Lynch syndrome is a heritable condition caused by a heterozygous germline inactivating mutation of the DNA mismatch repair (MMR) genes, most commonly the MLH1 gene. However, one third of the identified alterations are missense variants, for which the clinical significance is unclear in many cases. We have identified three MLH1 missense alterations (p.(Glu736Lys), p.(Pro640Thr) and p.(Leu73Pro)) in six individuals from large Tunisian families. For none of these alterations, a classification of pathogenicity was available, consequently diagnosis, predictive testing and targeted surveillance in affected families was impossible. We therefore performed functional laboratory testing using a system testing stability as well as catalytic activity that includes clinically validated reference variants. Both p.(Leu73Pro) and p.(Pro640Thr) were found to be non-functional due to severe defects in protein stability and catalytic activity. In contrast, p.(Glu736Lys) was comparable to the wildtype protein and therefore considered a neutral substitution. Analysis of residue conservation and of the structural roles of the substituted residues corroborated these findings. In conjunction with the available clinical data, two variants fulfil classification criteria for class 4 “likely pathogenic”. The findings of this work clarify the mechanism of pathogenicity of two unclear MLH1 variants and enables predictive testing and targeted surveillance in members of carrier families worldwide.

Terms of use and reuse: academic research for non-commercial purposes, see here for full terms.

BackgroundCardiac tumors are a very rare entity. Leiomyosarcoma represents less than 1% of cases.Case presentationa 51-year-old woman diagnosed with primary left atrium leiomyosarcoma. She was treated by optimal surgery and adjuvant chemotherapy. She is still alive after a follow-up of 24 months without evidence of local or distant recurrence.ConclusionsCardiac leiomyosarcoma is a rare tumor with a dismal prognosis. Surgery is the mainstay of treatment. Adjuvant treatment is still controversial.

Primary cutaneous leiomyosarcoma (PCL) are soft-tissue sarcoma, arising in the dermis, with or without extension into the subcutis. They are thought to have an indolent course compared to their subcutaneous counterparts, they may recur but rarely metastases. We report the case of a patient with a PCL arising in the anterior trunk wall who developed pulmonary, bone and retroperitoneal metastases 6 years after wide surgical excision of the primary tumor.

Rituximab, a chimeric monoclonal antibody against CD20, very rarely causes lung toxicity. Toxicity may present as interstitial lung disease, alveolar hemorrhage and adult respiratory distress syndrome. Sixteen cases of rituximab-induced interstitial lung disease (R-ILD) have been reported. With this case and a review of all other cases reported in the literature, we will try to identify the features of R-ILD, its treatment and why the early diagnosis of this complication is important.