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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 -
Practical Neurology Jun 2023
Topics: Humans; Metacarpal Bones; Basal Ganglia Diseases; Pseudohypoparathyroidism; Calcinosis; Basal Ganglia
PubMed: 36593114
DOI: 10.1136/pn-2022-003647 -
Zhonghua Yi Xue Yi Chuan Xue Za Zhi =... Jan 2023To explore the genetic etiology of a Chinese pedigree affected with pseudohypoparathyroidism.
OBJECTIVE
To explore the genetic etiology of a Chinese pedigree affected with pseudohypoparathyroidism.
METHODS
Peripheral blood samples of the proband and his parents were collected and subjected to trio-whole exome sequencing (trio-WES). Candidate variants were verified among the pedigree and 50 randomly selected healthy individuals through analysis of restriction fragment length polymorphism. Short tandem repeat (STR) linkage analysis was used to verify the parental origin of the pathogenic variants.
RESULTS
Trio-WES and Sanger sequencing showed that the proband and his mother had both harbored a c.121C>G (p.His41Asp) variant of the GNAS gene, which was not found in other family members and the 50 healthy controls. The variant was not found in international databases. Based on guidelines from the American College of Medical Genetics and Genomics, the variant was predicted to be likely pathogenic.
CONCLUSION
The novel c.121C>G variant of the GNAS gene probably underlay the disease in this pedigree. Above finding has enriched the spectrum of GNAS gene variants.
Topics: Female; Humans; Pedigree; East Asian People; Mothers; Exome Sequencing; Pseudohypoparathyroidism; Mutation; China; Chromogranins; GTP-Binding Protein alpha Subunits, Gs
PubMed: 36584997
DOI: 10.3760/cma.j.cn511374-20211220-01008 -
Diagnostics (Basel, Switzerland) Nov 2022Pseudo-anodontia consists in the clinical, not radiographic, absence of teeth, due to failure in their eruption. It has been reported as part of an extremely rare...
Pseudo-anodontia consists in the clinical, not radiographic, absence of teeth, due to failure in their eruption. It has been reported as part of an extremely rare syndrome, named GAPO syndrome. Pseudo-hypoparathyroidism type 1a (PHPT-1a) is a rare condition, characterized by resistance to the parathyroid hormone (PTH), as well as to many other hormones, and resulting in hypocalcemia, hyperphosphatemia, and elevated PTH. We report here the case of a 32-year-old woman with a long-standing history of non-treated hypocalcemia, in the context of an undiagnosed PHPT-1a. She had an intellectual disability, showed clinical features of the Albright hereditary osteodystrophy (AHO) and presented signs of multiple hormone resistances. She received treatment for seizures since the age of six. Examination of her mouth revealed a complete absence of teeth. Treatment of hypocalcemia and hormone deficiencies were started only at 29 years of age. Genetic testing demonstrated the presence of a frameshift variant in the gene in the proband as well as in her mother. A Single Nucleotide Polymorphism (SNP) array analysis failed to demonstrate pathogenic copy number variants (CNVs) but showed several regions with loss of heterozygosity (LOHs) for a final percentage of 1.75%, compatible with a fifth degree of relationship. Clinical exome sequencing (CES) ruled out any damaging variants in all the teeth agenesis-related genes. In conclusion, although we performed an extensive genetic analysis in search of possible additional gene alterations that could explain the presence of the peculiar phenotypic characteristics observed in our patient, we could not find any additional genetic defects. Our results suggest that the association of genetically confirmed PHPT-1a and complete pseudo-anodontia associated with persistent patchy alopecia areata is a new additional nonclassical feature related to the pathogenic variant.
PubMed: 36553004
DOI: 10.3390/diagnostics12122997 -
Pseudohypoparathyroidism during pregnancy and the postpartum period: A case series of five patients.Frontiers in Endocrinology 2022Pseudohypoparathyroidism (PHP) is a rare disease, especially when combined with pregnancy. We aimed to explore the changes in serum calcium/parathyroid hormone (PTH)...
OBJECTIVES
Pseudohypoparathyroidism (PHP) is a rare disease, especially when combined with pregnancy. We aimed to explore the changes in serum calcium/parathyroid hormone (PTH) level and medical treatment in a case series of PHP during pregnancy and the postpartum period.
METHODS
A total of five PHP patients with six pregnancies were enrolled. The classification of PHP was based on (epi)genetic analysis. Clinical characteristics, biochemical indices, and treatment strategies before, during, and after pregnancy were retrospectively collected.
RESULTS
All patients received calcium and vitamin D agents with nearly normal serum calcium before pregnancy except patient 2 who was found hypocalcemic during gestation. All patients chose Cesarean section, and one suffered preterm delivery due to oligoamnios. The neonatal birth weight ranged from 2,250 to 4,300 g, and all neonates were free of hypocalcemia-related symptoms. The change in calcium metabolism was inconsistent including stable, improved, or worsened during pregnancy. Serum PTH level remained low in the first two trimesters in patients with stable and improved conditions while increased in the last two trimesters in patients with a worsened condition. Serum calcium changed inconsistently while PTH increased consistently during lactation. For patients who did not breastfeed, calcium homeostasis improved after delivery.
CONCLUSION
Calcium homeostasis and medicine dosage changed differently in PHP patients during pregnancy and lactation. However, most patients had good pregnancy outcomes. Serum PTH levels might predict changes in calcium metabolism during pregnancy.
Topics: Pregnancy; Infant, Newborn; Humans; Female; Calcium; Cesarean Section; Retrospective Studies; Pseudohypoparathyroidism; Postpartum Period; Bone Density Conservation Agents
PubMed: 36465610
DOI: 10.3389/fendo.2022.1050305 -
Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... Oct 2022Pseudohypoparayhyroidism (PHP) is a rare autosomal dominant or recessive genetic disorder characterized by low calcium, high phosphorus, and target organ resistance to...
Pseudohypoparayhyroidism (PHP) is a rare autosomal dominant or recessive genetic disorder characterized by low calcium, high phosphorus, and target organ resistance to parathyroid. The clinical characteristics and genetic features in 4 patients with Type Ib PHP in the Third Xiangya Hospital, Central South University, have been reviewed. All 4 patients had low calcium, high phosphorus, and parathyroid resistance. Among them, 2 patients had slightly elevated thyroid stimulating hormone and mild features of Albright's hereditary osteodystrophy, and one patient had hypokalemia. No guanine nucleotide-binding protein alpha-stimulating activity polypeptide 1 () and gene variant associated with hypokalemia were identified using the whole exome sequencing. The results of the methylation-specific multiple ligation-dependent probe amplification showed that there were abnormal methylation of the upstream differentially methylated regions of in the 4 patients. There were phenotype overlap among the various subtypes of PHP. Detection of gene methylation in patients with clinical suspicion of Type Ib PHP is helpful for the diagnosis and treatment of PHP.
Topics: Humans; Chromogranins; GTP-Binding Protein alpha Subunits, Gs; Hypokalemia; Calcium; Pseudohypoparathyroidism; Phosphorus
PubMed: 36411698
DOI: 10.11817/j.issn.1672-7347.2022.220029 -
Bone Reports Dec 2022Pseudohypoparathyroidism 1A (PHP1A) and pseudopseudohypoparathyroidism (PPHP) are caused by loss-of-function variants of , which encodes Gsα. We present two unrelated...
Pathogenic variants of the gene introduce an abnormal amino acid sequence in the β6 strand/α5 helix of Gsα, causing pseudohypoparathyroidism type 1A and pseudopseudohypoparathyroidism in two unrelated Japanese families.
Pseudohypoparathyroidism 1A (PHP1A) and pseudopseudohypoparathyroidism (PPHP) are caused by loss-of-function variants of , which encodes Gsα. We present two unrelated Japanese families with PHP1A and PPHP harboring unreported pathogenic variants of (c.1141delG, p.Asp381Thrfs*23 and c.1117delC, p.Arg373Alafs*31). These variants introduce abnormal amino acids in the β6 strand/α5 helix of Gsα, which interact with G protein coupling receptor (GPCR). We conclude that these variants alter the association of Gsα with GPCR and cause PHP1A or PPHP.
PubMed: 36407415
DOI: 10.1016/j.bonr.2022.101637 -
Annales D'endocrinologie Dec 2022
Topics: Humans; Hypokalemia; Pseudohypoparathyroidism; DNA Methylation; GTP-Binding Protein alpha Subunits, Gs; Chromogranins
PubMed: 36371350
DOI: 10.1016/j.ando.2022.09.022 -
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 -
Endocrine Dec 2022The application of the third-generation parathyroid hormone (PTH) assay [PTH(1-84) assay] for evaluating PTH levels in patients with pseudohypoparathyroidism type-1...
Full-length versus intact PTH concentrations in pseudohypoparathyroidism type 1 and primary hyperparathyroidism: clinical evaluation of immunoassays in individuals from China.
PURPOSE
The application of the third-generation parathyroid hormone (PTH) assay [PTH(1-84) assay] for evaluating PTH levels in patients with pseudohypoparathyroidism type-1 (PHP1) is less popular than the second-generation assay. Therefore, we aimed at examining the conformity between the PTH(1-84) assay and the intact PTH (iPTH) assay, specifically examining their performance in individuals with PHP1 versus individuals with primary hyperparathyroidism (PHPT), compared to healthy controls.
METHODS
PTH(1-84) and iPTH assay were performed in patients with PHP1, patients with PHPT, and healthy volunteers. ∆PTH%, PTH(1-84)/iPTH (3/2 ratio), iPTH/upper limit of normal (ULN), and PTH (1-84)/ULN of each group were calculated for comparison. Linear regression, Kappa conformity test, and Bland-Altman analysis of ∆PTH/mean of iPTH and PTH(1-84) (percent bias) plotted against the mean of iPTH and PTH(1-84) were performed to determine the conformance of PTH(1-84) assay with iPTH assay.
RESULTS
A total of 54 patients with PHP1, 127 patients with PHPT, and 65 healthy volunteers were enrolled in this study. All the three groups showed strong linear relationship between iPTH and PTH (1-84) (r = 0.9661, 0.7733, and 0.9575, respectively). No significant differences were noted in 3/2 ratio (median 0.76 vs. 0.72) between the PHP1 and PHPT groups (p > 0.05). Conformity examination showed the Kappa value was 0.778 and 0.395 for PHP1 and PHPT groups respectively. No difference in the Kappa values was found between PHP1A and PHP1B subgroups. Bland-Altman plot demonstrated that the proportion of data points that were plotted within mean ± 1.96 SD in PHP1, PHPT and normal control groups were 96.3%, 93.7%, and 98.5%, respectively. The mean percent bias of the three groups were 26.1%, 31.2%, and 17.0%, respectively. The range of mean ± 1.96 SD of percent bias of the three groups were 2.2%-50.0%, -14.3%-76.6%, and 6.7%-27.2%, respectively.
CONCLUSION
Although iPTH and PTH(1-84) values were both lower in the present PHP1 cohort than in the PHPT cohort, there appear to be differences in the relative agreement between both immunoassays, and in the relationship between the two values, especially in comparison to healthy controls. Whether these differences are due to differential accumulation of C-terminal fragments or other factors requires further study.
Topics: Humans; Hyperparathyroidism, Primary; Parathyroid Hormone; Immunoassay; Pseudohypoparathyroidism; Linear Models; Calcium
PubMed: 36220966
DOI: 10.1007/s12020-022-03204-7