Constitutional mismatch repair deficiency presenting in childhood as three simultaneous malignancies

Area of Science:

• Oncology
• Genetics
• Pediatric Medicine

Background:

• Constitutional mismatch repair deficiency (CMMR-D) is a rare inherited cancer predisposition syndrome.
• It is typically associated with Lynch syndrome and an increased risk of early-onset colorectal and other cancers.
• Simultaneous occurrence of diverse malignancies is exceptionally rare in CMMR-D.

Observation:

• A 13-year-old female presented with three distinct and aggressive malignancies: glioblastoma multiforme, Burkitt lymphoma, and colonic adenocarcinoma.
• Despite treatment, the patient's condition progressed, leading to death within 8 months of diagnosis.
• Genetic testing identified a homozygous mutation in the PMS2 gene.

Findings:

• The homozygous PMS2 mutation confirmed the diagnosis of constitutional mismatch repair deficiency.
• Family screening revealed that both parents and three out of four siblings were heterozygous carriers of the PMS2 mutation.
• The fourth sibling was found to be negative for the mutation.

Implications:

• This case highlights the extreme phenotypic variability and aggressive nature of CMMR-D, even in pediatric patients.
• Genetic counseling and cascade screening are crucial for families with confirmed CMMR-D to identify at-risk individuals.
• Understanding the genetic basis of CMMR-D is vital for developing targeted therapies and improving patient outcomes.