Pediatric Summary Report

Secondary Findings in Pediatric Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Pediatric): Passed (Consensus scoring is Complete)
• Curation Status (Pediatric): Released 1.0.4
• Status (Adult): Passed (Consensus scoring is Complete)
• GENE/GENE PANEL: APC
• Condition: Familial Adenomatous Polyposis
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• APC ⇔ 0021057 (familial adenomatous polyposis 1; fap1): Definitive Actionability

Actionability Rationale

The evidence for effectiveness is from the exact population. The effectiveness of the intervention is supported by the fact that surveillance will lead to a more intensive intervention only if polyps are found. Penetrance evidence is from this population, although in adulthood. We have 2-3 decades of guidelines to start colonoscopy in the 2nd decade of life and follow up with colectomy in the early 3rd decade as appropriate.

Final Consensus Scores

Gene Condition Pairs: APC ⇔ 0021057 (OMIM:175100)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Morbidity and mortality due to colorectal cancer / Colonoscopic surveillance to determine polyp burden and guide (if appropriate) timing of (procto) colectomy	2	3C	3A	2	10CA

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

Estimates of the prevalence of familial adenomatous polyposis (FAP) vary from 1:3,333 to 1:43,478 live births. Attenuated FAP (AFAP) is likely underdiagnosed given the lower number of polyps and lower risk for colorectal cancer (CRC) compared to FAP. [1, 2, 3, 4, 5, 6, 7, 8]

Clinical Features

Classical FAP is characterized by the presence of ≥100 adenomatous polyps, with cases usually developing hundreds to thousands of adenomatous polyps, and extremely early onset and multifocal carcinogenesis. Most patients are asymptomatic for years until the adenomas are large and numerous, and cause rectal bleeding or even anemia, or cancer develops. Extracolonic manifestations are variably present and include polyps of the gastric fundus and duodenum, osteomas, dental anomalies, congenital hypertrophy of the retinal pigment epithelium (CHRPE), soft tissue tumors, desmoid tumors, epidermoid cysts, adrenal gland adenoma, hepatoblastoma (HPB), thyroid cancer, and brain tumors. AFAP is a milder phenotype of the disorder, which occurs in approximately 8% of cases and is characterized by fewer polyps (<100), frequent right-sided distribution of polyps, cancers occurring at older ages, and more variable extraintestinal manifestations. [1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, 8]

Natural History

The average age of classic FAP diagnosis in patients presenting with symptoms is 35.8 years (range: 4–72 years). Colorectal adenomatous polyps begin to appear, on average, by age 16 (range: 7-36 years). Approximately 75% of affected individuals will develop multiple polyps by the age of 20. By age 35, 95% of FAP patients have polyps. The mean age of CRC diagnosis in untreated individuals if has been reported between 34-50 years, with cancer developing nearly universally by age 50. Cancer occurs only rarely (estimates range from 0.2-1.3%) in patients with FAP who are younger than 20 years; however, these cases are usually associated with a severe polyposis phenotype. Although unusual, CRC has been reported as early as 6 years of age. Although rare, asymptomatic individuals in their 50s have been reported. Duodenal cancer and desmoid tumors are the most common causes of death in patients with FAP after CRC. Duodenal adenocarcinoma has been reported to occur between ages 17 and 81 years, with the mean age of diagnosis between 45 and 67 years. The incidence of desmoid tumors in FAP is highest in the second and third decades of life, with 80% occurring by age 40. Between 5-50% of individuals with FAP experience morbidity and/or mortality from desmoid tumors. The mean age of diagnosis of thyroid cancer is between 28 and 33 years, ranging from 12 to 62 years, with a female preponderance observed. The majority of HPBs occur prior to age five years, have a 25% mortality rate, and exhibit a male preponderance. Medulloblastoma accounts for most of the brain tumors found in patients with FAP, predominantly in females younger than age 20 years. CHRPE is most often multiple and bilateral.
While the phenotype of AFAP is not well defined, widely used clinical criteria include the following: a delay in onset of adenomatous polyposis and colorectal cancer of 10–25 years compared with classical FAP; <100 adenomatous polyps at 25 years of age or older; and/or a late onset of disease (≥45 years of age) irrespective of polyp number. [1, 16, 2, 3, 4, 9, 17, 5, 6, 7, 13, 14, 15]

2. How effective are interventions for preventing harm?

Patient Management

The American College of Medical Genetics and Genomics (ACMG) has developed ACT sheets to help clinical decision-making when one or more pathogenic variants in the APC gene are identified as secondary findings and for people with a family history of colon cancer:
Secondary Findings ACT sheet: https://www.acmg.net/PDFLibrary/Familial-Adenomatous-Polyposis.pdf

The recommendations detailed below are largely applicable to classic and AFAP; however AFAP, with its milder course, may be manageable by colonoscopy and polypectomy and these patients may never require colectomy depending on polyp burden. However, the decision to forego colectomy should only be considered if high quality surveillance and robust recall systems are in place. (Tier 1) [4, 6]

Treatment for FAP should include coordinated, timely and high-quality care to reduce cancer risk and improve compliance with recommendations for management and surveillance. Patients should be followed in dedicated units (national registries, genetic counseling centers, or high-risk cancer centers) where surveillance recommendations are monitored and audited, in order to improve adherence and provide the highest quality of care. Patients should also have access to a full range of management options that minimize the risk of morbidity and mortality. (Tier 1) [4, 6]

A systematic review of studies comparing CRC incidence and mortality before and after registry commencement, found 8 studies (3101 individuals) examining CRC incidence and 6 studies examining CRC mortality. Odds ratios for CRC incidence following registration range from 0.09-0.44, with all but one study showing a statistically significant effect. Odds ratios for CRC-related mortality range from 0.11-0.22, all significant. (Tier 1) [11]

Surgery is necessary to prevent CRC in adulthood. Therefore, endoscopic management of colorectal adenomas alone is not recommended in individuals with classic FAP. For most patients, the choice of surgery will be between total colectomy with ileorectal anastomosis (IRA) and proctocolectomy and ileal pouch anal anastomosis (IPAA). Decisions regarding the timing and type of operation should be discussed at a specialist center in a multidisciplinary setting and take into account disease phenotype (colon and rectal polyp burden, extensiveness of rectal involvement, presence and size of high-grade dysplasia, increase in polyp burden between screenings, severity of symptoms); genotype; family planning; personal and family history of desmoid disease; social, personal, and educational factors; likelihood of compliance with follow-up; and the pros and cons of the surgical options. The age of prophylactic colectomy is not fixed and is a topic that should be discussed in adolescence. (Tier 1) [2, 4, 6]

There remains a risk of adenoma and CRC cancer after colectomy, and the extent of risk is influenced by the type of procedure chosen and type of tissue-sparing. Risk of developing adenomas at 10-year follow-up after IPAA is 51%. Registry studies indicate that 50-53% of patients undergo additional surgeries after their initial rectal-sparing procedure. The cumulative risk of rectal cancer varies from 2-24%, while the cumulative risk of dying from rectal cancer is between 9-12.5% following rectal-sparing procedures. (Tier 1) [2, 4, 6]

Surveillance

Colonoscopic surveillance should start at age 12-14 years and be performed once every 1-3 years depending on colonic phenotype, including polyp burden. Colonoscopic surveillance enables assessment of adenoma burden and distribution, which can guide the timing and type of prophylactic surgery. Those with AFAP may not require such frequent colonoscopic surveillance as those with classical FAP. (Tier 1) [2, 4, 6]

A systematic review of patients with FAP found that 26 of 27 studies showed a statistically significant reduction in CRC incidence with surveillance (odds ratios ranged from 0.01 to 0.37) in screened patients compared to those who presented symptomatically with polyposis/CRC outside of a screening program. Eight studies examined CRC mortality, all of which showed a significant reduction in CRC mortality (odds ratios ranged from <0.01 to 0.16) in screened (N= 1028) versus symptomatic groups (N= 947). Two studies provided evidence for complete prevention of CRC-related deaths during surveillance, although the duration of follow-up was short (2-4 years). (Tier 1) [11]

Upper gastrointestinal surveillance with esophagogastroduodenoscopy (EGD) is recommended, with thorough gastric assessment and inspection and description of the duodenum and ampullary site at every surveillance, beginning at age 25 years, with surveillance interval based on endoscopic findings (Spigelman score for duodenal adenomatosis staging) at baseline. There is some evidence that screen-detection of duodenal cancer may improve survival; FAP patients have been shown to have a median survival after a screen-detected cancer of 8 years (95% CI, 5.9 – upper end not estimated), versus 0.8 years (95% CI, 0.03-1.7) after symptomatic cancer (p < 0.0001). (Tier 1) [2, 4, 6]

Two studies comparing patients with FAP who presented with symptoms compared with relatives of patients referred for screening, observed a much lower incidence of duodenal in those screened (incidence 2–10%) compared to those patients who presented with symptoms (47–70%). (Tier 1) [2, 4, 6]

In a meta-analysis of 3 studies of 103 children, 54.3% of children who had screening EGDs had duodenal adenoma, with a pooled detection rate of 58% (95% CI, 42%-75%). (Tier 1) [18]

A regular physical exam with evaluation for palpable masses suggestive of desmoids is recommended for both FAP and AFAP with consideration for the use of computed tomography or magnetic resonance imaging based on family history and APC variant. Surveillance should be considered when colorectal polyposis is diagnosed or at age 25-30 years, whichever comes first. (Tier 2) [10, 12, 15]

Data on the effectiveness of surveillance to prevent or mitigate desmoid outcomes was not available. However, the first line of treatment in patients with large or growing intra-abdominal or abdominal wall tumors is sulindac in combination with high-dose selective estrogen receptor modulators (SERMs). One case series that included 64 patients with FAP reported that 86% of those treated showed regression or had stable desmoid size with a mean response time (to reach at least stable size) of 16.0 (±9.8) months with one long-term recurrence after >10 years and 2 desmoid-related deaths. However, randomized controlled data are lacking and given the variable natural history of desmoids, it is difficult to establish and qualify the benefit of this treatment regimen. (Tier 1) [2, 4]

Annual surveillance for thyroid cancer should be conducted for both FAP and AFAP; however, whether this screening should occur via ultrasound (US) or palpation with physical exam is inconsistent across guidelines. Surveillance should be considered starting at age 25-30 years. There are no prospective studies comparing these screening strategies. A study comparing 15 patients with screen-detected cancer to 18 patients with incident cancer (from a case series of 205 FAP patients) showed that screening led to detection of smaller tumors (p = 0.04). (Tier 2) [5, 10, 12, 13, 15, 19]

Annual physical and neurologic examination may be considered for central nervous system (CNS) cancers, but data to support this practice are lacking. (Tier 2) [13]

Routine screening for HPBs in patients with FAP is not consistently recommended. One guideline notes that in children found to have HPB, there is no evidence that routine genetic testing or endoscopic screening for FAP is required. (Tier 1) [2]

Circumstances to Avoid

No circumstances-to-avoid recommendations have been provided for the Pediatric context.

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

Pathogenic variants in APC can be identified in between 70-95% of FAP cases and 10% in cases of AFAP, meaning that the prevalence of APC pathogenic variants should be lower, although similar, to the prevalence of FAP. (Tier 3) [2, 3, 4, 7, 10, 13]

Penetrance

The penetrance information presented here applies to classic FAP unless noted otherwise.

The penetrance of colon cancer is estimated at 90-100% in untreated individuals, within AFAP the risk of cancer approaches 70% by age 80. (Tier 3) [3, 4, 5, 6, 7, 13, 17]

Jejunal and ileal polyps can be found in 20-70% of FAP patients. (Tier 3) [5, 20]

The lifetime risk of duodenal polyposis approaches 100% in FAP. Adult studies have estimated the prevalence of duodenal adenomatoses in FAP to be approximately 65%. The lifetime risk of duodenal cancers has been estimated at 3-12%. (Tier 3) [2, 3, 4, 5, 6, 7, 12, 13, 18]

In a meta-analysis of 5 pediatric case series including 189 children, 41% were found to have duodenal adenoma. (Tier 1) [18]

While gastric polyps occur in 20-100% of patients. Gastric adenomatous polyps, which can lead to gastric cancer, represent 10% of the gastric polyps in these patients. The lifetime risk for gastric cancer in FAP in Western countries is estimated between 0.14-0.55%. (Tier 3) [2, 4, 5, 6]

In meta-analyses of cohort studies of patients with FAP, the pooled prevalence was 2.6% (95% CI: 1.3-4.8%) for thyroid cancer, 48.8% (95% CI: 34-64%) for benign thyroid masses, and 6.9% (95% CI: 4.5-10%) for endocrinologic thyroid disorders. Among thyroid cancer, 95% were in females, 46% was bilateral, and 59% was multicentric. (Tier 1) [16]

A second meta-analysis estimated the incidence of thyroid cancer in FAP as 1.6% (range of 0.4-11.8% across studies), with a female-to-male odds ratio of 6.9:1. (Tier 1) [9]

The lifetime pancreatic cancer risk is estimated as 1-1.7%. (Tier 2) [3, 5]

The absolute risk of HPB in FAP-affected children is 1-2%. (Tier 3) [2, 3, 5, 7, 13]

The absolute risk for CNS tumors is 1-2%. (Tier 3) [5]

In a meta-analysis of 10 studies (4625 patients), 559 (12%) developed desmoid tumor. (Tier 1) [14]

Adrenal masses occur in 7-13% of patients; however, most are asymptomatic incidental findings. (Tier 3) [3]

In a meta-analysis of observational studies in people with FAP estimated that osseous jaw lesions (including osteomas, dense bone islands, and hazy sclerosis) had an overall prevalence of 65% (95% CI: 47-82%) and dental anomalies (including odontomas, supernumerary teeth, and unerupted teeth) had an overall prevalence of 31% (95% CI: 19-43%). (Tier 1) [21]

Osteomas are estimated to occur in 20-90% of individuals with FAP. (Tier 4) [3, 7]

CHRPE is estimated to occur in 70-80% of individuals with FAP. (Tier 4) [3, 7, 21]

Relative Risk

The relative risk information presented here applies to classic FAP.

Although limited data exist, one study of 197 families with FAP revealed a relative risk for pancreatic cancer of 4.5-5 in individuals with FAP and their at-risk relatives compared to the general population risk. (Tier 3) [3, 5]

The risk for desmoid tumors in individuals with FAP is more than 800-1000 times the risk in the general population. (Tier 3) [2, 3, 14]

The risk of duodenal cancer is 100-300 times higher than in the general population. (Tier 3) [12]

The risk for adrenal masses are 2-4 times greater than the general population. (Tier 3) [3]

Up to two thirds of patients with FAP have CHRPE compared to a prevalence in the general population of 1-4%. (Tier 3) [2, 4]

The risk of HPB is 750-7500 times higher in children from FAP families than in the general population. Relative risk of HPB in patients with FAP is 847. (Tier 3) [2, 3]

Expressivity

Development of colorectal adenomas is variable, including variability in the number of adenomas within families with the same APC pathogenic variant. Both inter- and intrafamilial phenotypic variability are common, even with identical APC variants. (Tier 3) [3, 5]

4. What is the Nature of the Intervention?

Nature of Intervention

Endoscopic surveillance is burdensome for individuals. In children and young teenagers, most endoscopic procedures are performed under general anesthesia. [1, 2]

The morbidity and functional outcomes of colectomy can include poor sphincter function, changes in bowel movements, incontinence, sexual dysfunction, pelvic dissection and dietary restrictions and are partially dependent on the type of procedure chosen and whether the rectum is retained. In addition, an increased risk of desmoid tumors have been noted among individuals with FAP who have undergone abdominal surgery. There is some risk of loss of fertility in women following proctocolectomy, with some evidence estimating up to a 54% decrease, which is more common among women who had their first surgical procedure at a younger age. [2, 4, 12]

Mental health related quality of life scores are reported to be significantly lower in FAP patients under the age of 18 compared to adults, warranting psychological support for these patients. Psychological compliance of pediatric patients regarding colectomy surgery is also of concern due to the associated major functional and anatomical sequelae. [5, 17]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Most patients are asymptomatic for years until the adenomas are large and numerous, and cause rectal bleeding or even anemia, or cancer develops. (Tier 4) [8]

Due to the high proportion of de novo FAP cases (up to 40% of FAP patients), there is a 25% incidence of CRC in newly diagnosed FAP cases. Because of this presentation and the early onset of CRC in FAP patients (prior to population screening age), there is a high chance for FAP patients to escape clinical detection. (Tier 3) [5, 10, 17]

Date of Search: 10.01.2019

Reference List

1. Aretz S, Vasen HF, Olschwang S. Clinical Utility Gene Card for: Familial adenomatous polyposis (FAP) and attenuated FAP (AFAP)--update 2014. Eur J Hum Genet. (2015) 23(6).

2. Hyer W, Cohen S, Attard T, Vila-Miravet V, Pienar C, Auth M, Septer S, Hawkins J, Durno C, Latchford A. Management of Familial Adenomatous Polyposis in Children and Adolescents: Position Paper From the ESPGHAN Polyposis Working Group. J Pediatr Gastroenterol Nutr. (2019) 68(3):428-441.

3. KW Jasperson, RW Burt. APC-Associated Polyposis Conditions. 1998 Dec 18 [Updated 2014 Mar 27]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1345

4. Monahan KJ, Bradshaw N, Dolwani S, Desouza B, Dunlop MG, East JE, Ilyas M, Kaur A, Lalloo F, Latchford A, Rutter MD, Tomlinson I, Thomas HJW, Hill J. Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG). Gut. (2019)

5. Syngal S, Brand RE, Church JM, Giardiello FM, Hampel HL, Burt RW. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. (2015) 110(2):223-62; quiz 263.

6. van Leerdam ME, Roos VH, van Hooft JE, Dekker E, Jover R, Kaminski MF, Latchford A, Neumann H, Pellise M, Saurin JC, Tanis PJ, Wagner A, Balaguer F, Ricciardiello L. Endoscopic management of polyposis syndromes: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. (2019) 51(9):877-895.

7. Vasen HF, Moslein G, Alonso A, Aretz S, Bernstein I, Bertario L, Blanco I, Bulow S, Burn J, Capella G, Colas C, Engel C, Frayling I, Friedl W, Hes FJ, Hodgson S, Jarvinen H, Mecklin JP, Moller P, Myrhoi T, Nagengast FM, Parc Y, Phillips R, Clark SK, de Leon MP, Renkonen-Sinisalo L, Sampson JR, Stormorken A, Tejpar S, Thomas HJ, Wijnen J. Guidelines for the clinical management of familial adenomatous polyposis (FAP). Gut. (2008) 57(5):704-13.

8. Familial adenomatous polyposis. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=733

9. Sada H, Hinoi T, Ueno H, Yamaguchi T, Inoue Y, Konishi T, Kobayashi H, Kanemitsu Y, Ishida F, Ishida H, Tomita N, Matsubara N, Sugihara K. Prevalence of and risk factors for thyroid carcinoma in patients with familial adenomatous polyposis: results of a multicenter study in Japan and a systematic review. Surg Today. (2019) 49(1):72-81.

10. Stjepanovic N, Moreira L, Carneiro F, Balaguer F, Cervantes A, Balmana J, Martinelli E. Hereditary gastrointestinal cancers: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-updagger. Ann Oncol. (2019) 30(10):1558-1571.

11. Barrow P, Khan M, Lalloo F, Evans DG, Hill J. Systematic review of the impact of registration and screening on colorectal cancer incidence and mortality in familial adenomatous polyposis and Lynch syndrome. Br J Surg. (2013) 100(13):1719-31.

12. Herzig D, Hardiman K, Weiser M, You N, Paquette I, Feingold DL, Steele SR. The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Management of Inherited Polyposis Syndromes. Dis Colon Rectum. (2017) 60(9):881-894.

13. National Comprehensive Cancer Network. Genetic/Familial High-Risk Assessment: Colorectal Version 2.2019. (2019) Accessed: 2019-10-01. Website: https://nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf

14. Sinha A, Tekkis PP, Gibbons DC, Phillips RK, Clark SK. Risk factors predicting desmoid occurrence in patients with familial adenomatous polyposis: a meta-analysis. Colorectal Dis. (2011) 13(11):1222-9.

15. Stoffel EM, Mangu PB, Gruber SB, Hamilton SR, Kalady MF, Lau MW, Lu KH, Roach N, Limburg PJ. Hereditary colorectal cancer syndromes: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology Clinical Practice Guidelines. J Clin Oncol. (2015) 33(2):209-17.

16. Chenbhanich J, Atsawarungruangkit A, Korpaisarn S, Phupitakphol T, Osataphan S, Phowthongkum P. Prevalence of thyroid diseases in familial adenomatous polyposis: a systematic review and meta-analysis. Fam Cancer. (2019) 18(1):53-62.

17. Sandoval JA, Fernandez-Pineda I, Malkan AD. Risk-reduction surgery in pediatric surgical oncology: A perspective. J Pediatr Surg. (2016) 51(4):675-87.

18. Gutierrez Sanchez LH, Alsawas M, Stephens M, Murad MH, Absah I. Upper GI involvement in children with familial adenomatous polyposis syndrome: single-center experience and meta-analysis of the literature. Gastrointest Endosc. (2018) 87(3):648-656.

19. Cubiella J, Marzo-Castillejo M, Mascort-Roca JJ, Amador-Romero FJ, Bellas-Beceiro B, Clofent-Vilaplana J, Carballal S, Ferrandiz-Santos J, Gimeno-Garcia AZ, Jover R, Mangas-Sanjuan C, Moreira L, Pellise M, Quintero E, Rodriguez-Camacho E, Vega-Villaamil P. Clinical practice guideline. Diagnosis and prevention of colorectal cancer. 2018 Update. Gastroenterol Hepatol. (2018) 41(9):585-596.

20. Pennazio M, Spada C, Eliakim R, Keuchel M, May A, Mulder CJ, Rondonotti E, Adler SN, Albert J, Baltes P, Barbaro F, Cellier C, Charton JP, Delvaux M, Despott EJ, Domagk D, Klein A, McAlindon M, Rosa B, Rowse G, Sanders DS, Saurin JC, Sidhu R, Dumonceau JM, Hassan C, Gralnek IM. Small-bowel capsule endoscopy and device-assisted enteroscopy for diagnosis and treatment of small-bowel disorders: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline. Endoscopy. (2015) 47(4):352-76.

21. Almeida FT, Pacheco-Pereira C, Porporatti AL, Flores-Mir C, Leite AF, De Luca Canto G, Guerra EN. Oral manifestations in patients with familial adenomatous polyposis: A systematic review and meta-analysis. J Gastroenterol Hepatol. (2016) 31(3):527-40.