SUN-363 Hypophosphatemia Gene Panel Sponsored Program: A High Yield Of Molecular Diagnoses from Clinically Confirmed XLH and Suspected XLH/ Genetic Hypophosphatemia

X-linked hypophosphatemia (XLH), an X-linked dominant disorder caused by a pathogenic change (variant) in the PHEX gene, affects males and females of all ages. Rickets and osteomalacia may be present along with short stature, lower limb deformity, muscle pain and/or weakness/fatigue, bone pain, joint pain/stiffness, hearing difficulty, enthesopathy, osteoarthritis and dental abscesses. Patients with XLH have below-normal serum phosphate and elevated serum FGF23. XLH is one of multiple etiologies of hypophosphatemia; depending on genetic cause, management may differ. The program provides a no-cost test to confirm a clinical XLH diagnosis or to aid diagnosis of suspected XLH or other genetic hypophosphatemia. Methods Program eligibility criteria: >/=1y old and either clinical XLH diagnosis (confirmatory) or suspicion of XLH/ genetic hypophosphatemia (suspected) as evidenced by 2 or more clinical signs/ symptoms. The next generation sequencing gene panel includes 13 genes: ALPL, CLCN5, CYP2R1, CYP27B1, DMP1, ENPP1, FAH, FAM20C, FGF23, FGFR1, PHEX, SLC34A3 and VDR. Copy number variant (CNV) detection was performed. Results 317 unrelated probands have been tested as of October 2, 2019. Of 158 XLH confirmatory samples received, 143 (90.5%) had a PHEX variant: 14 (9.8%) were variants of uncertain significance (VUS) and 129 (90.2%) were either pathogenic or likely pathogenic (P/LP) XLH molecular diagnoses. Of the 15 patients (9.5%) where no PHEX variant was found, one had a P variant in FGF23 (autosomal dominant hypophosphatemic rickets molecular diagnosis) and another had P and LP variants in ENPP1 (autosomal recessive hypophosphatemic rickets Type 2 molecular diagnosis). Of 159 suspected samples, 101 (63.5%) had a PHEX variant: 14 (13.9%) were variants of uncertain significance (VUS) and 87 (86.1%) were P/LP (XLH molecular diagnoses). No PHEX variant was found for 58 (36.5%) of suspected samples; however, 5 of these had other findings: a dominant-negative heterozygous P variant for ALPL was detected in 3 samples (3 hypophosphatasia, HPP, molecular diagnoses); a fourth carried two P variants in ALPL; a fifth had a LP variant and a VUS in ENPP1 (autosomal recessive hypophosphatemic rickets Type 2). Of 121 unique P/LP PHEX variants detected, 59 were deletions duplications or insertions. A complex rearrangement and an Alu-mediated insertion were detected in the full cohort. To date, additional family member testing was performed for 10 probands with original VUS: in 4 cases the VUS was reclassified to P/LP; 2 were reclassified to P/LP due to more clinical info, highlighting the value of family testing and clinical info to resolve VUS. RNA analyses to resolve VUS and unidentified variants may further improve molecular diagnoses of genetic hypophosphatemia. Program results demonstrate a high diagnostic yield for confirmatory and suspected XLH/ genetic hypophosphatemia.

Early onset hearing loss in autosomal recessive hypophosphatemic rickets caused by loss of function mutation in ENPP1

Autosomal recessive hypophosphatemic rickets 2 (ARHR2) is a rare form of renal tubular phosphate wasting disorder. Loss of function mutations of the ecto-nucleotide pyrophosphatase/pyrophosphodiesterase 1 gene (

Mineralizing Enthesopathy Is a Common Feature of Renal Phosphate-Wasting Disorders Attributed to FGF23 and Is Exacerbated by Standard Therapy in Hyp Mice

We have previously confirmed a paradoxical mineralizing enthesopathy as a hallmark of X-linked hypophosphatemia. X-linked hypophosphatemia is the most common of the phosphate-wasting disorders mediated by elevated fibroblast growth factor 23 (FGF23) and occurs as a consequence of inactivating mutations of the PHEX gene product. Despite childhood management of the disease, these complications of tendon and ligament insertion sites account for a great deal of the disease's morbidity into adulthood. It is unclear whether the enthesopathy occurs in other forms of renal phosphate-wasting disorders attributable to high FGF23 levels. Here we describe two patients with autosomal recessive hypophosphatemic rickets due to the Met1Val mutation in dentin matrix acidic phosphoprotein 1 (DMP1). In addition to the biochemical and skeletal features of long-standing rickets with elevated FGF23 levels, these individuals exhibited severe, debilitating, generalized mineralized enthesopathy. These data suggest that enthesophytes are a feature common to FGF23-mediated phosphate-wasting disorders. To address this possibility, we examined a murine model of FGF23 overexpression using a transgene encoding the secreted form of human FGF23 (R176Q) cDNA (FGF23-TG mice). We report that FGF23-TG mice display a similar mineralizing enthesopathy of the Achilles and plantar facial insertions. In addition, we examined the impact of standard therapy for phosphate-wasting disorders on enthesophyte progression. We report that fibrochondrocyte hyperplasia persisted in Hyp mice treated with oral phosphate and calcitriol. In addition, treatment had the untoward effect of further exacerbating the mineralization of fibrochondrocytes that define the bone spur of the Achilles insertion. These studies support the need for newer interventions targeted at limiting the actions of FGF23 and minimizing both the toxicities and potential morbidities associated with standard therapy.