Outcome of adult patients with X-linked hypophosphatemia caused by PHEX gene mutations

Abstract

X-linked hypophosphatemia (XLH) is the most common monogenic disorder causing hypophosphatemia. This case-note review documents the clinical features and the complications of treatment in 59 adults (19 male, 40 female) with XLH. XLH is associated with a large number of private mutations; 37 different mutations in the PHEX gene were identified in this cohort, 14 of which have not been previously reported. Orthopaedic involvement requiring surgical intervention (osteotomy) was frequent. Joint replacement and decompressive laminectomy were observed in those older than 40 years. Dental disease (63%), nephrocalcinosis (42%), and hearing impairment (14%) were also common. The rarity of the disease and the large number of variants make it difficult to discern specific genotype-phenotype relationships. A new treatment, an anti-FGF23 antibody, that may affect the natural history of the disease is currently being investigated in clinical trials.

Keywords: Dental abcess; Enthesopathy; Nephrocalcinosis; Osteotomy; PHEX; Phosphate regulating endopeptidase homologue; X-linked hypophosphatemia; XLH.

Fig. 1

Orthopaedic complications of XLH. a Standing antero-posterior limb alignment radiograph of a 75 years old female demonstrating bilateral bowed coxa vara deformity of the proximal femur with hip osteoarthritis, femoral shaft bowing, bilateral total knee replacements (solid arrow), tibial shaft plates from osteotomies in adolescence (dashed arrow) and ankle arthritis with loss of joint space. b Antero-posterior pelvic radiograph of a 60 years old female demonstrating left hip osteoarthritis showing loss of joint space and osteophytes (solid arrow) and a right short stem un-cemented total hip replacement (dashed arrow). c-d Antero-posterior radiograph of the right femur of a 33 years old female with a Looser’s zone of the medial cortex of the femoral shaft (solid arrow) treated with a femoral shaft osteotomy (O) and intra-medullary rod fixation to realign the bone shape and aid fracture healing. e Lateral standing ankle radiograph of a 32 years old female showing a prominent posterior/superior corner Haglund’s deformity of the os calcis (dashed arrow) and insertional Achilles’ tendon bony spur enthesophytes (solid arrow)

Fig. 2

Spinal complications of XLH. a MRI lumbar spine showing significant canal stenosis at L4–5 secondary to ossification of the ligamentum flavum. b Post-operative MRI lumbar spine of the same patient showing significant improvement in the dimensions of the canal after lumbar laminectomy

Fig. 3

Dental complications of XLH. a Radiograph of a patient showing taurodont molars. Large pulp chambers are evident with an abscess on the upper right molar and large root canals (green arrows). Multiple teeth have been root filled (red arrow) and crowned (blue arrow). b Patient presenting with recurring abscesses associated with the lower incisor teeth. Note the discolouration (blue arrows) of the lower and upper incisor teeth (the 2 middle teeth). c Intraoral view showing the teeth; this patient had presented with unstable periodontal (gum) disease and caries (decay) which has now been treated and 2 teeth have been lost. d Patient wearing a lower denture (blue arrow) to replace the missing lower left incisors. e-f Dental pantomogram showing root fillings (blue arrow) in the upper right (UR) 2, 1 and upper left (UL) 1 and the lower right (LR) 1, 2 with wide canals and missing lower left (LL) 1, 2. The periapical view of the LR 1, 2 shows the apical infection and the unusual appearance of the bone (red arrow)