Polyposis syndromes have been managed in the past by geneticists and adult gastroenterologists but now increasingly fall into the remit of the pediatric gastroenterologists. Gastrointestinal polyps in children most commonly appear with rectal bleeding. Perhaps of more concern is their potential for malignant change. This article reviews the polyposis syndromes, their malignant potential, and their management algorithms. The genetics of these syndromes and future advances are also discussed.
Gastrointestinal polyps in children fall into two major categories: hamartomas (juvenile polyps and Peutz–Jeghers polyps) and adenomas. Solitary polyps in children are most commonly hamartomas, predominantly of the juvenile type, whereas solitary adenomas are extremely rare. Of the familial syndromes, however, familial adenomatous polyposis is more common than juvenile polyposis syndrome (JPS) or Peutz–Jeghers syndrome (PJS). The pathologic features of these polyps are described in Table 1 and shown in Figure 1, A, B, and C.
The most common manifestation of a large bowel polyp is painless rectal bleeding. The differential diagnosis of rectal bleeding is wide and includes anal fissure, trauma, infective colitis, allergic enteropathy, Meckel's diverticulum, congenital vascular anomalies, and inflammatory bowel disease. Of 730 patients with rectal bleeding referred to a single center, 29 children were found to have colorectal polyps. Twenty-four polyps were juvenile polyps, two were Peutz–Jeghers polyps, and one was an adenomatous polyp (1). Nine of the polyps were located proximal to the sigmoid-descending junction suggesting that such children should have a full colonoscopy and not a limited flexible sigmoidoscopy. Other reviews concluded that up to 60% of juvenile polyps may be found proximal to the sigmoid colon (2), which confirms the need for full colonoscopy in the assessment of rectal bleeding. Ultrasound with saline enemas before colonoscopy has been reported to have a high specificity and sensitivity for identifying polyps (3), but published data are from small samples. This procedure does not remove the need for colonoscopy and is therefore not favored in our practice.
To plan management appropriately, the pediatrician treating a child with a gastrointestinal polyp must know the histopathologic type, the number and site of polyps, and whether there is a family history of polyps or colorectal cancer. The clinician must also assess for associated extraintestinal manifestations of polyposis syndromes.
HAMARTOMATOUS POLYPOSIS SYNDROMES
Children with a solitary juvenile polyp show symptoms of painless rectal bleeding or perianal polyp protrusion, at a mean age of 4 years. The risk of malignant change is almost negligible; there are only eight cases in the literature of development of neoplasia in patients with solitary juvenile polyps. The age range of these patients was 1.5 to 67 years (mean age, 24 years) (4). In addition, a review of 82 patients with solitary juvenile polyps (mean age at diagnosis, 32 years; range, 3–71 years) showed no increased risk of colorectal cancer or of dying as a result of the polyp (5). However, it is unclear which patients with a solitary juvenile polyp at diagnosis may progress to formation of more polyps and development of the phenotype of JPS.
Although the risk of development of malignancy in a solitary juvenile polyp is very small, such polyps should be removed, even when discovered incidentally. If there is no relevant family history and if after full colonoscopy the polyp is found to be solitary, endoscopic polypectomy is sufficient treatment. If the patient is discharged, parents must be aware that juvenile polyps may be the first feature of JPS. If fresh symptoms arise, the child should undergo another investigation. When there is a positive family history or when multiple juvenile polyps are found, however, the possibility of JPS syndrome is raised, and a different management strategy should be used.
Juvenile Polyposis Syndrome
Juvenile polyposis is a rare autosomal dominant condition characterized by the occurrence of multiple juvenile polyps in the gastrointestinal tract. In children, the most common age of initial symptoms is 9 years with symptoms including rectal bleeding, anemia, or prolapse of either the polyp or rectum. Less commonly, the condition appears in infancy, with anemia and hemorrhage, diarrhea, protein-losing enteropathy, and rectal bleeding (6). The entire gastrointestinal tract is usually affected, and the prognosis is related to the severity and extent of gastrointestinal involvement. The course in such infants is fulminant, and death occurs before the age of 2 years in severe cases (7).
Compared with patients with solitary juvenile polyps, patients with JPS not only have more polyps, but are also more likely to have right-side polyps, polyps with adenomatous change, and anemia (8). As the condition progresses, the number of polyps increases to 50 to 200. Polyps are found primarily in the colon but also in the stomach and small intestine (9). The number of polyps needed to make the diagnosis remains controversial. Jass et al. (10) proposed five, whereas Giardiello et al. (4) suggested that patients with as few as three juvenile polyps should undergo screening for colorectal neoplasia. This arbitrary number was based on a retrospective review of 57 patients with JPS, in which it was reported that 9 of 19 patients with three or more polyps had development of colorectal neoplasia compared with only 1 of 28 patients with only one or two polyps.
A significant proportion of patients with JPS have been reported to have other morphologic abnormalities, including digital clubbing, macrocephaly, alopecia, cleft lip or palate, congenital heart disease, genitourinary abnormalities, and mental retardation (11). Infrequently, JPS occurs as part of the Bannayan–Riley–Ruvalcaba syndrome (macrocephaly, pigmentation of the genitalia, and psychomotor delay in childhood), or Cowden syndrome (multiple hamartomas of multiple organs, macrocephaly, thyroid, and breast disease).
There is little doubt that JPS is a premalignant condition. There is a 15% incidence of colorectal carcinoma in patients less than 35 years of age, leading to a cumulative risk of colorectal cancer of 68% by age 60 years (10). A retrospective study of 57 patients with JPS demonstrated a mean age of onset of colonic neoplasia of 38 years (range, 6–58 years) (4). Neoplastic changes have been documented both in the polyps and in flat, apparently normal colonic mucosa. Malignancies in the stomach, duodenum, and pancreas have been described in adults.
Patients with features suggestive of JPS should have surveillance colonoscopy with random biopsies of polyps and flat mucosa every 2 years. When the number of polyps is small, endoscopic polypectomy and follow-up may suffice, but it is not clear whether endoscopic surveillance is adequate to prevent malignancy. When there are numerous polyps or symptoms such as bleeding and diarrhea persist, prophylactic colectomy should be considered after adolescence. As yet, there are insufficient data to justify prophylactic colectomy solely for the risk of colorectal carcinoma. The role of cyclooxygenase (COX)-2 inhibitors in pediatric JPS is unclear at present.
In three of eight families affected by JPS, polyps were identified in asymptomatic first-degree relatives (8). Thus, first-degree relatives of patients with JPS should be screened by colonoscopy beginning at age 12 years. Even when the child is asymptomatic and even if the colonoscopy is negative, some authorities continue to screen at 3-year intervals.
Peutz–Jeghers syndrome (PJS) is a rare autosomal dominant condition in which gastrointestinal polyps occur in association with macular melanin pigmentation. Polyps arise primarily in the small bowel and to a lesser extent in the stomach and colon. Pigmentation occurs in most, but not all, patients and is seen most frequently on the lips and buccal mucosa and occasionally on the hands, feet, and eyelids. The primary concern to the pediatrician is the risk of small bowel intussusception, causing intestinal obstruction, vomiting, and pain. In addition, intestinal bleeding leading to anemia can occur. The risk of neoplasia is well documented in young adults and includes development of unusual tumors such as Sertoli cell tumor of the ovary and testicular tumors in prepubescent boys.
In most patients, PJS appears before adulthood with symptoms such as abdominal pain (and intussusception) or anemia. Of 70 cases of PJS in childhood summarized after a literature search, 50 had episodes of abdominal pain, 13 gastrointestinal bleeding, and 11 anemia (12). This study was biased, because complicated cases of PJS are more readily reported than uncomplicated cases.
There is controversy about the management of midgut polyps in the young child. There is a high reoperation rate after initial laparotomy for small bowel obstruction. This rate may be reduced in skilled hands by intraoperative enteroscopy (possibly through a surgical enterotomy) to remove other polyps. More than half the patients with PJS observed at St. Mark's Hospital from 1943 through 1987 had two or more laparotomies. The average age at initial laparotomy was 15 years (range, 2–39 years;n = 23). Polyp-induced complications were responsible for 75% (23/31) of second laparotomies (13). Intraoperative small bowel endoscopy detected 38% more polyps at laparotomy (17 additional polyps) than did external palpation and small bowel transillumination.
At present, it is not possible to be prescriptive about management of polyps of different sizes. The advantages and disadvantages of prophylactic polypectomy for asymptomatic patients should be discussed with the family and each case considered on its own merits. At diagnosis, treatment is according to the PJS algorithm (Fig. 2), and management is influenced by the size of the polyps and their locations. This protocol is adapted from adult practice, and therefore the size of polyps needing resection may be smaller in young children. Symptomatic children with sizable midgut polyps (larger than 1.5 cm) should be referred for laparotomy and intraoperative enteroscopy. For children who are asymptomatic with small polyps (less than 1.0 cm), the parents should be counseled about the risk of intussusception. If symptoms develop later, the child should be referred for investigation and consideration for laparotomy. The management of children with polyps between 5 and 10 mm depends on the number of polyps. Children with multiple midgut polyps may benefit from prophylactic polypectomy.
The risk of developing malignancy, both in the gastrointestinal tract and in extraintestinal sites, is greater in adults with PJS than in the general population. In the 70 cases reviewed in the literature in patients with PJS who were less than 16 years of age, five patients had tumors: Two had adenocarcinomas, one gastric, and the other jejunal (12). A survey of 72 patients at St. Mark's Hospital up to 1989, found 16 malignancies, of which 10 were gastrointestinal and pancreatic (14). The youngest affected from this cohort 26 years of age. Clinicians who treat adolescents with PJS should be aware of unusual symptoms (e.g., those due to a feminizing testicular tumor) and have a low threshold for investigating potential malignancies. A recommended screening program for patients with PJS after adolescence is shown in Table 2.
FAMILIAL ADENOMATOUS POLYPOSIS
In children, gastrointestinal adenomas are almost always associated with hereditary adenomatous polyposis syndromes. Therefore, whenever one colorectal adenoma is found in a child, total colonoscopy with dye spray is mandatory. Familial adenomatous polyposis (FAP) is the most common of the adenomatous polyposis syndromes. It is an autosomal dominant condition in which there is a defect in the APC gene on chromosome 5q21.
Patients with FAP typically have multiple adenomas throughout the large bowel—usually more than 100 and sometimes more than 1000. Polyps begin to appear in childhood or adolescence and increase in number with age. By the fifth decade, colorectal cancer is almost inevitable if colectomy is not performed. Adult patients with FAP are also at increased risk of malignancy of the duodenum, ampulla of Vater, thyroid, pancreas, and liver. Children less than 5 years of age may have hepatoblastoma. It may be advisable, therefore, to measure serum α-fetoprotein levels and/or perform abdominal ultrasound in such children, although this is not our current practice. Clinicians responsible for the care of families with FAP must be aware of the high potential for neoplasia at different sites.
There are three ways in which a patient with FAP may come to the attention of the pediatrician. Most are called for screening because of a positive family history, some have colorectal symptoms such as bleeding or diarrhea, and a minority have extracolonic manifestations (Table 3). General pediatricians treating a child with an unusual lesion such as maxillary osteoma or a rare tumor such as hepatoblastoma should consider the possibility of FAP (15), particularly if there are multiple tumors or another sibling is affected.
Diagnosis and Screening
No patient should undergo screening for FAP without detailed counselling. In FAP-affected families with a known gene mutation, direct DNA genotypic analysis can determine whether a family member has the condition. The diagnosis is confirmed by finding adenomas during flexible sigmoidoscopy. Alternatively, the presence on indirect ophthalmoscopy of more than four pigmented ocular fundus lesions (congenital hypertrophy of the retinal pigment epithelium) carries a 100% positive predictive value, particularly if the lesions are large. The absence of pigmentation, however, is of no predictive value.
Our practice for families with a known mutation is to offer genetic screening to first-degree relatives from the age of 11 years onward. At this age we believe the child is more able to understand the consequences of the result (16). Some children understand the genetic screening and its consequences at a younger age (e.g., 9 years). Each family situation should be considered individually. Genotype-negative individuals can be discharged without follow-up (unless the only genetic test used was linkage analysis alone). Some clinicians may want to perform endoscopic examination in the adolescent on one occasion. Affected individuals undergo annual flexible sigmoidoscopy from the age of 14 years until adenomas are found. Annual flexible sigmoidoscopy should be adequate, because there is rectal involvement early in the condition (Fig. 3).
Most children will have had a full colonoscopy by the age of 16 years to determine polyp density and location and degree of dysplasia. With this information, and understanding the family situation and the psychosocial and schooling needs of the child, a decision can be made regarding the timing and type of surgery. Further colonoscopies may be performed to reassess the extent of polyposis if the adolescent wants to delay surgery (e.g., to the age of 18 years), but clinicians and patient should be aware that colonoscopic surveillance alone is not a safe enough method of preventing colorectal malignancy (17).
It is important that the adolescent become familiar with the examinations. Children and adolescents should undergo colonoscopy in a pediatric gastroenterology unit to ensure that early screening experiences are seen in a positive light, because subsequent examinations are dependent on voluntary participation.
In families in which the genotype is not known, protocols vary. The St. Mark's approach is to perform annual sigmoidoscopy on all first-degree relatives until the age of 20 years and colonoscopy with dye spray at 5-year intervals thereafter.
Severe dysplasia and even malignancy have been documented in children with FAP who are less than 12 years of age. Consequently, although we prefer to test children when they are old enough to make their own informed decision, rarely, we may recommend colonoscopy in younger children in families in which severe dysplasia or carcinomas have been found at a young age (18). This is particularly so if the family has one of the mutations associated with a severe phenotype (e.g., codons 486/499 in exon 11 or codon 1309 in exon 15).
Timing of Screening
In the past 10 years, genetic testing has become available for those families in whom the gene defect is known. Ethical issues arise when DNA technology provides a reliable predictive test for a condition. Adults can decide for themselves whether to undergo the genetic test, but for children at risk, the decision must be made by the parents. Those children found not to carry the mutation are spared an uncomfortable annual sigmoidoscopy. On the other hand, early knowledge of the child's disease status may have detrimental effects, result in harm to the child's self concept, or even affect relationships within the family (16).
Questions arise about what age is optimal to test at-risk individuals for a disease that will not appear or need treatment before adolescence or adult life. There are strong arguments for not testing children until they are of an age at which they can contribute to an informed decision (19). The overriding factor should be to balance the benefit against possible damage to the child. Clearly, at the age of 12 to 14 there is a benefit for the 50% of children who are gene negative and need not undergo clinical screening. In contrast, at 1 year of age, the benefit is unclear, and there is a potential for problems arising from the stigma of being affected. In response to parents' request to have their child tested for FAP, it is important to determine what question must be answered. Is the test purely to put the parents' mind at rest or will it affect the child's treatment? Childhood testing for polyposis syndromes should be undertaken only when there is a clear justification in each situation.
Expert genetic counselling of patients with newly diagnosed disease and their relatives and the involvement of a clinical geneticist or genetic counsellor is recommended. It is essential that the individual who undergoes screening understand the nature of the test and its possible outcomes. Issues such as emotional, family, insurance, and employment implications of a positive result should be discussed before testing, and there should be a clear protocol for posttest management. Recent evidence demonstrates that many individuals who undergo genetic tests for FAP receive inadequate counselling and some have been given poorly interpreted results (20).
Colectomy is the only effective therapy that eliminates the inevitable risk of colorectal cancer. In the absence of severe dysplasia, colectomy is usually performed in patients aged in the mid to late teens or early 20s to accommodate work and school schedules. Some clinicians advocate colectomy before puberty so the patient can adapt to life without a colon before adolescence. Each case should be considered on its own merits. Almost all adolescents with screen-detected disease are asymptomatic and cannot contemplate interruptions in their schooling or effects on relationships. The surgical option, therefore, must not only be carefully timed but must also have low morbidity and excellent functional result.
The timing of primary preventative surgery may be influenced by knowledge of the mutation site and the likely severity of the polyposis. For example, patients with a deletion at exon 15 at codon 1309 may be offered earlier surgery, because this phenotype is characterized by a large numbers of polyps and a higher risk of cancer (21). Even though a low polyp density suggests a lower risk of malignancy (22), it is unsafe to delay surgery on the grounds of polyp density alone, although the choice of procedure may be affected (17).
Surgical options include subtotal colectomy with ileorectal anastomosis (IRA), or restorative proctocolectomy with ileoanal anastomosis (pouch procedure). The IRA is a low-risk operation with good functional results, but the rectum remains at risk of cancer. Six-month surveillance of the rectum is needed after surgery, but despite this, inexperience can result in early cancers being missed. A pouch procedure removes the colorectal cancer risk almost completely (except that residual large bowel epithelium remains with the stapled anal anastomosis, and mucosectomy after a hand-sewn anastomosis is not always complete). In addition, the pouch procedure is more complicated than an IRA, carrying a higher morbidity, and often requires a temporary ileostomy. Pouch creation is associated with an as yet unknown risk of pouch neoplasia, and the pouch should be examined regularly. These procedures have been comprehensively reviewed by a number of investigators (17,23), although some studies are invalidated by a range of underlying diseases such as Hirschsprung disease and ulcerative colitis. A nonrandomized study comparing 37 patients with FAP who had ileoanal pouches with 62 (mostly adults) treated by colectomy and IRA showed significantly more complications (60% vs. 21%) and reoperations (29% vs. 3%), as well as a longer hospital stay (24 vs. 11 days), in patients with pouches. Night evacuation was more common after a pouch procedure (45% vs. 10%), and sexual activity was more often affected (33% vs. 0%) (24). Other authors have differing experiences and report acceptable morbidity after pouch construction for FAP (25).
Our current practice is to recommend IRA in adolescents, because the operative morbidity is very low, and the postoperative cancer risk is minimal. Conversion to an ileoanal pouch can be performed when the patient is much older. Patients with a large number of rectal polyps or those with high-risk genotypes may have better results with a pouch procedure in the first instance, because of the greater risk of malignancy (26).
Much time and effort are taken discussing surgical options with children and their parents. Booklets are provided to patients, and the registry staff offer support and counselling. A permanent stoma is not considered unless there is coexistent desmoid disease (for which more aggressive surgery may be indicated), poor anal sphincter control, or malignancy in the lower rectum.
Upper endoscopic surveillance of the stomach, duodenum, and periampullary region with a side-viewing endoscope is recommended in patients after the age 20 years by experienced endoscopists, unless the patient has symptoms, such as upper abdominal pain, that warrant earlier investigation (27). Clinicians should be aware of the increased risk of extracolonic malignancies, as listed in Table 3, and investigate early.
Desmoids are locally aggressive but nonmetastasizing myofibroblastic lesions that occur with disproportionate frequency in patients with FAP. Associated causative factors include the germline mutation, estrogens, and surgical trauma. In series at St. Mark's, 74% of 34 instances of intra-abdominal desmoid were preceded by a surgical procedure after a median delay of 24 months (28). Desmoids occur most commonly in the peritoneal cavity and may infiltrate locally, leading to small bowel, ureteric, or vascular obstruction. These lesions may progress rapidly or may resolve spontaneously, their unpredictable nature making them difficult to treat (29). Patients found to have desmoid disease at laparotomy should be staged by computed tomographic (CT) scanning and referred for consideration of medical or surgical therapy. Attempted surgical resection carries high rates of morbidity and mortality (10–60%) and usually stimulates further growth of the lesion (30). Medical treatments including nonsteroidal anti-inflammatory drugs (NSAIDs) and antiestrogens have limited success. Cytotoxic chemotherapy is used as a last resort. Pediatricians who treat children with extraintestinal desmoid tumors should consider the possibility of FAP in the family (15).
OTHER POLYPOSIS SYNDROMES
Gorlin syndrome is an autosomal dominant condition comprising upper gastrointestinal hamartomas and pink or brown macules in exposed areas such as the face and hands. In addition, patients may have frontal and parietal bossing, hypertelorism, and variable skeletal abnormalities and intracranial calcification (31). Affected infants should be screened by ultrasound for medulloblastoma. Turcot syndrome is characterized by concurrence of a primary brain tumor and multiple colorectal adenomas. Patients with a polyposis syndrome and neurologic symptoms should undergo thorough neurologic examination and investigation for possible brain tumor (32). The management of the colonic polyps in Turcot syndrome is the same as for FAP.
Lymphoid nodular hyperplasia is a common normal variant of the terminal ileum and is often confused with polyposis. Inflammatory polyps (sometimes called pseudopolyps) appear as shiny tags of healthy and nonneoplastic tissue after healing of previous severe colitis. Those more than 1 cm tend to be removed to distinguish them from adenomas. Bannayan–Riley–Ruvalcaba and Cowden diseases have been discussed earlier.
Only skilled endoscopists should perform colonoscopic polypectomy in children and adolescents. It can be difficult even for an expert to snare some polyps. Apart from obtaining biopsy specimens for histology, polypectomy serves to remove the symptomatic polyp (e.g., the source of bleeding or intussusception).
Polyps may be removed with the advancing scope, especially if there is a risk of missing the lesion on exit. Alternatively, the whole colon may be viewed before attempting polypectomy, to determine the density and distribution of polyps. Modern video endoscopes, particularly those with new, high-resolution charge-coupled device (CCD) video chips provide unrivaled views of the colonic mucosa, and most polyps more than 1 mm are readily visible. Tiny adenomas, less than 1 mm, confirm the diagnosis of FAP and can be seen more easily by spraying 0.2% indigo carmine dye onto the colonic surface, either through specially designed spray catheters or directly down the biopsy channel (33). The clinical impact of dye spraying in pediatric practice is uncertain.
During endoscope withdrawal, it is important to turn the patient to optimize the view, thus increasing polyp detection. Position change and endoscopic rotation are also important to place the polyp in the convenient 5 o'clock position before attempting polypectomy. Small polyps less thn 5 mm can be removed using the hot biopsy forceps. This technique is relatively easy and almost always ensures adequate histology. Great care must be taken, however, to minimize heat damage to the bowel wall. It is probably best avoided in the thin walled right colon. Polyps more than 5 mm should be removed by snare polypectomy. Commercially available minisnares often make removal of small polyps easier. Small sessile polyps can be removed safely by a cold-snare technique (no diathermy), in which the polyp base is simply cheese-wired. In contrast, pedunculated polyps, in which larger vessels may be present within the stalk are best removed using coagulating diathermy (15 W) in preference to pulsed cutting therapy (34). This procedure requires an understanding of the principles of polyp electrosurgery and the correct placement and use of the snare. Newer noncontact techniques, such as argon plasma coagulation offer safe and rapid destruction of multiple polyps but do not provide histology. After polyp is snared, it can be retrieved by suction through the scope into a polyp suction trap, or directly through grasping forceps or a retrieval basket.
The risk of removing larger (more than 1 cm) sessile polyps is considerable, particularly in the right colon, and requires more advanced polypectomy techniques, such as submucosal injection of 1:10000 adrenaline or hypertonic saline to lift the mucosa away from the underlying muscle layer. Small bowel and gastric polyps can also be removed using similar techniques. Provided an experienced endoscopist performs the polypectomy, the risk of perforation and significant bleeding should be less than 1%.
GENETICS OF POLYPOSIS SYNDROMES
Familial Adenomatous Polyposis and APC Genetics
Familial adenomatous polyposis is the most common of the hereditary polyposis syndromes. The prevalence is estimated at 1 in 10,000. It is inherited as an autosomal dominant trait with high penetrance but with a variable age of onset. The rate of spontaneous mutations is relatively high—reported as 10–30%(35). This results in the development of FAP in the absence of a family history.
The gene responsible for FAP, adenomatous polyposis coli (APC), was localized to chromosome 5q21 in the late 1980s (36 37). The isolation and characterization of the APC gene followed (38,39). This large gene comprises 15 exons, encoding a protein of 2843 amino acids, with exon 15 being the largest (Fig. 4). The APC gene appears to be a tumor-suppressor gene. The APC protein interacts with catenins, which in turn attach to cadherin, and the catenins have a role in cell adhesion and control of cell growth. Most mutations are small deletions or insertions that result in the production of a truncated APC protein.
In FAP, a germline mutation inactivates one of the two APC alleles that underlie the predisposition to adenoma formation. Acquired APC point mutations have also been found in non-FAP adenomas and in colon cancers, suggesting that loss of APC function is also an early event in sporadic colorectal cancer.
Mutations are widely distributed throughout the 5´ half of the gene, although two hot spots are found at codons 1061 and 1309. These account for approximately one third of all mutations detected and are associated with a more severe phenotype. Other phenotype–genotype correlations have been observed (40). For example, a higher density of colonic adenomas is found when mutations are located in the central portion of exon 15. Congenital hypertrophy of the retinal pigment epithelium (CHRPE) is almost always present if the APC mutation is downstream of exon 9. A variant of FAP has been described that is characterized by fewer colonic polyps and a generally milder phenotype: attenuated FAP. APC mutations have been described for this condition at the 5´ and 3´ extremes of the gene (41).
These correlations are not absolute, and there may be considerable intrafamilial variation, which suggests that there are other factors involved in the pathogenesis of the disease. Some of the phenotypic variability seen in patients cannot be explained by the location of their APC mutation. Environmental factors and other genes—often termed modifier genes—may have critical effects on APC function and disease expression.
Genetic Testing for Familial Adenomatous Polyposis
The gold standard for genetic testing is seeking the mutation directly from DNA, usually purified from phlebotomy samples. The initial step may often be an RNA protein truncation test or DNA single-strand conformation polymorphism (SSCP) analysis. Direct sequencing can then be focused to areas identified by these techniques.
RNA truncated protein testing takes advantage of the truncation of the APC protein that occurs with most mutations (42). All FAP patients have two APC alleles, one normal and one mutated. An in vitro process to detect the protein product defines an APC protein of normal length as well as a truncated protein. This results in two bands separating on an electrophorectic gel. Conversely, if both alleles are normal, the proteins are of identical length, and only one band is observed. This method can detect a mutation in up to 87% of individuals, but, once observed, the accuracy in other family members approaches 100%.
Direct sequencing and mutation analysis is the optimal genetic test and directly detects the presence of the APC gene mutation (43). Once a specific mutation is identified in an affected family member, a restriction enzyme is designed to detect the new base-pair sequence. DNA is first amplified by polymerase chain reaction and then examined for the known mutation. More than 300 different germline mutations have been described, and finding the mutation may be a formidable task. Families should be aware that the mutation may be detected in only 60% to 80% of cases. It is only in these cases that a predictive test can be offered to at-risk individuals.
Families without easily detected mutations may still require linkage analysis for the purpose of risk estimation. In this test, small fragments of polymorphic DNA that lie close to or within the APC gene are used to track the mutant gene in a family. Once a diagnosis is made in two family members, these DNA markers can be used in other at-risk family members. A minimum of two affected individuals is necessary, and the test is therefore unsuitable for at-risk relatives of persons with isolated occurrences of FAP. These tests offer up to 98% accuracy. They allow the APC gene to be tracked in a family, even if the precise character of the mutation is not known (44).
Interpretation of the Genetic Test Result
The initial stage always involves the testing of a known FAP-affected patient for a mutation. At this stage, if a mutation cannot be found, the test is noninformative, and it is not possible to offer predictive testing to asymptomatic at-risk relatives. If the index case mutation is detected, at-risk relatives can be tested. A negative test result is considered accurate in excluding FAP, and the subject should be considered to hold an average population risk for the subsequent development of adenomas and cancer. A positive test result confirms the diagnosis of FAP, and patients should be screened and treated as has been outlined.
The gene for this condition has recently been identified. The mutated gene LBK1/ STK11 encodes a serine-threonine kinase and is located on chromosome 19p 13.3 (45,46). The function of the protein is as yet unknown, and there remain potential loci for alternative mutated genes predisposing to PJS. However, if the gene mutation is known in previous occurrences in the family, it may have a role in presymptomatic testing in those patients with no pigmentation (or even potential prenatal diagnosis).
Juvenile Polyposis Syndrome
A family history is found in 20% to 50% of patients, with the inheritance apparently being autosomal dominant. There is evidence for genetic heterogeneity in JPS. Subsets of families have mutations in PTEN (the gene associated with Cowden syndrome) located at 10q23.3 or in SMAD4/ DPC4 located at 18q21 (47,48). Further studies are needed to identify the genetic basis for JPS and explore the route leading to neoplastic transformation in these patients.
ROLE OF THE POLYPOSIS REGISTRIES
A polyposis register was started at St. Mark's Hospital in the 1920s, and similar registries exist worldwide. It now contains information on more than 600 families with polyposis syndromes, making it one of the largest polyposis registers in the world. The size and age of the database enable staff to trace and link distant family members, an obvious advantage when genetic testing is necessary.
Affected families are well known to staff, to whom they have open access. The registry advises patients, explores their family histories, coordinates their surveillance and clinical care, and oversees genetic testing. Children from affected families are encouraged by the registry to attend clinics with their parents, and so to become familiar with the hospital environment and have any potential fears allayed. As well as maintaining an active research role, the registry also provides information for hospital clinicians, general practitioners and pediatricians.
Characterization of genetic defects produces important practical benefits, including allowing the planning of screening and surgical management. In future, it may allow the early introduction of chemoprevention.
Findings in studies have suggested that NSAIDs may be protective against colon cancer (49). The NSAIDs inhibit prostaglandin synthesis through their effects on COX. Several trials have shown regression of adenomas using the NSAID sulindac (50,51). Widespread use of sulindac has been limited by concerns regarding gastrointestinal side effects with prolonged administration and case reports of rectal cancer despite treatment (52). The Concerted Action for Polyposis Prevention (CAPP) study is currently assessing the effectiveness of intervention strategies, such as the administration of aspirin and dietary manipulations with resistant starch (53). Cyclooxygenase has two separate isoforms, COX-1 and COX-2. COX-1 is constitutively expressed and responsible for protective prostaglandins, whereas COX-2 is upregulated in colorectal adenomas and cancers. Clinical trials using selective COX-2 inhibitors have reported a reduction in the number of colorectal polyps (54). This agent, and also the noncycloxygenase metabolite of sulindac, sulfone sulindac, may contribute to the future management of colorectal and duodenal adenomas and should have fewer gastrointestinal side effects. They may also have a role before surgery in adolescents and as such are the subject of small-scale trials in a pediatric setting. Developments in this area are likely to generate applications in other high-risk groups and in the treatment of sporadic adenomas and colorectal cancer.
The diagnosis of a polyposis syndrome requires knowledge of the site, number, and histologic type of the polyps and an appreciation of any relevant family history. Pediatricians treating children with unusual tumors should consider the possibility of a polyposis syndrome. Children and adolescents with a polyposis syndrome are faced not only with the immediate complications of the polyps, such as intussusception or bleeding, but also with the extraintestinal manifestations and the long-term risk of malignancy. Endoscopy should be appropriately timed, well tolerated, and properly interpreted. Polyposis-affected families need careful and well-informed genetic counselling that is optimally timed. The approach to care of these families should be multidisciplinary, involving a polyposis registry, an interested pediatrician, colorectal surgeon, pathologist, geneticist, and specialist nurses, all of whom must be familiar with the varied presentations and problems faced by these patients.
The authors thank Kay Neale, Polyposis Registry, St. Mark's Hospital, who manages the polyposis registry and has been involved in much of the original research quoted, and Dr. Brian Saunders, Senior Lecturer in Endoscopy, St. Mark's Hospital who performs all our pediatric endoscopies and advises on endoscopic polypectomy.
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