NTHL1 Tumor Syndrome

Roland Kuiper, Richarda M De Voer, Nicoline Hoogerbrugge

Research output: Contribution to journalArticlepeer-review


Clinical characteristics: NTHL1 tumor syndrome is characterized by an increased lifetime risk for colorectal cancer (CRC), breast cancer, and colorectal polyposis. Colorectal polyps can be adenomatous, hyperplastic, and/or sessile serrated. Duodenal polyposis has also been reported. Additional cancers reported in individuals with NTHL1 tumor syndrome include endometrial cancer, cervical cancer, urothelial carcinoma of the bladder, meningiomas, unspecified brain tumors, basal cell carcinomas, head and neck squamous cell carcinomas, and hematologic malignancies. The cumulative lifetime risk of developing extracolonic cancer by age 60 years has been estimated at 35% to 78%.

Diagnosis/testing: The diagnosis is established in a proband by identification of germline biallelic pathogenic variants in NTHL1 on molecular genetic testing.

Management: Treatment of manifestations: Colorectal polyps should be removed (polypectomy) until polypectomy alone cannot manage the large size and density of the polyps. At that point, either subtotal colectomy or proctocolectomy is performed based on polyp features and location. Large duodenal polyps or those polyps showing dysplasia or villous changes should be excised during endoscopy.

Surveillance: Due to the limited number of affected individuals reported, surveillance recommendations are likely to evolve. They currently include: colonoscopy with polypectomy every two years beginning at age 18-20 years; breast MRI examination annually between ages 30 and 60 years; mammography annually between ages 40 and 50 years, then every two years between ages 50 and 75 years; transvaginal ultrasound examination and endometrial biopsy to screen for endometrial cancer every two years between ages 40 and 60 years; upper endoscopy and side-viewing duodenoscopy every five years beginning at age 25 years.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an individual who has germline biallelic NTHL1 pathogenic variants in order to identify as early as possible those who would benefit from appropriate surveillance, early diagnosis, and treatment of NTHL1-associated tumors.

Genetic counseling: NTHL1 tumor syndrome is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for a pregnancy at increased risk are possible if the pathogenic variants in the family have been identified.
Original languageEnglish
Publication statusPublished - 2020


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