Effect of GH replacement therapy in two male siblings with combined X-linked hypophosphatemia and partial GH deficiency

Abstract

Objective: X-linked hypophosphatemia (XLH) is characterized by low serum phosphorus, relative 1,25-dihydroxyvitamin D 3 deficiency and rickets. It is caused by mutations in the phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX). The conventional treatment of XLH includes the administration of phosphate and calcitriol; however, treated patients usually present with a short stature. Therefore, additional coexistent defects, such as GH deficiency, are under debate. Patients and methods: Two male siblings presented with a disproportionate growth failure and rickets. Investigation of calcium and phosphate metabolism, molecular genetic analysis of the PHEX gene and GH function tests were initiated. Results: Both patients showed typical clinical and biochemical signs of XLH. Molecular genetic analysis revealed a 747 CGA (Arg)-TGA (End) mutation in exon 22 of the PHEX gene, confirming XLH. Since treatment with phosphate and calcitriol alone failed to improve growth in both patients, the GH axis was examined and a partial GH deficiency was diagnosed in both cases. Almost 3 years of additional therapy with recombinant human GH (rhGH) led to a significant improvement of height standard deviation scores (HtSDS). Conclusions: Poor growth in XLH may, in at least some patients, be aggravated by GH deficiency. Hence, GH deficiency should be considered in extremely poorly growing patients with XLH, because these patients are likely to benefit from rhGH therapy.

Growth in X-linked hypophosphatemic rickets

“…Despite the absence of a gene dose effect, and that of a phenotype-genotype correlation [4,6], most authors observed more severe a disease in affected boys than in girls [3,18,22]. In our series boys were also over-represented among short patients, even in those treated since a very young age; once again, absence of a statistical relationship between male gender and growth failure may be related to the sample size.…”

“…Further, rhGH in XLHR has been associated with disproportionate growth in favor of the trunk [17], viewed as a negative outcome [5], although most reports did not demonstrate such disproportionate growth [1,2,10,22,23]. Our experience with rhGH in short children with XLHR ( Fig.…”

“…However, the ultimate causes of inadequate linear growth are unknown [1]. The role of growth hormone (GH) in the inadequate statural growth has been proposed as a causative factor, and, poor growth may, in some patients, be aggravated by GH deficiency [22]. Further, treatment with recombinant human growth hormone (rhGH) in short patients with XLHR is controversial, due to the lack of controlled clinical trials [7].…”

X-linked hypophosphatemia and growth

“…Adults with XLH have a significantly reduced final height up to 20 cm, mean standard deviation score (SDS) of −1.9 [44], but there is a great variability among individuals. XLH patients are not abnormally small at birth [46]; XLH girls and boys seem to have normal growth spurt and adult men show a more severe Fig. 1 Phosphorus metabolism in XLH.…”

MAPK inhibition and growth hormone: a promising therapy in XLH

“…Addition of growth hormone (GH) to phosphate and 1-hydroxy vitamin D metabolite treatment has been used to improve growth in stunted children with XLH. Although 3-yr GH administration has been shown to accelerate longitudinal growth velocity without worsening body disproportion (9), there is the concern of increasing leg deformities in children responding to GH (9)(10)(11)(12). The effect of GH treatment on mineral and bone metabolism in patients with XLH is to a great extent unknown (13).…”