Burden of disease and clinical targets in adult patients with X-linked hypophosphatemia. A comprehensive review

Abstract

X-linked hypophosphataemia (XLH) is a lifelong condition. Despite the mounting clinical evidence highlighting the long-term multi-organ sequelae of chronic phosphate wasting and consequent hypophosphatemia over the lifetime and the morbidities associated with adult age, XLH is still perceived as a paediatric disease.

Introduction: Children who have XLH need to transition from paediatric to adult healthcare as young adults. While there is general agreement that all affected children should be treated (if the administration and tolerability of therapy can be adequately monitored), there is a lack of consensus regarding therapy in adults.

Methods: To provide guidance in both diagnosis and treatment of adult XLH patients and promote better provision of care for this potentially underserved group of patients, we review the available clinical evidence and discuss the current challenges underlying the transition from childhood to adulthood care to develop appropriate management and follow-up patterns in adult XLH patients.

Results and conclusions: Such a multi-systemic lifelong disease would demand that the multidisciplinary approach, successfully experienced in children, could be transitioned to adulthood care with an integration of specialized sub-disciplines to efficiently control musculoskeletal symptoms while optimizing patients' QoL. Overall, it would be desirable that transition to adulthood care could be a responsibility shared by the paediatric and adult XLH teams. Pharmacological management should require an adequate balance between the benefits derived from the treatment itself with complicated and long-term monitoring and the potential risks, as they may differ across age strata.

Keywords: Clinical targets; Phosphate; Transition to adulthood; X-linked hypophosphatemia.

Fig. 1

Algorithm for the diagnosis of an adult with radiological and clinical features suggestive of XLH and presenting with hypophosphatemia. Biochemical work-up should be carried out upon fasting. This algorithm requires prior exclusion of co-morbidities causing hypophosphatemia including sepsis, heart stroke, hepatic coma, myeloma, diabetic ketoacidosis, alcohol abuse, refeeding after prolonged malnutrition, severe respiratory alkalosis, and hyperparathyroidism. Increased renal phosphate secretion may be secondary to PTH-mediated mechanism and in presence of elevated PTH levels, abnormalities in vitamin D metabolism, calcium deficiency, and primary hyperparathyroidism should be excluded. Furthermore, this algorithm requires prior exclusion of co-administration of drugs causing hypophosphatemia including diuretics and antibiotics (that are found to induce hypophosphatemia through impairment of renal phosphate transport), antacids (by reducing intestinal absorption), bisphosphonates (trough secondary hyperparathyroidism), insulin (via shifts of extracellular phosphate into cells), ferric carboxymaltose (by transiently rising the levels of intact FGF23), and canagliflozin (that may induce hypophosphatemia as a result of euglycemic diabetic ketoacidosis). Abbreviations: ADHR, autosomal dominant hypophosphatemic rickets; BALP, bone alkaline phosphatase; ARHR, autosomal recessive hypophosphatemic rickets; Ca, calcium; FEPi, fractional phosphate excretion; GFR, glomerular filtration rate; HHRH, hereditary hypophosphatemic rickets with hypercalciuria; NPHLOP, nephrolithiasis; PTH, parathyroid hormone; TIO, tumour-induced osteomalacia; TmPi, tubular maximal reabsorption of phosphate; XLH, X-linked hypophosphatemia. ARHR encompasses ARHR type 1, type 2, and type 3 (also known as Raine syndrome)