ビタミンD抵抗性くる病／骨軟化症

Burosumab is effective in improving rickets in children with X-linked hypophosphatemia (XLH). Predictors of health-related quality of life (HRQoL) in pediatric XLH patients treated with burosumab are unknown. In this cross-sectional analysis of a prospective binational observational study, we investigated HRQoL in 64 pediatric XLH patients (36 female) on burosumab treatment, using the KIDSCREEN-52 questionnaire and qualitative interviews. Associations between HRQoL and clinical findings were analysed using multiple regression and receiver operating characteristics (ROC) curve analyses. Median age at investigation and duration of burosumab treatment were 13.1 (IQR 10.4; 14.8) and 2.8 (IQR 1.4; 3.8) years, respectively; 54.7% of patients received secondary burosumab treatment following prior active vitamin D and phosphate. Overall, HRQoL scores were comparable to national reference values. Caregivers rated Physical Well-Being, Moods & Emotions, and Bullying lower than the patients themselves. Burosumab dose was significantly associated with Physical Well-Being, Psychological Well-Being, and Self-Perception in self-report, and with total T-values and Physical Well-Being in proxy questionnaires. The duration of prior treatment with active vitamin D and phosphate was significantly associated with the dimension of Autonomy in self-report and proxy reports. A burosumab dosage above 0.6 mg/kg was associated with a good Physical Well-Being (above the mean of the general population) with a sensitivity and specificity of 75% and 70% in self-report, and 67% and 70% in proxy questionnaires, respectively. In this real-world study, HRQoL in burosumab-treated children with XLH was comparable to that of the general population and associated with burosumab dosage.

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare FGF23-independent renal phosphate-wasting disorder caused by biallelic variants in SLC34A3, typically diagnosed in childhood or early adulthood. Delayed recognition in elderly individuals is uncommon, and the clinical features leading to diagnosis in this population remain poorly characterized. We report a case of a 77-yr-old Japanese man with HHRH who remained undiagnosed until advanced age and was identified following a proximal humeral fracture sustained after a low-energy fall. The severity of the fracture, together with his history of multiple previous fractures, prompted biochemical evaluation for secondary causes of skeletal fragility. Biochemical assessment revealed hypophosphatemia with preserved renal function, elevated 1,25(OH)2D3 levels, hypercalciuria, and reduced renal phosphate reabsorption. Intact FGF23 was mildly above the assay reference limit and was not appropriately suppressed in the setting of hypophosphatemia. BMD was in the osteoporotic range at the FN, but it did not distinguish osteoporosis from an underlying mineralization disorder. Genetic analysis identified a homozygous synonymous variant in SLC34A3 (c.942G > C, p.Ala314=) in the context of a characteristic biochemical phenotype consistent with HHRH. Oral phosphate supplementation alone resulted in rapid normalization of serum phosphate levels, without deterioration in renal function or worsening hypercalciuria. This case suggests that SLC34A3-related phosphate-wasting disorders may remain clinically unrecognized until late adulthood. Importantly, it highlights the value of biochemical evaluation, including the measurement of serum phosphate and the assessment of renal phosphate handling, in patients with otherwise unexplained skeletal fragility. Phosphate-wasting disorders should be considered in patients with recurrent fractures or skeletal fragility that is not fully explained by BMD or the reported injury mechanism.

Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) is a rare metabolic bone disorder caused by biallelic loss-of-function variants in ENPP1, the gene encoding for Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), an enzyme essential for generating extracellular pyrophosphate, a key endogenous inhibitor of ectopic calcification. The clinical spectrum of ENPP1 deficiency varies widely, and recognition in adulthood is challenging due to phenotypic heterogeneity and overlap with more common metabolic bone and parathyroid disorders. We describe two brothers in their late 40s with a novel homozygous ENPP1 splice-site pathogenic variant (c.1437 + 1G > C) presenting with chronic hypophosphatemia, elevated serum PTH, extra-skeletal calcifications, and markedly abnormal bone microarchitecture on high-resolution peripheral quantitative computed tomography (HR-pQCT). Brother 1 exhibited long-standing hypophosphatemia, ossification of the posterior longitudinal ligament, conductive hearing loss, congenital hip dysplasia, and aortic valve calcification. Brother 2 presented with progressive myelopathy and spinal stenosis, and underwent parathyroidectomy for presumed normocalcemic primary hyperparathyroidism. Postoperative hypoparathyroidism led to initiation of calcitriol and calcium supplementation, and subsequent nephrolithiasis. Both patients demonstrated FGF23-mediated renal phosphate wasting, low-normal 1,25-dihydroxyvitamin D, elevated parathyroid hormone and normocalcemia, favored to represent secondary rather than primary hyperparathyroidism, and significant abnormalities in cortical and trabecular bone parameters by HR-pQCT. These cases highlight diagnostic pitfalls in adult-onset ARHR2, including delayed recognition of FGF23-mediated phosphate wasting and misdiagnosis as primary hyperparathyroidism. Accurate genetic diagnosis is essential because ARHR2 clinically mimics X-linked hypophosphatemia, underscoring the need for early recognition to guide safe and effective treatment.

Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) can obscure fibroblast growth factor 23 (FGF23)-mediated hypophosphatemic rickets/osteomalacia. We report two FD/MAS patients with recurrent fractures, hypophosphatemia, elevated FGF23, and serial imaging showing overlooked rachitic changes years before diagnosis. Burosumab improved serum phosphate levels after dose adjustment and was associated with mobility gains in Case 1 and increased growth velocity with physeal normalization in Case 2. Age-appropriate phosphate assessment and FGF23 testing are warranted when orthopaedic findings suggest impaired mineralization.

BACKGROUND: Refractory rickets comprises a heterogeneous group of inherited and acquired disorders characterized by persistent clinical, biochemical, and radiological evidence of rickets despite adequate vitamin D and calcium therapy. Owing to limited data from Eastern India, this study aimed to characterize the etiological spectrum of refractory rickets, compare the clinical, biochemical, and radiological characteristics across different etiologies, and evaluate treatment outcomes following six months of etiology-specific therapy. METHODS: This hospital-based prospective observational cohort study included 32 consecutive children with refractory rickets attending a tertiary pediatric endocrine centre in Eastern India. Demographic, clinical, biochemical, radiological, and genetic data (where available) were collected. Children were classified into distal renal tubular acidosis (DRTA), proximal renal tubular acidosis (PRTA), hypophosphatemic rickets (HPR), and vitamin D-dependent rickets (VDDR). All participants received etiology-specific treatment and were followed for six months. Treatment outcomes included radiological healing, biochemical response, and height gain. RESULTS: DRTA was the commonest etiology (43.8%), followed by HPR (28.1%), VDDR (18.8%), and PRTA (9.4%). Short stature was universal, while failure to thrive (75.0%), delayed motor development (78.1%), and skeletal deformities (93.8%) were common across all groups. Metabolic acidosis was confined to DRTA and PRTA, hyperparathyroidism predominated in VDDR, and reduced tubular maximum reabsorption of phosphate per glomerular filtration rate (TmP/GFR) was significantly associated with HPR and PRTA (all p<0.001). Radiological healing was achieved in all children after six months; however, complete biochemical healing occurred in only 18.8%, while 46.9% had persistent biochemical abnormalities. Median height gain was greatest in DRTA (2.7 cm). Baseline serum alkaline phosphatase (ALP) correlated with six-month ALP (ρ=0.776, p<0.001), and baseline parathyroid hormone independently predicted biochemical response (β=1.276, R²=0.412, p<0.05). CONCLUSIONS: DRTA was the predominant cause of refractory rickets in this cohort. Although clinical manifestations overlapped, characteristic biochemical abnormalities enabled accurate etiological differentiation. Etiology-specific therapy resulted in universal radiological healing but variable biochemical recovery, highlighting the importance of early diagnosis and individualized management.