ESPE Abstracts

Background: X linked hypophosphatemic rickets (XLHR; OMIM 307800) is an X linked dominant disorder caused by mutations in the phosphate regulating neutral endopeptidase homolog X linked (PHEX) gene, which is located at Xp22.11.

Objective: To clarify the underlying mechanism of a Brazilian family with hypophosphatemic rickets whose clinical manifestations were very broad among members of different generations.

Design and patients: The proband is an 8-year-old child. She and he 5-year-old brother show similar clinical features such as bowing of legs together with hypophosphatemia, but the brother developed also cranial synostosis and Arnold-Chiari malformation type I. Their mother has only mild features of the disease with no bone bowing, but presenting only mild short stature. Due to paucity of clinical manifestations in the mother, recessive hypophosphatemic rickets/osteomalacia (ARHR) was at first suspected.

Results: Sequencing of all coding exons and exon-intron junctions of DMP1 and FGF23 genes showed no mutation. Subsequent analysis revealed that there is a deletion of exons 10 and 11 in PHEX gene in the younger sib, later confirmed by studies with MLPA. His sister was found to be a heterozygote for the same deletion indicating that they are suffering, in fact, from XLH. The same deletion was detected in the mother.

Conclusion: Careful genetic analysis is mandatory for correct differential diagnosis of genetic hypophosphatemic rickets. Next generation sequencing (NGS) allowed the use of multi-gene panels as way to better analyze multiple genes at the same time. Nevertheless, large deletions in PHEX gene still need to be better characterized using techniques such as MLPA in combination with NGS.