Autosomal dominant hypophosphatemic rickets (ADHR) is a rare metabolic bone disease with variable clinical presentation, caused by pathogenic variants in the FGF23 gene. The disease typically manifests in childhood with growth retardation and rickets symptoms, but may also be diagnosed in adolescence or adulthood with atypical symptoms. We present a 14-year and 5-month-old female patient who presented with bilateral sacral insufficiency fractures following a subtle onset without a history of trauma. Diagnostic tests revealed findings consistent with hypophosphatemic rickets and a de novo heterozygous c.526C>T (p.Arg176Trp) variant in the FGF23 gene, leading to a diagnosis of ADHR. The patient had no significant history of rickets during childhood. She had lived for approximately one year with complaints of progressive pain in the lower lumbar region, which worsened with walking and sitting, without receiving a diagnosis. Bilateral sacroiliac insufficiency fractures and hypophosphatemia were detected, and genetic analysis was performed. The patient underwent bilateral sacroiliac fracture fixation by pediatric orthopedics, and phosphate and active vitamin D (calcitriol) therapy was initiated by pediatric endocrinology. Clinical symptoms improved significantly during follow-up. Due to its genetic and clinical heterogeneity, autosomal dominant hypophosphatemic rickets (ADHR) is a disease that can cause delays in diagnosis. The number of cases reported in the literature associated with this variant is limited, and this is, to the best of our knowledge, the first report of an adolescent with ADHR diagnosed with bilateral sacral insufficiency fractures. This case is important for raising awareness of ADHR and highlighting the broad clinical spectrum of the disease. Sharing the diagnostic and treatment processes will be helpful for clinicians encountering this rare disease.

Autosomal dominant hypophosphatemic rickets (ADHR) is an exceptionally rare condition with fewer than 50 cases reported in the literature Int J Environ Res Public Health 18(16):8771, 2021. We present the cases of two sisters who experienced late-onset ADHR with severe clinical manifestations. Genetic analysis revealed a previously unreported mutation in the FGF-23 gene (chr12:4.370.559 G > T), likely responsible for their condition. These cases highlight the diagnostic challenges, emphasizing the critical need for genetic analysis in all patients suspected of having Tumor-Induced Osteomalacia (TIO) when the tumor remains unidentified, particularly in the presence of iron deficiency anemia.

Autosomal dominant hypophosphatemic rickets (ADHR) is caused by pathogenic variants in the fibroblast growth factor 23 (FGF23) gene, which plays a key role in the regulation of phosphorus metabolism. FGF23 has the RXXR motif recognized by furin, leading to cleavage between R179 and S180 and thereby inactivating the protein's function. Previously reported variants in FGF23 causing ADHR occurred only affecting residues R176 or R179, which are located in the RXXR motif, leading to impaired cleavage. Impairment of protein cleavage increases bioactive FGF23 levels, subsequently resulting in the development of ADHR. A 13-year-old boy with ADHR with the appearance of rickets on bone radiographs as well as documented hypophosphatemia was found to have a novel S180I variant in the FGF23 gene. Unlike previously reported pathogenic variants, this novel variant was located outside the RXXR motif. Subsequently, Western blotting showed that the S180I mutant was resistant to proteolysis than the wildtype, similar to pathogenic variant model mutant (R176Q/R179Q). The novel variant in FGF23 presented herein, found in a patient with ADHR, is the first pathogenic variant found outside the typical furin recognition sequence. It exhibits proteolysis resistance due to impaired cleavage.

Autosomal hypophosphatemic rickets though a rare genetic disorder can lead to significant discomfort to the patient resulting in clinical deterioration and a poor quality of life. We describe a case of a 33-year-old woman G2P1001 at 6 weeks of gestation with complaints of myalgia and bony pains. Keeping her history of bony pains and fractures in mind, she was further evaluated. On evaluation, she was found to have low levels of phosphates 0.99 mg/dl (2.40-4.40) and high levels of fibroblast growth factor 23 (FGF 23) 231.70pg/ml (23.20-95.40). These biochemical parameters were suggestive of hypophosphatemic rickets and further on gene sequencing she was found to have autosomal dominant hypophosphatemic rickets (HR). During her follow-up visits, her checkup and antenatal investigations were normal. Pregnancy acts as a stressor and patients with asymptomatic ADHR may present during pregnancy for the first time with the symptoms of HR. So, a high index of suspicion is required for patients reporting musculoskeletal pains in pregnancy. Early diagnosis can help the mother have a better pregnancy experience. Phosphate and vitamin D supplementation during pregnancy can help these women reduce musculoskeletal pain symptoms. Unfortunately, this patient had a spontaneous abortion in the second trimester. The overall prevalence of ADHR is less than 1 per 1,00,000 live births. Data in pregnancy with ADHR is also minimal due to the condition's rarity. Hence, more and more studies are required in pregnancy with this disease to come to any conclusion and to find any association of ADHR with pregnancy outcomes. Genetic counselling and the need for testing in newborns if symptomatic is also an essential factor to remember when coming across such antenatal patients.