Kallmann Syndrome and MSI-H Colorectal Cancer in a Patient with a Germline PROKR2 Variant: A Case Report with Exploratory Cohort Analysis

PROKR2 is an established gene associated with Kallmann syndrome (KS), and preclinical studies have suggested a possible role in tumor development. In this study, we report a patient with KS and microsatellite instability-high (MSI-H) colon cancer and aim to explore the potential association between PROKR2 variants and MSI-H status in colorectal cancer (CRC). Peripheral blood samples from the proband and his parents underwent whole-exome sequencing (WES) to identify germline variants. The WES revealed that both the proband and his father carried a likely pathogenic variant in the KS-associated gene PROKR2 (NM_144773.4:c.337T>C, p.Tyr113His). To place this case in a broader context, we performed exploratory bioinformatic analyses of somatic PROKR2 variants in two public CRC cohorts, DFCI-CRC and TCGA-CRC, although these cohort analyses cannot inform germline risk. In the DFCI-CRC cohort, PROKR2 somatic variant status showed no statistically significant association with MSI-H status in either the unadjusted or TMB-adjusted analysis. In the TCGA-CRC cohort, PROKR2 somatic variants were associated with higher unadjusted odds of MSI-H (OR = 5.50, 95% CI = 1.003–30.20, p = 0.0248, BH-adjusted q = 0.0495). After TMB adjustment, this positive association was not retained and the adjusted estimate was in the opposite direction (adjusted OR = 0.093, 95% CI = 0.014–0.549, p = 0.00875, BH-adjusted q = 0.0175). Accordingly, this case report describes the co-occurrence of PROKR2-related KS and MSI-H CRC in a single patient, although a causal relationship between PROKR2-related KS and CRC remains unestablished.