Evaluation of dental manifestations in X-linked hypophosphatemia using orthopantomography.

BACKGROUND: X-linked hypophosphatemia (XLH) is the most common inherited form of rickets. The presence of sequence variations in the phosphate regulating endopeptidase homolog X-linked (PHEX) gene is associated with increased production of fibroblast growth factor 23 (FGF23). This results in renal phosphate wasting and impaired skeletal mineralization. Spontaneous dental abscesses, caused by endodontic infections resulting from hypomineralization of dentin, are a known dental complication of XLH. There is no objective method to evaluate the severity of dentin dysplasia. The purpose of this study was to develop a quantitative method to evaluate dentin dysplasia using orthopantomography that would allow the values in patients with XLH to be compared with the values in healthy participants of the same age. METHODS: The severity of dentin dysplasia was analyzed by measuring the pulp cavity area of the tooth using orthopantomographic images. The teeth analyzed were mandibular second primary molars and mandibular first permanent molars with complete root formation. Teeth with dental caries, restorations, or root resorption were excluded. RESULTS: This retrospective observational study included a total of 200 images of healthy participants (aged 2-15 years) divided into five age groups and 42 images of 17 patients with XLH. There was a significant tendency for the pulp cavity area to decrease with increasing age in primary and permanent teeth. The pulp chambers of patients with XLH were larger than those of healthy participants in primary and permanent teeth. CONCLUSION: We have established a method of using orthopantomography for quantitative assessment of dentin dysplasia in XLH from the primary dentition to the permanent dentition. Evaluating the severity of dentin hypomineralization by this method is useful in the diagnosis of the dental manifestations of XLH. Early diagnosis of XLH enables oral management and leads to prevention of dental abscesses.

Evaluation of bone density and microarchitecture in adult patients with X-linked hypophosphatemic rickets: A pilot longitudinal study.

X-linked Hypophosphatemia (XLH) is the most common type of inherited rickets. Although the clinical features are well characterized, bone structure, mineralization, and biomechanical properties are poorly known. Our aim was to analyze bone properties in the appendicular and axial skeleton of adults with XLH. In this observational case-control study, each affected patient (N = 14; 9 females; age 50 ± 15 years) was matched by sex, age and body mass index to a minimum of two healthy controls (N = 34). Dual-energy X-ray Absorptiometry (DXA) analyses revealed that areal bone mineral density (aBMD) was higher in XLH patients at the lumbar spine (Z score mean difference = +2.47 SD, P value = 1.4 × 10-3). Trabecular Bone Score was also higher at the lumbar spine (P value = 1.0 × 10-4). High Resolution peripheral Quantitative Computed Tomography (HRpQCT) demonstrated that bone cross-sectional area was larger at the distal radius (P value = 6 × 10-3). Total and trabecular volumetric BMD were lower at both sites. Trabecular bone volume fraction was also lower with fewer trabecular numbers at both sites. However, bone strength evaluated by micro-finite element analyzes revealed unaffected bone stiffness and maximum failure load. Evaluation of bone mineralization with aBMD by DXA at the distal radius correlated with vBMD by HRpQCT measurements at both sites. PTH levels were inversely correlated with trabecular vBMD and BV/TV at the tibia. We then followed a subset of nine patients (median follow-up of 4 years) and reassessed HRpQCT. At the tibia, we observed a greater decrease than expected from an age and sex standardized normal population in total and cortical vBMD as well as a trabecularization of the cortical compartment. In conclusion, in adult patients with XLH, bone mineral density is high at the axial skeleton but low at the appendicular skeleton. With time, microarchitectural alterations worsen. We propose that noninvasive evaluation methods of bone mineralization such as DXA including the radius should be part of the management of XLH patients. Larger studies are needed to evaluate the clinical significance of BMD changes in XLH patients under conventional or targeted therapies.

Hypophosphatemic rickets and short stature.

An 18-month-old male presented with gross motor delay and poor growth (weight z-score -2.21, length z-score -4.26). Radiographs showed metaphyseal irregularities suggesting metaphyseal dysplasia and sagittal craniosynostosis. Biochemical evaluation supported hypophosphatemic rickets [serum phosphorus 2.3 mg/dL (reference range (RR) 4.3-6.8), alkaline phosphatase 754 unit/L (RR 156-369)] due to renal phosphate wasting (TmP/GFR 4.3 mg/dL, normal for age 4.3-6.8), with C-terminal fibroblast growth factor 23 (FGF23) 125 RU/mL (>90 during hypophosphatemia suggests FGF23-mediated hypophosphatemia). Treatment was initiated with calcitriol and phosphate. Genetic analysis showed a pathogenic variant of FGF23: c.527G > A (p.Arg176Gln) indicative of autosomal dominant hypophosphatemic rickets (ADHR). Consistent with reports linking iron deficiency with the ADHR phenotype, low ferritin was detected. Following normalization of ferritin level (41 ng/mL) with oral ferrous sulfate replacement, biochemical improvement was demonstrated (FGF23 69 RU/mL, phosphorus 5.0 mg/dL and alkaline phosphatase 228 unit/L). Calcitriol and phosphate were discontinued. Three years later, the patient demonstrated improved developmental milestones, linear growth (length Z-score -2.01), radiographic normalization of metaphyses, and stabilization of craniosynostosis. While the most common cause of hypophosphatemic rickets is X-linked hypophosphatemia, other etiologies should be considered as treatment differs. In ADHR, normalization of iron leads to biochemical and clinical improvement.