A puzzling renal Fanconi syndrome

Abstract

Renal Fanconi syndrome (FS) can be either acquired or inherited. When FS presents at a young age, it is typically inherited, with cystinosis being the most common cause. In this report we describe a rare cause of autosomal dominant Fanconi syndrome, Fanconi renotubular syndrome type 3 (FRTS3), caused by the already reported heterozygous p.E3K variant in the EHHADH gene. Only two FRTS3 families have been reported in the literature, and the kidney function was stated as normal or only slightly decreased into late life. Our family expands the spectrum of FRTS3, with some individuals showing only glucosuria and mild low-molecular-weight proteinuria, while others exhibited complete Fanconi syndrome with rickets. Importantly, we observed impairment of kidney function at a young age in our proband, highlighting a broader phenotypic variability associated with FRTS3.

Keywords: EHHADH; Fanconi syndrome; GATM; HNF4A; tubulopathy.

Figure 1: (a)

Family pedigree. Phenotypes of I-1 and I-3 were unknown because they declined investigations; however, they necessarily carry the EHHADH p.E3K variant. (b) Abdominal pelvic CT scan of the proband at the age of 25 revealed only millimetric nephrolithiasis (arrowheads) that have been stable for 5 years. (c) Genes implicated in autosomal dominant Fanconi syndromes. (1) Contrary to wild-type homodimers, mutant GATM forms multimers that aggregate in the mitochondria, increasing ROS production. (2) L-PBE protein encoded by EHHADH is normally directed to the peroxisome. By contrast, the EHHADH p.E3K variant encodes a mutant L-PBE protein that is misdirected to the mitochondrion, impairing normal β-oxidation of fatty acids and disrupting normal energy production. (3) The HNF4A p.R85W variant, in the DNA-binding domain, is believed to modify the transcription of genes regulated by HNF4A, and might promote the nuclear export of HNF4A, generating cytotoxic aggregates in the cytosol [3, 5]. WT, wild-type; Mut, mutant. DNA image under CC BY license.