ビタミンD依存性くる病

Vitamin D-dependent rickets type 1A (VDDR1A) is a rare, inherited form of rickets caused by biallelic mutations in the CYP27B1 gene, leading to 1α-hydroxylase deficiency and impaired 1,25-dihydroxyvitamin D (1,25(OH)₂D) production. We report the case of a 25-year-old woman who was initially diagnosed at 12 months of age with "vitamin D-resistant rickets" and presented with motor delay, skeletal deformities, and a history of multiple orthopedic surgeries. At 25 years of age, etiologic evaluation identified a homozygous CYP27B1 p.Thr325Met variant, classified as likely pathogenic by the testing laboratory but previously reported as a variant of uncertain significance. The condition's rarity and its clinical overlap with more common forms of rickets hindered early diagnosis. Treatment with calcitriol and mineral supplementation was followed by sustained biochemical improvement over approximately one year, although established skeletal deformities persisted. This report underscores the importance of clinical and laboratory recognition, genetic testing, individualized management, and cautious interpretation of rare genetic variants.

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.

BACKGROUND: Molar Incisor Hypomineralisation (MIH) and Hypomineralised Second Primary Molars (HSPM) have been extensively studied; however the specific diagnostic boundaries distinguishing them from other developmental enamel defects remain unclear. OBJECTIVES: This review aims to systematically map the literature describing clinical, radiological, histological or structural features and patient-reported symptoms useful for the differential diagnosis of MIH and HSPM, and additionally to identify knowledge gaps for future research. METHODS: Primary studies addressing the differential diagnosis of developmental defects of enamel published in the period 1985-2025, written in English and involving human subjects were considered for inclusion in this scoping review. PubMed/MEDLINE, EMBASE, Cochrane Library and Scopus were searched. Two reviewers screened retrieved papers independently for eligibility and charted the data. The protocol was registered with the Open Science Framework registration number 10.17605/OSF.IO/P9UKD. RESULTS: A total of 23 reports were included in the review. More than half of the studies were case series (39.1%) and case reports (17.4%), including small samples (in 50.0% of the studies the sample size was fewer than 10 subjects). Amelogenesis Imperfecta (AI) was found in most papers (65.2%); other conditions included dental fluorosis, white spot lesions, and developmental defects associated with cleft lip and palate, antineoplastic therapy, syphilis, Turner syndrome and vitamin D-dependent rickets type 1. No single study directly compared MIH and HSPM with other enamel developmental defects in a controlled manner, representing a major limitation in establishing evidence-based differential diagnostic criteria. CONCLUSIONS: Future studies should include well-designed comparative analyses using standardized diagnostic criteria and objective measures in larger and more diverse patient samples.

BACKGROUND: Vitamin D-dependent rickets Type 1A (VDDR1A) is a rare autosomal recessive disorder caused by pathogenic variants in CYP27B1, resulting in impaired renal 1α-hydroxylation of 25-hydroxyvitamin D. The consequent deficiency of active vitamin D disrupts calcium-phosphate homeostasis and causes rickets. Although VDDR1A is monogenic, clinical severity may vary considerably even among patients with the same mutation. CASE PRESENTATION: We describe two unrelated Saudi boys with genetically confirmed VDDR1A who both harbored the same homozygous CYP27B1 c.1286G > C (p.Arg429Pro) variant but exhibited markedly different clinical courses. The first child presented at 7 months of age with hypocalcemic seizures and classical radiographic features of rickets but preserved growth. Early initiation of alphacalcidol and calcium supplementation was associated with biochemical improvement, resolution of seizures, and favorable clinical recovery by 2.5 years of age. In contrast, the second child was diagnosed at 16 months after developmental delay, recurrent respiratory infections, growth failure, and early skeletal deformities. Long-term follow-up into adolescence revealed severe bowing deformities, kyphoscoliosis, osteopenia, and healed fractures in the setting of delayed diagnosis and inconsistent treatment adherence, despite receiving the same therapy. CONCLUSION: These cases highlight substantial phenotypic variability in VDDR1A even in children harboring the same CYP27B1 mutation. Early recognition and sustained treatment with active vitamin D therapy are crucial to prevent severe skeletal complications and optimize growth, particularly in populations with high rates of consanguinity.

Background and Objectives: Pediatric-onset metabolic bone diseases, including osteogenesis imperfecta (OI), hypophosphatemic rickets (XLH), hypoparathyroidism, and McCune-Albright syndrome (MAS), require lifelong follow-up because of persistent skeletal fragility, biochemical abnormalities, and functional morbidity extending into adulthood. However, evidence regarding structured transition from pediatric to adult care in these rare disorders remains limited. This study evaluated one-year outcomes of a multidisciplinary transition program for adolescents and young adults with rare metabolic bone diseases. Materials and Methods: This retrospective cohort study included 20 patients aged ≥17 years who underwent evaluation through a structured transition pathway consisting of multidisciplinary team meetings, a joint pediatric-adult transition clinic, and subsequent follow-up in adult endocrinology. Demographic, clinical, treatment, and transition-related data were extracted from medical records. The primary outcome was successful transition, defined as at least one adult endocrinology visit within 12 months. Secondary outcomes included attendance at the transition clinic, follow-up continuity, and treatment modifications. Results: All patients underwent multidisciplinary evaluation, and 85% attended the joint transition clinic. Successful transfer to adult endocrinology was achieved in 90% (18/20), while regular follow-up during the first year was maintained in 75%. Retention was highest in patients with OI, MAS, XLH, vitamin D-dependent rickets, and DiGeorge syndrome (100%). Greater variability was observed in postoperative and primary hypoparathyroidism. Treatment adjustments were required in 40% of patients, including optimization of phosphate/calcitriol replacement and reassessment of bisphosphonate or burosumab therapy. Three patients were lost to follow-up. No acute transition-related complications were observed. Conclusions: In this small exploratory cohort, implementation of a structured multidisciplinary transition pathway was feasible and was accompanied by high transfer and one-year retention rates. Observed differences across diagnostic subgroups should be interpreted cautiously, and larger multicenter comparative studies are needed to evaluate the effectiveness of structured transition frameworks.