MO054EFFICACY OF ORAL PHOSPHATE SUPPLEMENTATION IN CHILDREN WITH HEREDITARY HYPOPHOSPHATEMIC RICKETS WITH HYPERCALCIURIA

Abstract

Abstract Background and Aims Hereditary hypophosphatemic rickets with hypercalciuria (HHRH; MIM #241530) is an autosomal recessive renal phosphate-wasting disorder caused by mutations in the SLC34A3/NPT2c gene. HHRH characterized by increased urinary phosphate excretion leading to hypophosphatemic rickets, short stature and elevated serum 1,25(OH)2D levels which result in hypercalciuria leads to nephrocalcinosis/urolithiasis due to enhanced intestinal calcium absorption and reduced PTH-dependent calcium reabsorption in the distal renal tubules. Treatment of HHRH involves administration of oral phosphate supplements alone to normalize of serum phosphate, alkaline phosphatase activity (ALP), PTH levels, urine calcium excretion for prevention of renal calcifications and progression of rickets. Currently there is no consensus on the optimal dose of oral phosphate in patients with HHRH. The aim of the study was to evaluate the efficacy of oral phosphate supplements in Russian cohort of children with HHRH. Method 9 children (7M/2F) with homozygous (n=6) and compound heterozygous (n=3) SLC34A3 mutations from unrelated families were examined. Treatment with oral phosphate supplements was started at the median age of patients 12.0 (IQR: 9.0; 13.0) years. The median dosage of oral phosphate supplements was 14.1 (IQR: 13.8; 14.8) mg/kg/day based on elemental phosphorus. The duration of follow-up was 36.0 (IQR: 16; 49) months. Blood electrolytes levels, ALP, PTH and 24-hour-urine excretion of calcium were evaluated in all children. ALP Z-scores were calculated using age- and sex-specific mean/standard deviation (SD) lab reference data. Bone mineral density with Z-score were measured in lumbar spine and whole body for all patients using a dual energy X-ray absorptiometry device. Molecular genetic analysis was performed in all children using by next generation sequencing. Results The median SD score of height at the first and last follow-up was -1.35 (IQR: -1.8; -0.87) and -1.51 (IQR: -2.0; -0.66) (p=0.6), respectively, short stature had 33.3% (3/9) of patients at first and 44.4% (4/9) at last follow-up (p=0.7). Treatment with low doses of oral phosphate supplements did not led to normalization of serum phosphorus:1.05 (IQR: 0.97; 1.39) vs. 0.93 (IQR: 0.81; 1.27) mmol/l (p=0.13), PTH: 8.3 (IQR: 5.8; 13.8) vs. 12.9 (IQR: 12.0; 16.0) pg/ml (p=0.34), Z-score in lumbar spine: -1.2 (IQR: -2.7; -0.1) vs. -1.8 (IQR: -2.8; -1.1) (p=0.48) and Z-score in total body: -2.1 (IQR -2.6; -1.5) vs. -2.4 (IQR: -3.0; -2.0) (p=0.37). Hypercalciuria had 88.8% (8/9) of children (0.15 (IQR: 0.12; 0.19) mmol/kg/day) at first follow-up and 44.4% (4/9) (0.09 (IQR: 0.08; 0.16) mmol/kg/day) in last examination (p=0.13). ALP blood levels were elevated in all patients (9/9) at first and most recent visit, but ALP Z-score were significant lower at last follow-up: 3.9 (IQR: 1.2; 5.1) vs. 0.57 (IQR: -0.36; 2.1) (p=0.04). There were significant correlations between doses of oral phosphate supplements and ALP Z-score (r=-0.68; p=0.04) and total body Z-score (r=0.78; p=0.03). There was no significant correlations between ALP Z-score and total body Z-score (r=-0.3) or lumbar spine Z-score (r=-0.1). Conclusion The present study demonstrated that treatment of HHRH with low doses (<20 mg/kg/day) of oral phosphorus supplements led to decreasing of ALP Z-score in 7/9 (77.8%) and hypercalciuria in 5/9 (55.6%) of patients. However, that therapy didn’t improve significantly height and severity of rickets, as well didn’t led to normalization of serum phosphorus in children with HHRH. It is therefore conceivable that higher daily doses of phosphate supplements are needed to normalize all clinical and radiological features of disease. Lack of association between ALP Z-score and bone mineral density severity on radiographs limits the value of serum ALP as the indicator of rickets activity.