Purpose Constitutional mismatch repair deficiency (CMMRD) is a rare hereditary cancer predisposition syndrome that frequently manifests with pediatric high-grade gliomas. However, recognition remains challenging, particularly in the absence of a clear family history. We report a pediatric high-grade glioma with PMS2 deficiency and complex molecular alterations to highlight key diagnostic clues and the importance of routine mismatch repair assessment. Methods Clinical, radiological, histopathological, immunohistochemical, and molecular findings of an 8-year-old girl presenting with a high-grade glioma were retrospectively evaluated. Immunohistochemistry included glial and mismatch repair markers. Targeted next-generation sequencing was performed to assess tumor mutational burden and pathogenic variants. Results Neuroimaging revealed a right frontoparietal mass associated with an adjacent developmental venous anomaly. Histopathology demonstrated a diffuse pediatric-type high-grade glioma with pseudopapillary architecture and marked mitotic activity. Immunohistochemistry showed diffuse p53 overexpression in tumor cells and complete loss of PMS2 expression in both tumor and non-neoplastic cells, supporting constitutional mismatch repair deficiency. Molecular analysis revealed an ultra-hypermutated profile with a tumor mutational burden of 117.4 mutations/Mb, a pathogenic PMS2 frameshift variant, and co-occurring alterations in TP53, PIK3CA, PIK3R1, and PTEN. The presence of PI3K-pathway mutations alongside a venous anomaly suggested a potential biological association. Conclusion This case illustrates the characteristic clinicopathological and molecular features of CMMRD-associated pediatric high-grade glioma and underscores the critical role of routine mismatch repair immunohistochemistry. Integrated histological and genomic evaluation is essential for accurate diagnosis, appropriate genetic counseling, and potential therapeutic implications.<Table Float="No" ID="Taba"> <tgroup cols="2"> <colspec align="left" colname="c1" colnum="1" /> <colspec align="left" colname="c2" colnum="2" /> <tbody> <row> <entry nameend="c2" namest="c1"> Key Points • This case represents a pediatric high-grade glioma arising in the setting of PMS2-related constitutional mismatch repair deficiency (CMMRD). • The tumor exhibited an ultra-hypermutated profile with co-occurring TP53, PIK3CA, PIK3R1, and PTEN mutations. • Loss of PMS2 expression in both tumor and non-neoplastic cells was critical in establishing the diagnosis of CMMRD. • The presence of a developmental venous anomaly may relate to underlying PIK3R1 pathway alterations. • Routine mismatch repair immunohistochemistry is essential in pediatric high-grade gliomas, even in the absence of a family history. </entry> </row> </tbody> </tgroup> </Table>

A PMS2-deficient pediatric high-grade glioma with PI3K-pathway mutations and adjacent developmental venous anomaly suggestive of CMMRD

期刊论文
发表日期：

2026年3月26日

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Ahmet Erbağcı,
Tuçe Söylemez Akkurt,
Başak Atalay,
Mehmet Sabri Gürbüz,
Muhammed Emin Aksu,
Fatma Betül Çakır,
Gülnihal Ay

摘要

Purpose

Constitutional mismatch repair deficiency (CMMRD) is a rare hereditary cancer predisposition syndrome that frequently manifests with pediatric high-grade gliomas. However, recognition remains challenging, particularly in the absence of a clear family history. We report a pediatric high-grade glioma with PMS2 deficiency and complex molecular alterations to highlight key diagnostic clues and the importance of routine mismatch repair assessment.

Methods

Clinical, radiological, histopathological, immunohistochemical, and molecular findings of an 8-year-old girl presenting with a high-grade glioma were retrospectively evaluated. Immunohistochemistry included glial and mismatch repair markers. Targeted next-generation sequencing was performed to assess tumor mutational burden and pathogenic variants.

Results

Neuroimaging revealed a right frontoparietal mass associated with an adjacent developmental venous anomaly. Histopathology demonstrated a diffuse pediatric-type high-grade glioma with pseudopapillary architecture and marked mitotic activity. Immunohistochemistry showed diffuse p53 overexpression in tumor cells and complete loss of PMS2 expression in both tumor and non-neoplastic cells, supporting constitutional mismatch repair deficiency. Molecular analysis revealed an ultra-hypermutated profile with a tumor mutational burden of 117.4 mutations/Mb, a pathogenic PMS2 frameshift variant, and co-occurring alterations in TP53, PIK3CA, PIK3R1, and PTEN. The presence of PI3K-pathway mutations alongside a venous anomaly suggested a potential biological association.

Conclusion

This case illustrates the characteristic clinicopathological and molecular features of CMMRD-associated pediatric high-grade glioma and underscores the critical role of routine mismatch repair immunohistochemistry. Integrated histological and genomic evaluation is essential for accurate diagnosis, appropriate genetic counseling, and potential therapeutic implications.

Key Points

• This case represents a pediatric high-grade glioma arising in the setting of PMS2-related constitutional mismatch repair deficiency (CMMRD).

• The tumor exhibited an ultra-hypermutated profile with co-occurring TP53, PIK3CA, PIK3R1, and PTEN mutations.

• Loss of PMS2 expression in both tumor and non-neoplastic cells was critical in establishing the diagnosis of CMMRD.

• The presence of a developmental venous anomaly may relate to underlying PIK3R1 pathway alterations.

• Routine mismatch repair immunohistochemistry is essential in pediatric high-grade gliomas, even in the absence of a family history.