Hereditary polyposis syndromes remain a challenging disease entity: Old dilemmas and new insights

Table 1 Hereditary polyposis syndromes

Gene (clinical entity)	Inheritance	Cancer risk	Extraintestinal manifestations
Adenomatous polyposis
APC (familial adenomatous polyposis)	Autosomal dominant	Colon, rectum, thyroid, gastric, hepatoblastoma	Osteomas, dental anomalies, desmoid tumors, epidermoid cysts, CHRPE
AXIN2 (oligodontia-colorectal cancer syndrome)	-	Colon, rectum	Tooth agenesis
POLD1 (polymerase proofreading-associated polyposis)	-	Colon, rectum, uterus, breast, bladder, brain
POLE (polymerase proofreading-associated polyposis)	-	Colon, rectum, uterus, duodenal, ovary
MBD4 (MBD4-associated neoplasia syndrome)	Autosomal recessive	Colon, rectum, myelodysplastic syndrome, acute myeloid leukemia
MLH1, MSH2, MSH6, PMS2 (constitutional mismatch repair syndrome)	-	Colon, rectum, hematologic, brain	Café-au-lait spots, neurofibromas
MLH3 (MLH3-related polyposis)	-	Uncertain; potentially colon, rectum, gastric, brain, breast
MSH3 (MSH3-related polyposis)	-	Uncertain; potentially colon, rectum, gastric, brain, breast
MUTYH (MUTYH-associated polyposis)	-	Colon, rectum, ovary, bladder, breast, uterus, gastric, pancreas, skin
NTHL1 (NTHL1 tumor syndrome)	-	Colon, rectum, breast, duodenum, uterus
Hamartomatous polyposis
BMPR1A (juvenile polyposis syndrome)	Autosomal dominant	Colon, rectum
PTEN (PTEN hamartoma tumor syndrome)	-	Colon, rectum, thyroid, breast, kidney, uterus	Macrocephaly, trichilemmomas, autism, hemangiomas, arteriovenous malformations
SMAD4 (juvenile polyposis syndrome)	-	Colon, rectum, gastric	HHT, thoracic aneurysm
STK11 (Peutz-Jeghers syndrome)	-	Colon, rectum, duodenum, breast, ovary, pancreas, gastric, cervical	Mucocutaneous pigmentation
Serrated polyposis
RNF43 (serrated polyposis syndrome)1	Autosomal dominant	Colon, rectum
Mixed-type polyposis
GREM1 (hereditary mixed polyposis syndrome)	Autosomal dominant	Colon, rectum

¹Ring finger 43 only accounts for a fraction of serrated polyposis syndromes.

APC: Adenomatous polyposis coli; AXIN2: Axis inhibition protein 2; BMPR1A: Type IA bone morphogenetic protein receptor; CHRPE: Multifocal/bilateral congenital hypertrophy of the retinal pigment epithelium; HHT: Hereditary hemorrhagic telangiectasia; MLH: MutL homolog; MSH: MutS homolog; MUTYH: MutY homologue; POLD1: Polymerase delta 1; POLE: Polymerase-epsilon; RNF43: Ring finger 43.