Intrafamilial Disease Heterogeneity in Primary Hyperoxaluria Type 1.

Introduction: Primary hyperoxaluria type 1 (PH1) is known for its variable clinical course, even within families. However, the extent of this heterogeneity has not been well-studied. We aimed to analyze intrafamilial clinical heterogeneity and disease course among siblings in a large cohort of familial PH1 cases.

Methods: A retrospective registry study was performed using data from OxalEurope. All PH1 families with 2 or more affected siblings were included. A 6-point PH1 clinical outcome scoring system was developed to grade heterogeneity within a family. Intrafamilial clinical heterogeneity was defined as a score ≥2. Kaplan-Meier analyses were used to analyze differences in kidney survival between index cases and siblings.

Results: We included 88 families, encompassing 193 patients with PH1. The median interquartile range (IQR) follow-up time was 7.8 (1.9-17) years. Intrafamilial clinical heterogeneity, as defined by our score, was found in 38 (43%) PH1 families. In 54% of the families, affected siblings had a better outcome than the index case. Clinically asymptomatic siblings at the time of their diagnosis had a significantly more favorable clinical outcome based on the authors' scoring system than siblings with clinical signs and index cases ( < 0.001). Kaplan-Meier analyses revealed that index cases reached kidney failure at an earlier age and earlier in follow-up compared to siblings ( < 0.001).

Conclusions: Intrafamilial clinical heterogeneity was found in a substantial number of familial PH1 cases. Compared to index cases, siblings had significantly better clinical outcomes and kidney survival; thereby supporting the policy of family screening to diagnose affected siblings early to improve their prognosis.