Second-to-fourth digit ratio in polycythemia vera: An exploratory anthropometric comparison with secondary polycythemia and healthy controls.

BACKGROUND: The second-to-fourth digit ratio (2D:4D) is a sexually dimorphic anthropometric trait that has been proposed as an indirect proxy of prenatal developmental-endocrine influences, although the validity of this interpretation remains debated. Although androgenic and sex-related biological pathways are known to influence erythropoiesis, whether 2D:4D differs across erythrocytosis phenotypes has not been investigated. This study aimed to compare 2D:4D ratios among patients with polycythemia vera (PV), patients with secondary polycythemia, and healthy controls.

METHODS: This observational comparative study included 424 participants: 139 patients with PV, 184 patients with secondary polycythemia, and 101 healthy controls. Right-hand and left-hand 2D:4D ratios were measured using both direct digital caliper-based and standardized image-based methods. The bilateral mean 2D:4D ratio was used as the primary digit-ratio parameter. Group comparisons were performed using Kruskal-Wallis and Mann-Whitney U tests. Age and sex-adjusted analyses were performed using ANCOVA. Patient-only sensitivity analyses additionally adjusted for erythropoietin (EPO) level. Binary logistic regression was used to evaluate the association between mean 2D:4D ratio and PV among patients with erythrocytosis.

RESULTS: The bilateral mean 2D:4D ratio differed significantly among study groups and was highest in the PV group (PV: 0.9874 ± 0.0361; secondary polycythemia: 0.9728 ± 0.0336; healthy controls: 0.9757 ± 0.0348; p < 0.001). In pairwise comparisons, PV patients had significantly higher mean 2D:4D ratios than both secondary polycythemia patients (p < 0.001) and healthy controls (p = 0.003), whereas secondary polycythemia and healthy controls did not differ (p = 0.498). The association between study group and mean 2D:4D ratio remained significant after adjustment for age and sex (F = 7.676, p < 0.001). In a patient-only model, the difference between PV and secondary polycythemia persisted after additional adjustment for EPO level (p = 0.032). In logistic regression, each 0.01-unit increase in mean 2D:4D ratio was independently associated with higher odds of PV after adjustment for age, sex, and EPO level (OR, 1.116; 95% CI, 1.024-1.216; p = 0.012).

CONCLUSION: In this cohort, patients with PV had higher 2D:4D ratios than both patients with secondary polycythemia and healthy controls, whereas secondary polycythemia patients and healthy controls had similar ratios. These findings are consistent with an exploratory association between 2D:4D ratio and the PV phenotype rather than erythrocytosis itself, but they do not establish causality or a prenatal hormonal mechanism. Further validation in independent cohorts integrating developmental, endocrine, and molecular variables is required.