Mismatch repair cancer syndrome (MMRCS)

Actionability Pediatric Summary Report

Secondary Findings in Pediatric Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Genes: MLH1 (HGNC:7127) MSH2 (HGNC:7325) MSH6 (HGNC:7329) PMS2 (HGNC:9122)
• Mode(s) of Inheritance: Autosomal Recessive
• Literature Search: 08/24/2022
• Curation Status: Released

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
MLH1	mismatch repair cancer syndrome (0031219)	276300	Strong Actionability
MSH2	mismatch repair cancer syndrome (0031219)	619096	Strong Actionability
MSH6	mismatch repair cancer syndrome (0031219)	619097	Strong Actionability
PMS2	mismatch repair cancer syndrome (0031219)	619101	Strong Actionability

Actionability Assertion Rationale

• Although the computed assertion was moderate, and a minority of the experts agreed with this assertion, the majority of experts thought that the available study in the pediatric age group shows a significant survival advantage which was consistent with strong actionability.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Morbidity and mortality from neoplasia / Evaluation and multi-modal neoplasia surveillance by specialist(s) to guide treatment	2	3C	2N	2	9CN

Severity of Outcome

Prevalence of the Genetic Condition

The prevalence of mismatch repair cancer syndrome (MMRCS; aka constitutional mismatch repair-deficiency syndrome (CMMR-D), biallelic mismatch repair deficiency (BMMRD)) is unknown. MMRCS will occur in 25% of the offspring of two individuals who have Lynch syndrome involving the same gene. The population prevalence of Lynch syndrome has been estimated at 1:279; consequently, MMRCS is quite rare. A 2014 review identified a total of 91 families, including 146 patients with MMRCS in the world literature. However, MMRCS is probably under-recognized.

Clinical Features (Signs / symptoms)

MMRCS is characterized by the development of a broad spectrum of malignancies, the most common of which are brain tumors, colorectal and small-bowel cancers, leukemias, and lymphomas. Premalignant and non-malignant lesions such as adenomas and polyps (ranging from a few up to >100) are frequently present before malignancy development. Endometrial and urinary tract cancers are rare and have been reported in fewer than 10 patients each. Central nervous system (CNS) embryonal tumors and medulloblastomas, and ovarian tumors have also been reported. Recent data reveal a large variety of other cancers including childhood sarcomas, neuroblastoma, and Wilms tumor. Patients often have features of neurofibromatosis (NF1) including café-au-lait macules and hyper- and hypopigmented skin alternations. As more patients with MMRCS undergo brain MRI, a CNS phenotype is emerging that includes agenesis of the corpus collosum, vascular changes, and gray matter heterotopias. Other features include developmental venous anomalies, pilomatricomas, and mild immunodeficiency.

Natural History (Important subgroups & survival / recovery)

The hallmark of MMRCS is early onset cancer, most often in childhood or young adulthood. The median age of onset of the first tumor is 7.5 years, with a wide range observed (0.4-39 years). A large portion (up to 40%) of patients develop metachronous second malignancies. The median survival after diagnosis of the primary tumor is less than 30 months. Prognosis depends on the possibility of complete resection, making early detection paramount. It is unclear what tumor spectrum will emerge among adults with MMRCS. Brain tumors are frequent and often diagnosed in the first decade of life. The rate of progression appears to be rapid in the brain tumors. The median age at diagnosis of brain tumors is 9 years (range, 2-40 years). Brain tumors are by far the most common cause of death. Colonic adenomatous oligopolyposis typically is diagnosed between 5 and 10 years of age. The progression of adenomas to malignancy in MMRCS is the most rapid of any inherited colorectal cancer syndrome. Among MMRCS patients presenting with colorectal cancer (CRC), the median age at diagnosis was 16 years (range, 8-48 years) with more than half of patients classified as pediatric-onset CRC. The age of onset of small-bowel adenomas is later; they typically develop in the second decade of life. The median age at diagnosis of small-bowel cancer was 28 years, with a range of 11-42 years. The lifetime risk of gastrointestinal cancer among MMRCS patients is the highest reported of all gastrointestinal cancer predisposition syndromes as a function of age. The median age at diagnosis of hematologic malignancy is 6.6 years. Endometrial cancer has been diagnosed between 19 and 44 years. The age at diagnosis of urinary tract tumors has ranged from 10 to 22 years.

Likelihood of Outcome

Mode of Inheritance

Autosomal Recessive

Prevalence of Genetic Variants

>1-2 in 100

The majority of individuals with MMRCS (approximately 60%) have pathogenic variants in PMS2. The remaining 40% of pathogenic variants are equally distributed among MSH6, MLH1, and MSH2.

Tier 3

Penetrance (Includes any high-risk racial or ethnic subgroups)

>= 40 %

Gastrointestinal and brain tumors are the most common malignancies described in MMRCS, occurring in more than half of these patients.

Tier 3

>= 40 %

Estimated penetrance in MMRCS:

• 50% develop small-bowel adenomas

• >90% develop colorectal adenomas

• 59 to 70% develop colorectal cancer

• 58 to 70% develop high-grade brain tumors

• 20-40% develop lymphoma

• 10-40% develop leukemia

• 10 to 18% develop small-bowel cancer

• <10% develop endometrial cancer

• <10% develop urinary tract cancer

• <10% develop cancer of other sites

Tier 3

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown

Information on relative risk was not identified.

Expressivity

An attenuated form of MMRCS has been described with significantly later onset.

Tier 3

Children with MMRCS are affected by a large variety of malignant neoplasms. Clinical heterogeneity related to different pathogenic variants in the four DNA-MMR genes is likely, but currently undefined.

Tier 4

Intervention Effectiveness

Patient Management

Educate parents on early suspicion of both abdominal masses and general symptoms and signs of hematologic malignancies to prompt early intervention. Parents and patients should be advised to contact their doctor in case of unusual signs or symptoms. A pamphlet should be available with information about the signs/symptoms that may occur.

Tier 2

Synchronous gastrointestinal and/or extraintestinal cancers occur frequently in MMRCS. Therefore, oncologists and gastroenterologists managing MMRCS patients need to assess the entire gastrointestinal tract for synchronous tumors before determining treatment plans.

Tier 2

Colectomy should be considered in patients with high-grade dysplasia or too many polyps to be excised endoscopically

Tier 2

Surveillance

The management of MMRCS is based on the current estimates of neoplasia risk and the early age of onset for the cancers, which have led to tentative guidelines for the management of these patients. The age at which to begin surveillance varies by guideline and is represented below as age ranges. In patients with MMRCS, the following surveillance is suggested:

• Screening for CRC by colonoscopy is recommended annually beginning at age 6 to 8 years. Once polyps are identified, colonoscopy every 6 months is recommended.

• Annual surveillance for small-bowel cancer by upper endoscopy and video capsule endoscopy is suggested beginning at 8 to 10 years of age. Monitoring of hemoglobin levels every 6 months also is suggested, beginning at 8 years of age.

• Surveillance for brain tumors by brain MRI every 6 to 12 months is suggested starting at the time of diagnosis even in the first year of life to age 2 years.

• Currently, no proven surveillance modalities for leukemia or lymphoma have been identified. Complete blood count to screen for leukemia is suggested every 6 months beginning at 1 year of age. Clinical examinations and abdominal ultrasounds to screen for lymphoma every 6 months may be considered by the treating physician.

• For individuals with a uterus, surveillance for endometrial cancer is suggested by transvaginal ultrasound, pelvic examination, and endometrial sampling annually starting at age 20 years.

• Surveillance for cancer of the urinary tract is suggested, with annual urinalysis starting at age 10 to 20 years.

• To screen for other types of tumors, whole-body MRI could be considered once a year starting at 6 years of age or when anesthesia is not needed. This method should not replace the need for ultrasound and brain MRI.

Tier 2

A patient registry and surveillance program reported 110 patients with confirmed MMRCS. The median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). Ongoing prospective data were collected for 89 patients and used for survival analysis. Patients in the prospective cohort were further divided into three groups: individuals undergoing full surveillance (n=33; median age at initiation of surveillance 9.9 years ranging from 1.5 to 38.5 years), partial surveillance (n=20; median age at initiation of surveillance 11.2 years ranging from 3.0 to 39.5 years), and no surveillance (n=36; mean age 11 years ranging from 2.3 to 27.2 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, 16% of hematologic malignancies were detected asymptomatically. Five-year overall survival (OS) was 90% and 50% when cancer was detected asymptomatically and symptomatically, respectively (p=.001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.0) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance (p<.0001).

Tier 5

No specific recommendations for adults with MMRCS exist

Tier 4

Circumstances to Avoid

Repeated CT scanning of the brain should be avoided because of the possible induction of tumors due to radiation.

Tier 2

Nature of Intervention

Nature of Intervention

The clinical management of MMRCS is highly complex and involves referral to medical specialists and specialty care centers. The interventions identified in this report involve extensive clinical lifelong surveillance. Tumor surveillance is time consuming and may incur substantial financial and psychosocial burdens. This may lead to noncompliance, particularly in children. Anesthesia is required for colonoscopy and upper endoscopy and may be required for MRI scans for young children. Claustrophobia can be a challenge for MRI. Brain MRI may reveal lesions of unknown significance. The only management is follow-up MRI at short interval, which may increase anxiety. There is a risk of retaining the capsule with video capsule endoscopy, a risk of perforation (1/1000) with colonoscopy, and a risk of bleeding (3-4%) after polypectomy. Laboratory tests can be difficult to perform on a child.

Context: Adult Pediatric

Chance to Escape Clinical Detection

Patients often have café-au-lait macules and other stigmata that can be mistaken for neurofibromatosis type 1.

Context: Adult Pediatric

Tier 3

Colonic adenomatous oligopolyposis may lead to an erroneous diagnosis of familial adenomatous polyposis.

Context: Adult Pediatric

Tier 4

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			MLH1			276300	0031219	0010159
MSH2			619096	0031219	0030840
MSH6			619097	0031219	0030841
PMS2			619101	0031219	0030843

References List

Constitutional mismatch repair deficiency syndrome. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=252202

Durno C, Boland CR, Cohen S, Dominitz JA, Giardiello FM, Johnson DA, Kaltenbach T, Levin TR, Lieberman D, Robertson DJ, Rex DK. (2017) Recommendations on Surveillance and Management of Biallelic Mismatch Repair Deficiency (BMMRD) Syndrome: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology. 152(1528-0012):1605-1614.

Durno C, Ercan AB, Bianchi V, et al.. Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance.. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Publisher: American Society of Clinical Oncology (2021) Accessed: 2022-08-24. URL: https://pubmed.ncbi.nlm.nih.gov/33945292/

Idos G, Valle L.. Lynch Syndrome. In: GeneReviews. Seattle (WA): University of Washington, Seattle; 1993. 2004 Feb 5 [updated 2021 Feb 4]. (2021) URL: https://pubmed.ncbi.nlm.nih.gov/20301390/

MISMATCH REPAIR CANCER SYNDROME 1; MMRCS1. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 276300, (2021) World Wide Web URL: http://omim.org/

MISMATCH REPAIR CANCER SYNDROME 2; MMRCS2. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 619096, (2020) World Wide Web URL: http://omim.org/

MISMATCH REPAIR CANCER SYNDROME 3; MMRCS3. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 619097, (2020) World Wide Web URL: http://omim.org/

MISMATCH REPAIR CANCER SYNDROME 4; MMRCS4. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 619101, (2020) World Wide Web URL: http://omim.org/

Tabori U, Hansford JR, Achatz MI, et al.. Clinical Management and Tumor Surveillance Recommendations of Inherited Mismatch Repair Deficiency in Childhood.. Clin Cancer Res. Publisher: American Association for Cancer Research (2017) Accessed: 2022-08-24. URL: https://pubmed.ncbi.nlm.nih.gov/28572265/

Vasen HF, Ghorbanoghli Z, Bourdeaut F, Cabaret O, Caron O, Duval A, Entz-Werle N, Goldberg Y, Ilencikova D, Kratz CP, Lavoine N, Loeffen J, Menko FH, Muleris M, Sebille G, Colas C, Burkhardt B, Brugieres L, Wimmer K, EU-Consortium Care for CMMR-D (C4CMMR-D). (2014) Guidelines for surveillance of individuals with constitutional mismatch repair-deficiency proposed by the European Consortium "Care for CMMR-D" (C4CMMR-D). Journal of medical genetics. 51(1468-6244):283-93.