Clinical Description
NTHL1 tumor syndrome has been described in 50 families with 72 affected individuals [Rivera et al 2015, Weren et al 2015, Chubb et al 2016, Belhadj et al 2017, Broderick et al 2017, Buchanan et al 2017, Fostira et al 2018, Altaraihi et al 2019, Belhadj et al 2019, Grolleman et al 2019, Groves et al 2019, Heald et al 2019, Terradas et al 2019, Boulouard et al 2021, Liu et al 2021, Opalič et al 2021, Esnakula et al 2022, Wakeling et al 2022, Pinto et al 2023, Weatherill et al 2023, Terlouw et al 2024]. The following description of the phenotypic features associated with this condition is based on these reports.
Colon polyps. Of the 40 individuals reported by Beck et al [2022] who had been evaluated by colonoscopy, all but two were found to have adenomatous polyps (range: 2-150). In addition, several individuals were reported to have had hyperplastic/sessile serrated polyps [Grolleman et al 2019].
Colorectal cancer (CRC). Thirty-seven of 72 individuals reported to date developed CRC. The median age of onset was 51 years (range: 31-73 years). Nineteen individuals were diagnosed with CRC before age 50 years [Rivera et al 2015, Weren et al 2015, Chubb et al 2016, Fostira et al 2018, Belhadj et al 2019, Grolleman et al 2019, Boulouard et al 2021, Beck et al 2022, Esnakula et al 2022, Wakeling et al 2022, Pinto et al 2023, Weatherill et al 2023, Terlouw et al 2024]. CRC in individuals with NTHL1 tumor syndrome was mostly right-sided, but has been observed throughout the colon, from the rectum to the appendix [Rivera et al 2015, Weren et al 2015, Belhadj et al 2017, Grolleman et al 2019, Terlouw et al 2024]. Metachronous or synchronous tumors were identified in at least nine individuals [Fostira et al 2018, Grolleman et al 2019, Wakeling et al 2022, Weatherill et al 2023, Terlouw et al 2024]. The limited number of families and the presence of a selection bias in the individuals reported to date hamper accurate cancer risk analysis. In the absence of timely surveillance, the lifetime risk for CRC in individuals with NTHL1 tumor syndrome is likely to be high.
Breast cancer has been observed in 12 of 22 females with NTHL1 tumor syndrome with a median age of onset of 49 years (range: 36-63 years) [Beck et al 2022]. At least three had bilateral breast cancer. The reported subtypes included ductal, lobular, and mixed ductal/papillary. Hormone receptor status (triple negative) was reported in one individual. One male was reported with breast cancer [Esnakula et al 2022].
Endometrial cancer has been diagnosed in five of 22 females with NTHL1 tumor syndrome, with a median age of diagnosis of 57 years (range: 47-74 years) [Grolleman et al 2019, Beck et al 2022].
Duodenal polyps and cancer. Multiple duodenal polyps were reported in two individuals with NTHL1 tumor syndrome [Weren et al 2015, Fostira et al 2018]. One individual also developed esophageal polyps. Two individuals developed duodenal cancer [Weren et al 2015, Boulouard et al 2021]. However, one individual with duodenal cancer also presented with a heterozygous germline pathogenic variant in MSH2 [Boulouard et al 2021, Beck et al 2022].
Meningiomas. To date, 11 meningiomas have been reported in individuals with NTHL1 tumor syndrome (10 females, 1 male) with a median age of onset of 46 years (range: 37-64 years) [Rivera et al 2015, Weren et al 2015, Fostira et al 2018, Belhadj et al 2019, Grolleman et al 2019, Boulouard et al 2021, Liu et al 2021, Esnakula et al 2022, Weatherill et al 2023].
Other cancers. Additional cancers reported in individuals with NTHL1 tumor syndrome include urothelial carcinoma of the bladder, unspecified brain tumors, basal cell carcinomas, head and neck squamous cell carcinomas, and hematologic malignancies [Rivera et al 2015, Weren et al 2015, Belhadj et al 2017, Grolleman et al 2019, Beck et al 2022]. Grolleman et al [2019] reported the presence of multiple primary tumors in 16 of 29 individuals (55%). Based on these findings, the cumulative lifetime risk of developing extracolonic cancer by age 60 years was estimated at 35% to 78% (95% CI) [Grolleman et al 2019].
Benign extraintestinal manifestations reported in some individuals include skin hemangiomas, seborrheic keratosis, and intradermal nevi; ovarian and hepatic cysts; and breast papillomas. To date, the number of individuals reported with these features is low and an association with NTHL1 tumor syndrome is unclear.
NTHL1 heterozygotes. To date, there is no evidence that NTHL1 heterozygotes are at increased risk for colorectal cancer [Elsayed et al 2020, Beck et al 2022]. A low-to-moderate increased risk for breast cancer has been reported [Li et al 2021, Nurmi et al 2023]. A previously reported individual with breast cancer had a germline heterozygous NTHL1 variant (NM_002528.6:c.859C>T [p.Gln287Ter]) and loss of heterozygosity in tumor tissue [Nik-Zainal et al 2016, Drost et al 2017].