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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 -
Minerva Endocrinologica Jun 2018The term pseudohypoparathyroidism (PHP) refers to a spectrum of rare disorders of mineral metabolism, characterized by features due to end-organ resistance to PTH. The... (Review)
Review
The term pseudohypoparathyroidism (PHP) refers to a spectrum of rare disorders of mineral metabolism, characterized by features due to end-organ resistance to PTH. The phenotypes of Albright hereditary osteodystrophy (AHO), originally described as associated to the disease, and progressive osseous heteroplasia, can be associated to the endocrine manifestations of hormonal resistance. Genetic or epigenetic alterations in the complex imprinted GNAS locus, encoding the alpha-subunit of the stimulatory G protein (GSα) and several other transcripts, give rise to the different forms oh PHP, which can be differentiated according to the phenotype, the response to PTH infusion and in vitro assays testing Gsα activity. Since PHP-related phenotypes are overlapping and other non GNAS-dependent disorders mimicking AHO, such as acrodysostosis, have been genetically characterized, the term PHP is today considered obsolete and better referred to the more comprehensive "inactivating PTH/PTHrP signaling disorder (iPPSD)" as proposed in a recent classification. This broad term include all the congenital rare disorders due to impaired PTH/PTHrP cAMP pathway. Genetic and epigenetic analyses, although not necessary for diagnosis made on the basis of major and minor criteria according to clinical and biochemical signs, will let to differentiate among the different forms for proper therapeutic planning, counseling and follow-up.
Topics: Humans; Hypocalcemia; Parathyroid Hormone; Pseudohypoparathyroidism
PubMed: 29125274
DOI: 10.23736/S0391-1977.17.02768-7 -
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 -
Best Practice & Research. Clinical... Oct 2018Calcium is vital for life, and extracellular calcium concentrations must constantly be maintained within a precise concentration range. Low serum calcium (hypocalcemia)... (Review)
Review
Calcium is vital for life, and extracellular calcium concentrations must constantly be maintained within a precise concentration range. Low serum calcium (hypocalcemia) occurs in conjunction with multiple disorders and can be life-threatening if severe. Symptoms of acute hypocalcemia include neuromuscular irritability, tetany, and seizures, which are rapidly resolved with intravenous administration of calcium gluconate. However, disorders that lead to chronic hypocalcemia often have more subtle manifestations. Hypoparathyroidism, characterized by impaired secretion of parathyroid hormone (PTH), a key regulatory hormone for maintaining calcium homeostasis, is a classic cause of chronic hypocalcemia. Disorders that disrupt the metabolism of vitamin D can also lead to chronic hypocalcemia, as vitamin D is responsible for increasing the gut absorption of dietary calcium. Treatment and management options for chronic hypocalcemia vary depending on the underlying disorder. For example, in patients with hypoparathyroidism, calcium and vitamin D supplementation must be carefully titrated to avoid symptoms of hypocalcemia while keeping serum calcium in the low-normal range to minimize hypercalciuria, which can lead to renal dysfunction. Management of chronic hypocalcemia requires knowledge of the factors that influence the complex regulatory axes of calcium homeostasis in a given disorder. This chapter discusses common and rare disorders of hypocalcemia, symptoms and workup, and management options including replacement of PTH in hypoparathyroidism.
Topics: Administration, Intravenous; Bone Density Conservation Agents; Calcium; Dietary Supplements; Hormone Replacement Therapy; Humans; Hypocalcemia; Hypoparathyroidism; Parathyroid Hormone; Reference Values; Vitamin D
PubMed: 30449546
DOI: 10.1016/j.beem.2018.05.006 -
Endocrinology and Metabolism Clinics of... Dec 2018Hypoparathyroidism is a metabolic disorder characterized by hypocalcemia, hyperphosphatemia, and inadequate levels of or function of parathyroid hormone (PTH). The... (Review)
Review
Hypoparathyroidism is a metabolic disorder characterized by hypocalcemia, hyperphosphatemia, and inadequate levels of or function of parathyroid hormone (PTH). The authors review the nonsurgical or medical causes of hypoparathyroidism. The most common of the nonsurgical causes is autoimmune destruction of the parathyroid. Magnesium deficiency or excess can cause a functional hypoparathyroidism. Genetic conditions result in hypoparathyroidism as part of a syndrome or in isolation. Pseudohypoparathyroidism reflects a resistance to PTH. Infiltrative, metastatic, radiation destruction, mineral deposition, or idiopathic are uncommon causes of hypoparathyroidism. This article reviews the causes of hypoparathyroidism and an approach to the evaluation of this condition.
Topics: Autoimmune Diseases; Hormone Replacement Therapy; Humans; Hypoparathyroidism; Parathyroid Hormone; Radiotherapy
PubMed: 30390814
DOI: 10.1016/j.ecl.2018.07.006 -
Frontiers of Hormone Research 2018Parathyroid glands are the main regulator of body mineral metabolism through parathormone (PTH) actions on bone and kidney. Experimental evidence suggests that PTH may... (Review)
Review
Parathyroid glands are the main regulator of body mineral metabolism through parathormone (PTH) actions on bone and kidney. Experimental evidence suggests that PTH may have non-classical target organs such as adipose tissue, arterial vascular wall, cardiac muscle cells, and adrenal cortex cells, where it may play a role in controlling body energy, blood pressure, and metabolism. Cardiometabolic features have been investigated in the wide spectrum of clinical parathyroid disorders, from hyperparathyroidism to pseudohypoparathyroidism and hypoparathyroidism. Indeed, in parathyroid disorders, besides altered PTH secretion, impaired serum calcium levels and vitamin D status occur. Both calcium and vitamin D have been shown to regulate metabolism and to be associated with cardiovascular diseases. However, despite the complexity of parathyroid disorders, features of metabolic syndrome, such as obesity, insulin resistance, and glucose intolerance, arterial blood hypertension, and dyslipidemia, are frequently diagnosed in primary and secondary hyperparathyroidism as well as in pseudohyperparathyroidism. Here, we reviewed the most consistent data highlighting challenges and providing clinical remarks.
Topics: Calcium; Humans; Metabolic Syndrome; Parathyroid Diseases; Parathyroid Hormone; Vitamin D
PubMed: 29895021
DOI: 10.1159/000486003 -
Frontiers of Hormone Research 2019Pseudohypoparathyroidism (PHP), pseudo-PHP, acrodysostosis, and progressive osseous heteroplasia are heterogeneous disorders characterized by physical findings,... (Review)
Review
Pseudohypoparathyroidism (PHP), pseudo-PHP, acrodysostosis, and progressive osseous heteroplasia are heterogeneous disorders characterized by physical findings, differently associated in each subtype, including short bones, short stature, a stocky build, ectopic ossifications (features associated with Albright's hereditary osteodystrophy), as well as laboratory abnormalities consistent with hormone resistance, such as hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone (PTH) and thyroid-stimulating hormone levels. All these disorders are caused by impairments in the cAMP-mediated signal transduction pathway and, in particular, in the PTH/PTHrP signaling pathway: the main subtypes of PHP and related disorders are caused by de novo or autosomal dominantly inherited inactivating genetic mutations, and/or epigenetic, sporadic, or genetic-based alterations within or upstream of GNAS, PRKAR1A, PDE4D, and PDE3A. Here we will review the impressive progress that has been made over the past 30 years on the pathophysiology of these diseases and will describe the recently proposed novel nomenclature and classification. The new term "inactivating PTH/PTHrP signaling disorder," iPPSD: (1) defines the common mechanism responsible for all diseases, (2) does not require a confirmed genetic defect, (3) avoids ambiguous terms like "pseudo," and (4) eliminates the clinical or molecular overlap between diseases.
Topics: Bone Diseases, Metabolic; Dysostoses; Humans; Intellectual Disability; Ossification, Heterotopic; Osteochondrodysplasias; Parathyroid Hormone; Parathyroid Hormone-Related Protein; Pseudohypoparathyroidism; Signal Transduction; Skin Diseases, Genetic
PubMed: 30641531
DOI: 10.1159/000491045 -
Nature Reviews. Endocrinology Jun 2016Pseudohypoparathyroidism exemplifies an unusual form of hormone resistance as the underlying molecular defect is a partial deficiency of the α subunit of the... (Review)
Review
Pseudohypoparathyroidism exemplifies an unusual form of hormone resistance as the underlying molecular defect is a partial deficiency of the α subunit of the stimulatory G protein (Gsα), a key regulator of the cAMP signalling pathway, rather than of the parathyroid hormone (PTH) receptor itself. Despite the first description of this disorder dating back to 1942, later findings have unveiled complex epigenetic alterations in addition to classic mutations in GNAS underpining the molecular basis of the main subtypes of pseudohypoparathyroidism. Moreover, mutations in PRKAR1A and PDE4D, which encode proteins crucial for Gsα-cAMP-mediated signalling, have been found in patients with acrodysostosis. As acrodysostosis, a disease characterized by skeletal malformations and endocrine disturbances, shares clinical and molecular characteristics with pseudohypoparathyroidism, making a differential diagnosis and providing genetic counselling to patients and families is a challenge for endocrinologists. Accumulating data on the genetic and clinical aspects of this group of diseases highlight the limitation of the current classification system and prompt the need for a new definition as well as for new diagnostic and/or therapeutic algorithms. This Review discusses both the current understanding and future challenges for the clinical and molecular diagnosis, classification and treatment of pseudohypoparathyroidism.
Topics: Bone Diseases, Metabolic; Chromogranins; Chromosome Deletion; Chromosomes, Human, Pair 2; Cyclic AMP; Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; Cyclic Nucleotide Phosphodiesterases, Type 4; Diagnosis, Differential; Dysostoses; Epigenesis, Genetic; GTP-Binding Protein alpha Subunits, Gs; Humans; Intellectual Disability; Ossification, Heterotopic; Osteochondrodysplasias; Pseudohypoparathyroidism; Signal Transduction; Skin Diseases, Genetic
PubMed: 27109785
DOI: 10.1038/nrendo.2016.52