Intrauterine sex hormone exposure, which affects the ratio of the second and fourth finger lengths (2D:4D), may be associated with hereditary angioedema (HAE) attack frequency and severity as well as laryngeal edema, according to a study published in Early Human Development.

The study authors evaluated 35 patients with HAE aged 19 to 66 years, 3 of whom were subsequently excluded from the study. Among the final cohort, 18 were female and 14 were male. All patients were instructed to complete a structured clinical questionnaire exploring the course of their illness and treatment over the previous year.

In addition, the researchers calculated the 2D:4D ratio by dividing the length of the second finger by that of the fourth finger for both hands.

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According to the findings, HAE patients with high 2D:4D ratios suffered significantly more laryngeal attacks than those with low 2D:4D ratios. Moreover, 93.3% of them experienced at least 5 HAE attacks annually. Among patients with type 2 HAE, 75% of those experiencing at least 5 attacks per year had high 2D:4D ratios and all patients with low ratios suffered fewer than 5 HAE attacks annually.

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The number of annual HAE attacks differed significantly between men and women, as 77.8% of female participants and only 35.7% of male patients experienced laryngeal spasms. However, there were no significant differences in the 2D:4D ratio between sexes.

The researchers also noted that these findings were reported for right-hand 2D:4D ratios but not for left-hand 2D:4D ratios.

“Female sex hormones play essential roles in terms of HAE onset and attack frequency. Increased exposure to estrogen during pregnancy and therapies featuring exogenous estrogen increase HAE severity in most patients of normal [C1-inhibitor] HAE status,” Evcen and colleagues wrote.

“Although [HAE] is an autosomal-dominant condition that affects men and women, women generally experience more intense and more frequent attacks.”

Previous studies have discovered a connection between low 2D:4D ratios and high fetal testosterone and low fetal estrogen levels, as well as between high 2D:4D ratios and low fetal testosterone and high fetal estrogen levels.


Evcen R, Çölkesen F, Saygın DA, et al. High digit ratio (2D:4D) is associated with attack frequency and severity in hereditary angioedema patients. Early Hum Dev. 2023;177-178:105724. doi:10.1016/j.earlhumdev.2023.105724