Phenotypic Spectrum of HNF4α-Associated Fanconi Renotubular Syndrome

Fanconi renal tubular syndrome 4 (FRTS4) is a very rare, autosomal dominant disease caused by heterozygous variants affecting the arginine residue at position 85 of the HNF4A gene.

We conducted an international, physician-based, anonymous data collection within the European Rare Kidney Disease Reference Network and beyond, focusing on clinical features, treatment, and the progression of chronic kidney disease (CKD) in patients with FRTS4.

Overall, we collected data on 25 patients. Twenty-four of these carried the classic p.R85W variant, and 1 carried a new p.R85L variant. Prematurity and macrosomia at birth were frequently observed. Congenital hyperinsulinism with postnatal hypoglycemia was documented in 14 of 21 patients. Renal Fanconi syndrome was diagnosed at a median age of 1.5 (interquartile range: 0.1-4.3) years. Common symptoms included failure to thrive (13/23), rickets (9/25), nephrocalcinosis (12/25), and CKD before age 10 years (13/19). All tested patients exhibited low-molecular-weight proteinuria, aminoaciduria, and glycosuria. Hyperphosphaturia, metabolic acidosis, and hypercalciuria were present in most patients. The main extrarenal symptoms were liver abnormalities and cardiac septal defects. During a median follow-up period of 8.1 years kidney function deteriorated slowly. All adult patients progressed to CKD stage 3. Four patients developed maturity-onset diabetes of the young (MODY).

These findings provide a comprehensive picture of FRTS4. The disease should be suspected in children presenting with renal Fanconi syndrome, especially if there was fetal macrosomia and if they have experienced neonatal hypoglycemia. Progression of CKD is invariably observed, and liver and cardiac involvement should always be investigated.