Concordant X-linked hypophosphatemic rickets in monozygotic twins: diagnostic challenges and a novel genetic insight.

Abstract

Summary: X-linked hypophosphatemic (XLH) is the most common inherited form of rickets, caused by inactivating mutations in the PHEX gene. Resultant overproduction of fibroblast growth factor 23 (FGF23) leads to renal phosphate wasting, reduced 1,25-dihydroxyvitamin D (1,25(OH)2D) levels, and impaired bone mineralization. We describe 26-year-old male monozygotic twins with lifelong skeletal deformities, short stature, and chronic bone pain. Despite hallmark features of rickets, both were misdiagnosed for decades and developed progressive functional impairment. Biochemical investigations revealed persistent hypophosphatemia, elevated alkaline phosphatase, reduced tubular maximum reabsorption of phosphate per glomerular filtration rate (TmP/GFR), normal calcium and parathyroid hormone, and inappropriately normal 1,25(OH)2D. Radiographs showed pseudofractures, consistent with osteomalacia. The twins were born from a triplet pregnancy; their dizygotic female sibling remained asymptomatic and biochemically normal. Genetic analysis revealed a novel de novo hemizygous deletion in exon 22 of PHEX, confirming the diagnosis of XLH. Both patients initiated conventional therapy with oral phosphate and calcitriol, resulting in notable clinical improvement, including restored ambulation and reduced pain. To our knowledge, this is the first documented case of phenotypically concordant XLH in monozygotic twins caused by a previously unreported PHEX mutation. The presentation underscores the risk of diagnostic delays in XLH, particularly in sporadic cases without family history, and highlights the value of early molecular testing in complex skeletal disorders. Timely recognition and treatment of XLH are essential to prevent irreversible complications and improve long-term outcomes, even when initiated in adulthood.

Learning points: XLH should be considered in patients with skeletal deformities, short stature, and recurrent dental abscesses. Diagnosis is frequently delayed due to variable phenotype and misdiagnosis as nutritional rickets or isolated orthopedic conditions. Biochemical findings of isolated hypophosphatemia with inappropriately normal 1,25(OH)2D levels should prompt evaluation for FGF23-mediated phosphate-wasting conditions. In cases without family history, genetic testing remains essential to confirm XLH and may reveal de novo mutations with clinical and research relevance. Conventional therapy with phosphate and calcitriol may lead to meaningful clinical improvement, including restored mobility, even in adults with long-standing disease. This case contributes to the understanding of genotype-phenotype relationships in XLH, highlighting the potential value of twin studies in elucidating the genetic and non-genetic modifiers of disease expression.