Lynch Syndrome and Early-Onset Colorectal Cancer in Pediatric Patients

Claudia Phen M.D.¹, Donovan Berens M.D.², Kelsey Moriarty M.S.³, Kenneth Ng D.O.⁴, Anita L. Sengupta M.D.⁵, Isabel Rojas M.D.¹

¹Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA²Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA³Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA⁴Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA⁵Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA Corresponding author: Isabel Rojas, M.D. email: Isabel.Rojas@UTSouthwestern.edu

Mailing address: 5323 Harry Hines Blvd, Dallas TX 75390. Department of Pediatrics, Gastroenterology

Phone number: 214-456-8000 Keywords/Abbreviations: Pediatric polyps, Polyposis syndromes, Colorectal cancer (CRC), Mismatch repair (MMR), Lynch Syndrome (LS) Acknowledgements: none Financial support and sponsorship: none Conflict of Interest: none The study was determined to be exempt from review by the University of Texas Southwestern Human Research Protection Program (HRPP).AbstractLynch syndrome (LS) is the most common hereditary colon cancer syndrome caused by

germline mutations in mismatch repair (MMR) genes. In this series, we outline 3 pediatric

patients who presented with vague symptoms due to colorectal cancer who were eventually

diagnosed with Lynch syndrome with multiple gene mutations. The diagnosis of

colorectal cancer in pediatrics warrants timely recognition, inclusion of Lynch syndrome in the

differential diagnosis, multi-gene testing, and genetic counseling for the patient and family.IntroductionLynch syndrome, formerly known as hereditary non-polyposis colorectal cancer (HNPCC), is the

most common hereditary colon cancer syndrome.¹ It has autosomal dominant inheritance due to

presence of a pathogenic variant in one of the MMR genes: MLH1 ,MSH2 , MSH6 , PMS2, or

EPCAM .² The clinical phenotype and cancer risk depends on which MMR gene is involved,

which in turn has implications on surveillance strategies.³ The MMR genes encode for proteins

responsible in the regulation of DNA repair in cells; therefore, mutations in MMR genes result in

higher rates of single nucleotide changes and microsatellite instability.¹ In LS, the adenoma to

carcinoma sequence is accelerated with colorectal cancer (CRC) occurring within 2 to 3 years

as opposed to 8 to 10 years.² Family history can be helpful to detect this syndrome before the

development of CRC, however sporadic cases have been reported due tode novo mutations

hence high clinical suspicion is needed.⁴Lynch syndrome carries the burden of malignancy within and outside of the gastrointestinal (GI)

tract. LS has a 46 to 74% lifetime risk for CRC with average age of onset of 44 years. ^5-7 Risk modifiers remain largely unknown. The clinical presentation can be highly variable and heterogeneous with different ages of onset and cancer penetrance. Cases of pediatric onset CRC in adolescence have been reported in the literature due to inherited orde novomutations.^8,9Polyposis and CRC in the pediatric population present with nonspecific symptoms such as weight loss and unexplained anemia which may result in delayed diagnosis and ominous outcome. Of the hereditary cancer predisposition syndromes, Lynch syndrome is particularly challenging as patients can present with colorectal cancer in the absence of a large colonic polyp burden and bloody stools . Additional barriers to diagnosis include low index of suspicion for CRC in the pediatric population and lack of knowledge of hereditary cancer predisposition syndromes, which lead to delayed referral and evaluation. Furthermore, diagnosis of LS involves a complex diagnostic work-up which includes a thorough family history, immunohistochemical testing, and genetic analysis which may not be available at all centers.MethodsFollowing IRB exemption, the electronic medical record at the University of Texas

Southwestern/Children’s Health was utilized to obtain clinical information about our 2 patients.

The third case was ascertained from a recently published case report following query of the

pediatric polyposis special interest group within our North American Society of Pediatric

Gastroenterology, Hepatology and Nutrition (NASPGHAN). De-identified patient information including age at presentation, clinical presentation, genetic

mutations, and outcomes were collected and tabulated (Figure 1). Diagnoses of Lynch

syndrome was confirmed with presence of a monoallelic germline variant in an MMR gene

following genetic testing without evidence of constitutional mismatch repair deficiency

(CMMRD), a distinct childhood cancer predisposition syndrome due to biallelic germline

mutations and high propensity toward formation of colon cancer, brain tumors, and leukemia.Case ReviewsWe report a series of three pediatric patients (median age 15 years) who presented first with

variable symptoms and were later found to have colorectal cancer. In all 3 cases, the diagnosis

of Lynch syndrome was ascertained after cancer diagnosis. Endoscopic tumor biopsies were

evaluated for immunohistochemical (IHC) staining patterns for mismatch repair proteins and

demonstrated loss of expression. Subsequently, genetic testing revealed mutations in an MMR

gene and additional gene variants. Patient 115-year-old male with history of a benign testicular tumor (excised at eight months of life)

presented to the emergency department (ED) for rectal prolapse. The patient had been straining

to defecate and passed a small stool with large amount of blood. Six months prior to

presentation, he had also witnessed blood in his stool. In the ED, sucrose was applied to the

rectal mass which was partially reduced. Patient was taken for sigmoidoscopy, which revealed a

large, pedunculated polypoid mass 10 centimeters from the anal verge, which was excised

using a hot snare (Figure 1A). Microscopic evaluation of the specimen revealed a microinvasive,

moderately differentiated adenocarcinoma arising within a tubulovillous adenoma.

Immunohistochemical staining was notable for a loss of MSH2 and MSH6 protein expression in

carcinoma cell nuclei (Figure 1B). Colorectal cancer gene panel revealed heterozygous,

pathogenic germline mutation in the MSH2 gene confirming a diagnosis of Lynch syndrome.

Notably, he also was a carrier of APC risk allele. The patient’s brother and father subsequently

underwent testing which revealed MSH2 gene mutation in both and father was also a carrier of the APC risk allele although neither had personal history of cancer. There was no family history of GI disorders or cancer aside from skin cancer in paternal grandmother and breast cancer in maternal great-aunt.

Patient 215-year-old male presented to the ED for difficulty walking. The patient had fatigue, anorexia,

and a 22-pound weight loss over a five-month period. Laboratory evaluation was notable for a

hemoglobin of 1.9 g/dL, a platelet count of 59 thousand/mm³, and an elevated erythrocyte

sedimentation rate of 86 mm/hour. The patient denied seeing blood in his stool, but a digital

rectal examination revealed maroon-colored stool. Family history was significant for multiple

family members on the maternal side with diagnoses of colon, breast, and ovarian cancers.

Colonoscopy revealed two pedunculated polyps in the cecum and hepatic flexure with near

occlusion of the lumen which were partially removed (Figure 2). Histopathology revealed

moderately differentiated adenocarcinoma invading through the submucosa with IHC with loss

of MLH1 and PMS2 expression. Colorectal cancer gene panel revealed heterozygous,

pathogenic germline mutation in the MLH1 and MSH3 genes. Maternal genetic evaluation was

also notable for MLH1 gene mutation.

Patient 315-year-old male presented to gastroenterology (GI) clinic for vomiting and 15-pound

unintentional weight loss over a 3-month period.¹⁰Initial evaluation included a normal upper GI

study with a delayed gastric emptying scan so a promotility agent was started. At follow-up,

patient continued to lose weight and was now complaining of lower abdominal pain, so an

ultrasound was obtained, which revealed a mass in the left lower quadrant. Abdominal

computed tomography (CT) scan showed an 8-cm mass in the descending colon. The patient

underwent a colonoscopy which identified a nearly obstructing descending colonic mass and

histopathology noted a poorly differentiated adenocarcinoma with medullary features and

extensive necrosis. Genetic testing revealed pathogenic mutations inMLH1 , APC , and SMAD4 .

There was no family history of GI disorders or cancer.