A simple clinical score to promote and enhance ferroportin disease screening.

Abstract Background and aims Ferroportin disease (FD) is a rare genetic iron overload disorder with usually normal transferrin saturation (TSat). Similarities with secondary iron overload in the setting of metabolic syndrome favors overlooked diagnosis. Recent data suggest higher prevalence than suspected. The lack of definite criteria prompting genetic testing and costs precludes large scale molecular screening. Our aim was to coin a readily available scoring system to promote and enhance FD screening. Methods Derivation cohort included probands tested for FD from 2008 to 2016 in our rare disease network. Data were prospectively recorded. Univariate and multivariate logistic regression were used to determine significant criteria, and odd ratios were used to build a weighted score. Cut-off was defined through ROC curve with a predefined aim of 90% sensitivity. An independent cohort was used for cross validation. Results Derivation cohort included 1306 patients. Mean age was 55±14 years, ferritin 1351±1357 μg/L, and liver iron content (LIC) 166±77 μmol/g. Pathogenic variants (N=32) were identified in 71 patients. In multivariate analysis female gender, younger age, higher ferritin, higher LIC and the absence of hypertension or diabetes were significantly associated with the diagnosis of FD (AUROC in whole derivation cohort 0.83[0.78-0.88]). The weighted score was based on gender, age, the presence of hypertension or diabetes, ferritin level and LIC. AUROC in derivation cohort without missing value was 0.83[0.77-0.88]. Using 9.5 as cut-off sensitivity was 93.6[91.7-98.3] %, specificity 49.5[45.5-53.6] %, positive likelihood ratio 1.8[1.6-2.0] and negative likelihood ratio 0.17[0.04 – 0.37]. Conclusion We describe a readily available score with definite criteria and good diagnosis performance that could help screening patients for Ferroportin disease in routine clinical practice. Lay summary Increased iron burden associated to metabolic syndrome is a very common condition. Ferroportin disease is a dominant genetic iron overload disorder which prevalence is higher than initially though. They can be difficult to distinguish from each other, but the limited availability of genetic testing and the lack of definite guidelines restrain proficient screening. We herein describe a simple and definite clinical score to help the clinicians in the decision for genetic testing.