Review
Paediatric intestinal cancer and polyposis due to bi-allelic PMS2 mutations: Case series, review and follow-up guidelines

https://doi.org/10.1016/j.ejca.2011.01.013Get rights and content

Abstract

Background

Bi-allelic germline mutations of one of the DNA mismatch repair genes, so far predominantly found in PMS2, cause constitutional MMR-deficiency syndrome. This rare disorder is characterised by paediatric intestinal cancer and other malignancies. We report the clinical, immunohistochemical and genetic characterisation of four families with bi-allelic germline PMS2 mutations. We present an overview of the published gastrointestinal manifestations of CMMR-D syndrome and propose recommendations for gastro-intestinal screening.

Methods and Results

The first proband developed a cerebral angiosarcoma at age 2 and two colorectal adenomas at age 7. Genetic testing identified a complete PMS2 gene deletion and a frameshift c.736_741delinsTGTGTGTGAAG (p.Pro246CysfsX3) mutation. In the second family, both the proband and her brother had multiple intestinal adenomas, initially wrongly diagnosed as familial adenomatous polyposis. A splice site c.2174+1G>A, and a missense c.137G>T (p.Ser46Ile) mutation in PMS2 were identified. The third patient was diagnosed with multiple colorectal adenomas at age 11; he developed a high-grade dysplastic colorectal adenocarcinoma at age 21. Two intragenic PMS2 deletions were found. The fourth proband developed a cerebral anaplastic ganglioma at age 9 and a high-grade colerectal dysplastic adenoma at age 10 and carries a homozygous c.2174+1G>A mutation.

Tumours of all patients showed microsatellite instability and/or loss of PMS2 expression.

Conclusions

Our findings show the association between bi-allelic germline PMS2 mutations and severe childhood-onset gastrointestinal manifestations, and support the notion that patients with early-onset gastrointestinal adenomas and cancer should be investigated for CMMR-D syndrome. We recommend yearly follow-up with colonoscopy from age 6 and simultaneous video-capsule small bowel enteroscopy from age 8.

Introduction

Lynch syndrome (hereditary non-polyposis colorectal cancer, HNPCC, MIM 114500) is an autosomal dominant condition with high penetrance caused by heterozygous germline mutations in the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, or PMS2. It is one of the most prevalent inherited cancer syndromes, responsible for approximately 2–5% of all colorectal cancers.1 Patients with Lynch syndrome have a high risk of developing colorectal carcinoma and endometrial carcinoma, typically in the fourth or fifth decade. There is also an increased risk for various other tumours, i.e. cancer of the stomach, small bowel, pancreas, hepatobiliary tract, ureter and renal pyelum, ovaries, skin and brain.2, 3

In contrast to Lynch syndrome, germline compound heterozygous or homozygous MMR gene mutations, which means inherited mutations in both alleles of an MMR gene, are a rare cause of paediatric colorectal cancer and other malignancies, mainly leukaemia and brain tumours.4 These malignancies in early childhood are often associated with multiple café-au-lait maculae (CALM) and some other features of neurofibromatosis type 1 (NF1), like freckling and Lisch nodules. Since the first publications on this syndrome in 1999,5, 6 several names have been proposed, including the acronym CoLoN (Colon tumours and/or Leukaemia/Lymphoma and/or Neurofibromatosis features),7 Lynch III syndrome,8 childhood cancer syndrome (CCS)9 and constitutional MMR-deficiency (CMMR-D) syndrome.10 Up to December 2009, 97 carriers with a bi-allelic MMR defect from 53 families had been reported.4, 5, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55

Here, we report on five children from four Dutch families carrying bi-allelic PMS2 germline mutations and focus on their gastrointestinal manifestations. We also present the results of an extensive literature search on the gastrointestinal and molecular data of CMMR-D syndrome patients and propose a guideline for surveillance of the gastrointestinal tract in this syndrome.

Section snippets

Family 1

A 2-year-old boy diagnosed with an infiltrating cerebral angiosarcoma was referred for genetic testing. Physical examination revealed multiple CALM and anal and axillary freckling. A clinical diagnosis of NF1 was suggested but NF1 mutation analysis was negative. Two years later, magnetic resonance imaging showed a local relapse, which was surgically removed. Just before his 7th birthday, he suffered from anal blood loss and colonoscopy revealed two tubular adenomas: one with a diameter of 1.5 cm

Tumour analysis

Microsatellite instability (MSI) analysis was performed on formalin-fixed, paraffin-embedded sections of tumours and corresponding normal tissue. Following DNA amplification using fluorescent-labelled primers, a panel of five microsatellites, including two mononucleotide repeats (BAT25, BAT26) and three dinucleotide repeats (D2S123, D5S346, D17S250), was analysed for allelic shift according to the international guidelines for evaluating MSI in families suspected of having Lynch syndrome.56, 57

Microsatellite analysis

The angiosarcoma tissue from the proband of family 1 showed a MSI-high phenotype. The jejunal adenocarcinoma and the bladder tumour from the index patient of family 2 and the anaplastic ganglioma of the proband of family 4 also displayed MSI.

Immunohistochemistry

Immunohistochemical staining of the MLH1, MSH2, MSH6 and PMS2 proteins showed complete loss of PMS2 staining but normal expression of MLH1, MSH2 and MSH6 in the tumours of all five patients. Normal tissue surrounding the tumours and the endothelial cells of

Discussion

Gastrointestinal cancers in young adults and children can be caused by the inheritance of mutations in both alleles of an MMR gene. Gastrointestinal cancers, mainly colorectal cancer, make up 37% of all tumours in CMMR-D syndrome patients.10 Approximately half of the families reported with constitutional MMR deficiency have germline PMS2 mutations (31 of 57 families, Table 1, Table 5). Of the PMS2 families, in 26 (84%) gastrointestinal manifestations were reported. In 19 out of 60 PMS2

Conflict of interest statement

None declared.

Contributions

Literature search, data extraction and writing of the first draft: Johanna C. Herkert; mutation analysis, tumour analysis and critical revision of the manuscript: Renée C. Niessen; collecting patient information, literature search, data extraction and critical revision of the manuscript: Maria J.W. Olderode-Berends; collecting patient information, data extraction and critical revision of the manuscript: Hermine E. Veenstra-Knol; mutation analysis of families 1 and 2, tumour analysis and

Grant support

None.

Acknowledgements

We thank the patients and their family members for their cooperation. We are indebted to Jackie Senior for editing the text.

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