An Unusual Case of Rickets and How Whole Exome Sequencing Helped to Correct a Diagnosis

ABSTRACT Objective: Rickets can be caused by a wide variety of underlying nutritional deficiencies or genetic defects. There is significant overlap in the clinical presentations of the various forms of rickets and the risk for misdiagnosis is great. This report describes a diagnostically challenging case of rickets that highlights important differences between two forms of rickets and demonstrates how gene sequencing technology can be instrumental in the identification and further characterization of these diseases. Methods: A patient diagnosed with X-linked hypophosphatemia (XLH) as a toddler did not develop many of the classic clinical features of this disease over time, calling the diagnosis into question. Whole exome sequencing (WES) was performed in this setting to determine the genetic basis of disease. Results: WES revealed that the patient did not have any mutations associated with XLH and instead was a compound heterozygote for 2 frameshift mutations in CYP27B1, leading to a revised diagnosis of 1α-hydroxylase deficiency. One of these two mutations in CYP27B1, an adenosine deletion in exon 7, has not previously been described. Conclusion: Clinical suspicion was aided by modern technology in correcting a decades-old mistaken diagnosis in this patient. This case highlights the potential of next-generation sequencing technology as an aide in establishing the correct diagnosis and management of complex diseases. Abbreviations: 1,25(OH)2D = 1,25-dihydroxyvitamin D3; FGF23 = fibroblast growth factor 23; PTH = parathyroid hormone; WES = whole exome sequencing; XLH = X-linked hypophosphatemia