Refractory Rickets: Evaluation and Management.

Refractory rickets refers to a set of diseases which are identified by a lack of response to therapeutic doses used to treat vitamin D deficiency. A child presenting with refractory rickets can pose a diagnostic dilemma as many kidney diseases have been identified as possible causes. Inherited (e.g., distal renal tubular acidosis, Fanconi syndrome, hypophosphatemic rickets, vitamin D-dependent rickets, nephronophthisis) and acquired tubular disorders [e.g., posterior urethral valves, reflux nephropathy leading to chronic kidney disease (CKD)-mineral bone disorder] may be complicated by refractory rickets. Rarely, chronic liver disease and malabsorption states can also result in refractory rickets. Hypophosphatemia is a feature of both calcipenic as well as phosphopenic rickets. Common features accompanying refractory rickets include polyuria, polydipsia, hypokalemic paralysis, fractures, limb deformities, failure-to-thrive, short-stature, tetany and nephrocalcinosis. A careful history, examination and biochemical evaluation is required to delineate the underlying cause. Using a rational algorithmic approach, it is possible to determine the correct diagnosis in these cases. Consequent upon easy availability of next generation sequencing (NGS), the accurate diagnoses can be promptly made aiding in targeted therapy. Children with refractory rickets need regular follow-up to optimise the biochemical abnormalities, monitor growth and retard the progression of CKD. This article describes the evaluation of a child with refractory rickets using an algorithmic approach, underscores the importance of the necessary blood and urine biochemical tests as well as NGS for identification of the precise etiology of refractory-rickets; and discusses the pathophysiology and management of the most important causes of refractory-rickets.