Table 4.

Selected Hereditary Polyposis and Colorectal Cancer Syndromes in the Differential Diagnosis of APC-Associated Polyposis Conditions

Gene(s) / Genetic MechanismDisorderMOIComment
15q15.3q22.1 duplication 1
BMPR1A
SMAD4		Hereditary mixed polyposis syndrome (HMPS) (OMIM 601228)ADAssoc w/↑ risk for CRC & multiple different types of colorectal polyps. Characteristic lesions are mixed juvenile-adenomatous colon polyps. Adenomas, hyperplastic serrated adenomas, & mixed hyperplastic-adenomatous polyps may also occur.
AXIN2 AXIN2-assoc polyposis (oligodontia-CRC syndrome) (OMIM 608615)ADEctodermal dysplasia
BMPR1A
SMAD4 		Juvenile polyposis syndrome (JPS)ADCharacterized by predisposition for hamartomatous polyps, which is often the distinguishing feature between FAP & JPS. Hamartomatous polyps occur in the GI tract – specifically stomach, small intestine, colon, & rectum. Most persons w/JPS have some polyps by age 20 yrs. Most juvenile polyps are benign, but malignant transformation can occur.
EPCAM
MLH1
MSH2
MSH6
PMS2 		Lynch syndrome (hereditary non-polyposis colon cancer)ADIt may be difficult to distinguish Lynch syndrome from attenuated FAP in persons w/early-onset CRC & few adenomatous colonic polyps. Family history of extracolonic cancers & manifestations, MSI testing, &/or IHC testing on tumor tissue may be helpful in distinguishing the 2 disorders.
MLH1
MSH2
MSH6
PMS2 		Constitutional mismatch repair deficiency (CMMRD) (See Lynch syndrome.)ARAffected persons frequently have brain tumors, hematologic malignancies, CRC, &/or other Lynch syndrome cancers in childhood. Café au lait macules &/or axillary/inguinal freckling are seen in most persons; multiple colorectal adenomas mimicking attenuated FAP may also be present.
MSH3 MSH3-assoc polyposis (OMIM 617100)ARColorectal & duodenal adenomas, CRC, gastric cancer, & early-onset astrocytoma
MUTYH MUTYH polyposis (MAP)ARAssoc w/predisposition to multiple adenomas or polyposis coli. The colonic phenotype of MAP can be similar to attenuated FAP. If an APC pathogenic variant is not identified in a person w/colonic polyposis, molecular genetic testing of MUTYH should be considered.
NF1 Neurofibromatosis type 1 (NF1)ADPersons w/NF1 may exhibit multiple intestinal polypoid neurofibromas or ganglioneuromas in small bowel, stomach, & colon.
NTHL1 NTHL1 tumor syndrome (NTHL1-assoc polyposis)ARCharacterized by ↑ lifetime risk for CRC, breast cancer, & colorectal polyposis. Addl cancers incl endometrial, cervical, urothelial carcinoma of the bladder, meningioma, unspecified brain tumors, basal cell carcinoma, head & neck squamous cell carcinoma, & hematologic malignancies.
POLD1 POLD1-assoc polyposis (polymerase proofreading-assoc polyposis) (OMIM 612591)ADColorectal & duodenal adenomas; MDPL syndrome (mandibular hypoplasia, deafness, progeroid features & lipodystrophy)
POLE POLE-assoc polyposis (polymerase proofreading-assoc polyposis) (OMIM 615083)ADColorectal & duodenal adenomas
PTEN Cowden syndrome (CS) (See PTEN Hamartoma Tumor Syndrome.)ADCS is assoc w/multiple colorectal polyps, but (unlike APC-assoc polyposis conditions) hamartomatous polyps, juvenile polyps, lipomas, & ganglioneuromas predominate. CS is assoc w/↑ risk of CRC, but breast, thyroid, & endometrial cancer are more common.
STK11 Peutz-Jeghers syndrome (PJS)ADCharacterized by assoc of GI PJS-type polyps & mucocutaneous pigmentation, neither of which are seen in APC-assoc polyposis conditions. PJS polyps are often symptomatic & most prevalent in small intestine (jejunum, ileum, & duodenum in order of prevalence) but can occur elsewhere in GI tract.

AD = autosomal dominant; AR = autosomal recessive; CRC = colorectal cancer; FAP = familial adenomatous polyposis; GI = gastrointestinal; IHC = immunohistochemistry; MOI = mode of inheritance; MSI = microsatellite instability

1.

HMPS can be caused by either a BMPR1A pathogenic variant or a duplication of 15q15.3q22.1 that leads to increased expression of GREM1 [Jaeger et al 2012]. Some families with mixed hereditary polyposis syndrome have SMAD4 pathogenic variants [Valle et al 2019].

From: APC-Associated Polyposis Conditions

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