Endocrine Abstracts (2019) 62 OC4 | DOI: 10.1530/endoabs.62.OC4

A novel PHEX mutation, p.(Trp749Ter), is associated with hypophosphataemia and rhabdomyolysis in adulthood

Kirsty Mills de Mezquita1, Mie Olesen2, Rebecca Brown3, Melissa Sloman4, Rajesh Thakker5 & Fadil Hannan1,2,5

1Department of Clinical Biochemistry and Metabolic Medicine, Royal Liverpool University Hospital, Liverpool, UK; 2Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK; 3Department of Nephrology, Royal Liverpool University Hospital, Liverpool, UK; 4Department of Molecular Genetics, Royal Devon & Exeter NHS Hospital, Exeter, UK; 5Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.

Case History: X-linked hypophosphataemia (XLH) manifests as rickets in infancy or childhood, and is caused by mutations of the phosphate-regulating neutral endopeptidase (PHEX) gene, which leads to excess production of the fibroblast growth factor-23 (FGF-23) hormone. We present a case illustrating that mutation of PHEX can also cause hypophosphataemia presenting in adulthood. The proband is a 56-year-old male, who was referred with persistent hypophosphataemia (serum phosphate ranging between 0.44–0.79 mmol/l, normal 0.80–1.50 mmol/l). He is of normal stature (height 1.78 m) with no osteomalacic symptoms or lower limb deformities. His 22-year-old daughter was also found to be hypophosphataemic (serum phosphate 0.42–0.61 mmol/l) following an episode of exercise-induced rhabdomyolysis. She is of normal stature with no prior rickets.

Investigations: Biochemical investigations in the proband showed: a normal serum calcium of 2.38 mmol/l (normal 2.20–2.60); eGFR of >90 ml/min per 1.73 m2; borderline elevated serum parathyroid hormone of 7.2 pmol/l (normal 1.1–6.9); normal serum 25-hydroxyvitamin D of 91 nmol/l (normal >50); normal serum 1,25-dihydroxyvitamin D of 116 pmol/l (normal 43–144); low tubular maximum of phosphate/glomerular filtration rate (TmP/GFR) of 0.53 (consistent with a renal tubular phosphate leak); and elevated serum FGF-23 of 117 RU/ml (normal <100). The proband’s affected daughter was also found to have a renal tubular phosphate leak (TmP/GFR of 0.58) and a borderline elevated serum FGF-23 of 95 RU/ml. Her rhabdomyolysis was considered to be due to the hypophosphataemia as a muscle biopsy revealed no other metabolic cause. The finding of renal phosphate loss and FGF-23 excess in the proband and his daughter suggested an underlying genetic aetiology.

Results: DNA sequence analysis of known phosphate-regulating genes (PHEX, FGF23, DMP1, ENPP1 and SLC34A3) in the proband revealed a novel germline p.(Trp749Ter) PHEX mutation, which is predicted to cause the loss of the PHEX carboxyl-terminus Trp749 residue. Homology modelling using the crystal structure of the related human neutral endopeptidase (NEP) enzyme showed the Trp749 residue to form part of an evolutionarily conserved carboxyl-terminus tetrapeptide motif, which is required for stabilising the catalytic domain of neutral endopeptidases. Thus, the p.(Trp749Ter) mutation would be predicted to disrupt PHEX catalytic activity.

Conclusion and points for discussion: These findings demonstrate that mutation of the PHEX gene can cause hypophosphataemia in the absence of rickets, and indicate that PHEX mutational analysis should be considered in hypophosphataemic adults harbouring a renal tubular phosphate leak and FGF-23 excess.

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