Wei-Sheng Li,Yan Li,Nai-Hui Zhou,Jing-Liu Liu,Zi-Liang Yang,Miao Sun,*,Min Li,*

1Institute for Fetology,2Department of Dermatology,The First Affiliated Hospital of Soochow University,Suzhou,Jiangsu 215006,China.

Abstract Introduction:Muir-Torre syndrome is a phenotypic variant of Lynch syndrome characterized by a predisposition for the development of visceral malignant disease and sebaceous gland neoplasms,and it is caused by germline mutations in the mismatch repair genes MSH2 and MLH1.

Keywords:case report,MLH1 gene,Muir-Torre syndrome,mutation,sebaceous neoplasm

Introduction

Lynch syndrome,also referred to as hereditary nonpolyposis colorectal cancer,is an autosomal-dominant disorder characterized by high penetrance of colorectal cancer and an increased risk of certain extra-colonic cancers.Germline mutations of DNA mismatch repair genes,1such as MLH1,MSH2,MSH6,and PMS2,are the underlying mechanism of most cases of Lynch syndrome.Muir-Torre syndrome(MTS)(MIM #158320)is a phenotypic variant of Lynch syndrome characterized by a predisposition for the development of visceral malignant disease and sebaceous gland neoplasms.2-5A patient is suspected to have MTS if one or more of the following clinical criteria are met:a history of one or more sebaceous tumors,age of＜60 years at the first presentation of sebaceous tumors,a personal history of Lynch-related cancers,or a family history of Lynch-related cancers.6Most of the internal malignancies associated with MTS are colorectal cancer.7-9As asubset ofLynchsyndrome,MTS is caused by germline mutations in the mismatch repair genes MSH2 and MLH1.10In this study,we found MLH1 c.199G＞A,which is a known pathogenic mutation of Lynch syndrome,in a patient with MTS who presented with synchronous colorectal adenocarcinoma and sebaceoma.

Case report

Figure 1.Pedigree,clinical features of MTS,and MLH1 gene mutation analysis.(A)Family pedigree.MTS was inherited in an autosomaldominant manner.(B)a:Sebaceoma on the head.b:The tumor consisted of several lumps of varying sizes.Dense eosinophilic connective tissue was present between the tumor masses.The tumor mass was mostly composed of basal cells and a few mature sebaceous gland cells.Sebaceous duct formation was present in and around the mass.(C-E)A missense mutation c.199G＞A(p.Gly67Arg)was located in exon 2 of the MLH1 gene of the proband(C),his daughter(D),and his mother(E).(F)Sequence of the wild-type allele located in exon 2 of the MLH1 gene.MTS:Muir-Torre syndrome.

A three-generation pedigree of MTS containing three affected patients is shown in Fig.1A.The MTS was inherited in an autosomal-dominant manner.The proband was a 42-year-old man who had undergone surgical resection of colorectal adenocarcinoma and sebaceoma at 28 and 37 years,respectively.He presented with macular rashes that were occasionally itchy.Red papules with occasional mild tenderness appeared on the surface of his skin.A lesion on his head was excised for pathological examination.Histological examination revealed that the neoplasm was composed of multiple variably sized masses with dense eosinophilic connective tissue between them.The tumor consisted mostly of basal cells and a few mature sebaceous gland cells,and sebaceous ducts were present in and around the mass(Fig.1B).The histopathological diagnosis was a sebaceoma.Follow-up of the family history revealed that the proband’s 65-year-old mother had been highly suspected to have Lynch syndrome with colorectal cancer at 40 years of age based on the results of a histopathological examination.The proband’s daughter underwent colonoscopy because of blood in the stool at the age of 13 years,but no abnormalities were found.

Peripheral blood samples were collected by standard procedures.Genomic DNA was extracted from blood samples of the affected family members using a QIAamp?DNA Blood Mini Kit(Qiagen,Hilden,Germany).All exons and their flanking intronic sequences of the MLH1 and MSH2 genes were amplified by polymerase chain reaction.Purified polymerase chain reaction products were sequenced directly using an ABI Prism?3730 automated sequencer(Applied Biosystems,Foster City,CA,USA).DNA sequences were analyzed by comparison with the human MLH1 reference sequence(NM_000249.4).The mutations were checked with the Human Gene Mutation Database,ClinVar(https://www.ncbi.nlm.nih.gov/clinvar/),and gnomAD(https://gnomad.broadinstitute.org/).A missense mutation c.199G＞A(p.Gly67Arg)located in exon 2 of the MLH1 gene was found in the proband and his mother and daughter(Fig.1C-E).

We followed up the patient using telephone by the writing,and there was no significant change.The study was approved by the ethics committee of the First Affiliated Hospital of Soochow University,and conducted in accordance with the principles of the Declaration of Helsinki.Written informed consent forms from the all individuals participated in this study were obtained.

Discussion

MTS is caused by germline mutations in one of the alleles of specific DNA mismatch repair genes,which are responsible for maintaining genomic integrity by correcting base pairing errors during DNA replication.Most of the mutations that cause MTS occur in the MLH1 and MSH2 genes.8-9Mutations in these genes can produce a high-frequency microsatellite instability phenotype that is confirmed in almost all skin and visceral tumors from patients with MTS.1

Table 1 MLH1 gene mutation-positive family members with Muir-Torre syndrome.

We have herein reported a pathogenic missense mutation c.199G＞A(p.Gly67Arg)in exon 2 of the MLH1 gene in patient with MTS.This mutation has been reported in patients with Lynch syndrome who have no skin tumors.We reviewed published reports describing patients with MTS(Table 1)and found that MTS is characterized by the association of at least one sebaceous skin tumor and at least one visceral malignancy.Sebaceous adenomas and sebaceous carcinomas are the most typical tumors in patients with MTS.Colorectal cancer is the most common visceral neoplasm associated with MTS.However,we also found that some patients with MTS had no history of any internal malignancy(Patient 4 in Table 1)or skin tumor(Patient 1 in Table 1).In our case,the mother of the proband(I2)had been diagnosed with Lynch syndrome because only a visceral malignancy was found.The proband(II2)carried the same mutation and exhibited typical symptoms of MTS with synchronous colorectal adenocarcinoma and sebaceoma,while his daughter(III1)showed no abnormalities.Our data support the idea that a hiatus of many years may pass before both elements-a sebaceous neoplasm and an internal cancer-are present in a patient,thus finally allowing the diagnosis of MTS.

In conclusion,a pathogenic Lynch syndrome mutation c.199G＞A(p.Gly67Arg)in exon 2 of the MLH1 gene was foundinapatientwithMTSwhopresentedwithasebaceous neoplasm.Identificationofpathogenicgermlinemutationsis very valuable for cancer screening in family members.In this case,the proband’s daughter was genetically tested and found to be positive for the reported mutation.Regular inspection of the gastrointestinal tract will be particularly important and helpful for her ongoing health.

Source of funding

This work was supported by the National Natural Science Foundation of China(Nos.31401071 and 81570960).