Endocrine Abstracts

The GNAS locus is a complex imprinted locus which encodes Gsa and four additional alternative transcripts including Xlas. Gsa is the ubiquitous α-subunit of the G-protein involved in major biological pathways including hormonal signaling and cell differentiation. Xlas is the only transcript sharing with Gsa the protein domain encoded by GNAS exons 2 to 13 of, which plays a key role in coupling activated receptors to adenylate cyclase stimulation. However, Xl...

The most common causes of hypoparathyroidism in children are the lack of or the impaired development of the parathyroid glands due to genetic/chromosomal alterations and the abnormal signaling of the Ca(2+)-sensing receptor (CaSR). The latter refers to autosomal dominant hypocalcemia (ADH) mainly caused by heterozygous activating mutations in CASR encoding CaSR (ADH type 1), and exceptionally caused by activating mutations of GNA11 encoding the Gq/11 protein (ADH ty...

Since the first description of pseudohypoparathyroidism (PHP) a remarkable clinical variability was observed. In 2016 a new classification of this group of diseases have been published by the European Network on PHP and related disorders, proposing “inactivating PTH/PTHrP signaling disorder” (iPPSD) as a new term that encompasses all the clinical entities. PHP and related disorders vary in clinical presentation and disease severity, and clinical features usually deve...

Idiopathic Infantile Hypercalcemia (IIH) is a rare inborn form of severe vitamin D hypersensitivity, with an estimated incidence of 1:33.000 live birth and a high degree of misdiagnosis. Since the identification of CYP24A1 loss-of-function variants inducing IIH in 2011, over 41 pathogenic variants have been described, and represent the major genetic drivers of IIH1. CYP24A1 encodes the main catalytic hydroxylase of the bioactive form of vitamin D (1,25D3). Upon bind...

The majority of patients affected with pseudohypoparathyroidism type 1b (PHP-1b) display loss of imprinting (LOI) encompassing the GNAS locus responsible for decreased Gsa expression in target tissues and PTH resistance. In other imprinting disorders like Silver-Russell, Wiedemann-Beckwith syndromes or transient neonatal diabetes mellitus due to LOI of the imprinted 11p15 and 6q24 regions respectively, we and others have shown that the LOI may spread over to other imprinted lo...

Pseudovitamin D deficiency rickets also called vitamin D-deficiency rickets type 1 (VDDR 1) is an autosomal recessive disorder in which 25-hydroxyvitamin D3 1 alpha-hydroxylase gene (CYP27B1) is deficient. VDDR1 is characterized by hypocalcemia,hypophosphatemia elevated serum PTH levels and low or undetectable serum concentrations of 1,25(OH)2D.We screened for mutations CYP27B1 in ten individuals from seven unrelated families wit...

Since the first description of inactivating PTH/PTHrP signaling disorders (iPPSDs, historically named pseudohypoparathyroidism (PHP)) a remarkable clinical variability was observed, especially in clinical presentation, which seems to be age-dependent. The main clinical features, including PTH resistance, brachydactyly and short stature, develop during mid and late childhood, whilst minor clinical features such as a round face, rapid weight gain and subclinical hypothyroidism a...

Inactivating PTH/PTHrP signaling disorders (iPPSDs, historically named pseudohypoparathyroidism (PHP)) are a group of rare disorders associated with resistance to parathormone (PTH) and other hormones due to impaired hormonal signaling via G protein coupled receptors. Hypercalcitoninemia has been reported in these patients, however very few reports are available. The aim of this study was to further investigate the prevalence and characteristics of hypercalcitoninemia in both ...

PHP1B -iPPSD3 per the new proposed classification- is a rare disorder characterized in most patients by proximal tubular resistance to PTH resulting in hypocalcemia, hyperphosphatemia and elevated PTH. Loss-of-methylation (LOM) at the Differentially Methylated Region (DMR) at GNAS exon A/B occurs in all PHP1B patients, but methylation changes at other DMRs within GNAS occur in some familial and most sporadic PHP1B cases. All patients with autosomal dominant PHP1B (AD-...

Objectives: X-linked hypophosphatemic Rickets (XLHR) is characterized by phosphate wasting and decreased production of 1,25OH-vitamin D, due, in most patients, to elevated FGF23 and PHEX mutation. In children, the disease has been extensively studied because of the devastating presentation of rickets, teeth abcesses, and growth retardation. In adults, however, metabolic complications, such as hyperparathyroidism or consequences on glucose and lipid metabolism of FGF23 excess, ...