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Review
. 2023 Nov;248(22):2175-2182.
doi: 10.1177/15353702231222023. Epub 2024 Jan 17.

X-linked hypophosphatemia, fibroblast growth factor 23 signaling, and craniosynostosis

Chelsey Grimbly  1   2 , Daniel Graf  2   3 , Leanne M Ward  4 , R Todd Alexander  1   2
Affiliations
Review

X-linked hypophosphatemia, fibroblast growth factor 23 signaling, and craniosynostosis

Chelsey Grimbly et al. Exp Biol Med (Maywood). 2023 Nov.

Abstract

This review summarizes the current knowledge of fibroblast growth factor 23 signaling in bone and its role in the disease pathology of X-linked hypophosphatemia. Craniosynostosis is an under-recognized complication of X-linked hypophosphatemia. The clinical implications and potential cellular mechanisms invoked by increased fibroblast growth factor 23 signaling causing craniosynostosis are reviewed. Knowledge gaps are identified and provide direction for future clinical and basic science studies.

Keywords: Rickets; X-linked hypophosphatemia; craniosynostosis; fibroblast growth factor 23; hypophosphatemia; phosphate.

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Conflict of interest statement

Declaration Of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
The impact of PHEX loss of function on bone mineralization. Pathogenic loss of function in PHEX has endocrine and paracrine/autocrine effects. Locally, PHEX loss of function contributes to osteocyte dysfunction, increased minhibins, increased FGFR–FGF23 activity, and decreased tissue non-specific alkaline phosphatase (TNALP) activity. This leads to osteomalacia and osteosclerosis; alterations in signaling of these pathways are hypothesized to cause craniosynostosis and a skeletal dysplasia phenotype (dashed arrow). PHEX loss of function also leads to increased FGF23 and endocrine effects, with subsequent decreased expression of sodium–phosphate cotransporters and decreased production of 1,25 dihydroxyvitamin D. This contributes to hypophosphatemia and rickets and osteomalacia. Together, the paracrine, autocrine, and endocrine effects of PHEX loss of function contribute to the including osteomalacia, leg deformities, bone pain, and impaired growth. FGFR: fibroblast growth factor receptor; FGF23: fibroblast growth factor 23; TNALP: tissue non-specific alkaline phosphatase; XLH: X-linked hypophosphatemia.
Figure 2.
Figure 2.
Craniosynostosis, endocortical scalloping, and Chiari 1 malformation (CM1) in XLH patients. (A/C/E) Normal cranial imaging in a 16-year-old female with XLH. Skull CT demonstrated normal sutures (A) and no endocortical scalloping (C). (E) Brain MRI demonstrated a normal craniocervical junction without a CM1. (B/D/E) Abnormal cranial imaging in individuals with XLH. (B) Sagittal synostosis in a 15-year-old male with XLH. Note the absence of the midline suture (red arrow) with lateral bulging of the skull and shortening of the anteroposterior axis. (D) Head CT in an 11-year-old male with XLH demonstrating endocortical scalloping. Note the ruffled appearance of the interior skull border (red arrows). (F) Brain MRI in a 13-year-old female with XLH and CM1. There is a 7-mm tonsillar ectopia (red arrow) through the foramen magnum (red line). Source: Images were obtained with participant consent, University of Alberta Research Ethics Board # PRO00088137. XLH: X-linked hypophosphatemia; CT: computed tomography; MRI: magnetic resonance imaging.
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