Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia

Abstract

X-linked hypophosphataemia (XLH) is the most common cause of inherited phosphate wasting and is associated with severe complications such as rickets, lower limb deformities, pain, poor mineralization of the teeth and disproportionate short stature in children as well as hyperparathyroidism, osteomalacia, enthesopathies, osteoarthritis and pseudofractures in adults. The characteristics and severity of XLH vary between patients. Because of its rarity, the diagnosis and specific treatment of XLH are frequently delayed, which has a detrimental effect on patient outcomes. In this Evidence-Based Guideline, we recommend that the diagnosis of XLH is based on signs of rickets and/or osteomalacia in association with hypophosphataemia and renal phosphate wasting in the absence of vitamin D or calcium deficiency. Whenever possible, the diagnosis should be confirmed by molecular genetic analysis or measurement of levels of fibroblast growth factor 23 (FGF23) before treatment. Owing to the multisystemic nature of the disease, patients should be seen regularly by multidisciplinary teams organized by a metabolic bone disease expert. In this article, we summarize the current evidence and provide recommendations on features of the disease, including new treatment modalities, to improve knowledge and provide guidance for diagnosis and multidisciplinary care.

Fig. 1. Determining levels of evidence and strength of recommendations (American Academy of Pediatrics grading matrix).

Reproduced with permission from ref.: Pediatrics 140, e20171904 Copyright © 2017 by the AAP.

Fig. 2. Radiographs of the lower extremities of children affected with X-linked hypophosphataemia.

The patients show disproportionate short stature with genu varum (bowed legs). The final panel on the right shows a patient with a windswept deformity (characterized by a valgus deformity in one knee in association with a varus deformity in the other knee). The radiographs reveal severe leg bowing, partial fraying and irregularity of the distal femoral and proximal tibial growth plates. Note the lack of bone resorption features.

Fig. 3. Algorithm for the evaluation of a child with rickets presenting with hypophosphataemia.

The differential diagnoses are based on the mechanisms leading to hypophosphataemia — namely, high parathyroid hormone (PTH) activity, inadequate phosphate absorption from the gut or renal phosphate wasting. The latter may be due to either primary tubular defects or high levels of circulating fibroblast growth factor 23 (FGF23). Further details of individual entities can be found in Table 2. XLH, X-linked hypophosphataemia. Adapted with permission from ref., Springer Nature Limited (this material is excluded from the CC-BY-4.0 license).