RXFP2 and Cryptorchidism

This summary describes the association between RXFP2 and cryptorchidism. Multiple lines of evidence from family studies and case series consistently support a strong relationship between recessive variants in RXFP2 and the development of cryptorchidism. In one seminal study, a consanguineous family with four affected boys was identified carrying a homozygous missense variant, which showed clear segregation with the phenotype (PMID:31167797). Additional case series and multi‐patient investigations have further reinforced the link, with several affected individuals and families demonstrating recessive inheritance alongside functional defects in receptor activity (PMID:19416190).

The genetic evidence for this association is robust. The primary mode of inheritance is autosomal recessive, as demonstrated by the homozygous presence of the RXFP2 variant in affected individuals and heterozygous states in the unaffected parents. The reported variant, c.1496G>A (p.Gly499Glu), was identified by whole exome sequencing and segregated in all affected family members, providing convincing genetic linkage (PMID:31167797). Several additional studies have similarly identified recessively inherited variants in RXFP2 that correlate with cryptorchid phenotypes (PMID:38430325).

On the functional front, experimental studies have demonstrated that RXFP2 plays a critical role in testicular descent. Functional assays in cell culture showed that the mutant receptor bearing the c.1496G>A (p.Gly499Glu) change exhibits poor cell surface expression, fails to bind its ligand INSL3, and does not trigger downstream cyclic AMP (cAMP) signaling cascades (PMID:31167797). Moreover, complementary analyses, including receptor localization studies and loss‐of‐function assessments, provide moderate experimental evidence supporting a mechanistic role for impaired RXFP2 function in the pathogenesis of cryptorchidism (PMID:16926383).

While a number of studies have reported contrasting findings with regards to specific RXFP2 mutations, such as the T222P missense variant which in some cohorts did not show a significant genetic association (PMID:18073304), the cumulative evidence from familial segregation, case‐control studies, and functional assays overwhelmingly supports a critical contribution of RXFP2 recessive variants to cryptorchidism. The weight of the genetic and experimental data surpasses the modest conflicting reports, thereby consolidating its clinical significance.

Integration of the genetic and experimental evidence argues for a strong association between RXFP2 and cryptorchidism, especially in familial cases with recessive inheritance patterns. Although additional variants, including non‐canonical splicing changes and other mutation types, have been identified in separate cohorts, the robust demonstration of receptor dysfunction through the c.1496G>A (p.Gly499Glu) variant underpins its diagnostic utility.

Key take‑home: RXFP2 genetic testing can provide critical diagnostic insights in patients with familial cryptorchidism, supporting targeted clinical management and future research directions.

References

• Journal of medical genetics • 2019 • Familial bilateral cryptorchidism is caused by recessive variants in RXFP2 PMID:31167797
• Journal of assisted reproduction and genetics • 2024 • Achieving an optimal pregnancy outcome through the combined utilization of micro-TESE and ICSI in cryptorchidism associated with a non-canonical splicing variant in RXFP2 PMID:38430325
• Annals of the New York Academy of Sciences • 2009 • Mutations in INSL3 and RXFP2 genes in cryptorchid boys PMID:19416190
• American journal of physiology. Endocrinology and metabolism • 2007 • T222P mutation of the insulin-like 3 hormone receptor LGR8 is associated with testicular maldescent and hinders receptor expression on the cell surface membrane PMID:16926383

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