Clinical Diagnosis is the Key

Introduction:
X - Linked Hypophosphatemia (XLH) is a disorder characterised by renal phosphate wasting leading to hypophosphatemia and skeletal manifestations of osteomalacia and slow growth. It can be inherited or sporadic.

Case Description:
32-year-old man presented to the clinic with progressively worsening fatigue, diffuse body aches and joint pains. He mentions that he had bone problems as a kid and had some surgeries but does not recall any details. Reports that his mother, sister and niece have bone problems too but he is unaware of the details and he does not stay in touch with his family. Physical exam was significant for findings of short stature, bowing of legs with 5 cm femoral bowing and multiple surgical scars were noted at the lateral side of knee joints bilaterally. Basic labs were sent and were notable for low phosphorous of 1.6 mg/dl (2.5-4.5) along with elevated alkaline phosphatase to 114 IU/L (32-91). Bone specific alkaline phosphate was elevated to 29.8 ug/dl (6.5-20.1). Other labs including total calcium, ionized calcium, parathyroid hormone, serum creatinine, Vitamin D were within normal reference ranges. Given the classic presentation of short stature and bowing of lower extremities in association with low serum phosphorous, X linked hypophosphatemia was suspected and further testing followed. Urine phosphorous was 42 mg/dl, urine creatinine was 85 mg/dl. Maximal tubular reabsorption of phosphate per glomerular filtration rate (TmP/GFR) was then calculated to be low at 1.6 mg/dl (normal age appropriate range was 2.6-3.8). Intact FGF-23 (fibroglast growth factor-23) levels were checked, found to be elevated to 118 micrograms/ml (normal <59 ) and genetic testing was sent, especially given the lack of detailed family history. Genetic testing for multiple genes including PHEX (Phosphate-regulating protein with homology to endopeptidases on the X chromosome), DMP 1 (Dentin matrix acidic phosphoprotein-1) and FGF-23 genes returned negative. Genetic sequencing for 3 prime untranslated region (3’ UTR) deletion defect was then performed and came back negative. Patient was initiated on human anti-fibroglast growth factor 23 monoclonal antibody Burosumab 1 mg/kg dose subcutaneous injections monthly. Patient followed up in the clinic after 3 months with remarkable improvement in his symptoms. He also mentioned that his sister and niece were both diagnosed with XLH but they also had negative genetic testing.

Discussion:
XLH diagnosis is established with hypophosphatemia and decreased tubular reabsorption of phosphorous in the kidneys. Our case highlights the need for exploration of newer genes responsible for familial XLH. It also reinforces the importance of detailed history and physical exam for diagnosis when genetic testing is unrevealing.