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Acta Bio-medica : Atenei Parmensis Jun 2022Pseudohypoparathyroidism (PHP) is a rare disease, which can occur in the youth, characterized by hypocalcemia and hyperphosphatemia due to resistance to parathyroid...
BACKGROUND AND AIM
Pseudohypoparathyroidism (PHP) is a rare disease, which can occur in the youth, characterized by hypocalcemia and hyperphosphatemia due to resistance to parathyroid hormone (PTH) in target organs. This condition encompasses different conditions which differ between one another by different clinical, biochemically, and genetic features.
METHODS
Herein we report the clinical history of a boy with PHP1B with an interesting clinical presentation. He came in fact to the attention of the Emergency Department because of a spontaneously resolving epileptic attack, lasting about 15 minutes, characterized by loss of consciousness, fall to the ground, tonic-clonic shocks, and sphincter release. Moreover, the personal history was characterized by congenital long QT syndrome (LQTS), with a documented mutation of the KCNQ1 gene, treated with beta-blockers (nadolol).
RESULTS
The simultaneous presence of symptomatic acute hypocalcemia and long QT syndrome undoubtedly required particular attention both in the management of the onset and in the more in-depth subsequent diagnostics. In this regard, laboratory tests and molecular analyzes have proved to be crucial in the diagnostic process. Conclusions: this case underlines the diagnostic path complexity in patients with PTH elevation and the importance of considering all the possible differential diagnoses in order to undertake a timely and correct course of treatment.
Topics: Adolescent; Humans; Hyperphosphatemia; Hypocalcemia; Long QT Syndrome; Male; Parathyroid Hormone; Pseudohypoparathyroidism
PubMed: 35666115
DOI: 10.23750/abm.v93iS3.13072 -
The Journal of Clinical Investigation Apr 2023Genetic defects of GNAS, the imprinted gene encoding the stimulatory G protein α-subunit, are responsible for multiple diseases. Abnormal GNAS imprinting causes...
Genetic defects of GNAS, the imprinted gene encoding the stimulatory G protein α-subunit, are responsible for multiple diseases. Abnormal GNAS imprinting causes pseudohypoparathyroidism type 1B (PHP1B), a prototype of mammalian end-organ hormone resistance. Hypomethylation at the maternally methylated GNAS A/B region is the only shared defect in patients with PHP1B. In autosomal dominant (AD) PHP1B kindreds, A/B hypomethylation is associated with maternal microdeletions at either the GNAS NESP55 differentially methylated region or the STX16 gene located approximately 170 kb upstream. Functional evidence is meager regarding the causality of these microdeletions. Moreover, the mechanisms linking A/B methylation and the putative imprinting control regions (ICRs) NESP-ICR and STX16-ICR remain unknown. Here, we generated a human embryonic stem cell model of AD-PHP1B by introducing ICR deletions using CRISPR/Cas9. With this model, we showed that the NESP-ICR is required for methylation and transcriptional silencing of A/B on the maternal allele. We also found that the SXT16-ICR is a long-range enhancer of NESP55 transcription, which originates from the maternal NESP-ICR. Furthermore, we demonstrated that the STX16-ICR is an embryonic stage-specific enhancer enabled by the direct binding of pluripotency factors. Our findings uncover an essential GNAS imprinting control mechanism and advance the molecular understanding of PHP1B pathogenesis.
Topics: Animals; Humans; Darbepoetin alfa; Chromogranins; Pseudohypoparathyroidism; GTP-Binding Protein alpha Subunits, Gs; DNA Methylation; Genomic Imprinting; Mammals
PubMed: 36853809
DOI: 10.1172/JCI167953 -
European Journal of Endocrinology Dec 2016Disorders caused by impairments in the parathyroid hormone (PTH) signalling pathway are historically classified under the term pseudohypoparathyroidism (PHP), which... (Review)
Review
OBJECTIVE
Disorders caused by impairments in the parathyroid hormone (PTH) signalling pathway are historically classified under the term pseudohypoparathyroidism (PHP), which encompasses rare, related and highly heterogeneous diseases with demonstrated (epi)genetic causes. The actual classification is based on the presence or absence of specific clinical and biochemical signs together with an in vivo response to exogenous PTH and the results of an in vitro assay to measure Gsa protein activity. However, this classification disregards other related diseases such as acrodysostosis (ACRDYS) or progressive osseous heteroplasia (POH), as well as recent findings of clinical and genetic/epigenetic background of the different subtypes. Therefore, the EuroPHP network decided to develop a new classification that encompasses all disorders with impairments in PTH and/or PTHrP cAMP-mediated pathway.
DESIGN AND METHODS
Extensive review of the literature was performed. Several meetings were organised to discuss about a new, more effective and accurate way to describe disorders caused by abnormalities of the PTH/PTHrP signalling pathway.
RESULTS AND CONCLUSIONS
After determining the major and minor criteria to be considered for the diagnosis of these disorders, we proposed to group them under the term 'inactivating PTH/PTHrP signalling disorder' (iPPSD). This terminology: (i) defines the common mechanism responsible for all diseases; (ii) does not require a confirmed genetic defect; (iii) avoids ambiguous terms like 'pseudo' and (iv) eliminates the clinical or molecular overlap between diseases. We believe that the use of this nomenclature and classification will facilitate the development of rationale and comprehensive international guidelines for the diagnosis and treatment of iPPSDs.
Topics: Bone Diseases, Metabolic; Dysostoses; Europe; Humans; Intellectual Disability; Ossification, Heterotopic; Osteochondrodysplasias; Parathyroid Hormone; Parathyroid Hormone-Related Protein; Pseudohypoparathyroidism; Skin Diseases, Genetic
PubMed: 27401862
DOI: 10.1530/EJE-16-0107 -
Frontiers in Endocrinology 2022Pediatric obesity is a multifactorial disease which can be caused by underlying medical disorders arising from disruptions in the hypothalamic leptin-melanocortin... (Observational Study)
Observational Study
BACKGROUND
Pediatric obesity is a multifactorial disease which can be caused by underlying medical disorders arising from disruptions in the hypothalamic leptin-melanocortin pathway, which regulates satiety and energy expenditure.
AIM
To investigate and compare resting energy expenditure (REE) and body composition characteristics of children and adolescents with severe obesity with or without underlying medical causes.
METHODS
This prospective observational study included pediatric patients who underwent an extensive diagnostic workup in our academic centre that evaluated endocrine, non-syndromic and syndromic genetic, hypothalamic, and medication-induced causes of obesity. REE was assessed by indirect calorimetry; body composition by air displacement plethysmography. The ratio between measured REE (mREE) and predicted REE (Schofield equations), REE%, was calculated, with decreased mREE defined as REE% ≤90% and elevated mREE ≥110%. Additionally, the influence of fat-free-mass (FFM) on mREE was evaluated using multiple linear regression.
RESULTS
We included 292 patients (146 [50%] with body composition measurements), of which 218 (75%) patients had multifactorial obesity and 74 (25%) an underlying medical cause: non-syndromic and syndromic genetic (n= 29 and 28, respectively), hypothalamic (n= 10), and medication-induced (n= 7) obesity. Mean age was 10.8 ± 4.3 years, 59% were female, mean BMI SDS was 3.8 ± 1.1, indicating severe obesity. Mean REE% was higher in children with non-syndromic genetic obesity (107.4% ± 12.7) and lower in children with hypothalamic obesity (87.6% ± 14.2) compared to multifactorial obesity (100.5% ± 12.6, both p<0.01). In 9 children with pseudohypoparathyroidism type 1a, mean REE% was similar (100.4 ± 5.1). Across all patients, mREE was decreased in 60 (21%) patients and elevated in 69 (24%) patients. After adjustment for FFM, mREE did not differ between patients within each of the subgroups of underlying medical causes compared to multifactorial obesity (all p>0.05).
CONCLUSIONS
In this cohort of children with severe obesity due to various etiologies, large inter-individual differences in mREE were found. Consistent with previous studies, almost half of patients had decreased or elevated mREE. This knowledge is important for patient-tailored treatment, e.g. personalized dietary and physical activity interventions and consideration of pharmacotherapy affecting central energy expenditure regulation in children with decreased mREE.
Topics: Adolescent; Body Composition; Calorimetry, Indirect; Child; Energy Metabolism; Female; Humans; Male; Obesity, Morbid; Pediatric Obesity
PubMed: 35898454
DOI: 10.3389/fendo.2022.862817 -
BMC Oral Health Dec 2019Pseudohypoparathyroidism (PHP) is a rare and inherited disease caused by mutations in the GNAS-gene or upstream of the GNAS complex locus. It is characterized by...
BACKGROUND
Pseudohypoparathyroidism (PHP) is a rare and inherited disease caused by mutations in the GNAS-gene or upstream of the GNAS complex locus. It is characterized by end-organ resistance to PTH, resulting in hypocalcemia and hyperphosphatemia. We aimed to investigate the dental anomalies according to tooth types and the orthodontic characteristics of patients with PHP.
METHODS
Using a cross-sectional design, 29 patients (23 females) with PHP, living in Denmark, were included, and their clinical intraoral photos and radiographs were examined.
RESULTS
Pulp calcification was found in 76% of the patients. Blunting of root apex was present in 55% and shortening of root in 48% of the examined patients. Blunting and shortening of roots were seen more often in premolars than in other tooth types (p < 0.01). Crowding of lower anterior teeth was frequently observed (36%) as well as diastema in the upper arch (25%), midline diastema (18%), and Class III malocclusion (11%).
CONCLUSION
In the present study population, the teeth were frequently affected by pulp calcification and/or deviation of the root morphology. Blunting and shortening of root(s) were more often seen in premolars than in other tooth types. Class III malocclusion was relatively prevalent. It is important to pay attention to dental anomalies and occlusion in order to provide adequate care for patients with PHP.
Topics: Chromogranins; Cross-Sectional Studies; Denmark; Diastema; Female; GTP-Binding Protein alpha Subunits, Gs; Humans; Male; Malocclusion; Mutation; Pseudohypoparathyroidism; Tooth Abnormalities
PubMed: 31892351
DOI: 10.1186/s12903-019-0978-z -
BMC Medical Genomics Mar 2019Thousands of long non-coding RNA (lncRNA) genes are annotated in the human genome. Recent studies showed the key role of lncRNAs in a variety of fundamental cellular... (Review)
Review
BACKGROUND
Thousands of long non-coding RNA (lncRNA) genes are annotated in the human genome. Recent studies showed the key role of lncRNAs in a variety of fundamental cellular processes. Dysregulation of lncRNAs can drive tumorigenesis and they are now considered to be a promising therapeutic target in cancer. However, how lncRNAs contribute to the development of hereditary diseases in human is still mostly unknown.
RESULTS
This review is focused on hereditary diseases in the pathogenesis of which long non-coding RNAs play an important role.
CONCLUSIONS
Fundamental research in the field of molecular genetics of lncRNA is necessary for a more complete understanding of their significance. Future research will help translate this knowledge into clinical practice which will not only lead to an increase in the diagnostic rate but also in the future can help with the development of etiotropic treatments for hereditary diseases.
Topics: Angelman Syndrome; Beckwith-Wiedemann Syndrome; Biomarkers; Genetic Diseases, Inborn; Genome-Wide Association Study; Humans; Prader-Willi Syndrome; Pseudohypoparathyroidism; RNA, Long Noncoding; Silver-Russell Syndrome
PubMed: 30871545
DOI: 10.1186/s12920-019-0487-6 -
Endocrine Connections Jul 2020Hypoparathyroidism and pseudohypoparathyroidism are rare endocrine disorders, characterized by low serum calcium due to inappropriate parathyroid hormone (PTH) levels or...
Hypoparathyroidism and pseudohypoparathyroidism are rare endocrine disorders, characterized by low serum calcium due to inappropriate parathyroid hormone (PTH) levels or resistance to its action. There is little epidemiological information regarding chronic hypoparathyroidism in Russia. This study aims to build a registry database of Russian patients with chronic hypoparathyroidism who were referred for hospital treatment in order to conduct initial analysis of clinical presentations and hospital management. The Italian registry model was taken to be able to integrate our data in the future. Two hundred patients with hypoparathyroidism (n = 194) and pseudohypoparathyroidism (n = 6) were enrolled over 2 years (2017-2019). The most frequent cause of hypoparathyroidism was neck surgery (82.5%, mostly females), followed by idiopathic hypoparathyroidism (10%), syndromic forms of genetic hypoparathyroidism (4.5%) and forms of defective PTH action (3%). Calcium supplements and alfacalcidol were prescribed in most cases. However, a minority of patients (n = 6) needed to receive teriparatide as the only way to maintain calcium levels and to prevent symptoms of hypocalcemia. Consequently, substitution treatment with parathyroid hormone should be available in certain cases of hypoparathyroidism. This database will be useful to estimate the potential requirement for recombinant PTH in Russia and standards for clinical and therapeutic approaches.
PubMed: 32580149
DOI: 10.1530/EC-20-0219 -
Sudanese Journal of Paediatrics 2018Neonatal hypocalcemia is defined as serum calcium (S-Ca) < 2.0 mmol/l in full-term newborns and <1.75 mmol/l in preterm newborns. Neonatal hypocalcemia is either early...
Neonatal hypocalcemia is defined as serum calcium (S-Ca) < 2.0 mmol/l in full-term newborns and <1.75 mmol/l in preterm newborns. Neonatal hypocalcemia is either early onset (<3 days of age) or late onset (>3 days of age). Newborns with hypocalcemia are often asymptomatic but may present with hypotonia, apnea, poor feeding, jitteriness, seizures, and cardiac failure. Signs of hypocalcemia rarely occur unless S-Ca drops below 1.75 mmol/l. Neonatal hypocalcemia can be a result of hypoparathyroidism (transient or primary), increased serum calcitonin, sepsis, asphyxia, hepatopathy, hypomagnesemia, high phosphate load, transient hypoparathyroidism, and, rarely, transient neonatal pseudohypoparathyroidism [transient resistance to biological actions of parathyroid hormone (PTH)]. We present the case of three boys (two with gestational age 39 weeks, one 36 weeks; none of them with either asphyxia or sepsis) with mild hypotonia, where S-Ca in the range of 1.67-1.9 mmol/l was detected within the first 3 days of life, together with hyperphosphatemia [serum phosphate (P) 2.5-2.6 mmol/l], normomagnesemia [serum magnesium (S-Mg) 0.77-0.88 mmol/l], normal alkaline phosphatase (ALP) activity (2.8-4.5 μkat/l), and high serum PTH (40-51 pg/ml; normal = 5-28). In spite of the gradual increase of S-Ca, the elevated serum PTH persisted beyond days 3, 4, and 6 in all three boys, together with normal or low-to-normal S-Ca, high or normal-to-high serum P, and no increases in serum ALP. The mothers S-Ca, P, Mg, ALP, and PTH levels were within normal reference ranges. With regard to laboratory results, the diagnosis of transient neonatal pseudohypoparathyroidism (due to immaturity of PTH-receptors) is highly probable in these three neonates.
PubMed: 30799898
DOI: 10.24911/SJP.106-1516889879 -
BMC Endocrine Disorders May 2020Cardiac damage triggered by severe hypocalcemia is well known. However, the role of chronic hypoparathyroidism (HP) and pseudohypoparathyroidism (PHP) in cardiac health...
BACKGROUND
Cardiac damage triggered by severe hypocalcemia is well known. However, the role of chronic hypoparathyroidism (HP) and pseudohypoparathyroidism (PHP) in cardiac health is still unclear. We investigated the effect of chronic HP and PHP on cardiac structure and conductive function in patients compiling with treatment.
METHODS
The study included 18 patients with HP and eight with PHP aged 45.4 ± 15.4 and 22.1 ± 6.4 years, respectively with a previously regular follow-up. In addition, 26 age- and sex-matched healthy controls were included. General characteristics and biochemical indices were recorded. Cardiac function and structure were assessed by estimation of myocardial enzymes, B-type natriuretic peptide (BNP), and echocardiography. The 12-lead electrocardiogram and 24-h Holter electrocardiography were performed to evaluate the conductive function.
RESULTS
Levels of serum calcium in HP and PHP were 2.05 ± 0.16 mmol/L and 2.25 ± 0.19 mmol/L, respectively. The levels of myocardial enzyme and BNP were within the normal range. Adjusting for age at evaluation and body mass index, all M-mode measurements, left ventricular mass (LVM), LVM index (LVMI) and relative wall thickness (RWT) were comparable between patients and controls. Prolongation of corrected QT (QTc) intervals occurred in 52.6% (10/19) of patients, and 6.7% (1/15) of patients manifested more than 100 episodes of supraventricular and ventricular extrasystoles, as well as supraventricular tachycardia. None of the above arrhythmias was related to a severe clinical event.
CONCLUSIONS
From this pilot study, patients diagnosed with HP and PHP and well-controlled serum calcium levels manifested normal cardiac morphology and ventricular function, except for prolonged QTc intervals, and a small percentage of mild arrhythmias needing further investigation.
Topics: Adolescent; Adult; Arrhythmias, Cardiac; Atrial Premature Complexes; Calcium; Case-Control Studies; Chronic Disease; Echocardiography; Electrocardiography; Electrocardiography, Ambulatory; Female; Humans; Hypoparathyroidism; Long QT Syndrome; Male; Middle Aged; Natriuretic Peptide, Brain; Pilot Projects; Pseudohypoparathyroidism; Tachycardia, Supraventricular; Ventricular Dysfunction, Left; Ventricular Premature Complexes; Young Adult
PubMed: 32393234
DOI: 10.1186/s12902-020-0541-6 -
Annals of Indian Academy of Neurology 2022
PubMed: 36211181
DOI: 10.4103/aian.aian_896_21