This Consensus Statement covers recommendations for the diagnosis and management of patients with pseudohypoparathyroidism (PHP) and related disorders, which comprise metabolic disorders characterized by physical findings that variably include short bones, short stature, a stocky build, early-onset obesity and ectopic ossifications, as well as endocrine defects that often include resistance to parathyroid hormone (PTH) and TSH. The presentation and severity of PHP and its related disorders vary between affected individuals with considerable clinical and molecular overlap between the different types. A specific diagnosis is often delayed owing to lack of recognition of the syndrome and associated features. The participants in this Consensus Statement agreed that the diagnosis of PHP should be based on major criteria, including resistance to PTH, ectopic ossifications, brachydactyly and early-onset obesity. The clinical and laboratory diagnosis should be confirmed by a molecular genetic analysis. Patients should be screened at diagnosis and during follow-up for specific features, such as PTH resistance, TSH resistance, growth hormone deficiency, hypogonadism, skeletal deformities, oral health, weight gain, glucose intolerance or type 2 diabetes mellitus, and hypertension, as well as subcutaneous and/or deeper ectopic ossifications and neurocognitive impairment. Overall, a coordinated and multidisciplinary approach from infancy through adulthood, including a transition programme, should help us to improve the care of patients affected by these disorders.

The peroxisome biogenesis disorders (PBDs) are a group of lethal autosomal-recessive diseases caused by defects in peroxisomal matrix protein import, with the concomitant loss of multiple peroxisomal enzyme activities. Ten complementation groups (CGs) have been identified for the PBDs, with CG1 accounting for 51% of all PBD patients. We identified the human orthologue of yeast PEX1, a gene required for peroxisomal matrix protein import. Expression of human PEX1 restored peroxisomal protein import in fibroblasts from 30 CG1 patients, and PEX1 mutations were detected in multiple CG1 probands. A common PEX1 allele, G843D, is present in approximately half of CG1 patients and has a deleterious effect on PEX1 activity. Phenotypic analysis of PEX1-deficient cells revealed severe defects in peroxisomal matrix protein import and destabilization of PEX5, the receptor for the type-1 peroxisomal targetting signal, even though peroxisomes were present in these cells and capable of importing peroxisomal membrane proteins. These data demonstrate an important role for PEX1 in peroxisome biogenesis and suggest that mutations in this gene are the most common cause of the PBDs.

Although the AHO phenotype for PHP1a and pseudoPHP has been thought to be similar, we have found that obesity is a more prominent feature in PHP1a than in pseudoPHP and that severe obesity is characteristic of PHP1a specifically. These findings may implicate paternal imprinting of Galpha(s) in the development of human obesity.

The stimulatory a-subunit of trimeric G-proteins Ga s , which upon ligand binding to seven-transmembrane receptors activates adenylyl cyclases to produce the second messenger cAMP, constitutes one of the archetypal signal transduction molecules that have been studied in much detail. Over the past few years, however, genetic as well as biochemical approaches have led to a range of novel insights into the Ga s encoding guanine nucleotide binding protein, a-stimulating (Gnas) locus, its alternative protein products and its regulation by genomic imprinting, which leads to monoallelic, parental origin-dependent expression of the various transcripts. Here, we summarise the major characteristics of this complex gene locus and describe the physiological roles of Ga s and its 'extra large' variant XLa s at post-natal and adult stages as defined by genetic mutations. Opposite and potentially antagonistic functions of the two proteins in the regulation of energy homeostasis and metabolism have been identified in Gnasand Gnasxl (XLa s )-deficient mice, which are characterised by obesity and leanness respectively. A comparison of findings in mice with symptoms of the corresponding human genetic disease 'Albright's hereditary osteodystrophy'/'pseudohypoparathyroidism' indicates highly conserved functions as well as unresolved phenotypic differences.

Purpose of the review-In this review we define hypercalcemia levels, common etiologies for hypercalcemia in children, and treatment in order to aid the practicing pediatrician.Recent Findings-One rare cause of hypercalcemia in the child is Familial hypocalciuric hypercalcemia (FHH) [also termed familial benign hypercalcemia (FBH)]. Mutations that inactivate the Ca 2+ -sensing receptor gene FHH have been described as an autosomal dominant disorder, but recently milder mutations in the CASR have been shown to cause hypercalcemia when homozygous.Summary-Normal serum levels of calcium are maintained through the interplay of parathyroid, renal, and skeletal factors. In this review, we have distinguished the neonate and infant from the older child and adolescent because the causes and clinical features of hypercalcemia can differ in these two age groups. However the initial approach to the medical treatment of severe or symptomatic hypercalcemia is to increase the urinary excretion of calcium in both groups. In most cases, hypercalcemia is due osteoclastic bone resorption, and agents that inhibit or destroy osteoclasts are therefore effective treatments. Parathyroid surgery, the conventional treatment for adults with symptomatic primary hyperparathyroidism, is recommended for all children with primary hyperparathyroidism.

Albright hereditary osteodystrophy is caused by heterozygous inactivating mutations in GNAS, a gene that encodes not only the alpha-chain of Gs (Galphas), but also NESP55 and XLalphas through use of alternative first exons. Patients with GNAS mutations on maternally inherited alleles are resistant to multiple hormones such as PTH, TSH, LH/FSH, GHRH, and glucagon, whose receptors are coupled to Gs. This variant of Albright hereditary osteodystrophy is termed pseudohypoparathyroidism type 1a and is due to presumed tissue-specific paternal imprinting of Galphas. Previous studies have shown that mice heterozygous for a targeted disruption of exon 2 of Gnas, the murine homolog of GNAS, showed unique phenotypes dependent on the parent of origin of the mutated allele. However, hormone resistance occurred only when the disrupted gene was maternally inherited. Because disruption of exon 2 is predicted to inactivate Galphas as well as NESP55 and XLalphas, we created transgenic mice with disruption of exon 1 to investigate the effects of isolated loss of Galphas. Heterozygous mice that inherited the disruption maternally (-m/+) exhibited PTH and TSH resistance, whereas those with paternal inheritance (+/-p) had normal hormone responsiveness. Heterozygous mice were shorter and, when the disrupted allele was inherited maternally, weighed more than wild-type littermates. Galphas protein and mRNA expression was consistent with paternal imprinting in the renal cortex and thyroid, but there was no imprinting in renal medulla, heart, or adipose. These findings confirm the tissue-specific paternal imprinting of GNAS and demonstrate that Galphas deficiency alone is sufficient to account for the hormone resistance of pseudohypoparathyroidism type 1a.

Albright hereditary osteodystrophy (AHO) is a genetic disorder caused by heterozygous inactivating mutations in GNAS1, the gene encoding the alpha-chain of G(s), and is associated with short stature, obesity, brachydactyly, and sc ossifications. AHO patients with GNAS1 mutations on maternally inherited alleles also manifest resistance to multiple hormones (e.g. PTH, TSH, LH, FSH), a variant termed pseudohypoparathyroidism (PHP) type 1a, due to paternal imprinting of G alpha(s) transcripts in specific tissues. Recent evidence has shown that G alpha(s) transcripts are also imprinted in the pituitary somatotrophs that secrete GH. Because this imprinting could influence GHRH-dependent stimulation of somatotrophs, we hypothesized that maternally inherited GNAS1 mutations would impair GH secretion. We studied GH status in 13 subjects with PHP type 1a. GH responses to arginine/L-dopa and arginine/GHRH were deficient in nine subjects, all of whom were obese and had low serum concentrations of IGF-I. By contrast, none of the four GH-sufficient subjects were obese, and all had normal IGF-I levels. Our data indicate that GH deficiency is common (69%) in PHP type 1a and may contribute to the obesity and short stature typical of AHO. We propose that GH status be evaluated in all patients with PHP type 1a.

Patients affected by pseudohypoparathyroidism (PHP) or related disorders are characterized by physical findings that may include brachydactyly, a short stature, a stocky build, early-onset obesity, ectopic ossifications, and neurodevelopmental deficits, as well as hormonal resistance most prominently to parathyroid hormone (PTH). In addition to these alterations, patients may develop other hormonal resistances, leading to overt or subclinical hypothyroidism, hypogonadism and growth hormone (GH) deficiency, impaired growth without measurable evidence for hormonal abnormalities, type 2 diabetes, and skeletal issues with potentially severe limitation of mobility. PHP and related disorders are primarily clinical diagnoses. Given the variability of the clinical, radiological, and biochemical presentation, establishment of the molecular diagnosis is of critical importance for patients. It facilitates management, including prevention of complications, screening and treatment of endocrine deficits, supportive measures, and appropriate genetic counselling. Based on the first international consensus statement for these disorders, this article provides an updated and readyto-use tool to help physicians and patients outlining relevant interventions and their timing. A lifelong coordinated and multidisciplinary approach is recommended, starting as far as possible in early infancy and continuing throughout adulthood with an appropriate and timely transition from pediatric to adult care.