Fadil Hannan

Chapter 34 – Hypoparathyroidism

Hypoparathyroidism is characterized by hypocalcemia and hyperphosphatemia due to a lack of parathyroid hormone (PTH) secretion or action. Hypoparathyroidism may occur as part of a pluriglandular autoimmune disorder or as a complex congenital defect, as for example in the autosomal dominant DiGeorge or hypoparathyroidism, deafness, and renal dysplasia (HDR) syndromes. In addition, hypoparathyroidism may occur as a solitary endocrinopathy and this has been called isolated or idiopathic hypoparathyroidism. Familial occurrences of isolated hypoparathyroidism with autosomal dominant, autosomal recessive, and X-linked inheritances have been established. Studies of patients with these forms of hypoparathyroidism and mouse models with parathyroid defects have elucidated important roles for: transcription factors (e.g., TBX1, GATA3, GCMB, AIRE1, and SOX3), the tubulin-specific chaperone (TBCE), and the mitochondrial genome in determining parathyroid development; the calcium-sensing receptor (CaSR) and G-protein subunit α11 in regulating extracellular calcium and PTH secretion; and PTH gene expression for synthesis and secretion of PTH. Moreover, recombinant PTH and drugs targeting the CaSR have been shown to be of benefit for the management of hypoparathyroidism.

Identification of a novel loss-of-function PHEX mutation, Ala720Ser, in a sporadic case of adult-onset hypophosphatemic osteomalacia

Adults presenting with sporadic hypophosphatemia and elevations in circulating fibroblast growth factor-23 (FGF23) concentrations are usually investigated for an acquired disorder of FGF23 excess such as tumor induced osteomalacia (TIO). However, in some cases the underlying tumor is not detected, and such patients may harbor other causes of FGF23 excess. Indeed, coding-region and 3UTR mutations of phosphate-regulating neutral endopeptidase (PHEX), which encodes a cell-surface protein that regulates circulating FGF23 concentrations, can lead to alterations in phosphate homeostasis, which are not detected until adulthood. Here, we report an adult female who presented with hypophosphatemic osteomalacia and raised serum FGF23 concentrations. The patient and her parents, who were her only first-degree relatives, had no history of rickets. The patient was thus suspected of having TIO. However, no tumor had been identified following extensive localization studies. Mutational analysis of the PHEX coding-region and 3UTR was undertaken, and this revealed the patient to be heterozygous for a novel germline PHEX mutation (c.2158G>T; p.Ala720Ser). In vitro studies involving the expression of WT and mutant PHEX proteins in HEK293 cells demonstrated the Ala720Ser mutation to impair trafficking of PHEX, with ~20% of the mutant protein being expressed at the cell surface, compared to ~80% cell surface expression for WT PHEX (p<0.05). Thus, our studies have identified a pathogenic PHEX mutation in a sporadic case of adult-onset hypophosphatemic osteomalacia, and these findings highlight a role for PHEX gene analysis in some cases of suspected TIO, particularly when no tumor has been identified.