Clinical and Molecular Genetic Characteristics of Patients with Hereditary Hypophosphatemia

Hereditary hypophosphatemia (HH), is a rare condition related to decreased renal tubular phosphate reabsorption. Although X-linked hypophosphatemia or PHEX gene variant is the most frequent cause of HH, recent advances in next-generation sequencing (NGS) techniques enable the identification of genetic etiologies as a whole.

This work aimed to identify genetic causes of HH using various genetic testing methods and to compare clinical features between FGF23-dependent and FGF23-independent HH groups.

Fifty patients (24 males) from 39 unrelated families were included. Based on initial evaluation, PHEX gene sequencing was performed in patients with clinical and biochemical findings suggestive of FGF23-dependent HH. If sequencing showed no alterations, multiplex ligation-dependent probe amplification (MLPA) analysis for PHEX was conducted. Initially, a specific gene panel was performed for FGF23-independent HH or those in whom the PHEX gene showed no genetic alteration.

Genetic etiology was revealed in 43 patients from 33 families. PHEX gene variants (4 novel) were identified in 24 patients from 19 unrelated families (50%). SLC34A3 was the second most common (16.6%) and the rest were rarer causes of hypophosphatemia (DMP1 n = 3, SLC34A1 n = 2, CLCN5 n = 2, OCRL n = 2, FAM20C n = 1, SLC2A2 n = 1). When the genetically proven FGF23-dependent (n = 28) and FGF23-independent (n = 15) HH groups were compared for clinical and biochemical features; lower phosphate and TmP/GFR SDSs and higher ALP SDS with more severe clinical rickets were detected in FGF23-dependent group, whereas higher serum and urine calcium and lower PTH levels were detected in FGF23-independent group.

The application of MLPA provided an additional explanatory value of 10% to the molecular etiology. However, 10% of the cases of HH still remain unexplained even after a comprehensive genetic work-up. Biochemical findings suggest distinct biochemical profiles between FGF23-dependent and FGF23-independent HH groups.