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Journal of Molecular Endocrinology Jan 2024Several human disorders are caused by genetic or epigenetic changes involving the GNAS locus on chromosome 20q13.3 that encodes the alpha-subunit of the stimulatory G... (Review)
Review
Several human disorders are caused by genetic or epigenetic changes involving the GNAS locus on chromosome 20q13.3 that encodes the alpha-subunit of the stimulatory G protein (Gsα) and several splice variants thereof. Thus, pseudohypoparathyroidism type Ia (PHP1A) is caused by heterozygous inactivating mutations involving the maternal GNAS exons 1-13 resulting in characteristic abnormalities referred to as Albright's hereditary osteodystrophy (AHO) that are associated with resistance to several agonist ligands, particularly to parathyroid hormone (PTH), thereby leading to hypocalcemia and hyperphosphatemia. GNAS mutations involving the paternal Gsα exons also cause most of these AHO features, but without evidence for hormonal resistance, hence the term pseudopseudohypoparathyroidism (PPHP). Autosomal dominant pseudohypoparathyroidism type Ib (PHP1B) due to maternal GNAS or STX16 mutations (deletions, duplications, insertions, and inversions) is associated with epigenetic changes at one or several differentially methylated regions (DMRs) within GNAS. Unlike the inactivating Gsα mutations that cause PHP1A and PPHP, hormonal resistance is caused in all PHP1B variants by impaired Gsα expression due to loss of methylation at GNAS exon A/B, which can be associated in some familial cases with epigenetic changes at the other maternal GNAS DMRs. The genetic defect(s) responsible for sporadic PHP1B, the most frequent variant of this disorder, remain(s) unknown for the majority of patients. However, characteristic epigenetic GNAS changes can be readily detected that include a gain of methylation at the neuroendocrine secretory protein (NESP) DMR. Multiple genetic or epigenetic GNAS abnormalities can thus impair Gsα function or expression, consequently leading to inadequate cAMP-dependent signaling events downstream of various Gsα-coupled receptors.
Topics: Humans; Chromogranins; Pseudohypoparathyroidism; GTP-Binding Protein alpha Subunits, Gs; Epigenesis, Genetic; DNA Methylation
PubMed: 37965945
DOI: 10.1530/JME-23-0104 -
Current Opinion in Endocrinology,... Feb 2017To provide readers with a review of contemporary literature describing the evolving understanding of the pseudohypoparathyroidism type 1A (PHP1A) phenotype. (Review)
Review
PURPOSE OF REVIEW
To provide readers with a review of contemporary literature describing the evolving understanding of the pseudohypoparathyroidism type 1A (PHP1A) phenotype.
RECENT FINDINGS
The classic features of PHP1A include multihormone resistance and the Albright Hereditary Osteodystrophy phenotype (round facies, short stature, subcutaneous ossifications, brachydactyly, and early-onset obesity. Obesity may be because of a decrease in resting energy expenditure because most patients do not report significant hyperphagia. Patients with PHP1A have an increased risk of type 2 diabetes. In addition to brachydactyly and short stature, orthopedic complications can include spinal stenosis and carpal tunnel syndrome. Hearing loss, both sensorineural and conductive, has been reported in PHP1A. In addition, ear-nose-throat findings include decreased olfaction and frequent otitis media requiring tympanostomy tubes. Sleep apnea was shown to be 4.4-fold more common in children with PHP1A compared with other obese children; furthermore, asthma-like symptoms have been reported. These new findings are likely multifactorial and further research is needed to better understand these nonclassic features of PHP1A.
SUMMARY
Along with the Albright Hereditary Osteodystrophy phenotype and hormone resistance, patients with PHP1A may have additional skeletal, metabolic, ear-nose-throat, and pulmonary complications. Understanding these nonclassic features will help improve clinical care of patients with PHP1A.
Topics: Diabetes Mellitus, Type 2; Drug Resistance; Energy Metabolism; Hormones; Humans; Obesity; Phenotype; Pseudohypoparathyroidism
PubMed: 27875418
DOI: 10.1097/MED.0000000000000306 -
Current Osteoporosis Reports Jun 2023Pseudohypoparathyroidism (PHP) is a disorder caused by mutations and/or epigenetic changes at the complex GNAS locus. It is characterized by hypocalcemia,... (Review)
Review
PURPOSE OF REVIEW
Pseudohypoparathyroidism (PHP) is a disorder caused by mutations and/or epigenetic changes at the complex GNAS locus. It is characterized by hypocalcemia, hyperphosphatemia, and an elevated parathyroid hormone concentration secondary to the resistance of target tissues to the biological actions of parathyroid hormone. PHP is divided into several subtypes with different yet overlapping phenotypes. Research on the bone status in patients with PHP is sparse and has yielded inconsistent results. This review was performed to summarize the current knowledge on the bone phenotypes and possible mechanisms of PHP.
RECENT FINDINGS
Patients with PHP exhibit highly variable bone phenotypes and increased concentrations of bone turnover markers. Long-standing elevation of the parathyroid hormone concentration may lead to hyperparathyroid bone diseases, including rickets and osteitis fibrosa. Compared with normal controls, patients with PHP may exhibit similar, increased, or decreased bone mineral density. Higher bone mineral density has been found in patients with PHP type 1A than in normal controls, whereas decreased bone mass, osteosclerosis, and osteitis fibrosa cystica have been reported in patients with PHP type 1B, indicating more variable bone phenotypes in PHP type 1B. Bone tissues show partial sensitivity to parathyroid hormone in patients with PHP, leading to heterogeneous reactions to parathyroid hormone in different individuals and even in different regions of bone tissues in the same individual. Regions rich in cancellous bone are more sensitive and show more obvious improvement after therapy. Active vitamin D and calcium can significantly improve abnormal bone metabolism in patients with PHP.
Topics: Humans; Bone and Bones; Pseudohypoparathyroidism; Parathyroid Hormone; Bone Diseases; Phenotype; GTP-Binding Protein alpha Subunits, Gs; Chromogranins
PubMed: 37014531
DOI: 10.1007/s11914-023-00787-6 -
The Application of Clinical Genetics 2015Progressive osseous heteroplasia (POH) is an ultrarare genetic condition of progressive ectopic ossification. Most cases of POH are caused by heterozygous inactivating... (Review)
Review
Progressive osseous heteroplasia (POH) is an ultrarare genetic condition of progressive ectopic ossification. Most cases of POH are caused by heterozygous inactivating mutations of GNAS, the gene encoding the alpha subunit of the G-stimulatory protein of adenylyl cyclase. POH is part of a spectrum of related genetic disorders, including Albright hereditary osteodystrophy, pseudohypoparathyroidism, and primary osteoma cutis, that share common features of superficial ossification and association with inactivating mutations of GNAS. The genetics, diagnostic criteria, supporting clinical features, current management, and prognosis of POH are reviewed here, and emerging therapeutic strategies are discussed.
PubMed: 25674011
DOI: 10.2147/TACG.S51064 -
Journal of Clinical and Diagnostic... Sep 2014
PubMed: 25386477
DOI: 10.7860/JCDR/2014/8197.4897 -
MMW Fortschritte Der Medizin Sep 2015
Topics: Hand Bones; Humans; Male; Pseudohypoparathyroidism; Pseudopseudohypoparathyroidism; Radiography
PubMed: 26349724
DOI: 10.1007/s15006-015-3494-3 -
QJM : Monthly Journal of the... May 2018
Topics: Adolescent; Brain; Calcinosis; Calcium; Female; Hand; Humans; Hypocalcemia; Parathyroid Hormone; Pseudohypoparathyroidism; Tomography, X-Ray Computed
PubMed: 29474689
DOI: 10.1093/qjmed/hcy038 -
Journal of Pediatric Endocrinology &... Feb 2023The past 50 years of research in pediatric bone and mineral metabolism have led to remarkable progress in the identification and characterization of disorders that... (Review)
Review
The past 50 years of research in pediatric bone and mineral metabolism have led to remarkable progress in the identification and characterization of disorders that affect the developing skeleton. Progress has been facilitated through advances in both technology and biology and this paper provides a brief description of some but not all of the key findings, including identification of the calcium sensing receptor and the polypeptides parathyroid hormone and parathyroid hormone-related protein as well as their shared receptor and signal generating pathways; the elucidation of vitamin D metabolism and actions; discovery of fibroblast growth factor 23 (FGF23), the sodium-phosphate co-transporters and the other components that regulate phosphate metabolism. Moreover, the past half-century of research has led to the delineation of the molecular bases for genetic forms of hypoparathyroidism, pseudohypoparathyroidism, and primary hyperparathyroidism as well as the determination of the genetic causes of osteogenesis imperfecta, osteopetrosis, hypophosphatasia, and other disorders of mineral/bone homeostasis. During the next decade we expect that many of these fundamental discoveries will lead to the development of innovative treatments that will improve the lives of children with these disorders.
Topics: Child; Adolescent; Humans; Bone and Bones; Parathyroid Hormone; Osteogenesis Imperfecta; Hypophosphatasia; Phosphates; Fibroblast Growth Factors; Calcium; Vitamin D
PubMed: 36636022
DOI: 10.1515/jpem-2022-0624 -
Neuro-Chirurgie Nov 2019Some metabolic bone disorders may result in the premature closure of one or more calvarial sutures during childhood, potentially leading to a cranioencephalic... (Review)
Review
INTRODUCTION
Some metabolic bone disorders may result in the premature closure of one or more calvarial sutures during childhood, potentially leading to a cranioencephalic disproportion. The aim of this paper is to review the characteristics and consequences of craniosynostosis associated with metabolic disorder.
MATERIAL AND METHODS
A review of the literature on metabolic forms of craniosynostosis was performed.
RESULTS
The most common forms of craniosynostosis associated with metabolic bone disorder were isolated sagittal suture fusion with or without scaphocephaly, and sagittal suture fusion associated with coronal suture fusion (oxycephaly) or also with lambdoid suture fusion (pansynostosis). Synostosis may be well-tolerated, but in some subjects results in neurodevelopmental and functional impairment that is sometimes severe.
CONCLUSION
The impact of metabolic synostosis is very variable, depending on the specific underlying metabolic disease, with a large spectrum of morphological and functional consequences. Diagnosis should be early and management should be carried out by a multidisciplinary team with expertise in both rare skeletal disorders and craniosynostosis. The impact of emergent medical therapies recently developed for some of these diseases will be assessed by systematic coherent follow-up of international registries.
Topics: Bone Diseases, Metabolic; Cranial Sutures; Craniosynostoses; Humans; Minerals; Mucopolysaccharidoses; Rickets
PubMed: 31562881
DOI: 10.1016/j.neuchi.2019.09.008 -
Best Practice & Research. Clinical... Apr 2018Metabolic disorders deriving from the non-responsiveness of target organs to hormones, which manifest clinically similar to the deficiency of a given hormone itself,... (Review)
Review
Metabolic disorders deriving from the non-responsiveness of target organs to hormones, which manifest clinically similar to the deficiency of a given hormone itself, derive from molecular alterations affecting specific hormone receptors. Pseudohypoparathyroidism (PHP) and related disorders exemplify 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 cAMP signaling pathway, or, as more recently described, of downstream effector proteins of the same pathway, such as PKA regulatory subunit 1A (R1A) and phosphodyestarase type 4D (PDE4D). In this group of diseases, resistance to hormones such as PTH, TSH, gonadotropins and GHRH may be variably present, so that the clinical and molecular overlap among these different but related disorders represents a challenge for endocrinologists as to differential diagnosis and genetic counseling. This review will describe the presenting features of multiple resistance in PHP and related disorders, focusing on both our current understanding and future challenges.
Topics: Drug Resistance; Endocrine System Diseases; Hormones; Humans; Parathyroid Hormone; Pseudohypoparathyroidism; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 29678282
DOI: 10.1016/j.beem.2018.01.002