ビタミンD抵抗性くる病／骨軟化症

Burosumab is a monoclonal antibody targeting fibroblast growth factor 23 (FGF23) and is approved for the treatment of X-linked hypophosphatemia. Its use during pregnancy has not been studied, and fetal exposure may affect neonatal mineral metabolism. We report a neonate exposed to Burosumab throughout gestation who developed prolonged phosphate retention, suppressed parathyroid hormone, and transient hypercalcemia after birth. Serial biochemical monitoring demonstrated persistently elevated tubular phosphate reabsorption and low urinary phosphate excretion beyond the early neonatal period, consistent with sustained pharmacodynamic effects of FGF23 inhibition. These abnormalities gradually resolved over time, and the infant remained clinically well with normal growth and no evidence of nephrocalcinosis. Genetic testing excluded the familial pathogenic PHEX variant, confirming that the observed phenotype was due to transient pharmacologic exposure rather than intrinsic disease. This case demonstrates that antenatal Burosumab exposure can result in prolonged postnatal alterations in calcium-phosphate homeostasis. Careful biochemical monitoring is warranted in exposed infants, and continuation of Burosumab beyond mid-pregnancy should be approached with caution.

Vitamin D is essential for calcium and phosphate homeostasis and skeletal development. Variants in the vitamin D receptor gene (VDR) cause vitamin D-dependent rickets type 2A (VDDR2A), characterized by end-organ resistance to 1,25-dihydroxyvitamin D (1,25(OH)2D). We describe a child of nonconsanguineous Middle Eastern parents who presented at age 9 months with poor linear growth and inadequate weight gain. Initial evaluation showed normocalcemia, hypophosphatemia, hyperparathyroidism, markedly elevated alkaline phosphatase, and radiographic rickets, leading to an initial diagnosis of hypophosphatemic rickets. Despite treatment with low-dose calcitriol, cholecalciferol, calcium, phosphate, and bicarbonate, biochemical abnormalities persisted. Further evaluation revealed markedly elevated 1,25(OH)2D, and whole-exome sequencing identified a homozygous pathogenic VDR c.1027C>T (p.R343C) variant, confirming VDDR2A. High-dose calcitriol therapy resulted in progressive biochemical improvement and catch-up growth. This case highlights that VDDR2A may initially present with hypophosphatemia without hypocalcemia, leading to misclassification as hypophosphatemic rickets. Early recognition of elevated 1,25(OH)2D and timely genetic testing are essential for accurate diagnosis and management.

X-linked hypophosphatemia (XLH) is a rare genetic rachitic/osteomalacic and dental disorder caused by pathogenic variants in PHEX gene resulting in fibroblast growth factor 23 (FGF23) excess leading to hypophosphatemia by renal phosphate wasting and decreased 1,25-dihydroxyvitamin D production. The aim of the study was to provide insight into natural history and phenotype in untreated adults with XLH (no phosphate supplements and active vitamin D metabolites or burosumab). Clinical, biochemical, skeletal features, co-morbidities, and patient-reported outcomes (PROs) were examined in 52 patients (51.5 ± 12.2 years; 18 men and 34 women). Mean height Z-score and mean leg length Z-score were lower than normal (P < 0.0001) and were lower (P < 0.01) in men (-3.8 ± 1.2 and -4.2 ± 1.2, respectively) than in women (-2.9 ± 0.8 and -3.4 ± 0.9, respectively). BMI was in the range of overweight in 30 patients (57.7%) and in the range of obesity in 15 patients (28.8%). Most of patients had severe skeletal deformities and dental-periodontal abnormalities. Pseudofractures were documented in 17 patients (33%). Mean concentration of intact FGF23, osteocalcin, PINP, CTX, and BALP was higher in men compared to women (P < 0.05-P < 0.001). PROs ranged from moderate to severe scores, with no difference (P = NS) between sexes. The phenotype in adult individuals with XLH was characterized by severe and disproportionate short stature, overweight/obesity, severe skeletal deformities with difficulty walking, osteoarticular pain, poor dental health, and reduced quality of life. Stature and biochemical markers of bone turnover were more compromised in men than in women.

Hereditary hypophosphatemic rickets/osteomalacia encompasses a group of disorders characterized by impaired bone mineralization resulting from phosphate deficiency, which can lead to skeletal deformities and growth retardation when onset occurs in early childhood. A patient with autosomal recessive hypophosphatemic rickets type 1 (ARHR1) caused by a mutation in the dentin matrix protein 1 (DMP1) gene was admitted to the Department of Endocrinology at the First Medical Center of Chinese PLA General Hospital in December 2024. The patient presented with frontal bossing, short stature, lower limb deformities, and generalized bone pain. Laboratory evaluation revealed hypophosphatemia, hyperphosphaturia, a decreased phosphate clearance index, elevated serum alkaline phosphatase, increased fibroblast growth factor 23, slightly reduced 25-hydroxyvitamin D, and normal serum calcium and parathyroid hormone levels. Genetic testing confirmed the presence of a homozygous mutation in the DMP1 gene. Literature retrieval indicated that more than 10 distinct mutations in this gene have been reported in approximately 30 patients worldwide. Most of these documented mutations are located within exon 6, likely because this region harbors up to 80% of the total coding sequence. However, whole-exome sequencing identified a novel homozygous variant c.457C>T (p.Gln153*) in exon 3 in this patient, as confirmed by database and literature review. ARHR1 remains an extremely rare disease, and hereditary genetic testing plays a vital role in establishing a definitive diagnosis.

PURPOSE OF REVIEW: Conditions resulting in elevated fibroblast growth factor 23 (FGF23) cause hypophosphatemic rickets and osteomalacia. The most common of these is X-linked hypophosphatemia. In this review we will broadly discuss the other less common and clinically distinct forms of renal hypophosphatemia, with a focus on the autosomal dominant and autosomal recessive types. RECENT FINDINGS: Variants in multiple genes cause dominant (FGF23, SGK3, FGFR1), recessive (DMP1, ENPP1, FAM20C, INPPL1) or even somatic (NRAS, HRAS, GNAS, gene fusions) conditions of FGF23 excess, with important phenotypic differences. For example, in autosomal dominant hypophosphatemic rickets due to FGF23 variants, iron deficiency drives the phenotype, while ENPP1 variants cause phenotypes ranging from severe neonatal vascular calcifications to rickets or osteoporosis. Other gene abnormalities cause FGF23-independent hypophosphatemia, often involving kidney disease. Recognizing the different mechanisms and phenotypes of hypophosphatemic conditions is critical to prognosis, management and to developing more effective therapies.