Background: Hypophosphatemic rickets (HR) stands for a heterogenous group of rare disorders in which excessive renal phosphate wasting is observed. The main characteristics of X-linked HR (XLHR) (OMIM #307800) caused by mutation in PHEX (phosphate-regulating endopeptidase) gene (OMIM *300550) include bone deformities, disproportionately short stature, dental anomalies and hypophosphatemia with coexisting low renal phosphate reabsorption. The patient's growth may be improved by early treatment with vitamin D, phosphate, as well as recombinant human growth hormone (rhGH) which acts on growth cartilage directly, and increases renal phosphate reabsorption and serum phosphate levels. Recently, the new treatment option is burosumab, a monoclonal antibody which attaches to the FGF23 protein.
Objective: The aim of the study was to investigate the clinical phenotype and molecular background of HR in a patient in which XLHR was suspected as well as to analyze the effects of rhGH treatment on growth.
Patient and Methods: A girl aged 13 yrs and 2 months was diagnosed with HR at the age of 7 yrs and then treated with alfacalcidol (42 ng/kg/d) and phosphorus (75 mg/kg/d). Because of severe bowing of lower limbs the girl underwent several orthopedic operations. Mother of the girl is also affected. Due to the diagnosis of growth hormone deficiency (max GH after stimulation was 7.4 ng/ml; N>10) rhGH therapy was initiated at the age of 10.5 years (current dose of rhGH is 0,029 mg/kg/d). Molecular analysis was performed using total genomic DNA. PHEX gene was analyzed using standard PCR and direct sequencing method.
Results: The dominant clinical signs in a patient were bowing of legs, short stature and lumbar hyperlordosis. HtSDS at the time of diagnosis was -2.6. Current htSDS is -2.2 and the height gain during rhGH therapy was 0.4 +SD. Molecular analysis of PHEX gene revealed the presence of a known heterozygous mutation c.1645+1G>A in 5' splicing site of intron 15 (HGMD ID: CS992468) as well as a known polymorphism c.1769-10C>T (rs3752433) in intron 17.
Conclusions: Molecular analysis of PHEX gene is very important to confirm the clinical diagnosis of hypophosphatemic rickets, which is extremely important for early proper treatment to prevent severe bone deformities, improve final height as well as for appropriate genetic counseling in families with HR patients. rhGH therapy in patients with XHLR may be very effective in those with coexisting growth hormone deficiency.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology