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Review
. 2021 Aug 6:12:688309.
doi: 10.3389/fendo.2021.688309. eCollection 2021.

X-Linked Hypophosphatemic Rickets: Multisystemic Disorder in Children Requiring Multidisciplinary Management

Giampiero Igli Baroncelli  1 , Stefano Mora  2
Affiliations
Review

X-Linked Hypophosphatemic Rickets: Multisystemic Disorder in Children Requiring Multidisciplinary Management

Giampiero Igli Baroncelli et al. Front Endocrinol (Lausanne). .

Abstract

X-linked hypophosphatemic rickets (XLH) is the commonest inherited form of rickets. It is caused by an impaired regulation of fibroblast growth factor 23 (FGF23) due to a PHEX gene mutation, which leads to reduced tubular reabsorption of phosphate and renal 1α-hydroxylase activity and increased renal 24-hydroxylase activity. Hypophosphatemia associated with renal phosphate wasting, normal serum levels of calcium, parathyroid hormone, and 25-hydroxyvitamin D represents the main biochemical sign in affected patients. Patients with XLH show rickets and osteomalacia, severe deformities of the lower limbs, bone and muscular pain, stunted growth, and reduced quality of life. However, XLH is a multisystemic disorder requiring multidisciplinary approaches in specialized subdisciplines. Severe complications may occur in patients with XLH including craniosynostosis, hearing loss, progressive bone deformities, dental and periodontal recurrent lesions, and psychosocial distress. Moreover, long-term conventional treatment with active vitamin D metabolites and oral inorganic phosphate salts may cause endocrinological complications such as secondary or tertiary hyperparathyroidism, and adverse events in kidney as hypercalciuria, nephrocalcinosis, and nephrolithiasis. However, conventional treatment does not improve phosphate metabolism and it shows poor and slow effects in improving rickets lesions and linear growth. Recently, some trials of treatment with recombinant human IgG1 monoclonal antibody that targets FGF23 (burosumab) showed significant improvement of serum phosphate concentration and renal tubular reabsorption of phosphate that were associated with a rapid healing of radiologic signs of rickets, reduced muscular and osteoarticular pain, and improved physical function, being more effective for the treatment of patients with XLH in comparison with conventional therapy. Therefore, a global management of patients with XLH is strongly recommended and patients should be seen regularly by a multidisciplinary team of experts.

Keywords: X-linked hypophosphatemic rickets; burosumab; complication; conventional treatment; management.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Severe genu-varum in a 3.2-year-old female patient with XLH at diagnosis with disproportionate short stature.
Figure 2
Figure 2
Spontaneous gingival fistulae (black arrow) corresponding to deciduous left maxillary canine and deciduous right maxillary lateral incisor in a 4.3-year-old male patient with XLH.
Figure 3
Figure 3
(A) X-ray features of the wrist in a 3-month-old male patient affected by XLH at diagnosis: widening and fraying of the epiphyseal plate (white arrow) and metaphyseal concavity of the ulna (black arrow). (B) X-ray features of the lower limbs in a 2.5-year-old female patient with XLH at diagnosis: genu-varum and distal medial femoral and tibial bowing with widening and fraying of the distal epiphyseal plate of the femur (red arrow) and the proximal medial epiphyseal plate of the tibia (yellow arrow). Metaphyseal concavity of the proximal and distal fibula (green arrow) and metaphyseal concavity of the distal epiphyseal plate of the tibia (light blue arrow).
Figure 4
Figure 4
(A) 3D-reformatted axial computed tomography scan showing fusion of the sagittal suture and classic scaphocephalic head shape in a 3.2-year-old male patient with XLH. Frontal (white arrow) and occipital (red arrow) bossing with open coronal (black arrow) and lambdoid (blue arrow) sutures is also evident. (B) 3D-reformatted axial computed tomography scan showing the neurosurgical correction of scaphocephaly in a 8-month-old male patient with XLH.
Figure 5
Figure 5
Midsagittal magnetic resonance image of the head in an 11.5-year-old male patient with XLH showing caudal descent of the cerebellar tonsils through the foramen magnum (Arnold-Chiari 1 malformation) (white arrow). He reported transient headache. Scaphocephaly was also evident.
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