X-linked hypophosphatemic rickets: a study (with literature review) of linear growth response to calcitriol and phosphate therapy.

Not all children with X-linked hypophosphatemia (XLH) have demonstrated improved linear growth with calcitriol [1,25-(OH)2D3] and inorganic phosphate (Pi) therapy. To assess which factors are associated with a favorable growth response during this treatment, we retrospectively compared demographics and biochemical parameters of bone metabolism to the linear growth patterns of 20 children with XLH who were prepubertal and had not required osteotomy. A total of 15 patients had family histories consistent with XLH; 5 appeared to be sporadic cases. During 3 years of therapy, the growth velocities of 12 patients had been at or above the mean for age (good growers) and those of 8 patients had been below the mean (poor growers). Data from the two groups were contrasted. We found no difference between the good growers and poor growers before or after the 3 year period of therapy in mean age, dietary calcium, calcitriol dose or compliance, or Pi dose or compliance. Both groups increased their mean fasting serum Pi levels with treatment. The TmP/GFR (mean +/- SEM) of the good growers improved with therapy (1.9 +/- 0.2 to 2.6 +/- 0.2 mg/dl, p = 0.01), and their posttreatment value was higher compared to that of the poor growers (2.6 +/- 0.1 versus 2.2 +/- 0.1 mg/dl, p = 0.02). However, their enhanced TmP/GFR was not associated with a reduction in serum iPTH levels (before, 693 +/- 50; after, 688 +/- 76 pg/ml; p = 0.9). The Z test for binomial proportions showed that the group that grew well contained a disproportionate number of girls (10 of 12, p = 0.04). Our findings suggest that calcitriol may exert a direct effect on the renal tubule to improve Pi reclamation in XLH. The observation that heterozygous girls appear to respond better than hemizygous boys to calcitriol and Pi therapy provides evidence for a gene dosage effect in the expression of this X-linked dominant disorder.

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.

Significant developmental elevation in serum parathyroid hormone levels in a large kindred with familial benign (hypocalciuric) hypercalcemia.

PURPOSE: A large kindred with familial benign hypercalcemia (FBH) is described because of the new observation of developmental increases in serum immunoreactive parathyroid hormone (iPTH) levels in affected individuals that lead to significantly elevated values in adults. PATIENTS AND METHODS: After identification of the proposita, 46 kindred members spanning 5 generations, ages 1.5 to 91 years, were surveyed biochemically and/or studied by chart review. Two hypercalcemic adults underwent biopsy of the iliac crest following tetracycline labeling for histomorphometric study. RESULTS: Of the 46 individuals studied, 19 were found to be affected. Serum iPTH levels, determined in three separate immunoassays, became supranormal by about age 30 years in the group of 15 hypercalcemic subjects examined biochemically and appeared to increase further thereafter. Serum alkaline phosphatase activity and creatinine levels were normal in these individuals, but inorganic phosphate levels were lower than in unaffected kindred members. Three of five affected adults older than age 40 years who were studied radiographically had changes suggestive of osteomalacia. Biopsy of the iliac crest of one of the subjects, a 51-year-old woman, confirmed the presence of defective skeletal mineralization. CONCLUSIONS: In this kindred, FBH in adults can be especially difficult to distinguish from primary hyperparathyroidism because serum iPTH levels may be elevated. Furthermore, the disorder may not be totally benign. Osteomalacia, perhaps due to mild hypophosphatemia, can develop during adulthood. Review of data from other kindreds for evidence of developmental elevations in serum iPTH levels with careful search for skeletal disease in late adult life will help to clarify if we have observed an unusual variant of FBH.

Hypercalciuria in children severely affected with osteogenesis imperfecta.

To investigate our impression that hypercalciuria is relatively common in children with osteogenesis imperfecta, we performed a retrospective study of data accumulated from our pediatric population with this skeletal disorder. Children with osteogenesis imperfecta (17 girls, 30 boys; mean (+/- SD) age 7.8 +/- 4.6 years; range 0.7 to 16.8 years) had undergone detailed inpatient evaluation of mineral homeostasis during periods of clinical stability and controlled dietary calcium intake. Hypercalciuria was found in 36% of the patients and averaged (+/- SEM) 6.1 +/- 0.3 mg/kg per 24 hours (0.15 +/- 0.01 mmol/kg per 24 hours) or 392 +/- 28 mg/gm of creatinine (1.10 +/- 0.07 mmol calcium/mmol creatinine) in the group with hypercalciuria. There were no statistically significant differences in age, gender, or dietary calcium intake (per kilogram of body weight) between the normocalciuric and hypercalciuric children. However, the group with hypercalciuria was shorter than the normocalciuric group and had a greater lifelong fracture rate. When patient height z scores were regressed against urinary calcium levels, a significant negative correlation was found in the group with hypercalciuria (r = -0.76; p less than 0.001). Although serum alkaline phosphatase activity was lower in the group with hypercalciuria, no difference was found between groups with regard to serum levels of calcium, phosphate, magnesium, creatinine, immunoreactive parathyroid hormone, or osteocalcin. The groups were also similar with respect to both their total body mineral density, as determined by dual-photon absorptiometry (n = 17), and their static indexes of bone formation and resorption, as assessed histomorphometrically with iliac crest specimens (n = 19). We conclude that hypercalciuria occurs frequently in children with osteogenesis imperfecta, and that its magnitude appears to reflect the severity of the skeletal disease.