Polyposis syndromes
Last update: October 2025
Adenomatous polyposis syndromes are characterised by the occurrence of tens to thousands of adenomas (i.e. polyps of a certain type) mainly in the large bowel, and often also in the upper gastrointestinal tract. When not detected early and removed, some polyps invariably will develop into colorectal cancer. The minimum number of adenomas to diagnose adenomatous polyposis is not clearly defined, and also depends on the localisation, the age of onset, and family history. However, at least ten confirmed colorectal adenomas are usually required in an adult patient. In some conditions, other polyp types can be found in addition to adenomas, like serrated polyps in MUTYH-related polyposis.
Currently, several different inherited forms of adenomatous polyposis, caused by genetic changes (germline pathogenic variants) in different genes, can be identified (see below). While all types are defined by the presence of multiple colorectal adenomas, a marked clinical variability concerning the number of polyps and age of onset can be observed, even within families. In addition, the upper gastrointestinal tract is frequently affected, and most forms are accompanied by a spectrum of benign and malignant tumours outside the gastrointestinal tract.
Inherited forms of adenomatous polyposis are caused by pathogenic variants that are usually present in all cells of the body (germline pathogenic variants). Most causative variants have been transmitted from one or both parents, but some can also occur for the first time (as de novo variant) in a patient. If this happens at a later stage of embryonic development, the causative variant might only be present in a subset of the cells of the body including the gastrointestinal tract (as so-called mosaic). The causative genes are usually responsible for the correction of DNA changes (DNA repair genes) or the suppression of cell growth and proliferation (tumour suppressor genes). In patients where no genetic cause is identified with current methods, a hereditary basis is still possible.
Depending on the underlying affected gene, the condition is named in a different way (some types include already the gene name). Familial adenomatous polyposis (FAP, ORPHA:733; OMIM:175100, MONDO:0021057) is the most common and well-known form, which is caused by germline pathogenic variants of the APC gene. The second most frequent type of adenomatous polyposis is MUTYH-related polyposis (MAP, ORPHA:247798, OMIM:608456, MONDO:0012041). All the other conditions such as AXIN2-related polyposis (ORPHA: 401911, OMIM:608615, MONDO:0012075), Polymerase proofreading-related polyposis (PPAP, ORPHA:447877, caused by germline variants in the genes POLE (OMIM:615083, MONDO:0100287 or POLD1 (OMIM:612591, MONDO:0100351), NTHL1-related polyposis (NAP, ORPHA:454840; OMIM:616415; MONDO:0100502), MBD4-associated neoplasia syndrome (MANS, OPRHA: 661526, OMIM:619975; MONDO:0859267) and MSH3-related polyposis (ORPHA:480536, OMIM:617100; MONDO:0044300), are very rare and have been identified more recently, so the characterisation of the full spectrum and tumour risk has not been completely established. But an increased risk for extraintestinal cancers has been shown for some of these syndromes (like endometrial cancer in MAP or breast cancer in NAP).
Approximately 10-20% of individuals with more than 100 adenomas, and 60-70% with 10-100 adenomas, do not have identifiable germline PVs in one of these genes.
In conditions such as FAP, PPAP or AXIN2-related polyposis only one of the two copies of the gene is affected. Children of an affected mother or father are at a 50% risk of inheriting the pathogenic variant and therefore also the increased risk for tumour development (autosomal dominant mode of inheritance). If a child does not inherit the causative variant, they will most probably not develop the disease. Typically, there can be multiple affected individuals throughout many generations in a family. However, it is also possible that the pathogenic variant originates in the affected individual for the first time (usually de novo mutation). If a variant occurred new in a patient (see above), he or she might be the first affected person in the family but can still pass on the variant to the next generation.
In contrast, in conditions such as MAP, NAP, MANS or MSH3-related polyposis both copies of the gene need to harbour pathogenic variants for the disease to develop (autosomal recessive mode of inheritance). Siblings of an affected individual are at a 25% recurrence risk, while the parents and children are usually not affected. Therefore, the disease is usually characterized by a single affected individual in a family or affected individuals in a sibship or single generation. Nevertheless, children of patients might also be affected, if the other parent is a (healthy) carrier of a pathogenic variant in the same gene. The risk that this occurs is higher in case the patient and his or her partner are consanguineous. Therefore, genetic consultation with the partner in terms of family planning should be recommended.
Affected individuals, as well as all family members in whom the disease is genetically diagnosed or individuals who are at risk of having inherited the disorder and have not been or cannot be tested, should undergo established intense surveillance / cancer prevention programs. The spectrum, frequency, and onset of the different surveillance examinations depend on the underlying condition and clinical presentation. Appropriate measures may include endoscopic examinations and imaging, as well as preventive surgical treatment.
The most important and effective surveillance measure in all adenomatous polyposis syndromes are frequent colonoscopies and endoscopic examinations of the upper gastrointestinal tract with removal of polyps. In case of high polyp numbers, a colectomy (that is the complete or partial removal of the large bowel) may be considered. Medications to reduce adenoma burden and tumour risk are under development. In FAP surveillance already starts from about 12 years of age, whereas in more late-onset (attenuated) conditions surveillance usually is recommended from 18 - 20 years of age. For individuals with very rare and recently identified conditions such as PAPP and NAP, no detailed surveillance programmes exist so far. In these syndromes, surveillance examinations usually follow the recommendations for the well-established conditions (FAP, MAP).
For patients with an unknown molecular cause, screening (every 1-5 years depending on age and polyp count) for patients and first-degree relatives is advised in some guidelines. However, only a few studies have explored outcomes from colon and gastroduodenal screenings for these patients, and the results for family members are limited.
Juvenile polyposis syndrome (ORPHA:2929, OMIM:174900, 175050; MONDO:0008278, 0017380) comprises an increased risk for the development of juvenile polyps in the large and small bowel, which are often misdiagnosed as other (e. g. inflammatory) polyps. As other polyps (like adenomas) also develop in these patients and polyp numbers per colonoscopy are usually small, clinical diagnosis is often difficult. Presentation in the second decade of life is most common by rectal bleeding or cancer. Patients with Juvenile polyposis syndrome are also at increased risk to develop gastric polyps and cancer.
Pathogenic variants in the tumour suppressor genes SMAD4 (50% of cases) and BMPR1A are causative and inherited in an autosomal dominant manner. Patients with causative SMAD4 variants have a more prominent phenotype (more symptoms) and generally also develop Hereditary Haemorrhagic Telangiectasia (HHT), also known as Rendu-Osler-Weber disease. Surveillance for juvenile polyposis is offered from the age of 8 years.
A severe polyposis can occur in case of a chromosomal deletion of both BMPR1A and PTEN, with among other symptoms like macrocephaly and developmental delay, prominent juvenile polyps already in infancy (10q23 deletion). Treatment of these children should take place in a center of expertise.
Peutz-Jeghers syndrome (ORPHA:2869, OMIM:175200; MONDO: 0008280) also shows autosomal dominant inheritance and is characterised by specific hamartomatous polyps (Peutz Jeghers polyps), most commonly involving the small intestine (predominantly the ileum), but also the colon and stomach, while the mouth and oesophagus are spared. Symptoms include rectal bleeding, anaemia or bowel pain. The most dangerous complication of the polyps is small bowel obstruction (intussusception) for which urgent surgery might be needed. Patients with Peutz-Jeghers syndrome also show a typical (but not specific) mucocutaneous hyperpigmentation involving the mouth, fingers and toes. These occur already in childhood and those on the lips often diminishes during lifetime. In addition to the hamartomatous polyps, that occur from a young age, in adulthood there is in an increased risk for cancer like colorectal breast and pancreatic cancer. Patients with Peutz-Jegher syndrome are offered extensive surveillance programs, starting at the age of 8 years.
Serrated Polyposis Syndrome (SPS, ORPHA:157798, OMIM:617108) is the most common gastrointestinal polyposis syndrome in which multiple serrated polyps (including hyperplastic polyps and sessile serrated lesions) are identified in the large bowel. However, to date no clear genetic predisposition to SPS has been described. Variants especially in RNF43 have been suggested as causative but are more likely part of the cause in the context of a multifactorial disease. Most patients are singular cases in their family and the recurrence risk for children is low. First degree family members of Serrated Polyposis patients are usually offered regular colonscopic surveillance every 5 years.
Hereditary mixed polyposis syndrome (HMPS, ORPHA:157794, OMIM:601228, MONDO:0011023) describes a very rare autosomal dominantly inherited large-bowel disease characterized by the presence of a mixture of hyperplastic, atypical juvenile and adenomatous polyps that are associated with an increased risk of developing colorectal cancer if left untreated. Specific duplications in the promotor region of the GREM1 gene have been identified as the underlying cause of this syndrome.
Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS, ORPHA:314022, OMIM:619182, MONDO:0017790) is a rare familial gastric cancer syndrome with an autosomal dominant pattern of inheritance. It is characterised by fundic gland polyposis of the gastric body and is associated with a significant risk of gastric adenocarcinoma. Unlike in case of FAP, causal pathogenic variants in patients with GAPPS have been detected only in the regulatory region – the B1 promoter, which activates transcription of the APC gene along with the A1 promoter.
Adenomatous polyposis syndromes
Familial adenomatous polyposis (FAP)
GeneReviews® - APC-Associated Polyposis Conditions
Orphanet: Familial adenomatous polyposis
OMIM: familial adenomatous polyposis 1
ClinGen: classic or attenuated familial adenomatous polyposis
ERN ERNICA (regarding gastroenterological diseases: FAP)
MUTYH-related polyposis (MAP)
GeneReviews® - MUTYH Polyposis
Orphanet: MUTYH-related polyposis
OMIM: familial adenomatous polyposis 2
ClinGen: familial adenomatous polyposis 2
AXIN2-related polyposis
Orphanet: AXIN2-related polyposis
OMIM: Oligodontia-colorectal cancer syndrome
ClinGen: oligodontia-cancer predisposition syndrome
Polymerase proofreading-related polyposis
Orphanet: Polymerase proofreading-related polyposis
OMIM: Colorectal cancer-12 (POLE, POLD1)
ClinGen: POLE-related polyposis and colorectal cancer syndrome
ClinGen: POLD1-related polyposis and colorectal cancer syndrome
NTHL1-related polyposis
GeneReviews® - NTHL1 Tumor Syndrome
Orphanet: NTHL1-related polyposis
OMIM: familial adenomatous polyposis 3
ClinGen: NTHL1-deficiency tumor predisposition syndrome
MSH3-related polyposis
Orphanet: MSH3-related polyposis
OMIM: familial adenomatous polyposis-4
ClinGen: familial adenomatous polyposis 4
MBD4-associated neoplasia syndrome
TG4: MBD4-associated neoplasia syndrome
Orphanet: MBD4-related tumor predisposition syndrome
OMIM: tumor predisposition syndrome-2
ClinGen: tumor predisposition syndrome 2
Hamartomatous polyposis syndromes
Peutz-Jeghers syndrome
GeneReviews® - Peutz-Jeghers Syndrome
Orphanet: Peutz-Jeghers Syndrome
OMIM: Peutz-Jeghers syndrome
ClinGen: Peutz-Jeghers syndrome
Juvenile polyposis syndrome
GeneReviews® - Juvenile Polyposis Syndrome
Orphanet: Juvenile Polyposis Syndrome
OMIM: juvenile polyposis syndrome
OMIM: juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome
ClinGen: juvenile polyposis syndrome
ClinGen: juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome
Other polyposis syndromes
Serrated polyposis syndrome
Orphanet: Serrated polyposis syndrome
OMIM: sessile serrated polyposis cancer syndrome
Hereditary mixed polyposis syndrome
Orphanet: Hereditary mixed polyposis syndrome
OMIM: hereditary mixed polyposis syndrome
ClinGen: hereditary mixed polyposis syndrome
Gastric adenocarcinoma and proximal polyposis of the stomach
Orphanet: Gastric adenocarcinoma and proximal polyposis of the stomach
OMIM: gastric adenocarcinoma and proximal polyposis of the stomach
ClinGen: gastric adenocarcinoma and proximal polyposis of the stomach
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Endorsed guidelines for Lynch and polyposis, and hereditary CRC |
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Thematic Group 2: Lynch syndrome and polyposis Adenomatous polyposis syndromes Hamartomatous and other polyposis syndromes
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