PMC10471184_01
(A) Preoperative cranial MRI of the proband (from left to right: axial T1-weighted with gadolinium injection, axial T2 FLAIR-weighted, axial apparent diffusion coefficient). There is a solid intra-axial mass within the right frontal lobe with marked ring-like enhancement and an internal necrotic area. The enhancing component of the lesion shows diffusion restriction. (B) Timeline showing the clinical history of the patient. (C) Family pedigree. The black arrow indicates the proband case. The age of the first tumor is given below the proband and the two affected brothers.
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Imaging revealed a right frontal mass involving the corpus callosum with a marked ring-like gadolinium enhancement, central necrosis, and peritumoral edema ( Figure 1A ). A timeline depicting patient care is shown in  Figure 1B . The proband and his family were referred to genetic consultation, and a six-generation pedigree was established ( Figure 1C ).
(A) Sanger sequencing results of the segregation study of the MLH1 c.1918C>A variant, including a chromatogram of the proband showing the homozygous MLH1 c.1918C>A variant, chromatograms of the father, the mother, and the unaffected brother showing the heterozygous MLH1 c.1918C>A variant, and a chromatogram of the wild type sequence. (B) The constitutional MSI (cMSI) scores of 123 control, 40 Lynch syndrome (LS; MLH1 n = 10, MSH2 n = 10, MSH6 n = 10, PMS2 n = 10), 56 constitutional mismatch repair deficiency syndrome (CMMRD; MLH1 n = 4, MSH2 n = 5, MSH6 n = 18, PMS2 n = 29), and 43 control patients using data from Gallon et al., compared to the cMSI score of the proband. The y-axis is scaled based on a logit transformation.
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The variant was also identified in a heterozygous state in the father, the mother, and the eldest brother ( Figure 2A ). The proband had a cMSI score of 44.3, which falls within the published cMSI score range of known CMMRD patients (20.9-300.0) and is much greater than the cMSI scores of LS carriers (0.0-11.3) and controls (0.0-3.6). cMSI analysis, therefore, confirmed the CMMRD diagnosis ( Figure 2B ).
Histology (hematoxylin and eosin (H&E)) and immunohistochemical staining for all four MMR proteins (MLH1, PMS2, MSH2, and MSH6) in all tumor specimens of the proband (colonic and parotid tumor at 40x magnification, brain tumor and pancreatic tumor at 100x magnification). As the representative images show, immunostaining for MLH1 and PMS2 revealed a loss of expression in neoplastic cells and surrounding normal cells.
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Immunostaining was retained for MSH2 and, to a lesser extent, for MSH6 ( Figure 3 ).