• Wimmer, Katharina
• Tellez, James
• Husain, Akhtar
• Fostier, William
• Gallon, Richard
• Martin, Richard
• Burn, John
• Rajan, Neil
• Holt, Georgie

Abstract

<jats:title>Abstract</jats:title><jats:p>Constitutional mismatch repair deficiency (CMMRD) is a rare autosomal recessive condition typically diagnosed in childhood. It is caused by biallelic inheritance of pathogenic variants within the MLH1, MSH2, MSH6 and PMS2 genes (DNA mismatch repair pathway). It confers a high risk of cancer, with many patients developing brain, gastrointestinal or haematological malignancy in the first two decades of life. The cutaneous features of CMMRD share similarities with neurofibromatosis, with café au lait macules, Lisch nodules, neurofibromas and axillary/inguinal freckling reported. Herein, we report a case of a 31-year-old woman with colorectal polyposis and multiple primary cancers presenting with an eruption of seborrhoeic keratoses (SKs), consistent with the paraneoplastic sign of Leser–Trélat (LTS). Aged 23 years, the proband underwent a prophylactic subtotal colectomy for multiple adenomatous large-bowel polyps. During colectomy, analysis of an enlarged mesenteric lymph node revealed a synchronous diffuse large B-cell lymphoma. This was treated with excision and chemotherapy. When she was aged 24 years, an ampulla of Vater adenoma was excised. Aged 29 years, she developed triple-negative invasive ductal carcinoma of the breast, treated with surgery and chemotherapy. The proband also developed basal cell carcinoma on her forehead and the tarsal edge of her right eye at ages 28 and 31 years, respectively. Her family history revealed that her father died at age 33 years of colorectal cancer, while her mother died at age 60 years due to cerebral haemorrhage. Concurrently to the proband’s breast cancer diagnosis, cutaneous examination revealed widespread small skin-coloured and brown plaques, which were confirmed on biopsy to be SKs in a predominantly acral distribution, with sparing of the trunk. Immunohistochemical assessment of the SKs demonstrated loss of expression of PMS2, with loss of expression also seen in normal perilesional skin. Microsatellite instability (MSI) analysis of peripheral leucocyte DNA revealed high levels of constitutional MSI, indicative of CMMRD. Germline genetic testing revealed compound heterozygous pathogenic variants in PMS2, confirming the diagnosis. LTS is characterized by an eruption of SKs in association with concurrent development of cancers arising from the breast, lung and gastrointestinal tract. A putative mechanism is that tumour-secreted factors, such as epidermal growth factor, drive SK growth. The responsible tumour may be difficult to determine in patients with multiple primary cancers; however, temporally, the breast cancer in our patient was most closely linked to her presentation of LTS. This case emphasizes the importance of recognizing the sign of LTS, a novel feature in the context of CMMRD.</jats:p>

Topics

• impedance spectroscopy
• compound