X-linked hypophosphatemia: A search for gender, race, anticipation, or parent of origin effects on disease expression in children

X-Linked hypophosphatemia (XLH) is a sex-linked dominant disorder. It is possible that females are more mildly affected than males. No information is available regarding other potential genetic influences on XLH expression in patients, such as race, anticipation, parent of origin, or molecular heterogeneity. We investigated the above potential genetic influences on XLH expressivity using data from 116 pediatric patients. To compare biochemical parameters, we used data from the 30 prepubertal children (23 girls and 7 boys) selected because they had been without medical therapy for at least 3 months (25 of 30 never treated). To compare height z-scores, we used data from the 27 patients (pre- or postpubertal) selected because they had never received medical or surgical treatment. Ascertainment bias (i.e. referral of girls who were severely affected) was not apparent (observed female/male ratio, 1.64; expected, 2.00; P = 0.29). Parameters of mineral homeostasis did not show statistically significant differences between girls vs. boys, sporadic vs. multigenerational cases (except lower fasting serum phosphate levels in sporadic cases; mean ± SEM, 2.68 ± 0.10 vs. 3.02 ± 0.04 mg/dL; P = 0.049), blacks vs. whites, or for the girls for whom affected fathers vs. mothers transmitted the disorder. Height z-scores correlated with renal phosphate reclamation (i.e. tubular maximum of phosphorus/glomerular filtration rate; r = 0.68; P = 0.014), but were not different for the groupings above. Furthermore, we found no evidence for meiotic drive or for a parental age effect to explain the 18.3% of patients that were new mutations for XLH. Our data fail to show any evidence for genetic heterogeneity or for gender, race, anticipation, or parent of origin effects on XLH expression in children. Despite the recent discovery of a gene (PEX) that is mutated in XLH, the sex-linked dominant phenotype and apparent absence of a gene dose effect in XLH expression in children require explanation.