A recent preprint reported by medRxiv explores the complex relationship between genetic mutations and clinical presentation in Colombian patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD). While the study is still awaiting peer review—a process in which independent experts evaluate and validate the research before it is accepted by scientific journals—its findings offer important insights into a rare endocrine disorder with diverse clinical outcomes.
Background and Purpose
CAH caused by 21OHD can manifest anywhere from life-threatening salt-wasting crises to milder, nonclassical forms. Understanding how a patient’s genetic mutations (genotype) correspond to their symptoms (phenotype) is crucial for diagnosis, treatment, and counseling. Although this correlation has been studied extensively worldwide, there is limited information from Latin American populations. Additionally, the concept of mutational burden—the total number of harmful gene variants a person carries—has not been thoroughly investigated as a predictor of disease severity.
Study Methods
The researchers examined 48 Colombian patients enrolled in a rare disease program. Patients were grouped according to the predicted severity of their enzyme deficiency (Null, A, B, C) and categorized clinically as salt-wasting (SW), simple virilizing (SV), or nonclassical (NC). Concordance was defined as a perfect match between genotype and clinical presentation. The team also assessed mutational burden, dividing patients into low (two or fewer mutations) or high (more than two mutations) groups, and used advanced statistical methods to explore these relationships.
Key Findings
The study found that genotype–phenotype agreement was strongest in patients with the most severe mutations—100% for the Null group and nearly 86% for Group A. However, this concordance dropped sharply in less severe groups: only about a third of Group B and less than half of Group C showed matching clinical and genetic categorization. Notably, over a third of patients in the mildest (Group C) genetic category experienced symptoms more serious than their genotype would predict.
A significant discovery was that patients with a high mutational burden were much less likely to have genotype–phenotype concordance. This suggests that the sheer number of damaging mutations, rather than just their predicted severity, can influence how the disease appears clinically. The analysis found no significant difference based on sex.
Implications
These results support the value of genotype-based predictions for severe cases of CAH, but highlight the limitations in milder forms, particularly when patients carry multiple mutations. Clinicians and genetic counselors may need to consider the total mutational burden when assessing risk and planning care.
Ethics, Funding, and Disclosure
The study followed rigorous ethical standards, with approval from the Hospital Pablo Tobón Uribe ethics committee and utilized anonymized medical records without direct patient contact. The authors declare no external funding and minimal conflicts of interest.
Conclusion
This research underscores the importance of both the type and number of genetic mutations in understanding CAH, paving the way for more personalized approaches to diagnosis and management in Latin American populations.
