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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 -
Journal of the Endocrine Society Dec 2021Pseudohypoparathyroidism (PHP) is a rare hormone resistance syndrome caused by mutations in . This cross-sectional study investigated whether PHP patients with...
Pseudohypoparathyroidism (PHP) is a rare hormone resistance syndrome caused by mutations in . This cross-sectional study investigated whether PHP patients with parathyroid hormone (PTH), thyrotropin (thyroid stimulating hormone; TSH), and free thyroxine (T4) levels at goal required higher doses of levothyroxine and calcitriol than recommended by current guidelines to overcome mineral ion abnormalities due to hormone resistance. Baseline demographic and clinical data of participants enrolled in PHP research studies between 2012-2021 were collected via retrospective chart review. Longitudinally, data were recorded at a maximum frequency of once a year starting at 1 year of age. The PTH at goal (PAG) group was defined as PTH < 150 pg/mL and calcium ≥ 8.4 mg/dL, and the TSH and free T4 at goal (TAG) group was defined as TSH < 5 mIU/L and free T4 ≥ 0.8 ng/dL. The PAG group (n = 74) was prescribed higher calcitriol doses than the PTH not at goal (PNAG) group (n = 50) (0.9 ± 1.1 vs 0.5 ± 0.9 mcg/day, = 0.04) and 21% of individual patients were prescribed ≥ 1.5 mcg of calcitriol daily. This remained true after normalization for body weight (0.013 ± 0.015 vs 0.0067 ± 0.0095 mcg/kg/day, = 0.008). There was no statistically significant difference in levothyroxine dosing between the TAG group (n = 122) and TSH and free T4 not at goal (TNAG) group (n = 45) when normalized for weight (2.0 ± 0.7 vs 1.8 ± 0.7 mcg/kg/day, = 0.2). More than one-third of patients with PHP had PTH levels not at goal and some patients required calcitriol doses ≥ 1.5 mcg/day to meet current treatment goals.
PubMed: 34765856
DOI: 10.1210/jendso/bvab161 -
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 -
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 -
Journal of Clinical Research in... Mar 2020Imprinting disorders are a group of congenital diseases caused by dysregulation of genomic imprinting, affecting prenatal and postnatal growth, neurocognitive... (Review)
Review
Imprinting disorders are a group of congenital diseases caused by dysregulation of genomic imprinting, affecting prenatal and postnatal growth, neurocognitive development, metabolism and cancer predisposition. Aberrant expression of imprinted genes can be achieved through different mechanisms, classified into epigenetic - if not involving DNA sequence change - or genetic in the case of altered genomic sequence. Despite the underlying mechanism, the phenotype depends on the parental allele affected and opposite phenotypes may result depending on the involvement of the maternal or the paternal chromosome. Imprinting disorders are largely underdiagnosed because of the broad range of clinical signs, the overlap of presentation among different disorders, the presence of mild phenotypes, the mitigation of the phenotype with age and the limited availability of molecular techniques employed for diagnosis. This review briefly illustrates the currently known human imprinting disorders, highlighting endocrinological aspects of pediatric interest.
Topics: Abnormalities, Multiple; Child; Diabetes Mellitus; Genomic Imprinting; Humans; Infant, Newborn, Diseases; Intellectual Disability; Pseudohypoparathyroidism; Puberty, Precocious; Syndrome; Uniparental Disomy
PubMed: 30968677
DOI: 10.4274/jcrpe.galenos.2019.2018.0249 -
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 -
Endocrine Connections May 2021'Snow White and the Seven Dwarfs', a fairytale that is widely known across the Western world, was originally written by the Brothers Grimm, and published in 1812 as... (Review)
Review
'Snow White and the Seven Dwarfs', a fairytale that is widely known across the Western world, was originally written by the Brothers Grimm, and published in 1812 as 'Snow White'. Though each dwarf was first given an individual name in the 1912 Broadway play, in Walt Disney's 1937 film 'Snow White and the Seven Dwarfs', they were renamed, and the dwarfs have become household names. It is well known that myths, fables, and fairytales, though appearing to be merely children's tales about fictional magical beings and places, have, more often than not, originated from real facts. Therefore, the presence of the seven brothers with short stature in the story is, from an endocrinological point of view, highly intriguing, in fact, thrilling. The diversity of the phenotypes among the seven dwarfs is also stimulating, although puzzling. We undertook a differential diagnosis of their common underlying disorder based on the original Disney production's drawings and the unique characteristics of these little gentlemen, while we additionally evaluated several causes of short stature and, focusing on endocrine disorders that could lead to these clinical features among siblings, we have, we believe, been able to reveal the underlying disease depicted in this archetypal tale.
PubMed: 33878729
DOI: 10.1530/EC-20-0615 -
JCEM Case Reports Nov 2023Fahr syndrome is a rare neurologic disorder, usually affecting young and middle-aged adults, that can present with symptoms ranging from extrapyramidal to...
Fahr syndrome is a rare neurologic disorder, usually affecting young and middle-aged adults, that can present with symptoms ranging from extrapyramidal to neuropsychiatric abnormalities. Pseudohypoparathyroidism (PHP), characterized by parathyroid hormone (PTH)-resistance or PTH-unresponsiveness at target organs, is associated with Fahr syndrome and typically presents with hypocalcemia. The following case presents a 39-year-old-woman with PHP complicated by symptomatic hypocalcemia, hypokalemia, and movement disturbances, who had computed tomography imaging showing basal ganglia calcifications consistent with Fahr syndrome. She initially presented with headache and was hospitalized for hypertensive emergency and severe hypocalcemia. Examination, including the neurologic examination, was unrevealing aside from hypertension and central adiposity. Laboratory tests were consistent with PHP, showing hypocalcemia with elevated PTH, and negative for hyperaldosteronism. Management of hypocalcemia consisted of intravenous calcium infusion, oral calcium carbonate, oral vitamin D3, and oral calcitriol. Patients with severe hypocalcemia and elevated PTH who present with new neurological symptoms despite normal general neurologic examination may warrant consideration for brain imaging to evaluate for Fahr syndrome. Further investigations are necessary to determine the prevalence of Fahr syndrome and hypokalemia in patients with PHP, explore if these findings are significantly associated with PHP-1b subtype, and ultimately inform potential new screening pathways for these patients.
PubMed: 38045865
DOI: 10.1210/jcemcr/luad147 -
Biomedical Papers of the Medical... Dec 2023Obesity has become a serious medical condition where many factors can contribute to excess weight gain. The most common type of childhood obesity is simple obesity,... (Review)
Review
Obesity has become a serious medical condition where many factors can contribute to excess weight gain. The most common type of childhood obesity is simple obesity, which is due to gene-obesogenic environment interaction. Only a minority are due to pathological causes. Secondary causes of obesity, while less common, include these: genetic syndromes, drug-related obesity, as well as endocrine disorders (hypothyroidism, Cushing's syndrome, growth hormone deficiency, hypogonadism, pseudohypoparathyroidism type Ia, insulinoma, hypothalamic obesity and polycystic ovary syndrome). Given that some conditions may be treatable, physicians must be aware of obesity due to endocrinopathies and distinguish them from simple obesity, and treat them properly. Although rare among children, early detection of the endocrine cause of obesity leads to reduced morbidity and, in some cases, reduced mortality in these individuals. The aim of this review is to summarize the current findings on obesity-related endocrinopathies in children (illustrated by clinical examples), highlighting aspects of pathogenetic mechanisms, genetics, the clinical diagnosis, growth, body mass index and possible therapeutic approaches. Early detection and correction of endocrine obesity is of paramount importance for obese children who could benefit from timely diagnosis and an improved management of obesity as many disturbances related to obesity can be reversed at the early stage, if weight loss is achieved.
Topics: Female; Child; Adolescent; Humans; Pediatric Obesity; Overweight; Endocrine System Diseases; Hypothyroidism; Obesity, Morbid
PubMed: 37712247
DOI: 10.5507/bp.2023.036