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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.

Male sexual differentiation is the result of complex mechanisms involving developmental genetics and endocrinology. Formation of the bipotential gonads and subsequently the testes is dependent on a series of sex chromosome-linked and autosomal genes. The testes secrete both peptide and steroid hormones essential for the formation of internal and external genitalia. Hormone action is mediated via specific receptors, functioning as transcription regulators. Disruption of these genetic events leads to sexual dimorphism involving external and internal genitalia, and may also interfere with the development of other organs.