This type of polyps is usually associated with polyposis syndromes such as familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), and MYH-associated polyposis (MAP). FAP is the most common, while the other two conditions rarely present with intestinal lesions during childhood or adolescence and are no further described in this chapter. FAP is an inherited condition characterized by early onset of multiple adenomas (>100) throughout the large bowel. Its estimated frequency is 1 in 13,000–18,000 live births [16]. It is caused by a mutation of the adenomatous polyposis coli (APC) gene, usually inherited in an autosomal dominant manner, but in 20–30 % of cases represents a de novo condition. Even if the most common alteration is a truncating mutation, many other causative mutations have been reported to date. Genotype–phenotype correlations have been observed and should be taken into consideration in decision making [17]. Adenomas first appear at an average age of 16, and progression to colorectal cancer is almost inevitable by the age of 50 [14]. Usually patients present to physicians’ attention either because of symptoms of multiple and large adenomas, e.g., rectal bleeding or anemia or other nonspecific complaints such as change in bowel habits, constipation, diarrhea, and abdominal pains, or for evaluation after a family member has been diagnosed. In the first setting, the finding of multiple adenomas (>10) should address the patient to comprehensive genetic testing for one of the various polyposes, including APC and MUTYH gene mutation analysis [3]. In more than 90 % of cases, it is possible to identify the causative mutation by commercially available gene sequencing on a routine blood sample [14]. Nevertheless, the absence of a mutation does not definitively rule out a clinical diagnosis if the phenotype is striking. On the contrary, a negative test in a relative of a patient with known pathogenetic mutation allows the physicians to exclude the diagnosis. The main goal in managing these patients is cancer prevention. For colorectal cancer screening, a sigmoidoscopy is recommended every 1–2 years starting at 10–12 years of age and should include registration of polyp number, size, and distribution and multiple biopsies [3]. Colectomy remains the cornerstone of cancer prevention and is usually recommended between 15 and 25 years of age [13]. Early surgery is mandatory in the case of documented or suspected cancer and should be taken into consideration in case of large polyps (>10 mm), high-grade dysplasia polyps, and marked increase in number of polyps and symptoms. Surgical procedures of choice are colectomy with IRA (ileal–rectal anastomosis) or proctocolectomy with IPAA (ileal pouch–anal anastomosis). Number and localization of polyps and type of APC mutation are to be considered in determining the optimal procedure. Of note, adenomas and cancer may still develop in the remaining rectal epithelium or in the anal transition zone; therefore, postsurgical surveillance should include yearly endoscopy of the rectum or ileal pouch and examination of the ileostomy every 2 years [3]. In individuals with FAP, there is also an increased risk for upper GI adenomas and cancer, even if mean age of duodenal cancer diagnosis is later in the course of the disease (usually between 47 and 51) [16]. Upper GI screening should therefore be performed starting at the age of 25–30 [3]. Another important cause of morbidity and the second cause of death in these patients are desmoid tumors, occurring in 15 % of them. The usual sites are small bowel mesentery and abdominal wall, with few arising in the trunk or limbs, ranging from 1 to 10 per individual. They could remain asymptomatic or cause bowel or ureteric obstruction, perforation, fistula, or hemorrhage, and their treatment still remains a challenge for the risk of bleeding, recurrence, or consequent short bowel syndrome [16]. Other malignancies associated with FAP are thyroid cancer, for which annual thyroid ultrasound is also recommended; hepatoblastoma, for which the need of screening with α-fetoprotein monitoring and liver ultrasound is still debated [3]. Congenital hypertrophy of the retinal pigment epithelium (CHRPE) is another typical feature of FAP, present in roughly 70–80 % of patients. It refers to the presence of characteristic pigmented fundus lesions that are usually present at birth, asymptomatic, and with no malignant potential, but ophthalmological examination could be a useful early diagnostic test for at-risk family members, combined with genetic analysis [16].