Abstract #1413209: An Interesting Case of Hereditary Adult Onset Hypophosphatemic Osteomalacia

Abstract

Hereditary rickets/osteomalacia is uncommon disorder previously being referred as Vitamin D -resistant rickets. This group of rare disorder can be differentiated from other causes of rickets by inheritance pattern, hypophosphatemia with normocalcemia, FGF-23 dependent or independent nature and detection of genetic defects. Here we present an interesting case of autosomal dominant hypophosphatemic rickets/osteomalacia (ADHR). A 32-year-old lady presented with complains of bony pains, proximal myopathy and recurrent insufficiency fractures for last 15 years. She was evaluated elsewhere and was found to have FGF23 dependent hypophosphatemic osteomalacia. She underwent Ga68 DOTATATE scan twice in the span of last 5 years as she was thought to have tumor induced osteomalacia (TIO), however both the scans were not able to localize any definitive lesion. She was advised to take oral phosphorus supplements, calcitriol and to undergo serial functional imaging every 3-5 years to localize FGF-23 secreting tumor. She was re-evaluated in our center for these complaints and was found to have low serum phosphorus, low TMP/GFR, normal serum calcium & electrolytes and elevated FGF-23 levels. On reexamining her history, she told that her mother as well as her 5-year-old daughter have knock knees. She also told that both she and her daughter started walking late at the age of 20 months. With this additional history, we considered the possibility of hereditary hypophosphatemic rickets and genetic testing in the form of clinical exome by next generation sequencing with further confirmation by sanger sequencing was done. Both index patient and her daughter were found to have a pathogenic heterogenous missense mutation in exon 3 of the FGF23 gene (chr12:c.527G >A ;p.Arg176Gln) confirming the diagnosis of ADHR. ADHR is a rare disorder caused by mutations in FGF-23 gene. This gain of function mutation leads to resistance of FGF-23 to proteolytic cleavage and processing resulting in its impaired inactivation. ADHR exhibits incomplete penetrance with variable age of onset as well as presentation. Some patients present in childhood with lower extremity deformity and phosphate wasting similar to classical presentation of X-linked hypophosphatemic rickets whereas other patients present clinically in adolescence or adulthood with bony pains, insufficiency fractures without lower extremity involvement. Patients with adult onset ADHR have clinical and biochemical profile similar to TIO. Hence clinical history of similar milder illness in other family members is an important clue to differentiate ADHR from TIO as was with this index case.