Growth hormone therapy in HHRH

Abstract

Background: Hereditary Hypophosphatemic Rickets with Hypercalciuria (HHRH) (SLC34A3 gene, OMIM 241530) is an autosomal recessive disorder that results in a loss of function of the sodium-phosphate NPT2c channel at the proximal tubule. Phosphate supplementation rarely improves serum phosphate, hypercalciuria, nephrocalcinosis, 1,25(OH)₂ vitamin D (1,25(OH)₂D) levels or short stature.

Methods: We describe ²³Na MRI and the successful use of recombinant human growth hormone (rhGH) and Fluconazole to improve growth (possibly confounded by puberty) and hypercalciuria in a now 12-year-old male with HHRH (novel homozygous SLC34A3 mutation, c.835_846 + 10del.T).

Results: The patient had chronic bone pain, hypophosphatemia (0.65 mmol/L[reference interval 1.1-1.9]), pathological fractures and medullary nephrocalcinosis/hypercalciuria (urinary calcium/creatinine ratio 1.66 mol/mmol[<0.6]). TmP/GFR was 0.65 mmol/L[0.97-1.64]; 1,25(OH)₂D was >480 pmol/L[60-208]. Rickets Severity Score was 4. Treatment with 65 mg/kg/day of sodium phosphate and potassium citrate 10 mmol TID failed to correct the abnormalities.Adding rhGH at 0.35 mg/kg/week to the phosphate therapy, improved bone pain, height z-score from -2.09 to -1.42 over 6 months, without a sustained effect on TmP/GFR. Fluconazole was titrated to 100 mg once daily, resulting for the first time in a reduction of the 1,25(OH)₂D to 462 and 426 pmol/L; serum phosphate 0.87 mmol/L, and calcium/creatinine ratio of 0.73.²³Na MRI showed normal skin (z-score + 0.68) and triceps surae muscle (z-score + 1.5) Na⁺ levels; despite a defect in a sodium transporter, hence providing a rationale for a low sodium diet to improve hypercalciuria.

Conclusions: The addition of rhGH, Fluconazole and salt restriction to phosphate/potassium supplementation improved the conventional therapy. Larger studies are needed to confirm our findings.

Keywords: 23Na MRI; Hereditary hypophosphatemic rickets with hypercalciuria; Recombinant human growth hormone; Sodium phosphate cotransporter; Tubular phosphate wasting.

Fig. 1

(black and white): Evolution of serum phosphate, 1,25(OH)₂ vitamin D, height z-score, oral phosphate dose and TmP/GFR in relationship to the initiation of the therapy with recombinant growth hormone.

Fig. 2

(color). HHRH mutation map with novel patient mutation. Figure adapted from Bergwitz and Miyamoto, 2018 (Bergwitz and Miyamoto, 2019; Dasgupta et al., 2014), represents mutations in SLC34A3 gene resulting in HHRH. The patient's novel mutation is represented by a black circle in the loop region of intron 8. The orange boxes represent a transport domain whereas the purple boxes represent a scaffold domain.

Fig. 3

(color): ²³Na MRI of the leg in a healthy 11-year-old male (A) and the 11-year-old male patient with HHRH (B). Images show a normal whole leg [Na⁺] (18.4 mmol/L, z-score + 1.31), skin [Na⁺] (14.5 mmol/L, z-score + 0.68) and triceps surae muscle [Na⁺] (21.2 mmol/L, z-score + 1.5) despite a defect in a sodium transporter. [Na⁺] measurement was possible by linear trend analysis as detailed in (Filler et al., 2021a; Filler et al., 2021b; Qirjazi et al., 2020), using four calibration vials containing increasing concentrations of NaCl solution (from left to right: 40, 30, 20, 10 mmol/L). Tissue [Na⁺] is displayed as heat map, with greater signal intensity proportional to tissue [Na⁺].