Spitz_Genodermatoses, 3e

Lynch syndrome, Muir-Torre variant

Synonym(s)

Muir-Torre syndrome hereditary nonpolyposis colon cancer (HNPCC), Muir-Torre variant Torre syndrome; Torre-Muir syndrome AD; MSH1 and MSH2 genes on 3p22.2 and 2p21-p16.3, respectively; less commonly MSH6 , PMS2, or EPCAM

Inheritance

Prenatal Diagnosis

DNA analysis

Incidence

Lynch syndrome: 1:270; incidence of Muir-Torre subvariant unknown

Age of Presentation

Fifth to sixth decades of life (internal malignancies usually precede cutaneous lesions)

Pathogenesis

Muir-Torre syndrome refers to a Lynch syndrome variant in individuals with characteristic sebaceous adenomas, epitheliomas, carcinomas, and/or keratoacanthomas of the skin and with characteristic Lynch syndrome internal malignancy. MSH1 , MSH2 , MSH6 , PMS2 , and EPCAM encode mismatch repair genes; MSH2 and MSH6 or MSH3 form a dimer com plex that locates DNA mismatch replication errors; MLH1, complexed with PMS2 ,then binds and removes the error and places a corrected replication product; disrupted DNA mismatch repair genes produce phenotype MSH2 : higher risk of Muir-Torre variant, sebaceous neoplasms; MLH1 : highest colorectal cancer risk Biallelic mutations in MLH1 , MSH2 , MSH2 , or PMS2 result in severe childhood cancer syndrome, Constitutional Mismatch Repair deficiency ( CMMRD ) with café-au-lait macules similar to neurofibromatosis type I Skin Multiple sebaceous tumors: adenomas (most common), carcinomas, hyperplasias, epitheliomas, BCC with sebaceous differentiation Keratoacanthomas Neoplasms Adenocarcinoma of the colon (most common), other gastrointestinal tract, endometrial, genitourinary tract, lung, breast, brain, prostate, and hematologic malignancies described Skin biopsy with immunohistochemical staining for loss of MLH1, MSH2, MSH6, and PMH2 followed by confirmatory molecular testing for germline mutation Endoscopy/gastrointestinal x-ray Close follow-up screening for internal malignancy according to published guidelines for those with confirmed germline mutation; prophylactic hysterectomy after childbearing Referral to dermatologist Referral to gastroenterologist Cowden syndrome (p. 210) Gardner syndrome (p. 206)

Genotype/Phenotype Correlation

Key Features

Differential Diagnosis

Laboratory Data

Management

Prognosis

May have normal life span with close surveillance and early detection of malignancy

Almost any sebaceous adenoma or carcinoma warrants immunohistochemical staining for loss of MSH2, MSH6, and MLH1 on skin biopsy . . . A germline mutation in tissue other than lesional skin is needed to confirm the diagnosis of Lynch syndrome or Muir-Torre variant . . . Sebaceous hyperplasia and sebaceous epitheliomas arising within nevus sebaceous of Ja dassohn are not part of the syndrome . . . The associated visceral malignancies may be indo lent, and detection can lead to prolonged survival . . . The National Comprehensive Cancer Network (NCCN) provides annual surveillance guidelines . . . Both hereditary nonpolyposis colorectal cancer and the Muir-Torre variant are caused by a heritable DNA mismatch repair defect . . . Mutations in the MSH2 gene located on 2p are commonly implicated . . . JH

CLINICAL PEARLS

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