Jill Simmons, MD, highlights the need to recognize XLH early in pediatric practice

Early recognition of X-linked hypophosphatemia (XLH) remains a critical challenge in general pediatric practice, where subtle growth abnormalities and lower extremity bowing may initially be mistaken for normal developmental variation. Delays in diagnosis can contribute to progressive skeletal deformities, impaired growth, chronic pain, and the need for surgical intervention.

In this discussion, Jill H. Simmons, MD, outlines the early clinical signs that should raise suspicion for XLH, explores common reasons for missed or late diagnosis, and explains how advances in disease-specific therapy have transformed outcomes for affected children. She also highlights the importance of timely referral, comprehensive monitoring, and longitudinal psychosocial support to optimize both medical and quality-of-life outcomes for patients and their families.

Contemporary Pediatrics:

In general pediatric practice, what early signs or growth patterns should prompt clinicians to consider X-linked hypophosphatemia in the differential diagnosis?

Jill H. Simmons, MD:

Patients with XLH often develop lower extremity bowing (genu varum) that may become apparent prior to age 6 months, but this more commonly becomes clear once patients begin to bear weight. Patients may also have craniosynostosis. In older children, short stature is also typical of this disorder. In addition, patients may have dental abnormalities, including dental abscesses.

Contemporary Pediatrics:

Many rare diseases face delayed diagnosis. From your perspective, what contributes most to missed or late recognition of XLH in children, even among experienced clinicians?

Simmons:

The most common delay is the assumption that lower extremity bowing (genu varum) is the physiologic bowing that we sometimes see in toddlers, and that patients will simply grow out of it. It can be particularly helpful to obtain lower extremity radiographs in young patients with genu varum, particularly if it continues at >18 months of age, as rachitic findings will likely be noted on these films. Then, blood and urine evaluation can help to determine the etiology of the rachitic changes.

If there is a family history of XLH, the diagnosis is less likely to be missed, but it is critical for pediatricians to realize that approximately one-third of patients with XLH have a de novo variant and are therefore the first one in the family to be affected. Even without a family history, patients can certainly be affected with this disorder. However, studies have demonstrated that there remains a delay in diagnosis in many patients even with a known family history of XLH.

Contemporary Pediatrics:

How can earlier identification and referral meaningfully alter skeletal outcomes, growth trajectories, and long-term morbidity in pediatric patients with XLH?

Simmons:

Patients with XLH require treatment, as the significant phosphate loss from the renal tubules leads to impaired mineralization/ rickets/ osteomalacia. These bone mineralization defects cause the genu varum noted during physical examination as well as on skeletal radiographs. Prolonged phosphate deficiency therefore leads to lower limb deformation that causes abnormal gait, pain, and sometimes limited ambulation. Historically, many pediatric patients with XLH required surgical procedures due to these findings. However, it is now recognized that early therapy can significantly improve lower extremity deformities, often eliminating the need for surgery, and can also improve growth, decrease pain, and improve health-related quality of life. Treatment by age 6 months is ideal for optimal outcomes, so early identification is critical.

Contemporary Pediatrics:

Treatment options for XLH have evolved in recent years. How have these advances changed management strategies for pediatric patients, and what should general pediatricians understand about ongoing care and monitoring?

Simmons:

Prior to 2018, treatment for XLH required oral phosphate supplementation 3 to 5 times daily, as well as activated vitamin D (1, 25 OH vitamin D) 1 to 2 times daily. This was challenging from a compliance standpoint, due to gastrointestinal side effects as well as frequency of dosing. In addition, this therapy rarely led to fully healed rickets, and patients frequently required surgical procedures (osteotomies, for example). In addition, this therapy was associated with secondary hyperparathyroidism as well as renal nephrocalcinosis.

Since 2018, a monoclonal antibody to FGF-23 (burosumab) has been available to patients in the United States with XLH, and this has resulted in improved outcomes and decreased severity of disease manifestations. This is the first disease-specific therapy approved by the FDA. The medication is given at home as a subcutaneous injection every 2 weeks. Oral supplementation with activated vitamin D and phosphorus is no longer required while on burosumab. Patients on burosumab have been demonstrated to have healed rickets, decreased lower limb deformities and pain, and improved growth and health-related quality of life. However, they continue to require frequent evaluation, including serum and urine evaluations, as well as periodic radiographs and renal ultrasounds.

Contemporary Pediatrics

Beyond the metabolic and orthopedic manifestations, what psychosocial challenges do children with XLH and their families commonly face, and how can pediatricians provide more comprehensive, longitudinal support?

Simmons:

There continues to be a lack of subspecialists who are knowledgeable about XLH, particularly for patients who live in rural areas. A recent patient survey identified that patients with XLH often have difficulty finding providers who are knowledgeable about their disease, and even for those who have providers available, they often have to travel significant distances for medical care. Costs are also significant for these patients and their families, as patients have associated dental problems, travel costs, medical and surgical costs, and sometimes even requirements for home modifications.