Clinical and genetic characteristics of 15 families with hereditary hypophosphatemia: Novel Mutations in PHEX and SLC34A3

Abstract

BackgroundHereditary hypophosphatemia is a group of rare renal phosphate wasting disorders. The diagnosis is based on clinical, radiological, and biochemical features, and may require genetic testing to be confirmed.MethodologyClinical features and mutation spectrum were investigated in patients with hereditary hypophosphatemia. Genomic DNA of 23 patients from 15 unrelated families were screened sequentially by PCR-sequencing analysis for mutations in the following genes: PHEX, FGF23, DMP1, ENPP1, CLCN5, SLC34A3 and SLC34A1. CytoScan HD Array was used to identify large deletions.ResultsGenetic evaluation resulted in the identification of an additional asymptomatic but intermittent hypophosphatemic subject. Mutations were detected in 21 patients and an asymptomatic sibling from 13 families (86.6%, 13/15). PHEX mutations were identified in 20 patients from 12 families. Six of them were novel mutations present in 9 patients: c.983_987dupCTACC, c.1586+2T>G, c.1206delA, c.436+1G>T, c.1217G>T, and g.22,215,887–22,395,767del (179880 bp deletion including exon 16–22 and ZNF645). Six previously reported mutations were found in 11 patients. Among 12 different PHEX mutations, 6 were de novo mutations. Patients with de novo PHEX mutations often had delayed diagnosis and significantly shorter in height than those who had inherited PHEX mutations. Novel compound heterozygous mutations in SLC34A3 were found in one patient and his asymptomatic sister: c.1335+2T>A and c.1639_1652del14. No mutation was detected in two families.ConclusionsThis is the largest familial study on Turkish patients with hereditary hypophosphatemia. PHEX mutations, including various novel and de novo variants, are the most common genetic defect. More attention should be paid to hypophosphatemia by clinicians since some cases remain undiagnosed both during childhood and adulthood.

Die X-Chromosomale Hypophosphatämie – XLH

“…Bei ADHR ist FGF-23 durch Mutationen somit resistenter gegen SPC, wodurch die Konzentration an full-length FGF-23 erhöht ist (10). Derzeit sind insgesamt 5 verschiedene Mutationen bekannt (17). Die Phasen verminderter Krankheitsaktivität bei ADHR korrelieren mit normalen Phosphat-und FGF-23-Spiegeln und Phasen erhöhter Krankheitsaktivität mit erhöhten FGF-23-Spiegeln und Hypophosphatämie.…”

“…DMP1 hemmt die Expression von FGF-23. Durch inaktivierende Genveränderungen entfällt diese Hemmung, was eine vermehrte FGF-23-Synthese nach sich zieht (17).…”

“…Eine weitere sehr seltene Form von Phosphatdiabetes die mit hohen intakten FGF-23 Spiegeln einher geht ist die autosomal rezessive hypophosphatämische Rachitis Typ 2 (ARHR2) (17). Sie beruht ursächlich auf loss-of-function Mutationen im Ectonucleotide-Pyrophosphatase/Phosphodiesterase-1-Gen (ENPP1-Gen).…”

“…Mutationen im SLC34A1-Gen, welches für den NaP i -IIa-Transporter kodiert, bedingen das renotubuläre Fanconi-Syndrom 2 (FRTS2) (17). Diesem kann sowohl ein autosomal-dominanter, als auch ein autosomal-rezessiver Erbgang zugrunde liegen.…”

Nationwide Turkish Cohort Study of Hypophosphatemic Rickets

“…Information about the clinical, laboratory, genetic and follow-up characteristics of HR patients is very scarce for our population and only a few small series have been reported (7,8).…”