Congenital Conditions of Hypophosphatemia in Children.

Great strides over the past few decades have increased our understanding of the pathophysiology of hypophosphatemic disorders. Phosphate is critically important to a variety of physiologic processes, including skeletal growth, development and mineralization, as well as DNA, RNA, phospholipids, and signaling pathways. Consequently, hypophosphatemic disorders have effects on multiple systems, and may cause a variety of nonspecific signs and symptoms. The acute effects of hypophosphatemia include neuromuscular symptoms and compromise. However, the dominant effects of chronic hypophosphatemia are the effects on musculoskeletal function including rickets, osteomalacia and impaired growth during childhood. While the most common causes of chronic hypophosphatemia in children are congenital, some acquired conditions also result in hypophosphatemia during childhood through a variety of mechanisms. Improved understanding of the pathophysiology of these congenital conditions has led to novel therapeutic approaches. This article will review the pathophysiologic causes of congenital hypophosphatemia, their clinical consequences and medical therapy.

Congenital Conditions of Hypophosphatemia Expressed in Adults.

The main congenital conditions of hypophosphatemia expressed in adulthood include several forms of hereditary hypophosphatemic rickets and a congenital disorder of vitamin D metabolism characterized by osteomalacia and hypophosphatemia in adult patients. Hypophosphatemia in adults is defined as serum phosphate concentration < 0.80 mmol/L. The principal regulators of phosphate homeostasis, as is well known, are parathyroid hormone (PTH), activated vitamin D, and Fibroblast Growth Factor 23 (FGF23). Differential diagnosis of hypophosphatemia is based on the evaluation of mechanisms leading to this alteration, such as high PTH activity, inadequate phosphate absorption from the gut, or renal phosphate wasting, either due to primary tubular defects or high FGF23 levels. The most common inherited form associated to hypophosphatemia is X-linked hypophosphatemic rickets (XLH), caused by PHEX gene mutations with enhanced secretion of the FGF23. Until now, the management of hypophosphatemia in adulthood has been poorly investigated. It is widely debated whether adult patients benefit from the conventional treatments normally used for pediatric patients. The new treatment for XLH with burosumab, a recombinant human IgG1 monoclonal antibody that binds to FGF23, blocking its activity, may change the pharmacological management of adult subjects with hypophosphatemia associated to FGF23-dependent mechanisms.