Nthl1 Tumor Syndrome
Summary
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 diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified.
Diagnosis
Formal diagnostic criteria for NTHL1 tumor syndrome have not been established.
Suggestive Findings
NTHL1 tumor syndrome should be suspected in an individual with the following clinical findings, family history, and/or molecular genetic findings on tumor tissue.
Clinical findings
- Presence of multiple primary cancers before age 50 years, especially including breast, colon, or urothelial cell cancer, brain tumors, head and neck squamous cell carcinoma, hematologic malignancies, endometrial malignancies and premalignancies, and/or basal cell carcinoma
- Colorectal cancer (CRC) diagnosed before age 40 years
- One or more colorectal adenomas in an individual age ≤40 years
- A personal cumulative lifetime history of ten or more colorectal adenomas in an individual age ≤60 years
- A personal cumulative lifetime history of any combination of 20 or more colorectal adenomas, hyperplastic polyps, and/or sessile serrated polyps in an individual of any age
Family history of multiple cancers (especially when including breast, colorectal, or urothelial cell cancer, brain tumors, head and neck squamous cell carcinoma, hematologic malignancies, endometrial malignancies and premalignancies, and/or basal cell carcinoma) consistent with autosomal recessive inheritance
Molecular genetic findings on tumor tissue. Identification of a specific mutational signature on tumor tissue testing due to a high percentage of somatic C>T transversions (e.g., COSMIC Signature 30) [Grolleman et al 2019]
Establishing the Diagnosis
The diagnosis of NTHL1 tumor syndrome is established in a proband with biallelic germline NTHL1 pathogenic variants identified on molecular genetic testing [Weren et al 2015] (see Table 1).
Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel, single-gene testing) and comprehensive genomic testing (exome sequencing, genome sequencing).
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of NTHL1 tumor syndrome is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of NTHL1 tumor syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When phenotypic findings suggest the diagnosis of NTHL1 tumor syndrome, molecular genetic testing approaches can include use of a multigene panel or single-gene testing:
- A CRC and polyposis multigene panel that includes NTHL1, APC, MUTYH, and other genes of interest (see Differential Diagnosis) is most likely to identify NTHL1 tumor syndrome at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of NTHL1 tumor syndrome, some cancer-predisposition multigene panels may not include NTHL1. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
- Single-gene testing. Sequence analysis of NTHL1 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants. Sequence analysis of all six exons of NTHL1 is recommended. No large exon or whole-gene deletions or duplications in NTHL1 have yet been reported, but their contribution to NTHL1 tumor syndrome cannot be excluded. Therefore, copy number analysis is recommended, particularly when only one germline NTHL1 pathogenic variant has been identified in an individual with findings suggestive of NTHL1 tumor syndrome.
Option 2
When the diagnosis of NTHL1 tumor syndrome is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
If exome sequencing is not diagnostic, an exome array (when clinically available) may be considered to detect the known pathogenic variants as well as (multi)exon deletions or duplications. Thus far, NTHL1 copy number aberrations have not been described in individuals with NTHL1 tumor syndrome.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in NTHL1 Tumor Syndrome
| Gene 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method |
|---|---|---|
| NTHL1 | Sequence analysis 3 | 23/23 4 |
| Gene-targeted deletion/duplication analysis 5 | None reported 6 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Rivera et al [2015], Weren et al [2015], Chubb et al [2016], Belhadj et al [2017], Fostira et al [2018], Altaraihi et al [2019], Belhadj et al [2019], Grolleman et al [2019], Groves et al [2019]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole.
- 6.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Clinical Characteristics
Clinical Description
NTHL1 tumor syndrome has been described in 20 families including 33 affected individuals [Rivera et al 2015, Weren et al 2015, Belhadj et al 2017, Broderick et al 2017, Fostira et al 2018, Altaraihi et al 2019, Belhadj et al 2019, Grolleman et al 2019, Groves et al 2019]. The following description of the phenotypic features associated with this condition is based on these reports.
Colon polyps. The 24 individuals reported by Grolleman et al [2019] who had been evaluated by colonoscopy were all found to have adenomatous polyps (range 1-100). Seven of these individuals had hyperplastic/sessile serrated polyps.
Colorectal cancer (CRC). Nineteen of 33 individuals reported to date developed CRC. The median age of onset was 61 years (range 33-73 years). Nine individuals were diagnosed with CRC before age 50 years [Fostira et al 2018, Belhadj et al 2019, Grolleman et al 2019]. 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]. Metachronous or synchronous tumors were identified in six individuals [Grolleman et al 2019]. 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 was observed in nine of 15 women with NTHL1 tumor syndrome with a median age of onset of 49 years (range 38-63 years) [Grolleman et al 2019]. Three women had bilateral breast cancer. The reported subtypes included ductal, lobular, and mixed ductal/papillary. Hormone receptor status (triple negative) was reported in one individual.
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. Another individual developed duodenal cancer at age 52 years [Weren et al 2015].
Other cancers. Endometrial cancer has been diagnosed in five of the 17 women with NTHL1 tumor syndrome reported thus far, with a median age of diagnosis of 57 years (range 47-74 years). Additional cancers reported in individuals with NTHL1 tumor syndrome include cervical cancer, urothelial carcinoma of the bladder, meningiomas, 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]. 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 as yet unclear.
NTHL1 heterozygotes. The risk of developing CRC or other malignancy in individuals with a heterozygous germline NTHL1 pathogenic variant is unclear. In the eleven families reported by Grolleman et al [2019], three confirmed heterozygotes developed cancer. A previously reported individual with breast cancer was found to have a germline heterozygous NTHL1 variant (p.Gln287Ter) and loss of heterozygosity in tumor tissue [Nik-Zainal et al 2016, Drost et al 2017].
Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
Nomenclature
This condition has been referred to as NTHL1 polyposis and familial adenomatous polyposis 3 (OMIM 616415), terms which emphasize the similarity with MUTYH polyposis [Belhadj et al 2017, Groves et al 2019, Valle et al 2019]. Considering the broad tumor spectrum reported in individuals with biallelic NTHL1 pathogenic variants, and the fact that the diagnosis has been identified in individuals without CRC and/or (suspected) polyposis, the term NTHL1 tumor syndrome is preferred.
Prevalence
The prevalence of NTHL1 tumor syndrome is unknown. Based on the prevalence of NTHL1 pathogenic variants in the population, it has been estimated that in Europeans, NTHL1 tumor syndrome would occur with a frequency approximately one fifth (1:114,770) that of MUTYH polyposis (1:19,079) [Weren et al 2018].
Differential Diagnosis
Table 2.
Genes to Consider in the Differential Diagnosis of NTHL1 Tumor Syndrome
| MOI | Gene(s) 1 | Disorder | Clinical Features of Differential Disorder | |
|---|---|---|---|---|
| Overlapping w/NTHL1 tumor syndrome | Distinguishing from NTHL1 tumor syndrome | |||
| AR | MSH3 | Familial adenomatous polyposis 4 (OMIM 617100) |
| No other cancer risk reported |
| MUTYH | MUTYH polyposis |
| ||
| AD | APC | Attenuated familial adenomatous polyposis |
| Extracolonic manifestations (e.g., desmoid tumors, fundic gland polyps, congenital hypertrophy of retinal pigmented epithelium, dental abnormalities, fibromas, lipomas, & osteomas) |
| BMPR1A SMAD4 | Juvenile polyposis syndrome | ↑ CRC risk |
| |
| EPCAM MLH1 MSH2 MSH6 PMS2 | Lynch syndrome |
|
| |
| Duplication upstream of GREM1 | Hereditary mixed polyposis syndrome (OMIM 601228) |
| Mixed polyposis (hyperplastic, atypical juvenile & adenomatous polyps) | |
| POLD1 | CRC, susceptibility to, 10 (OMIM 612591) |
| Astrocytoma risk | |
| POLE | CRC, susceptibility to, 12 (OMIM 615083) |
| ↑ risk for ovarian, gastric cancer, & astrocytoma | |
| PTEN | PTEN hamartoma tumor syndrome | ↑ CRC, breast, & endometrial cancer risk |
| |
| STK11 | Peutz-Jeghers syndrome | ↑ CRC & breast cancer risk |
| |
| TP53 | Li-Fraumeni syndrome | ↑ CRC & breast cancer risk | ↑ risk for sarcoma, lung cancer, adrenocortical carcinoma, choroid plexus carcinoma, & additional cancers | |
AD = autosomal dominant; AR = autosomal recessive; GI = gastrointestinal; MOI = mode of inheritance; CRC = colorectal cancer
- 1.
Listed by mode of inheritance, then alphabetically by gene
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with NTHL1 tumor syndrome, the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Due to the lifelong increased cancer risk and the diversity of tumors associated with NTHL1 tumor syndrome, evaluations for cancer in individuals with NTHL1 tumor syndrome need to be ongoing and comprehensive (see Surveillance). Individuals with NTHL1 tumor syndrome should seek a cancer genetics consultation to review the diagnosis and medical management recommendations.
Treatment of Manifestations
In general, the treatment regarding gastrointestinal tumors is similar to that of familial adenomatous polyposis (FAP) and attenuated familial adenomatous polyposis (AFAP) (see APC-Associated Polyposis Conditions).
Colon polyps and colon cancer. Colonoscopy is effective surveillance for colon cancer; 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 [Lipton & Tomlinson 2006, Sampson & Jones 2009].
Breast cancer, endometrial cancer, and other cancers. The treatment for these cancers in individuals with NTHL1 tumor syndrome is the same as for that of the general population.
Duodenal polyps. Management of polyps is similar to that in individuals with FAP. In particular, large polyps or those polyps showing dysplasia or villous changes should be excised during endoscopy.
Surveillance
Table 3.
Recommended Surveillance for Individuals with NTHL1 Tumor Syndrome
| Concern | Evaluation | Frequency |
|---|---|---|
| Colon cancer | Colonoscopy | Every 2 yrs starting at age 18-20 yrs |
| Breast cancer | Breast MRI | Annually between ages 30 & 60 yrs; MRI sensitivity is greater than that of mammography. |
| Mammography |
| |
| Endometrial cancer | Transvaginal ultrasound examination & endometrial biopsy | Every 2 yrs between ages 40 & 60 yrs |
| Duodenal polyps/cancer | Upper endoscopy | Starting at age 25 yrs; frequency per Spigelman criteria (at least every 5 yrs) [Spigelman et al 1989] |
Individuals heterozygous for a germline NTHL1 pathogenic variant. To date, there is no evidence that NTHL1 heterozygotes are at increased risk for cancer and there are no specific screening recommendations for heterozygous relatives of individuals with NTHL1 tumor syndrome. NTHL1 heterozygotes are advised to participate in population screening measures for colorectal cancer and breast cancer, or could be offered screening based on their family history (e.g., incidence of CRC and/or breast cancer in family members who do not have biallelic NTHL1 pathogenic variants).
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 biallelic germline NTHL1 pathogenic variants in order to identify as early as possible those who would benefit from appropriate surveillance (beginning at age 18 years), early diagnosis, and treatment of NTHL1-associated tumors.
In general, molecular genetic testing for NTHL1 tumor syndrome is not recommended for at-risk individuals younger than age 18 years. However, predictive testing should be considered if there is a history of early-onset cancer in the family. For unaffected individuals with biallelic NTHL1 pathogenic variants, screening should begin by age 18 years, or two to five years earlier than the earliest diagnosis in the family [NCCN 2016]. Therefore, a history of early cancers in the family may warrant testing prior to age 18.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.