EP289 - ECE_3799 - Recognizing X-linked hypophosphatemia: the role of family screening in patients with short stature

Abstract

X-linked hypophosphatemia (XLH) is a rare inherited disorder caused by pathogenic variants in the PHEX gene. It is characterized by increased fibroblast growth factor 23 (FGF-23) activity, leading to renal phosphate wasting, hypophosphatemia, reduced 1,25(OH)₂ vitamin D synthesis, and impaired bone mineralization. Clinical manifestations include growth failure, skeletal deformities, dental abnormalities, muscle weakness, and chronic pain. Diagnostic delay is frequent, particularly in adults and in patients initially evaluated for isolated short stature. We report three members of the same family diagnosed with XLH, emphasizing the pivotal role of targeted family screening. The diagnostic process was initiated in Case 1, a 43-year-old woman with lifelong disproportionate short stature, who had previously been misdiagnosed with pituitary dwarfism and later achondroplasia. Persistent hypophosphatemia identified during routine evaluation raised the suspicion of XLH. Upon further questioning, the patient reported multiple relatives with short stature. Subsequent construction of a detailed family pedigree revealed a pattern consistent with X-linked dominant inheritance, prompting systematic family screening. Case 2, the nephew of Case 1, had been diagnosed at 2 years of age with familial hypophosphatemic rickets resistant to vitamin D and treated with active vitamin D analogues and phosphate supplementation until the age of 7 years. Case 3, the mother of Case 2, had never undergone endocrinological evaluation despite marked short stature and skeletal deformities. All three patients presented with chronic musculoskeletal pain, disproportionate short stature, waddling gait, genu varum, and poor dentition. Biochemical evaluation demonstrated persistent hypophosphatemia, normal serum calcium, low-normal 1,25(OH)₂ vitamin D levels, elevated or high-normal alkaline phosphatase, increased urinary phosphate excretion, and reduced tubular phosphate reabsorption. Radiological examination revealed pseudofractures in Case 2. Genetic testing confirmed a pathogenic PHEX mutation in all affected family members. Cases 1 and 3 received conventional therapy with active vitamin D analogues and oral phosphate, with limited clinical improvement. Case 2 initiated treatment with burosumab, resulting in normalization of serum phosphate levels and improvement in biochemical parameters, while clinical symptoms improved modestly. This case series demonstrates that recognition of hypophosphatemia in a single patient with short stature should prompt thorough family history assessment, pedigree analysis, and targeted family screening. Early identification of XLH allows timely treatment and may prevent irreversible skeletal complications and long-term impairment in quality of life.