ESPE Yearbook of Paediatric Endocrinology

Cochrane Database Syst Rev, 2021. 10: p. CD004447 PMID: 34618915

Brief Summary: This systematic review examined the effects of rhGH treatment in children with X-linked hypophosphatemia. Despite a significant improvement in height SDS from baseline, evidence from the 2 identified studies was limited to support its clinical use in these patients.

X-linked hypophosphatemia (XLH) is an inherited disorder of phosphate homeostasis, caused by mutations in the PHEX gene, which encodes a membrane-bound endopeptidase expressed in bones and teeth. XLH is the most common cause of inherited phosphate wasting and is characterized by rickets and osteomalacia, disproportionate short stature, hypophosphatemia, abnormal phosphate reabsorption and altered vitamin D metabolism.

Conventional treatment, based on oral phosphate and calcitriol supplementation does not always normalize serum phosphate concentrations and linear growth. Therapy with recombinant human growth hormone (rhGH) therapy has been suggested for improving linear growth but results are conflicting, some showing acceleration of growth velocity and improvement of phosphate retention and bone mineral density, but some others showing a worsening of the pre-existent disproportionate stature [1].

This systematic review assessed the efficacy and safety of rhGH treatment in children with XLH. Linear growth, mineral metabolism, endocrine function, renal function, bone mineral density, body proportions and the incidence of adverse effects were the outcome measures taken into consideration. It included randomized controlled studies (both published and unpublished) in children aged 0-18 years treated with rhGH alone or in combination with calcitriol and oral phosphate, compared with either placebo or conventional treatment alone.

Based on the selection criteria only 2 studies (comprising only 20 patients) (2,3) could be included. One was a cross-over study with 5 participants (Seikaly 1997, 2) and the second was a 3-year study with 15 participants (Živicnjak 2011, 3). Seikaly et al. randomized patients to receive either placebo or rhGH (0.08 mg/kg/daily) for 12 months, and then crossed-over to the other study arm for a further 12 months. Živicnjak et al. gave rhGH 0.4 mg/kg once a week for 3 years whilst the control group received no additional treatment and no placebo (Živicnjak 2011). Both studies reported a significant improvement in height SDS from baseline with rhGH. However, the review authors found no difference in height SDS after three years of treatment. Seikaly et al. reported significant increase in phosphate levels after 3 months of rhGH but it was not maintained at 6, 9 and 12 months. Improvement in TmP/GFR was reported in the cross-over Seikaly study after 3 months of rhGH treatment, but the changes after 6, 9, and 12 months were not significantly different from baseline. Živicnjak et al. found a transient increase in TmP/GFR in the rhGH treated group but these results were not confirmed upon re-analysis. Therefore, the efficacy of rhGH on renal function in terms of TmP/GFR remains uncertain as well as change in alkaline phosphatase levels.

Neither study reported a change in urinary calcium to creatinine ratio between the rhGH treated or control groups. No difference in sitting height, arm and leg length SDS was found after one year in the rhGH treated as compared to the control group in Živicnjak study. The treatment was overall well-tolerated.

In conclusion, data on the efficacy and safety of rhGH therapy in children with XLH were insufficient to provide recommendations for clinical practice. Although rhGH therapy may be potentially beneficial to children with XLH, its clinical use cannot be recommended on the basis of the available evidence.

References: 1. Haffner, D., et al., Disproportionate growth following long-term growth hormone treatment in short children with X-linked hypophosphataemia. Eur J Pediatr, 1995. 154(8): p. 610–3. 2. Seikaly MG, Brown R, Baum M. The effect of recombinant human growth hormone in children with X-linked hypophosphatemia. Pediatrics1997;100(5):879–84. 3. Živičnjak M, Schnabel D, Staude H, Even G, Marx M, Beetz R, et al. Three-year growth hormone treatment in short children with X-linked hypophosphatemic rickets: effects on linear growth and body disproportion. Journal of Clinical Endocrinology and Metabolism2011;96(12):E2097–105.