The Diagnosis and Therapy of XLH

Abstract

X-linked hypophosphatemia is a rare genetic disease caused by pathogenic variants in the PHEX (phosphate-regulating endopeptidase homolog X-linked) gene with X-linked dominant inheritance that causes metabolic bone disease and other severe complications. PHEX dysfunction results in increased production and secretion of the phosphaturic hormone fibroblast growth factor 23 (FGF23) from bone. The consequences of FGF23 excess are renal phosphate wasting and decreased calcitriol synthesis, leading to hypophosphatemia and subsequently rickets and osteomalacia. Children with XLH usually become symptomatic in the second year of life presenting with progressive disproportionate short stature, bone pain, frontal bossing, enlarged joints, bowed legs, and a waddling gait. Various other symptoms may develop later, including dental abscesses, peritonitis, hearing loss, pseudofractures, spinal stenosis, osteoarthritis, and enthesopathies, often leading to a diminished quality of life and ultimately disability. Here, we provide an overview of the current knowledge of the pathophysiology and treatment insights of this rare and challenging disease, including the targeting of FGF23 as a therapeutic approach that has significantly improved patient outcomes.

Keywords: Burosumab; FGF23; Osteomalacia; Phosphate; Rickets; XLH.

Fig. 1

Radiographs of the lower extremities of children with X-linked hypophosphatemia. The patients show disproportionate short stature with genu varum (bowed legs). 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. Reproduced with permission from ref. [9]

Fig. 2

Oral manifestations of X-linked hypophosphatemia. A Oral clinical view of a 5-year-old male patient with XLH showing a spontaneous dental abscess on the right upper temporary central incisor. The tooth shows no discoloration or carious lesion and the child and his mother reported no history of trauma. B Maxillo-facial cellulitis due to spontaneous necrosis of the left upper temporary canine in the same patient at the age of 7 years. C Panoramic radiograph of the same patient at the age of 8 years showing mixed dentition with characteristic dental features of XLH, including a normal (slightly thin) enamel layer, a radiolucent dentin layer with enlarged pulp chambers and prominent pulp horns on both temporary and permanent teeth. D. Oral clinical view of a 49-year-old woman with XLH who was diagnosed at the age of 4 years. The patient was treated with oral phosphate supplements and active vitamin D during growth for 12 years before the treatment was stopped at the age of 16 years. This treatment was resumed for 4 years from the age of 40 years before being replaced with burosumab, which had been taken for 5 years. E. Panoramic radiograph of the same patient showing generalized horizontal alveolar bone loss and teeth treated endodontically due to dental infections. Reproduced with permission from ref. [9]

Fig. 3

Algorithm for the diagnosis of X-linked hypophosphatemia (XLH). Patients usually present with rickets or osteomalacia and concomitant hypophosphatemia. The differential diagnosis is based on the mechanisms leading to hypophosphatemia, namely, high parathyroid hormone (PTH) activity (leading to calcipenic rickets or osteomalacia), and inadequate phosphate absorption from the gut or renal phosphate wasting (leading to phosphopenic rickets or osteomalacia). A family history of X-linked inheritance with full penetrance in female carriers strongly supports the diagnosis of XLH, which can be confirmed by genetic testing. FGF23, fibroblast growth factor 23; LMW, low molecular weight. Reproduced with permission from ref. [9]