disease (IBD) and matched controls. They concluded that there are no significant differences between these groups. Their findings contrast with earlier experimental and clinical studies. By using markers such as interleukin 6, osteocalcin, parathyroid hormone, and N-telopeptide cross-linked type 1 collagen (NTX), Pollak et al.2 showed that chronic IBD is associated with increased bone loss with inflammatory factors like interleukin 6 playing a significant role in this process. This has been confirmed in other studies.3 On the basis of these studies, patients with IBD reasonably might be expected to have reduced bone mineral density at diagnosis compared with controls. In support of this contention, in an earlier clinical study, Gosh et al.4 concluded that, at diagnosis, low bone mineral density is indeed a feature of Crohn’s disease. With the advent of therapy for osteoporosis, this is an important area and the conflict of results between Gosh et al. and Erik et al. must be resolved. Possible explanations for the difference in results between the 2 studies may be found in the demographics of the patient populations studied. There were a number of methodological problems in the early report of Gosh et al. including small patient numbers, wide age range, a large proportion of patients with proctitis, and the absence of information on menopausal status in female patients. In addition, in the study by Erik et al., the majority of Crohn’s patients (16/24) were female, and in total 33 of 36 female patients studied were using oral contraceptives. Although controversial, oral contraceptives may influence bone mineral density and metabolism in premenopausal women.5– 8 This is worthy of consideration in view of the contrasting results with the study by Ghosh et al. The rate of bone turnover and renal tubular reabsorption of calcium are affected by estrogens, and studies have shown that in premenopausal women, use
a median follow-up of 81 months. In 200 patients, the APC mutation was known. They reported that a location of the mutation within the region of codon 1250 –1464 and the presence of colon cancer at the primary IRA were independent predictive factors for the development of rectal cancer.2 The small discrepancy between the 2 studies with respect to location of mutation may be caused by the fact that the Italian series included substantially more patients with a mutation at codon 1309 (n ⫽ 23, of whom 7 developed rectal cancer), compared with the Scandinavian-Dutch series (n ⫽ 8, of whom none developed rectal cancer). Another difference is the follow-up. According to the authors, regular follow-up has only been available in Italy for the last 15–20 years, whereas in Scandinavia and the Netherlands regular follow-up has been used since the 1940s, and one of our inclusion criteria was in fact regular follow-up. In our series, the cumulative risk of secondary rectal cancer was 12% after 20 years and 18% after 30 years, compared with 23% after 20 years in the Italian study. An important finding in our study was the high risk of secondary proctectomy (47%) at 30 years after colectomy. This risk was highest in patients with a mutation in the region of codon 1250 –1500. This finding and the good quality of life after restorative proctocolectomy3 was the basis for our recommendation to offer IRA only to young patients with a few rectal adenomas and a mild polyposis phenotype in the family and to patients with attenuated polyposis. STEFFEN BU¨LOW HANS VASEN CHARLOTTE BU¨LOW MARIE LUISE BISGAARD HEIKKI JA¨RVINEN ¨ RK JAN BJO 1. Bu¨low C, Vasen H, Ja¨rvinen H, et al. Ileorectal anastomosis is appropriate for a subset of patients with familial adenomatous polyposis. Gastroenterology 2000;119:1454 –1460. 2. Bertario L, Russo A, Radice P, et al. Genotype and phenotype as determinants for rectal stump cancer in patients with familial adenomatous polyposis. Ann Surg 2000;231:538 –543. 3. van Duijvendijk P, Slors JF, Taat CW, et al. Quality of life after total colectomy with ileorectal anastomosis or proctocolectomy with an ileal pouch-anal anastomosis for familial adenomatous polyposis. Br J Surg 2000;87:590 –596.
Ileorectal Anastomosis Is Appropriate for a Subset of Patients With Familial Adenomatous Polyposis Dear Sir: The report by Bu¨low et al.1 evaluates the risk of rectal cancer and the frequency of subsequent proctectomy for nonmalignant causes in patients with familial adenomatous polyposis (FAP) who had previously undergone colectomy with ileorectal anastomosis (IRA). The investigators conclude that IRA is appropriate for a subset of FAP patients. They recommend IRA for (young) patients with few rectal adenomas and a family history of a mild phenotype and for patients with attenuated FAP (AAPC), and ileal pouch-anal anastomosis (IPAA) for patients with many rectal polyps. We agree with this recommendation of Bu¨low et al. However, we raise an objection to the additional statement defining AAPC and typical FAP by the site of mutation in the APC gene. This would imply to use the site of mutation as an alternative indicator to recommend either IRA or IPAA. Our reservations are based on the following considerations.
CORRESPONDENCE
503
There is a statistical correlation between site of mutation and phenotype. Nevertheless, the definition of AAPC should be based on clinical evidence and not on the “site of mutation before codon 200 or after 1500” (or whatever exact boundaries will be given). Nasioulos et al.2 reported a family with typical FAP and a mutation encompassing codons 116 –118. Additionally, late onset FAP with distribution of adenomas characteristic of AAPC has been described in most, but not all, affected members of a large FAP family with a nonsense mutation at codon 233.3 Thus, there is obviously no clear boundary in the APC gene that separates AAPC from typical FAP. Furthermore, mutations in the alternatively spliced sequence of exon 9 are known to be associated with AAPC.4,5 Mutations in different introns located at splice site sequences may result in a variable reduction of splicing efficiency with a different residual APC expression and thus, in a hardly predictable phenotype. For example, it has been shown that a base exchange in the splice-donor site of exon 9 (IVS9 ⫹ 5g 3 t) results in a partial deletion of the entire exon 9 leading to a mild, although variable, polyposis phenotype in an extended FAP kindred.6 In a patient with typical FAP, we observed a similar mutation in the splice acceptor site of exon 11 (IVS10 ⫺ 5a 3 g) that creates a new splice site leading to a frameshift and complete loss of normal APC product. These are only few examples showing that the AAPC phenotype is not limited to (and cannot be predicted by) mutations at defined sites of the APC gene. About 60% of published germline APC mutations are frameshift mutations caused by small insertions/deletions that are predicted to lead to truncated proteins. However, the premature stop codon generated by these mutations may arise shortly after the frameshift, but also after more than 60 “false” codons.7 Such “false” proteins of different length may lead to unstable APC proteins, or may induce variable immunogenic or other effects. Their influence on residual function of the mutant APC protein can be variable, and so can be the patient’s phenotype. Many FAP patients carry a unique mutation. We identified diseaserelevant APC mutations in 327 of 680 unrelated patients. In 88 of them, we found the 2 most common mutations, but in the remaining 247 patients, we identified 168 different mutations, of which 86 have not been reported before.8 The clinical relevance in terms of phenotype and recommended surgical procedure of these “private” mutations detected in 1 patient (or 1 family) only can hardly be predicted. When FAP patients have to undergo colectomy, it is the clinician’s difficult task to decide on the extent of surgical intervention. It would be of great help if mutation analysis could indeed be of use in each individual decision, but in fact it is not. From our long-term experience in the field, we feel that clinicians frequently overestimate the value of mutation data. It might even be confusing to draw conclusions from the mutation analysis for the surgical procedure when the observed phenotype of the patient does not coincide with the phenotype “predicted” by the site of the APC mutation. Therapeutic decisions regarding timing and degree of surgical intervention should be based on the present colonic manifestation, e.g., number, size, and site of adenomas, considering age and family history and the clinical situation of the patient, rather than on mutation data. WALTRAUT FRIEDL ELISABETH MANGOLD Institute of Human Genetics REINER CASPARI CHRISTOF LAMBERTI Department of Medicine I
504
CORRESPONDENCE
PETER PROPPING Institute of Human Genetics University of Bonn Bonn, Germany 1. Bu¨low C, Vasen H, Ja¨rvinen H, et al. Ileorectal anastomosis is appropriate for a subset of patients with familial adenomatous polyposis. Gastroenterology 2000;119:1454 –1460. 2. Nasioulos S, Jones I, St John DJB, et al. Does there really exist an APC gene “5⬘ boundary,” separating attenuated from typical FAP? In: 2nd Joint Meeting Leeds Castle Polyposis Group and International Collaborative Group for Hereditary Non-Polyposis Colorectal Cancer; 1999. Melbourne&Lorne, Australia, 1999:49. 3. Smith Ravin J, Pack K, Hodgson S, et al. APC mutation associated with late onset of familial adenomatous polyposis. J Med Genet 1994;31:888 – 890. 4. Soravia C, Berk T, Madlensky L, et al. Genotype-phenotype correlations in attenuated adenomatous polyposis coli. Am J Hum Genet 1998;62:1290 –1301. 5. Van der Luijt RB, Vasen HFA, Tops CMJ, et al. APC mutation in the alternatively spliced region of exon 9 associated with late onset familial adenomatous polyposis. Hum Genet 1995;96:705–710. 6. Varesco L, Gismondi V, Presciuttini S, et al. Mutation in a splicedonor site of the APC gene in a family with polyposis and late age of colonic cancer death. Hum Genet 1994;93:281–286. 7. Scott RJ, van der Luijt R, Spycher M, et al. Novel germline APC gene mutation in a large familial adenomatous polyposis kindred displaying variable phenotypes. Gut 1995;36:731–736. 8. Friedl W, Caspari R, Sengteller M, et al. Can APC mutation analysis contribute to therapeutic decisions in familial adenomatous polyposis? Experience from 680 FAP families. Gut 2001 (in press). doi:10.1053/gast.2001.26939
Reply. We agree with Friedl et al. that attenuated familial adenomatous polyposis (AFAP) is mainly a clinical diagnosis, which may be difficult. When in a given family the numbers of adenomas in the relatives vary from ⬍100 to ⬎100, the diagnosis of polyposis and colorectal cancer is made at a higher age than usual in FAP, and most of the adenomas are right-sided, the diagnosis of AFAP should be suspected. When considering these criteria, the age of the patients and the mode of diagnosis (symptomatic or screen-detected) should be taken into account as well. Because of the diagnostic difficulties, most investigators also add information on the genotype. When polyposis families are reported in the literature with features of AFAP in association with a specific mutation, the identification of this mutation in a family with a similar expression of the disease might support the diagnosis of AFAP. Many investigators have tried to establish correlation between mutations in specific regions within the APC gene and certain manifestations of the disease, e.g., desmoid tumors, the finding of CHRPE, and AFAP. The Friedl group has suggested that mutations in certain regions are associated with specific manifestations of the disease. In a recent study by the group, presented at the AGA 2000 in San Diego, FAP patients were subdivided according to the site of the mutation, and a variation of the average age of onset of the disease was found in subgroups of the patients. We agree with Friedl et al. that it is difficult and often not possible to define exact boundaries. On the other hand, our present study showed a very low risk of secondary proctectomy in polyposis patients with a mutation in codon 0 –200 or ⬎1500, which we used as our definition of AFAP. Based on this, we recommended IRA in AFAP, which corresponds to the international attitude. Apart from this subset of polyposis patients,
GASTROENTEROLOGY Vol. 121, No. 2
we agree that knowledge about genotype-phenotype correlation is still too limited to justify strict recommendations about therapy. We agree that the reported associations are not absolute. For example, patients with mutations in codon 1309 on average have a higher risk of developing profuse polyposis at an early age, but not all patients with this mutation will develop this aggressive form of polyposis.1 We believe that no surgeons will make decisions about surgical method solely on the basis of the genotype. We would like to emphasize that decisions about the type of surgery should be made on the basis of the age of the patient, the endoscopic findings, the phenotype of the disease in the family, the genotype, and, most importantly, the opinion of the patient after a detailed analysis about the natural history of the disease and the pros and cons of the available surgical options. ¨ LOW STEFFEN BU HANS VASEN ¨ LOW CHARLOTTE BU MARIE LUISE BISGAARD HEIKKI JA¨RVINEN JAN BJO¨RK 1. Giardiello FM, Krush AJ, Petersen GM, et al. Phenotypic variability of familial adenomatous polyposis in 11 unrelated families with identical APC mutation. Gastroenterology 1994;106:1542–1547.
Osteoporosis in Newly Diagnosed Inflammatory Bowel Disease Dear Sir: We read with interest the recent article by Erik et al.1 They compared bone mineral density in newly diagnosed patients with inflammatory bowel disease (IBD) and matched controls. They concluded that there are no significant differences between these groups. Their findings contrast with earlier experimental and clinical studies. By using markers such as interleukin 6, osteocalcin, parathyroid hormone, and N-telopeptide cross-linked type 1 collagen (NTX), Pollak et al.2 showed that chronic IBD is associated with increased bone loss with inflammatory factors like interleukin 6 playing a significant role in this process. This has been confirmed in other studies.3 On the basis of these studies, patients with IBD reasonably might be expected to have reduced bone mineral density at diagnosis compared with controls. In support of this contention, in an earlier clinical study, Gosh et al.4 concluded that, at diagnosis, low bone mineral density is indeed a feature of Crohn’s disease. With the advent of therapy for osteoporosis, this is an important area and the conflict of results between Gosh et al. and Erik et al. must be resolved. Possible explanations for the difference in results between the 2 studies may be found in the demographics of the patient populations studied. There were a number of methodological problems in the early report of Gosh et al. including small patient numbers, wide age range, a large proportion of patients with proctitis, and the absence of information on menopausal status in female patients. In addition, in the study by Erik et al., the majority of Crohn’s patients (16/24) were female, and in total 33 of 36 female patients studied were using oral contraceptives. Although controversial, oral contraceptives may influence bone mineral density and metabolism in premenopausal women.5– 8 This is worthy of consideration in view of the contrasting results with the study by Ghosh et al. The rate of bone turnover and renal tubular reabsorption of calcium are affected by estrogens, and studies have shown that in premenopausal women, use