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Nature Reviews. Endocrinology Aug 2018This Consensus Statement covers recommendations for the diagnosis and management of patients with pseudohypoparathyroidism (PHP) and related disorders, which comprise... (Review)
Review
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.
Topics: Consensus; Delayed Diagnosis; Drug Resistance; Female; Genetic Predisposition to Disease; Humans; Infant, Newborn; Male; Neonatal Screening; Parathyroid Hormone; Practice Guidelines as Topic; Prognosis; Program Development; Pseudohypoparathyroidism; Risk Assessment
PubMed: 29959430
DOI: 10.1038/s41574-018-0042-0 -
Endocrinology and Metabolism Clinics of... Dec 2018Pseudohypoparathyroidism (PHP) refers to a heterogeneous group of uncommon, yet related metabolic disorders that are characterized by impaired activation of the... (Review)
Review
Pseudohypoparathyroidism (PHP) refers to a heterogeneous group of uncommon, yet related metabolic disorders that are characterized by impaired activation of the Gsα/cAMP/PKA signaling pathway by parathyroid hormone (PTH) and other hormones that interact with Gsa-coupled receptors. Proximal renal tubular resistance to PTH and thus hypocalcemia and hyperphosphatemia, frequently in presence of brachydactyly, ectopic ossification, early-onset obesity, or short stature are common features of PHP. Registries and large cohorts of patients are needed to conduct clinical and genetic research, to improve the still limited knowledge regarding the underlying disease mechanisms, and allow the development of novel therapies.
Topics: Adult; Bone Diseases; Child; Drug Resistance; Humans; Parathyroid Hormone; Pseudohypoparathyroidism
PubMed: 30390819
DOI: 10.1016/j.ecl.2018.07.011 -
Hormone Research in Paediatrics 2020Patients affected by pseudohypoparathyroidism (PHP) or related disorders are characterized by physical findings that may include brachydactyly, a short stature, a stocky... (Review)
Review
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 ready-to-use tool to help physicians and patients outlining relevant interventions and their timing. A life-long 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.
Topics: Adult; Child; Diabetes Mellitus, Type 2; Dwarfism, Pituitary; Humans; Hypothyroidism; Practice Guidelines as Topic; Pseudohypoparathyroidism; Transition to Adult Care
PubMed: 32756064
DOI: 10.1159/000508985 -
The Journal of Clinical Endocrinology... May 2021Pseudohypoparathyroidism (PHP) and pseudopseudohypoparathyroidism (PPHP) are caused by mutations and/or epigenetic changes at the complex GNAS locus on chromosome... (Review)
Review
Pseudohypoparathyroidism (PHP) and pseudopseudohypoparathyroidism (PPHP) are caused by mutations and/or epigenetic changes at the complex GNAS locus on chromosome 20q13.3 that undergoes parent-specific methylation changes at several differentially methylated regions (DMRs). GNAS encodes the alpha-subunit of the stimulatory G protein (Gsα) and several splice variants thereof. PHP type Ia (PHP1A) is caused by heterozygous inactivating mutations involving the maternal exons 1-13. Heterozygosity of these maternal GNAS mutations cause PTH-resistant hypocalcemia and hyperphosphatemia because paternal Gsα expression is suppressed in certain organs thus leading to little or no Gsα protein in the proximal renal tubules and other tissues. Besides biochemical abnormalities, PHP1A patients show developmental abnormalities, referred to as Albright's hereditary osteodystrophy (AHO). Some, but not all of these AHO features are encountered also in patients affected by PPHP, who carry paternal Gsα-specific mutations and typically show no laboratory abnormalities. Autosomal dominant PHP type Ib (AD-PHP1B) is caused by heterozygous maternal deletions within GNAS or STX16, which are associated with loss of methylation at the A/B DMR alone or at all maternally methylated GNAS exons. Loss of methylation of exon A/B and the resulting biallelic expression of A/B transcript reduces Gsα expression thus leading to hormonal resistance. Epigenetic changes at all differentially methylated GNAS regions are also observed in sporadic PHP1B, which is the most frequent PHP1B variant. However, this disease variant remains unresolved at the molecular level, except for rare cases with paternal uniparental isodisomy or heterodisomy of chromosome 20q (patUPD20q).
Topics: Chromogranins; DNA Methylation; Epigenesis, Genetic; GTP-Binding Protein alpha Subunits, Gs; Humans; Molecular Diagnostic Techniques; Pseudohypoparathyroidism
PubMed: 33529330
DOI: 10.1210/clinem/dgab060 -
Frontiers in Endocrinology 2022The actions of several bone-mineral ion regulators, namely PTH, FGF23, Klotho and 1,25(OH)2 vitamin D (1,25(OH)D), control calcium and phosphate metabolism, and each of... (Review)
Review
The actions of several bone-mineral ion regulators, namely PTH, FGF23, Klotho and 1,25(OH)2 vitamin D (1,25(OH)D), control calcium and phosphate metabolism, and each of these molecules has additional biological effects related to cell signaling, metabolism and ultimately survival. Therefore, these factors are tightly regulated at various levels - genetic, epigenetic, protein secretion and cleavage. We review the main determinants of mineral homeostasis including well-established genetic and post-translational regulators and bring attention to the epigenetic mechanisms that affect the function of PTH, FGF23/Klotho and 1,25(OH)D. Clinically relevant epigenetic mechanisms include methylation of cytosine at CpG-rich islands, histone deacetylation and micro-RNA interference. For example, sporadic pseudohypoparathyroidism type 1B (PHP1B), a disease characterized by resistance to PTH actions due to blunted intracellular cAMP signaling at the PTH/PTHrP receptor, is associated with abnormal methylation at the locus, thereby leading to reduced expression of the stimulatory G protein α-subunit (Gsα). Post-translational regulation is critical for the function of FGF-23 and such modifications include glycosylation and phosphorylation, which regulate the cleavage of FGF-23 and hence the proportion of available FGF-23 that is biologically active. While there is extensive data on how 1,25(OH)D and the vitamin D receptor (VDR) regulate other genes, much more needs to be learned about their regulation. Reduced VDR expression or VDR mutations are the cause of rickets and are thought to contribute to different disorders. Epigenetic changes, such as increased methylation of the VDR resulting in decreased expression are associated with several cancers and infections. Genetic and epigenetic determinants play crucial roles in the function of mineral factors and their disorders lead to different diseases related to bone and beyond.
Topics: Calcium; Cytosine; Epigenesis, Genetic; Fibroblast Growth Factors; GTP-Binding Proteins; Glucuronidase; Histones; Minerals; Parathyroid Hormone; Phosphates; Phosphorus; Receptor, Parathyroid Hormone, Type 1; Receptors, Calcitriol; Vitamin D; Vitamins
PubMed: 36246903
DOI: 10.3389/fendo.2022.992666 -
Neurological Sciences : Official... Nov 2019Basal ganglia calcifications could be incidental findings up to 20% of asymptomatic patients undergoing CT or MRI scan. The presence of neuropsychiatric symptoms... (Review)
Review
Basal ganglia calcifications could be incidental findings up to 20% of asymptomatic patients undergoing CT or MRI scan. The presence of neuropsychiatric symptoms associated with bilateral basal ganglia calcifications (which could occur in other peculiar brain structures, such as dentate nuclei) identifies a clinical picture defined as Fahr's Disease. This denomination mainly refers to idiopathic forms in which no metabolic or other underlying causes are identified. Recently, mutations in four different genes (SLC20A2, PDGFRB, PDGFB, and XPR1) were identified, together with novel mutations in the Myogenic Regulating Glycosylase gene, causing the occurrence of movement disorders, cognitive decline, and psychiatric symptoms. On the other hand, secondary forms, also identified as Fahr's syndrome, have been associated with different conditions: endocrine abnormalities of PTH, such as hypoparathyroidism, other genetically determined conditions, brain infections, or toxic exposure. The underlying pathophysiology seems to be related to an abnormal calcium/phosphorus homeostasis and transportation and alteration of the blood-brain barrier.
Topics: Autoimmune Diseases of the Nervous System; Basal Ganglia Diseases; Calcinosis; Cockayne Syndrome; Humans; Hypoparathyroidism; Lupus Vasculitis, Central Nervous System; Mitochondrial Diseases; Nervous System Malformations; Neurodegenerative Diseases; Neurotoxicity Syndromes; Pseudohypoparathyroidism; Xenotropic and Polytropic Retrovirus Receptor
PubMed: 31267306
DOI: 10.1007/s10072-019-03998-x -
Current Opinion in Pediatrics Aug 2019This review is timely given the 2018 publication of the first international Consensus Statement for the diagnosis and management of pseudohypoparathyroidism (PHP) and... (Review)
Review
PURPOSE OF REVIEW
This review is timely given the 2018 publication of the first international Consensus Statement for the diagnosis and management of pseudohypoparathyroidism (PHP) and related disorders. The purpose of this review is to provide the knowledge needed to recognize and manage PHP1A, pseudopseudohypoparathyroidism (PPHP) and PHP1B - the most common of the subtypes - with an overview of the entire spectrum and to provide a concise summary of management for clinical use. This review will draw from recent literature as well as personal experience in evaluating hundreds of children and adults with PHP.
RECENT FINDINGS
Progress is continually being made in understanding the mechanisms underlying the PHP spectrum. Every year, through clinical and laboratory studies, the phenotypes are elucidated in more detail, as are clinical issues such as short stature, brachydactyly, subcutaneous ossifications, cognitive/behavioural impairments, obesity and metabolic disturbances. Headed by a European PHP consortium, experts worldwide published the first international Consensus that provides detailed guidance in a systematic manner and will lead to exponential progress in understanding and managing these disorders.
SUMMARY
As more knowledge is gained from clinical and laboratory investigations, the mechanisms underlying the abnormalities associated with PHP are being uncovered as are improvements in management.
Topics: Adult; Animals; Child; Child, Preschool; Chromogranins; Female; GTP-Binding Protein alpha Subunits, Gs; Growth Hormone; Humans; Infant; Male; Mice; Obesity; Pseudohypoparathyroidism; Pseudopseudohypoparathyroidism
PubMed: 31145125
DOI: 10.1097/MOP.0000000000000783 -
Journal of Endocrinological... Jun 2023Parathyroid diseases are related to parathyroid hormone (PTH) dysregulation by parathyroid cells or alteration of PTH function. They include hyperparathyroidism (PTH... (Review)
Review
PURPOSE
Parathyroid diseases are related to parathyroid hormone (PTH) dysregulation by parathyroid cells or alteration of PTH function. They include hyperparathyroidism (PTH excess), hypoparathyroidism (PTH deficiency) and pseudohypoparathyroidism (PTH resistance). Little is known about correlation between parathyroid diseases and metabolic syndrome (MetS).
METHODS
An electronic-based search using PubMed was performed until October 2022 and articles were selected based on relevance of title, abstract, English language and publication in peer-reviewed journals.
RESULTS
Possible association between PTH alterations and the diverse manifestation of MetS have been proposed and it could be supposed that MetS may negatively influence parathyroid diseases. Available data show significant association for hyperparathyroidism and pseudohypoparathyroidism.
CONCLUSIONS
This review highlights the possible implications between MetS and parathyroid diseases. Given the increasing MetS global prevalence and the higher parathyroid diseases awareness and diagnosis, it may be interesting to further explore the possible role of alterations in parathyroid homeostasis in the development of MetS components with dedicated prospective studies.
Topics: Humans; Metabolic Syndrome; Prospective Studies; Parathyroid Diseases; Parathyroid Hormone; Hypoparathyroidism; Pseudohypoparathyroidism; Hyperparathyroidism
PubMed: 36773188
DOI: 10.1007/s40618-023-02018-2