Intrafamilial Disease Heterogeneity in Primary Hyperoxaluria Type 1

Abstract

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 (P < 0.001). Kaplan-Meier analyses revealed that index cases reached kidney failure at an earlier age and earlier in follow-up compared to siblings (P < 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.

Keywords: PH1; discordance; families; intrafamilial heterogeneity; kidney failure; primary hyperoxaluria.

Graphical abstract

Figure 1

Six-point PH1 clinical outcome scoring system for calculating intrafamilial clinical heterogeneity. Here, an example is given of 1 family within the study. PH1, primary hyperoxaluria type 1; U, index case; Y, siblings of the index case; Z, heterogeneity score of family 1 (6 − 2 = 4).

Figure 2

The number of patients diagnosed by family screening by age at diagnosis. Each bar represents a 5-year range.

Figure 3

The distribution of heterogeneity score of all 88 families. For each family member with PH1, the clinical outcome was graded using a 6-point PH1 score. The heterogeneity score of each family was then calculated by subtracting the lowest score from the highest score among all siblings. PH1, primary hyperoxaluria type 1.

Figure 4

Distribution of heterogeneity scores in families with and without (partly) vitamin B6 (VB6) –responsive variants. Shown are the heterogeneity scores of families stratified by AGXT variant. Heterogeneity score is calculated by subtracting the lowest score from the highest score among the siblings, using the 6-point PH1 clinical outcome scoring system. The number of families with a specific heterogeneity score is noted in the boxes. PH1, primary hyperoxaluria type 1. ∗The group “missense” encompasses all families with a homozygous missense AGXT variant. The group “other” includes mostly families with a homozygous null variant (n = 16) and 1 heterozygous missense/null variant.

Figure 5

Kaplan-Meier analysis including confidence bands of death-censored kidney survival by age, stratified by index case, siblings asymptomatic at time of diagnosis and siblings symptomatic at time of diagnosis. Log-rank test analysis showed a significant difference (P < 0.001) between the groups. Dx, diagnosis.

Figure 6

Kaplan-Meier analysis of death-censored kidney survival by years since diagnosis, stratified by index case, siblings symptomatic at the time of diagnosis, and siblings asymptomatic at the time of diagnosis. Log-rank test analysis showed a significant difference (P < 0.001) between the groups. Dx, diagnosis.