Correspondence

Gastrointestinal Polyposis and Nonpolyposis Syndromes

N Engl J Med 1995; 332:1518-1520June 1, 1995

Article

To the Editor:

The review of gastrointestinal polyposis and nonpolyposis syndromes by Rustgi (Dec. 22 issue)1 inappropriately distinguishes the hereditary flat adenoma syndrome from attenuated adenomatous polyposis coli (and in doing so perpetuates the misnomer “hereditary flat adenoma syndrome”). These are, in fact, two names for the same syndrome. Attenuated adenomatous polyposis coli is characterized clinically by many, but usually fewer than 100, colonic adenomatous polyps, increased risk of colon cancer, and an age of onset of colon cancer that is between the age of onset of classic polyposis coli and that of sporadic colon cancer. Genetic analysis of a Utah kindred with this phenotype revealed a linkage to the adenomatous polyposis coli (APC) gene on chromosome 5.2 A group headed by Dr. Henry Lynch independently described several other families with this phenotype.3,4 Before undertaking a genetic analysis of these families and believing (mistakenly, as it turned out) that the adenomatous polyps in members of these families were morphologically distinctive, Dr. Lynch called the phenotype “hereditary flat adenoma syndrome.” Our subsequent genetic analysis of these and other families revealed a linkage to the APC gene, and mutational analysis of the APC gene in these families and in the previously described kindred from Utah2 revealed characteristic mutations in the 5' end of the gene.5,6 The syndrome was then renamed “attenuated adenomatous polyposis coli” to reflect the fact that it was a less expressive variant of classic adenomatous polyposis coli. Dr. Lynch's group has now conceded that what they called a “flat adenoma” most likely “represents an early stage of adenoma development” in sporadic and inherited adenomas alike and “does not provide a marker for a hereditary colon cancer–prone syndrome.”7

Wade S. Samowitz, M.D.
Randall W. Burt, M.D.
Mark Leppert, Ph.D.
University of Utah Health Sciences Center, Salt Lake City, UT 84132

7 References

1. 1

   Rustgi AK. Hereditary gastrointestinal polyposis and nonpolyposis syndromes. N Engl J Med 1994;331:1694-1702
   Full Text | Web of Science | Medline

2. 2

   Leppert M, Burt R, Hughes JP, et al. Genetic analysis of an inherited predisposition to colon cancer in a family with a variable number of adenomatous polyps. N Engl J Med 1990;322:904-908
   Full Text | Web of Science | Medline

3. 3

   Lynch HT, Smyrk T, Lanspa SJ, et al. Flat adenomas in a colon cancer-prone kindred. J Natl Cancer Inst 1988;80:278-282
   CrossRef | Web of Science | Medline

4. 4

   Lynch HT, Smyrk TC, Lanspa SJ, et al. Phenotypic variation in colorectal adenoma/cancer expression in two families: the hereditary flat adenoma syndrome. Cancer 1990;66:909-915
   CrossRef | Web of Science | Medline

5. 5

   Spirio L, Otterud B, Stauffer D, et al. Linkage of a variant or attenuated form of adenomatous polyposis coli to the adenomatous polyposis coli (APC) locus. Am J Hum Genet 1992;51:92-100
   Web of Science | Medline

6. 6

   Spirio L, Olschwang S, Groden J, et al. Alleles of the APC gene: an attenuated form of familial polyposis. Cell 1993;75:951-957
   CrossRef | Web of Science | Medline

7. 7

   Lanspa SJ, Rouse J, Smyrk T, Watson P, Jenkins JX, Lynch HT. Epidemiologic characteristics of the flat adenoma of Muto: a prospective study. Dis Colon Rectum 1992;35:543-546
   CrossRef | Web of Science | Medline

To the Editor:

We believe that the description of Turcot's syndrome by Rustgi maintains the confusion that has existed in the literature since the original description1 of the association between polyposis and central nervous system tumors. We think that there are two distinct conditions: autosomal dominant familial adenomatous polyposis with central nervous system tumors as extracolonic features and autosomal recessive Turcot's syndrome with central nervous system tumors as primary features.

In families with otherwise typical autosomal dominant familial adenomatous polyposis, isolated cases of central nervous system tumors occur with an increased incidence. These tumors are medulloblastomas in 50 percent of the cases. In one such case, Nagase et al. found the APC mutation.2 In our patient with congenital hypertrophy of the retinal pigment epithelium, we found a deletion of four base pairs in exon 15 of the APC gene.3

The colonic polyps occur earlier, are less numerous and larger, and undergo an even earlier malignant transformation in autosomal recessive Turcot's syndrome than in familial adenomatous polyposis.4 The central nervous system tumors in autosomal recessive Turcot's syndrome are mainly glioblastomas. In a family with this disorder Tops et al. did not find a linkage to the APC gene.5

M.J.M. Dupuis, M.D.
Clinique St.-Pierre, 1340 Ottignies, Belgium

C. Verellen-Dumoulin, M.D.
Université Catholique de Louvain, 1200 Brussels, Belgium

5 References

1. 1

   Turcot J, Despres J-P, St Pierre F. Malignant tumors of the central nervous system associated with familial polyposis of the colon: report of two cases. Dis Colon Rectum 1959;2:465-468
   CrossRef | Medline

2. 2

   Nagase H, Miyoshi Y, Horii A, et al. Screening for germ-line mutations in familial adenomatous polyposis patients: 61 new patients and a summary of 150 unrelated patients. Hum Mutat 1993;1:467-473
   CrossRef

3. 3

   Dupuis MJM, Walon C, Boucquey D, Harmant-van Rijckevorsel K, Lannoy N, Verellen-Dumoulin C. Identification of an APC gene mutation in a familial adenomatous polyposis coli associated with cerebral tumor. J Neurol 1994;241:Suppl 1:S147-S147 abstract.
   

4. 4

   Itoh H, Ohsato K. Turcot syndrome and its characteristic colonic manifestations. Dis Colon Rectum 1985;28:399-402
   CrossRef | Web of Science | Medline

5. 5

   Tops CMJ, van der Klift HM, van der Luijt RB, et al. Non-allelic heterogeneity of familial adenomatous polyposis. Am J Med Genet 1993;47:563-567
   CrossRef | Web of Science | Medline

To the Editor:

In his review of hereditary gastrointestinal polyposis and nonpolyposis syndromes, Dr. Rustgi recommends screening relatives of patients with Turcot's syndrome with colonoscopy and computed tomography or magnetic resonance imaging of the brain. Effective cancer-screening programs must provide an early diagnosis, which must, in turn, allow for an intervention that improves the overall prognosis or allow for less radical treatment.1 By this standard, the recommendation of colonoscopy appears to be appropriate, since colonic polyposis may be detected in a precancerous state, and affected patients may benefit from prophylactic colectomy or colonoscopic polypectomy. Unfortunately, similar benefits cannot reliably be obtained from radiographic imaging of the brain. Mastronardi et al.2 reviewed the reported cases of Turcot's syndrome and hypothesized that there were two distinct syndromes: medulloblastoma in young patients in kindreds affected by familial adenomatous polyposis, and glioma in older patients in kindreds with autosomal recessive inheritance, which appear to be distinct from kindreds with familial adenomatous polyposis, including the original kindred described by Turcot. Certainly, for this latter group, there is little evidence to suggest that early diagnosis would affect the natural history of the disorder, since there is no curative therapy currently available for malignant glioma, and the treatment is essentially palliative. For medulloblastoma, the rate of disease-free survival at five years has been reported to be approximately 50 percent, with the prognosis linked to the extent of disease at the time of diagnosis.3 It is not known, however, whether the patients with a better prognosis are those with an earlier diagnosis or biologically less aggressive disease.

Thomas Coyle, M.D.
SUNY Health Science Center at Syracuse, Syracuse, NY 13210

3 References

1. 1

   Miller AB. Cancer screening. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles & practice of oncology. 4th ed. Vol. 1. Philadelphia: J.B. Lippincott, 1993:564-73.
   

2. 2

   Mastronardi L, Ferrante L, Lunardi P, Cervoni L, Fortuna A. Association between neuroepithelial tumor and multiple intestinal polyposis (Turcot's syndrome): report of a case and critical analysis of the literature. Neurosurgery 1991;28:449-452
   CrossRef | Web of Science | Medline

3. 3

   Levin VA, Rodriguez LA, Edwards MS, et al. Treatment of medulloblastoma with procarbazine, hydroxyurea, and reduced radiation doses to whole brain and spine. J Neurosurg 1988;68:383-387
   CrossRef | Web of Science | Medline

To the Editor:

In the review by Rustgi, the use of congenital hypertrophy of the retinal pigment epithelium as a predictive marker in identifying relatives at risk for familial adenomatous polyposis requires clarification.

Rustgi does not differentiate between sporadic congenital hypertrophy of the retinal pigment epithelium and that associated with familial adenomatous polyposis. Sporadic congenital hypertrophy of the retinal pigment epithelium is often found in the general population and carries no associated risk of familial adenomatous polyposis.1 A person without familial adenomatous polyposis can have sporadic congenital hypertrophy of the retinal pigment epithelium with up to four lesions.2 The lesions associated with familial adenomatous polyposis are multiple and differ in appearance from those of sporadic congenital hypertrophy of the retinal pigment epithelium.1-3 The presence of four or more atypical lesions, in one or both eyes, is accepted as the criterion signifying that a particular family has the trait for these ocular lesions.4

Mark F. Ellis, M.B., B.S.
St. Vincent's Hospital, Fitzroy 3065, Australia

4 References

1. 1

   Shields JA, Shields CL, Shah PG, Pastore DJ, Imperiale SM Jr. Lack of association among typical congenital hypertrophy of the retinal pigment epithelium, adenomatous polyposis, and Gardner syndrome. Ophthalmology 1992;99:1709-1713
   Web of Science | Medline

2. 2

   Traboulsi EI, Krush AJ, Gardner EJ, et al. Prevalence and importance of pigmented ocular fundus lesions in Gardner's syndrome. N Engl J Med 1987;316:661-667
   Full Text | Web of Science | Medline

3. 3

   Morton DG, Gibson J, MacDonald F, et al. Role of congenital hypertrophy of the retinal pigment epithelium in the predictive diagnosis of familial adenomatous polyposis. Br J Surg 1992;79:689-693
   CrossRef | Web of Science | Medline

4. 4

   Traboulsi EI, Maumenee IH, Krush AJ, et al. Congenital hypertrophy of the retinal pigment epithelium predicts colorectal polyposis in Gardner's syndrome. Arch Ophthalmol 1990;108:525-526
   Web of Science | Medline

To the Editor:

Rustgi states that in the case of familial adenomatous polyposis, if congenital hypertrophy of the retinal pigment epithelium is present in the index case or proband but absent in the offspring, colonic polyposis will not develop in the offspring. Polkinghorne et al., however, described two patients with pathologically verified familial adenomatous polyposis coli who did not have congenital hypertrophy of the retinal pigment epithelium, yet other affected members of their families did.1 Although it may be rare, such a finding, in my opinion, limits the value of congenital hypertrophy of the retinal pigment epithelium as a diagnostic marker and makes the author's recommendations potentially unsafe.

Rustgi also states that gastric cancer has not been reported in patients with familial juvenile polyposis of the stomach. Although this is true with regard to the familial disorder, gastric cancer has been reported in association with juvenile polyposis of the stomach on two occasions.2,3

Stuart Whitelaw, M.B., Ch.B.
Glasgow Royal Infirmary, Glasgow G31 2ER, United Kingdom

3 References

1. 1

   Polkinghorne PJ, Ritchie S, Neale K, Schoeppner G, Thomson JP, Jay BS. Pigmented lesions of the retinal pigment epithelium and familial adenomatous polyposis. Eye 1990;4:216-221
   CrossRef | Web of Science | Medline

2. 2

   Watanabe A, Nagashima H, Motoi M, Ogawa K. Familial juvenile polyposis of the stomach. Gastroenterology 1979;77:148-151
   Web of Science | Medline

3. 3

   Sassatelli R, Bertoni G, Serra L, Bedogni G, Ponz de Leon M. Generalized juvenile polyposis with mixed pattern and gastric cancer. Gastroenterology 1993;104:910-915
   Web of Science | Medline

Author/Editor Response

Dr. Rustgi replies:

To the Editor: My review of gastrointestinal polyposis and nonpolyposis syndromes covers their clinical and, in particular, genetic features. Emerging from recent advances is an appreciation that classification or subclassification of these clinical syndromes is largely dependent on the identification of the relevant gene or genes and the biochemical characterization of the gene products.1 In this context, the earlier distinction between familial adenomatous polyposis and Gardner's syndrome has been reassessed on the basis of the finding that APC gene mutations are responsible for phenotypic features in both syndromes. Attenuated adenomatous polyposis coli is an extremely rare genetic variant of familial adenomatous polyposis. Hereditary flat adenoma syndrome may represent the same disorder or may at least be considered part of a continuum. Definitive proof, however, will require the demonstration that patients with hereditary flat adenoma syndrome have the same spectrum of APC mutations as those observed in attenuated adenomatous polyposis coli. As with the hereditary nonpolyposis colorectal cancer syndromes,2 a consensus conference may help resolve the differences in nomenclature predicated on genetic findings.

Extraintestinal features of familial adenomatous polyposis and Gardner's syndrome are helpful from the viewpoint of diagnostic screening and provide a means of investigating the biology of these syndromes. One of the more remarkable features is congenital hypertrophy of the retinal pigment epithelium. There is a wealth of literature indicating its usefulness as a predictor of colonic polyposis in children and young adults.3 Furthermore, the absence of congenital hypertrophy of the retinal pigment epithelium in this population may also be helpful information. It is difficult to know to what extent inferences, if any, should be made from isolated case reports. All in all, detection of congenital hypertrophy of the retinal pigment epithelium constitutes a simple, safe, and effective screening method in familial adenomatous polyposis and Gardner's syndrome and helps supplement information provided by flexible sigmoidoscopy and genetic testing.4 Al-though congenital hypertrophy of the retinal pigment epithelium may be present in the sporadic form, its usefulness clearly lies in providing predictive information about patients with familial adenomatous polyposis or Gardner's syndrome.

Turcot's syndrome is a rare inherited adenomatous polyposis syndrome. As I clearly state in my review, there have been varying opinions about whether it is an autosomal dominant or autosomal recessive disorder. The development of brain tumors, especially gliomas, and the associated poor prognosis may lead to an underestimation of the frequency of colonic polyposis in a patient or a family, since the colon may not be examined. Thus, a hypothetical or arbitrary scheme for the clinical classification of Turcot's syndrome should be used cautiously. Clinical screening with flexible sigmoidoscopy and a technique to detect brain tumors seems prudent, given the natural history of the disease. As was the case with familial adenomatous polyposis and Gardner's syndrome, Turcot's syndrome must now be reassessed in the light of recent genetic observations — namely, the demonstration of germ-line APC mutations and germ-line mutations in the DNA-mismatch-repair gene hMLH1 or hPMS2 in different families with Turcot's syndrome.5

Anil K. Rustgi, M.D.
Massachusetts General Hospital, Boston, MA 02114

5 References

1. 1

   Kinzler KW, Nilbert MC, Vogelstein B, et al. Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers. Science 1991;251:1366-1370
   CrossRef | Web of Science | Medline

2. 2

   Groden J, Thliveris A, Samowitz W, et al. Identification and characterization of the familial adenomatous polyposis coli gene. Cell 1991;66:589-600
   CrossRef | Web of Science | Medline

3. 3

   Vasen HF, Mecklin JP, Khan PM, Lynch HT. The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum 1991;34:424-425
   CrossRef | Web of Science | Medline

4. 4

   Traboulsi EI, Maumenee IH, Krush AJ, et al. Congenital hypertrophy of the retinal pigment epithelium predicts colorectal polyposis in Gardner's syndrome. Arch Ophthalmol 1990;108:525-526
   Web of Science | Medline

5. 5

   Hamilton SR, Liu B, Parsons RE, et al. The molecular basis of Turcot's syndrome. N Engl J Med 1995;332:839-847
   Full Text | Web of Science | Medline