Poorer Growth in XLH Infants Sustained Into Adolescence, Study Says

Children with X-linked hypophosphatemia (XLH) show a diminished growth curve as 1-year-olds relative to healthy toddlers, and their relative rate of growth progressively diminishes through early adolescence, a study reported.

These data provide a reference to evaluate the effectiveness of new interventions targeting growth in children with XLH. 

The study, “Growth Curves for Children with X-linked Hypophosphatemia,” was published in the Journal of Clinical Endocrinology & Metabolism.

XLH is an inherited disorder characterized by loss of phosphate from the kidneys, resulting in low phosphate levels in the blood. This can make bones weak and soft, leading to skeletal deformities.

While impaired growth is a hallmark of XLH, studies that characterize the course of growth over time are limited, particularly when the rate of growth (velocity) slows. 

Scientists at Ultragenyx Pharmaceuticals, along with collaborators at academic institutions across the U.S., constructed growth curves for children based on data from four studies. 

One study, UX023-CL002, investigated the medical records of XLH children. The other three studies were clinical trials assessing the efficacy of Crysvita (burosumab, developed by Kyowa Kirin and Ultragenyx; marketed by Ultragenyx): UX023-CL201 (NCT02163577), UX023-CL205 (NCT02750618), and UX023-CL301 (NCT02915705). 

For this analysis, the clinical trials’ data were collected before Crysvita was used or from participants who had not been treated. Before the trials, all patients had low phosphorus levels and evidence of rickets, the softening and weakening of bones. 

A total of 2,381 height measurements from 228 children (132 girls and 96 boys) were analyzed. Participants’ ages ranged from birth to 14 years. Most (72%) had confirmed PHEX gene mutations — the underlying cause of XLH — while the remaining children had a confirmed family history with mutations and consistent biochemical profiles.

Nearly all children (99%) reported using supplement therapy with oral phosphates and active vitamin D.

Compared to standardized growth curves provided by the Centers for Disease Control and Prevention (CDC), boys with XLH boys had a 46% median height percentile at 3 months of age — meaning they were shorter than most healthy infants of the same age.

At 6 months old, boys with XLH had a median height percentile of 37%; at 9 months, 26%; at 1 year, it was 18%, and at 2 years old, 5%. For girls, the median height percentile was 52% at 3 months, 37% at 6 months, 25% at 9 months, 18% at 1 year, and 7% at 2 years old. 

The annual incremental change in height began to deviate from healthy children at 6 months of age, with significantly different Z-scores — a measure of deviation from standard height — for both boys and girls. 

Increases in height progressively declined during early childhood, with all median height percentiles under 8% between the ages of 2 and 12 years. A similar pattern was found in those approaching 1 year of age. 

The annual height gain for boys with XLH, from birth to age 1, was 21.5 cm (about 8.46 inches), and for girls was 22.5 cm (about 8.86 inches). Notably, in healthy boys and girls , the reference height increase is 25 cm.

This greater annual height gain in healthy children than in those with XLH was seen through childhood and early adolescence.

“In conclusion, children with XLH manifest decreased height velocity by 1 year of age,” the investigators wrote. “Growth curves generated here from children with XLH, nearly all of whom were receiving supplementation therapy, provide an important reference for objective evaluations of new interventions on growth in children/adolescents with XLH.”