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Human Mutation Jan 2015Pseudohypoparathyroidism type 1a (PHP1a) is characterized by hypocalcaemia and hyperphosphatemia due to parathyroid hormone resistance, in association with the features... (Review)
Review
Pseudohypoparathyroidism type 1a (PHP1a) is characterized by hypocalcaemia and hyperphosphatemia due to parathyroid hormone resistance, in association with the features of Albright's hereditary osteodystrophy (AHO). PHP1a is caused by maternally inherited inactivating mutations of Gs-alpha, which is encoded by a complex imprinted locus termed GNAS. Paternally inherited mutations can lead either to pseudopseudohypoparathyroidism (PPHP) characterized by AHO alone, or to progressive osseous heteroplasia (POH), characterized by severe heterotopic ossification. The clinical aspects and molecular genetics of PHP1a and its related disorders are reviewed together with the 343 kindreds with Gs-alpha germline mutations reported so far in the literature. These 343 (176 different) mutations are scattered throughout the 13 exons that encode Gs-alpha and consist of 44.9% frameshift, 28.0% missense, 14.0% nonsense, and 9.0% splice-site mutations, 3.2% in-frame deletions or insertions, and 0.9% whole or partial gene deletions. Frameshift and other highly disruptive mutations were more frequent in the reported 37 POH kindreds than in PHP1a/PPHP kindreds (97.3% vs. 68.7%, P < 0.0001). This mutation update and respective genotype-phenotype data may be of use for diagnostic and research purposes and contribute to a better understanding of these complex disorders.
Topics: Animals; Bone Diseases, Metabolic; Chromogranins; GTP-Binding Protein alpha Subunits, Gs; Genetic Association Studies; Genetic Predisposition to Disease; Genomic Imprinting; Humans; Mutation; Ossification, Heterotopic; Pseudohypoparathyroidism; Skin Diseases, Genetic
PubMed: 25219572
DOI: 10.1002/humu.22696 -
Journal of Clinical and Diagnostic... Sep 2014
PubMed: 25386477
DOI: 10.7860/JCDR/2014/8197.4897 -
Molecular Genetics & Genomic Medicine Oct 2020Paroxysmal kinesigenic dyskinesia (PKD) and epilepsy share common pathogenic mechanisms but their pathophysiological connections remain unknown. Our study reports an...
BACKGROUND
Paroxysmal kinesigenic dyskinesia (PKD) and epilepsy share common pathogenic mechanisms but their pathophysiological connections remain unknown. Our study reports an individual with both disorders as a consequence of pseudohypoparathyroidism (PHP). This observation suggests potential shared pathophysiological mechanisms between PKD and epilepsy.
METHODS
We report the case of a 15-year-old male with pre-diagnosed PKD and symptomatic epilepsy. We recorded the symptoms and carried out comprehensive biochemical, genetic, imaging, and EEG analyses to examine the characteristics and potentially shared etiology of these conditions.
RESULTS
In this case, the patient's PKD and symptomatic epilepsy were secondary to pseudohypoparathyroidism (PHP). The patient had a seven-year history of intermittent, involuntary paroxysmal episodic movements, and a six-year history of a loss of consciousness with convulsions. The electroencephalography results showed that the paroxysmal low and medium amplitude slow waves, isolated sharp waves, and sharp slow-wave release occurred in the right prefrontal temporal cortex. Serum analysis indicated a calcium concentration of 1.91 mmol/L, a phosphorus concentration of 2.68 mmol/L, an alkaline phosphatase concentration of 114 IU/L, and a parathyroid hormone concentration of 109 pg/ml. Computerized tomography and magnetic resonance imaging results showed multiple calcifications in the bilateral frontal and parietal lobe cortex, bilateral thalamus, basal ganglia, and centrum semiovale. Furthermore, GNAS methylation abnormalities were discovered during methylation testing. There was no recurrence of abnormal movements or epileptic seizures, and calcium concentrations returned to healthy levels, following the pharmacological treatment of PHP.
CONCLUSION
In this case, PKD and symptomatic epilepsy were caused by PHP. This report underscores the importance of looking for biochemical abnormalities in PKD and symptomatic epilepsy patients. We suggest that all such intractable epilepsy seizure patients should be screened for PHP.
Topics: Adolescent; Brain; Calcium; Chorea; Chromogranins; DNA Methylation; Epilepsy; GTP-Binding Protein alpha Subunits, Gs; Humans; Male; Pseudohypoparathyroidism
PubMed: 32715645
DOI: 10.1002/mgg3.1423 -
Archives of Endocrinology and Metabolism 2016To identify a clinical profile and laboratory findings of a cohort of hypoparathyroidism patients and determine the prevalence and predictors for renal abnormalities. (Observational Study)
Observational Study
OBJECTIVES
To identify a clinical profile and laboratory findings of a cohort of hypoparathyroidism patients and determine the prevalence and predictors for renal abnormalities.
MATERIALS AND METHODS
Data from medical records of five different visits were obtained, focusing on therapeutic doses of calcium and vitamin D, on laboratory tests and renal ultrasonography (USG).
RESULTS
Fifty-five patients were identified, 42 females and 13 males; mean age of 44.5 and average time of the disease of 11.2 years. The most frequent etiology was post-surgical. Levels of serum calcium and creatinine increased between the first and last visits (p < 0.001 and p < 0.05, respectively); and serum levels of phosphate decreased during the same period (p < 0.001). Out of the 55 patients, 40 had USG, and 10 (25%) presented with kidney calcifications. There was no significant difference in the amount of calcium and vitamin D doses among patients with kidney calcifications and others. No correlation between serum and urinary levels of calcium and the presence of calcification was found. Urinary calcium excretion in 24h was significantly higher in patients with kidney calcification (3.3 mg/kg/d) than in those without calcification (1.8 mg/kg/d) (p < 0.05).
CONCLUSIONS
The reduction of hypocalcemia and hyperphosphatemia suggest an effectiveness of the treatment, and the increase in serum creatinine demonstrates an impairment of renal function during follow-up. Kidney calcifications were prevalent in this cohort, and higher urinary calcium excretion, even if still within the normal range, was associated with development of calcification. These findings suggest that lower rates of urinary calcium excretion should be aimed for in the management of hypoparathyroidism.
Topics: Adult; Calcinosis; Calcium; Creatinine; Female; Humans; Hypoparathyroidism; Kidney Diseases; Male; Middle Aged; Nephrocalcinosis; Phosphates; Pseudohypoparathyroidism; Retrospective Studies; Ultrasonography; Vitamin D
PubMed: 27901178
DOI: 10.1590/2359-3997000000221 -
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 -
Clinical Endocrinology Oct 2022Disorders of calcium homeostasis are the most frequent metabolic bone and mineral disease encountered by endocrinologists. These disorders usually manifest as primary... (Review)
Review
Disorders of calcium homeostasis are the most frequent metabolic bone and mineral disease encountered by endocrinologists. These disorders usually manifest as primary hyperparathyroidism (PHPT) or hypoparathyroidism (HP), which have a monogenic aetiology in 5%-10% of cases, and may occur as an isolated endocrinopathy, or as part of a complex syndrome. The recognition and diagnosis of these disorders is important to facilitate the most appropriate management of the patient, with regard to both the calcium-related phenotype and any associated clinical features, and also to allow the identification of other family members who may be at risk of disease. Genetic testing forms an important tool in the investigation of PHPT and HP patients and is usually reserved for those deemed to be an increased risk of a monogenic disorder. However, identifying those suitable for testing requires a thorough clinical evaluation of the patient, as well as an understanding of the diversity of relevant phenotypes and their genetic basis. This review aims to provide an overview of the genetic basis of monogenic metabolic bone and mineral disorders, primarily focusing on those associated with abnormal calcium homeostasis, and aims to provide a practical guide to the implementation of genetic testing in the clinic.
Topics: Calcium; Calcium, Dietary; Humans; Hypercalcemia; Hyperparathyroidism, Primary; Phenotype; Receptors, Calcium-Sensing
PubMed: 34935164
DOI: 10.1111/cen.14644 -
Anales de Pediatria Aug 2023Pseudohypoparathyroidism (PHP) is a spectrum of diseases characterized by insensitivity of target tissues to the action of parathyroid hormone and, consequently, by the...
Pseudohypoparathyroidism (PHP) is a spectrum of diseases characterized by insensitivity of target tissues to the action of parathyroid hormone and, consequently, by the presence of hyperphosphatemia and hypocalcaemia of varying severity. Early-onset obesity is a feature of PHP type 1A. This article discusses the need to establish uniform criteria to guide the nutritional management of patients with PHP. A decrease in energy expenditure calls for an adjustment of the energy content of the diet. Reducing the intake of foods rich in inorganic phosphorus helps to manage hyperphosphataemia. Targeted nutrition should be part of the treatment plan of children and adolescents with PHP, since it contributes to modulating the calcium and phosphorus metabolism imbalances characteristic of these patients.
Topics: Adolescent; Child; Humans; Pseudohypoparathyroidism; Parathyroid Hormone; Nutritional Status; Phosphorus
PubMed: 37481364
DOI: 10.1016/j.anpede.2023.05.007 -
Endocrine Connections Oct 2022This study aimed to report on 15 Japanese patients with acrodysostosis and pseudohypoparathyroidism (PHP) and analyze them using the newly proposed classification of the...
OBJECTIVE
This study aimed to report on 15 Japanese patients with acrodysostosis and pseudohypoparathyroidism (PHP) and analyze them using the newly proposed classification of the EuroPHP network to determine whether this classification system is suitable for Japanese patients.
DESIGN
We divided the patients into three groups based on hormone resistance, the number of fingers with short metacarpals, the existence of cone-shaped epiphyses and gene defects.
METHODS
We carried out clinical, radiological and genetic evaluations of two patients in group A (iPPSD5), six patients in group B (iPPDS4) and seven patients in group C (iPPSD2).
RESULTS
Group A consisted of two siblings without hormone resistance who had the most severe bone and physical developmental delays. PDE4D gene defects were detected in both cases. Group B consisted of six patients who showed hormone resistance without hypocalcemia. Short metacarpal bones with corn-shaped epiphyses were observed in all patients. In two cases, PRKAR1A gene defects were detected; however, their clinical and radiological features were not identical. The facial dysmorphism and developmental delay were less severe and PRKAR1A gene defects were detected in case B-3. Severe facial dysmorphism and deformity of metacarpal bones were observed, but no gene defect was detected in case B-1. Group C consisted of seven patients with PHP1a, four of whom had maternally inherited heterozygous inactivating mutations in one of the GNAS genes. The clinical and radiological features of the patients in group C were not identical either.
CONCLUSIONS
The newly proposed classification is suitable for Japanese patients; however, heterogeneities still existed within groups B and C.
PubMed: 36006853
DOI: 10.1530/EC-22-0151 -
Orphanet Journal of Rare Diseases Oct 2021Hypoparathyroidism (HypoPT) or pseudo-hypoparathyroidism (pseudo-HypoPT) during pregnancy may cause maternal and fetal/neonatal complications. In this regard, only a few... (Observational Study)
Observational Study
BACKGROUND
Hypoparathyroidism (HypoPT) or pseudo-hypoparathyroidism (pseudo-HypoPT) during pregnancy may cause maternal and fetal/neonatal complications. In this regard, only a few case reports or case series of pregnant or lactating women have been published. The purpose of this study was to describe clinical and biochemical course, pharmacological management, and potential adverse events during pregnancy and post-partum in pregnant women with HypoPT or pseudo-HypoPT. This was a retrospective, observational, multicenter, study involving nine Italian referral centers for endocrine diseases affiliated with the Italian Society of Endocrinology and involved in "Hypoparathyroidism Working Group".
RESULTS
This study identified a cohort of 28 women (followed between 2005 and 2018) with HypoPT (n = 25, 84% postsurgical, 16% idiopathic/autoimmune) and pseudo-HypoPT (n = 3). In HypoPT women, the mean calcium carbonate dose tended to increase gradually from the first to third trimester (+ 12.6%) in pregnancy. This average increase in the third trimester was significantly greater compared to the pre-pregnancy period (p value = 0.03). However, analyzing the individual cases, in 44% the mean calcium dosage remained unchanged throughout gestation. Mean calcitriol doses tended to increase during pregnancy, with a statistically significant increase between the third trimester and the pre-pregnancy period (p value = 0.02). Nevertheless, analyzing the individual cases, in the third trimester most women with HypoPT (64%) maintained the same dosage of calcitriol compared to the first trimester. Both mean calcium carbonate and calcitriol doses tended to decrease from the third trimester to the post-partum six months. Most identified women (~ 70%) did not display maternal complications and (~ 90%) maintained mean serum albumin-corrected total calcium levels within the low-to-mid normal reference range (8.5 ± 0.8 mg/dl) during pregnancy. The main complications related to pregnancy period included: preterm birth (n = 3 HypoPT women), and history of miscarriages (n = 6 HypoPT women and n = 2 pseudo-HypoPT women).
CONCLUSION
This study shows that mean serum albumin-corrected total calcium levels were carefully monitored during pregnancy and post-pregnancy, with limited evaluation of other biochemical parameters, such as serum phosphate, 24 h urinary calcium, 25-OH vitamin D, and creatinine clearance. To avoid complications in mothers affected by (HypoPT) or (pseudo-HypoPT) and offspring, intense biochemical, clinical and pharmacological monitoring during pregnancy and breastfeeding is highly recommended.
Topics: Female; Humans; Hypoparathyroidism; Infant, Newborn; Italy; Lactation; Pregnancy; Premature Birth; Pseudohypoparathyroidism
PubMed: 34627337
DOI: 10.1186/s13023-021-02053-3 -
BMJ Case Reports Nov 2013
Topics: Adolescent; Basal Ganglia Diseases; Brain; Calcinosis; Female; Humans; Neurodegenerative Diseases; Pseudohypoparathyroidism; Seizures; Tomography, X-Ray Computed
PubMed: 24272987
DOI: 10.1136/bcr-2013-201556