Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.496
Filtrar
1.
PLoS One ; 18(1): e0280463, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36662765

RESUMO

BACKGROUND: Albright hereditary osteodystrophy (AHO) is caused by heterozygous inactivating mutations in GNAS. Patients with maternally-inherited mutations develop pseudohypoparathyroidism type 1A (PHP1A) with multi-hormone resistance and aberrant craniofacial and skeletal development among other abnormalities. Chiari malformation type 1 (CM1), a condition in which brain tissue extends into the spinal canal when the skull is too small, has been reported in isolated cases of PHP1A. It has been hypothesized to be associated with growth hormone (GH) deficiency. Given the adverse clinical sequelae that can occur if CM1 goes unrecognized, we investigated the previously undetermined prevalence of CM1, as well as any potential correlations with GH status, given the known increased prevalence of GH deficiency in PHP1A. We also investigated these metrics for low lying cerebellar tonsils (LLCT), defined as tonsillar descent less than 5 mm below the foramen magnum. In addition, we investigated possible correlations of CM1/LLCT with advanced hand/wrist bone ages and craniofacial abnormalities known to occur in PHP1A to determine whether premature chondrocyte differentiation and/or aberrant craniofacial development could be potential etiologies of CM1/LLCT through both human studies and investigations of our AHO mouse model. METHODS: We examined patients with PHP1A in our clinic and noticed CM1 more frequently than expected. Therefore, we set out to determine the true prevalence of CM1 and LLCT in a cohort of 54 mutation-confirmed PHP1A participants who had clinically-indicated brain imaging. We examined potential correlations with GH status, clinical features, biological sex, genotype, and hand/wrist bone age determinations. In addition, we investigated the craniofacial development in our mouse model of AHO (Gnas E1+/-m) by histologic analyses, dynamic histomorphometry, and micro-computerized tomographic imaging (MCT) in order to determine potential etiologies of CM1/LLCT in PHP1A. RESULTS: In our cohort of PHP1A, the prevalence of CM1 is 10.8%, which is at least 10-fold higher than in the general population. If LLCT is included, the prevalence increases to 21.7%. We found no correlation with GH status, biological sex, genotype, or hand/wrist bone age. Through investigations of our Gnas E1+/-m mice, the correlate to PHP1A, we identified a smaller cranial vault and increased cranial dome angle with evidence of hyperostosis due to increased osteogenesis. We also demonstrated that there was premature closure of the spheno-occipital synchondrosis (SOS), a cartilaginous structure essential to the development of the cranial base. These findings lead to craniofacial abnormalities and could contribute to CM1 and LLCT development in PHP1A. CONCLUSION: The prevalence of CM1 is at least 10-fold higher in PHP1A compared to the general population and 20-fold higher when including LLCT. This is independent of the GH deficiency that is found in approximately two-thirds of patients with PHP1A. In light of potential serious consequences of CM1, clinicians should have a low threshold for brain imaging. Investigations of our AHO mouse model revealed aberrant cranial formation including a smaller cranium, increased cranial dome angle, hyperostosis, and premature SOS closure rates, providing a potential etiology for the increased prevalence of CM1 and LLCT in PHP1A.


Assuntos
Malformação de Arnold-Chiari , Pseudo-Hipoparatireoidismo , Humanos , Animais , Camundongos , Prevalência , Pseudo-Hipoparatireoidismo/epidemiologia , Pseudo-Hipoparatireoidismo/genética , Pseudo-Hipoparatireoidismo/complicações , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Desenvolvimento Ósseo , Genótipo , Malformação de Arnold-Chiari/diagnóstico por imagem , Malformação de Arnold-Chiari/epidemiologia , Malformação de Arnold-Chiari/genética , Cromograninas/genética
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 40(1): 31-35, 2023 Jan 10.
Artigo em Chinês | MEDLINE | ID: mdl-36584997

RESUMO

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.


Assuntos
Pseudo-Hipoparatireoidismo , Feminino , Humanos , Linhagem , Mães , Pseudo-Hipoparatireoidismo/genética , Mutação , China , Cromograninas/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética
3.
Front Endocrinol (Lausanne) ; 13: 1050305, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36465610

RESUMO

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.


Assuntos
Conservadores da Densidade Óssea , Pseudo-Hipoparatireoidismo , Gravidez , Recém-Nascido , Humanos , Feminino , Cálcio , Cesárea , Estudos Retrospectivos , Pseudo-Hipoparatireoidismo/complicações , Pseudo-Hipoparatireoidismo/tratamento farmacológico , Período Pós-Parto
4.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 47(10): 1461-1466, 2022 Oct 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-36411698

RESUMO

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 (GNAS) 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 GNAS in the 4 patients. There were phenotype overlap among the various subtypes of PHP. Detection of GNAS gene methylation in patients with clinical suspicion of Type Ib PHP is helpful for the diagnosis and treatment of PHP.


Assuntos
Hipopotassemia , Pseudo-Hipoparatireoidismo , Humanos , Cromograninas/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Cálcio , Pseudo-Hipoparatireoidismo/genética , Fósforo
5.
Endocrine ; 78(3): 605-614, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36220966

RESUMO

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 (3rd/2nd 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) (r2 = 0.9661, 0.7733, and 0.9575, respectively). No significant differences were noted in 3rd/2nd 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.


Assuntos
Hiperparatireoidismo Primário , Pseudo-Hipoparatireoidismo , Humanos , Hormônio Paratireóideo , Imunoensaio , Modelos Lineares , Cálcio
6.
Front Endocrinol (Lausanne) ; 13: 1012658, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36213284

RESUMO

Objective: This study aimed to present the spectrum of thyroid dysfunction, including hormonal and ultrasound aspects, in a cohort of paediatric and adult patients diagnosed with inactivating parathyroid hormone (PTH)/PTH-related protein signalling disorders 2 and 3 (iPPSD). Methods: The medical records of 31 patients from 14 families diagnosed with iPPSD between 1980 and 2021 in a single tertiary unit were retrospectively analysed. Biochemical, hormonal, molecular, and ultrasonographic parameters were assessed. Results: In total, 28 patients from 13 families were diagnosed with iPPSD2 (previously pseudohypoparathyroidism [PHP], PHP1A, and pseudo-PHP) at a mean age of 12.2 years (ranging from infancy to 48 years), and three patients from one family were diagnosed with iPPSD3 (PHP1B). Thyroid dysfunction was diagnosed in 21 of the 28 (75%) patients with iPPSD2. Neonatal screening detected congenital hypothyroidism (CH) in 4 of the 20 (20%) newborns. The spectrum of thyroid dysfunction included: CH, 3/21 (14.2%); CH and autoimmune thyroiditis with nodular goitre, 1/21 (4.8%); subclinical hypothyroidism, 10/21 (47.6%); subclinical hypothyroidism and nodular goitre, 1/21 (4.8%); primary hypothyroidism, 4/21 (19%); and autoimmune thyroiditis (Hashimoto and Graves' disease), 2/21 (9.6%). Thyroid function was normal in 7 of the 28 (25%) patients with iPPSD2 and in all patients with iPPSD3. Ultrasound evaluation of the thyroid gland revealed markedly inhomogeneous echogenicity and structure in all patients with thyroid dysfunction. Goitre was found in three patients. Conclusion: The spectrum of thyroid dysfunction in iPPSD ranges from CH to autoimmune thyroiditis and nodular goitre. Ultrasonography of the thyroid gland may reveal an abnormal thyroid parenchyma.


Assuntos
Hipotireoidismo Congênito , Bócio Nodular , Doença de Graves , Pseudo-Hipoparatireoidismo , Doenças da Glândula Tireoide , Tireoidite Autoimune , Adulto , Criança , Hipotireoidismo Congênito/diagnóstico , Doença de Graves/diagnóstico , Humanos , Recém-Nascido , Hormônio Paratireóideo , Proteína Relacionada ao Hormônio Paratireóideo , Pseudo-Hipoparatireoidismo/diagnóstico , Estudos Retrospectivos , Doenças da Glândula Tireoide/diagnóstico por imagem , Ultrassonografia
7.
Med Sci (Paris) ; 38(8-9): 655-662, 2022.
Artigo em Francês | MEDLINE | ID: mdl-36094235

RESUMO

Pseudohypoparathyroidism (PHP) is an uncommon disorder which is characterized by end-organ PTH resistance. The genetic defect is located at the GNAS locus that encodes the alpha-subunit of the stimulatory G protein (Gαs) and several splice variants thereof. This complex locus undergoes parental specific methylation changes that result in tissue-specific silencing of the paternal allele. Heterozygous inactivating mutations that disrupt Gαs function or epigenetics changes that impair Gαs expression contribute to a wide clinical spectrum of the disease: PHP1A, PHP1B, osseous heteroplasia, osteodystrophy, obesity, intrauterine growth retardation… whose mechanisms at the molecular level remain unresolved.


Title: Pseudo-hypoparathyroïdie et ses variants - Un succès de la médecine translationnelle. Abstract: Les pseudohypoparathyroïdies (PHP) sont des maladies rares, caractérisées par une résistance à l'action rénale de la parathormone. Le défaut génétique est localisé au locus GNAS, qui code la sous-unité alpha stimulatrice des protéines G (Gαs). Ce locus est le siège de régulations complexes, épissage alternatif et empreinte parentale éteigant de façon tissu-spécifique l'expression de l'allèle paternel. Des mutations hétérozygotes perte de fonction, des épimutations responsables d'une perte d'expression sont associées à un large spectre pathologique : PHP1A, PHP1B, ossification hétérotopique, ostéodystophie, obésité, retard de croissance in utero, etc., dont les mécanismes restent encore incomplètement connus.


Assuntos
Cromograninas , Pseudo-Hipoparatireoidismo , Cromograninas/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Heterozigoto , Humanos , Pseudo-Hipoparatireoidismo/genética , Ciência Translacional Biomédica
8.
Behav Neurol ; 2022: 8710989, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35992960

RESUMO

Objective: To characterize the cerebral imaging and electroclinical features and investigate their etiological contributions to seizures in pseudoparathyroidism (PHP). Methods: The clinical symptoms, biochemical imaging by magnetic resonance imaging (MRI) and computed tomography (CT) tests, and electroencephalogram (EEG) manifestations of five PHP patients with seizures were retrospectively collected and analyzed. Results: Physical examination showed an average stature in cases 2~4 and short stature in cases 1 and 5. X-ray tests suggested ectopic calcification in four patients. The seizures in four cases were effectively controlled with antiseizure medicines (ASMs). Cerebral CT scans showed extensive brain calcifications in the bilateral basal ganglia (all five cases), cerebellum (cases 1, 3, and 5), thalamus (case 4), and cerebral cortex. Cerebral MRI showed short T1 signals mainly in the basal ganglia. EEG records revealed focal EEG abnormalities, including abnormal slow waves and epileptiform discharges, mainly over the temporal and frontal lobes. The brain areas with focal EEG abnormalities and calcification did not always coincide. Conclusion: The seizures in PHP can be focal to bilateral tonic-clonic. ASMs are effective in epilepsy combined with PHP. Intracranial calcification is not a reliable etiological cause of epilepsy in PHP patients.


Assuntos
Epilepsia , Pseudo-Hipoparatireoidismo , Eletroencefalografia , Epilepsia/complicações , Epilepsia/diagnóstico por imagem , Humanos , Pseudo-Hipoparatireoidismo/complicações , Pseudo-Hipoparatireoidismo/diagnóstico por imagem , Estudos Retrospectivos , Convulsões/complicações , Convulsões/diagnóstico por imagem
9.
Front Endocrinol (Lausanne) ; 13: 928284, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35846276

RESUMO

PTH resistance is characterized by elevated parathyroid hormone (PTH) levels, hypocalcemia, hyperphosphatemia and it is classically associated with GNAS locus genetic or epigenetic defects. Inactivating PTH/PTHrP signaling disorders (iPPSD) define overlapping phenotypes based on their molecular etiology. iPPSD1 is associated with PTH1R variants and variable phenotypes including ossification anomalies and primary failure of tooth eruption but no endocrine disorder. Here we report on a 10-month-old child born from consanguineous parents, who presented with mild neurodevelopmental delay, seizures, enlarged fontanelles, round face, and bilateral clinodactyly. Hand x-rays showed diffuse delayed bone age, osteopenia, short metacarpal bones and cone-shaped distal phalanges. A diagnosis of PTH resistance was made on the basis of severe hypocalcemia, hyperphosphatemia, elevated PTH and normal vitamin D levels on blood sample. The patient was treated with calcium carbonate and alfacalcidol leading to rapid bio-clinical improvement. Follow-up revealed multiple agenesis of primary teeth and delayed teeth eruption, as well as Arnold-Chiari type 1 malformation requiring a ventriculoperitoneal shunt placement. GNAS gene analysis showed no pathogenic variation, but a likely pathogenic homozygous substitution c.723C>G p.(Asp241Glu) in PTH1R gene was found by trio-based whole exome sequencing. We studied the deleterious impact of the variant on the protein conformation with bioinformatics tools. In conclusion, our study reports for the first time PTH resistance in a child with a biallelic PTH1R mutation, extending thereby the clinical spectrum of iPPSD1 phenotypes.


Assuntos
Hiperfosfatemia , Hipocalcemia , Pseudo-Hipoparatireoidismo , Humanos , Hipocalcemia/complicações , Hormônio Paratireóideo/metabolismo , Proteína Relacionada ao Hormônio Paratireóideo , Pseudo-Hipoparatireoidismo/diagnóstico , Pseudo-Hipoparatireoidismo/genética
10.
J Bone Miner Res ; 37(10): 1850-1859, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35859320

RESUMO

Loss of methylation (LOM) at GNAS-A/B:TSS-differentially methylated regions (DMRs) in the GNAS locus is observed in pseudohypoparathyroidism type 1B (PHP1B). Many PHP1B cases are sporadic, but autosomal dominant-PHP1B has a deletion involving NESP55 expressed from the maternal allele or STX16 located upstream of the GNAS locus on the maternal allele. We report the possible first familial PHP1B cases with retrotransposon insertion in the GNAS locus on the maternal allele. To our knowledge, they are the possible first cases with imprinting disorders caused by retrotransposon insertion. The two sibling cases experienced tetany and/or cramps from school age and had hypocalcemia and an increased serum intact parathyroid hormone (PTH) level together with overweight, round face, and normal intellectual levels. Methylation analysis for DMRs in the GNAS locus showed only LOM of the GNAS-A/B:TSS-DMR. Copy number abnormalities at STX16 and the GNAS locus were not detected by array comparative genomic hybridization. Whole-genome sequencing and Sanger sequencing revealed an approximately 1000-bp SVA retrotransposon insertion upstream of the first exon of A/B on the GNAS locus in these siblings. Whole-genome methylome analysis by Enzymatic Methyl-Seq in the siblings showed normal methylation status in the region surrounding the insertion site and mild LOM of the GNAS-A/B:TSS-DMR. We conducted transcriptome analysis using mRNA from skin fibroblasts and induced pluripotent stem cells (iPSCs) derived from the siblings and detected no aberrant NESP55 transcripts. Quantitative reverse-transcriptase PCR (qRT-PCR) analysis in skin fibroblasts showed increased A/B expression in the patients and no NESP55 expression, even in a control. qRT-PCR analysis in iPSCs showed decreased NESP55 expression with normal methylation status of the GNAS-NESP:TSS-DMR in the patients. The retrotransposon insertion in the siblings likely caused decreased NESP55 expression that could lead to increased A/B expression via LOM of the GNAS-A/B:TSS-DMR, subsequent reduced Gsα expression, and finally, PHP1B development. © 2022 American Society for Bone and Mineral Research (ASBMR).


Assuntos
Pseudo-Hipoparatireoidismo , Retroelementos , Humanos , Cromograninas/genética , Cromograninas/metabolismo , Hibridização Genômica Comparativa , Pseudo-Hipoparatireoidismo/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , RNA Mensageiro/metabolismo , Hormônio Paratireóideo/genética , RNA Polimerases Dirigidas por DNA/genética , RNA Polimerases Dirigidas por DNA/metabolismo , Metilação de DNA/genética
11.
Neurol India ; 70(3): 1159-1161, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35864655

RESUMO

Fahr's disease is an idiopathic basal ganglia calcification with autosomal dominant inheritance. Prior to diagnosing Fahr's disease based on computed tomography (CT) and/or magnetic resonance imaging (MRI) of the brain, one should rule out hypoparathyroidism (HP), and pseudohypoparathyroidism (PHP). Treatments of these conditions are entirely different. HP- and PHP-related hypocalcemia requires calcium, calcitriol, and vitamin D therapy in a long run to avoid recurrent seizures whereas Fahr's disease is treated with an antiepileptic alone.


Assuntos
Doenças dos Gânglios da Base , Calcinose , Hipoparatireoidismo , Doenças Neurodegenerativas , Pseudo-Hipoparatireoidismo , Doenças dos Gânglios da Base/diagnóstico , Doenças dos Gânglios da Base/diagnóstico por imagem , Calcinose/complicações , Calcinose/diagnóstico , Humanos , Hipoparatireoidismo/complicações , Hipoparatireoidismo/diagnóstico , Pseudo-Hipoparatireoidismo/complicações , Pseudo-Hipoparatireoidismo/diagnóstico
12.
Ital J Pediatr ; 48(1): 123, 2022 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-35871092

RESUMO

BACKGROUND: Albright's hereditary osteodystrophy (AHO) is an inherited disorder which is caused by an inactivating variant in the GNAS gene. AHO appears associated to either pseudohypoparathyroidism 1a (PHP1a) when GNAS gene is maternally inherited or to pseudo-pseudohypoparathyroidism (PPHP) when it is paternally inherited. We describe the clinical and biochemical characteristics of two patients, a boy and his mother with a novel heterozygous missense variant of GNAS gene. CASE PRESENTATION: The boy presented with typical AHO phenotype (early-onset obesity, round face, short neck, shortened fifth metacarpal bone, developmental retardation, but without short stature and subcutaneous calcifications), multiple hormone resistance including PTH, TSH and ACTH, and mild calcification in the right basal ganglia. The mother only presented with brachydactyly and short stature, without hormone resistance and other signs of AHO. Whole-exome sequencing identified in the son and his mother a novel heterozygous missense variant (p. Val375Leu) in exon 13 of GNAS gene. The diagnosis of PHP-1a for the son and PPHP for the mother were confirmed. CONCLUSION: This study further expands the spectrum of known GNAS pathogenic variants, and also demonstrates the heterogeneous phenotype of AHO due to a novel GNAS pathogenic variant.


Assuntos
Cromograninas , Pseudo-Hipoparatireoidismo , China , Cromograninas/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Hormônios , Humanos , Fenótipo , Pseudo-Hipoparatireoidismo/diagnóstico , Pseudo-Hipoparatireoidismo/genética
13.
J Bone Miner Res ; 37(9): 1711-1719, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35811283

RESUMO

Pseudohypoparathyroidism type Ib (PHP1B) is characterized predominantly by resistance to parathyroid hormone (PTH) leading to hypocalcemia and hyperphosphatemia. These laboratory abnormalities are caused by maternal loss-of-methylation (LOM) at GNAS exon A/B, which reduces in cis expression of the stimulatory G protein α-subunit (Gsα). Paternal Gsα expression in proximal renal tubules is silenced through unknown mechanisms, hence LOM at exon A/B reduces further Gsα protein in this kidney portion, leading to PTH resistance. In a previously reported PHP1B family, affected members showed variable LOM at exon A/B, yet no genetic defect was found by whole-genome sequencing despite linkage to GNAS. Using targeted long-read sequencing (T-LRS), we discovered an approximately 2800-bp maternally inherited retrotransposon insertion nearly 1200 bp downstream of exon XL not found in public databases or in 13,675 DNA samples analyzed by short-read whole-genome sequencing. T-LRS data furthermore confirmed normal methylation at exons XL, AS, and NESP and showed that LOM comprising exon A/B is broader than previously thought. The retrotransposon most likely causes the observed epigenetic defect by impairing function of a maternally derived NESP transcript, consistent with findings in mice lacking full-length NESP mRNA and in PHP1B patients with deletion of exon NESP and adjacent intronic sequences. In addition to demonstrating that T-LRS is an effective strategy for identifying a small disease-causing variant that abolishes or severely reduces exon A/B methylation, our data demonstrate that this sequencing technology has major advantages for simultaneously identifying structural defects and altered methylation. © 2022 American Society for Bone and Mineral Research (ASBMR).


Assuntos
Cromograninas , Pseudo-Hipoparatireoidismo , Animais , Cromograninas/genética , Cromograninas/metabolismo , Metilação de DNA/genética , Darbepoetina alfa/genética , Darbepoetina alfa/metabolismo , Éxons/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Camundongos , Pseudo-Hipoparatireoidismo/genética , Retroelementos
14.
Clin Epigenetics ; 14(1): 71, 2022 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-35643636

RESUMO

BACKGROUND: Beckwith-Wiedemann syndrome (BWS) and Pseudohypoparathyroidism type 1B (PHP1B) are imprinting disorders (ID) caused by deregulation of the imprinted gene clusters located at 11p15.5 and 20q13.32, respectively. In both of these diseases a subset of the patients is affected by multi-locus imprinting disturbances (MLID). In several families, MLID is associated with damaging variants of maternal-effect genes encoding protein components of the subcortical maternal complex (SCMC). However, frequency, penetrance and recurrence risks of these variants are still undefined. In this study, we screened two cohorts of BWS patients and one cohort of PHP1B patients for the presence of MLID, and analysed the positive cases for the presence of maternal variants in the SCMC genes by whole exome-sequencing and in silico functional studies. RESULTS: We identified 10 new cases of MLID associated with the clinical features of either BWS or PHP1B, in which segregate 13 maternal putatively damaging missense variants of the SCMC genes. The affected genes also included KHDC3L that has not been associated with MLID to date. Moreover, we highlight the possible relevance of relatively common variants in the aetiology of MLID. CONCLUSION: Our data further add to the list of the SCMC components and maternal variants that are involved in MLID, as well as of the associated clinical phenotypes. Also, we propose that in addition to rare variants, common variants may play a role in the aetiology of MLID and imprinting disorders by exerting an additive effect in combination with rarer putatively damaging variants. These findings provide useful information for the molecular diagnosis and recurrence risk evaluation of MLID-associated IDs in genetic counselling.


Assuntos
Síndrome de Beckwith-Wiedemann , Pseudo-Hipoparatireoidismo , Síndrome de Beckwith-Wiedemann/diagnóstico , Síndrome de Beckwith-Wiedemann/genética , Metilação de DNA , Impressão Genômica , Humanos , Proteínas/genética , Pseudo-Hipoparatireoidismo/genética
15.
Acta Biomed ; 93(S3): e2022194, 2022 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-35666115

RESUMO

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.


Assuntos
Hiperfosfatemia , Hipocalcemia , Síndrome do QT Longo , Pseudo-Hipoparatireoidismo , Adolescente , Humanos , Hipocalcemia/diagnóstico , Hipocalcemia/tratamento farmacológico , Hipocalcemia/etiologia , Síndrome do QT Longo/complicações , Masculino , Hormônio Paratireóideo , Pseudo-Hipoparatireoidismo/complicações , Pseudo-Hipoparatireoidismo/diagnóstico , Pseudo-Hipoparatireoidismo/genética
18.
BMC Endocr Disord ; 22(1): 98, 2022 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-35410271

RESUMO

BACKGROUND: Pseudohypoparathyroidism (PHP) encompasses a highly heterogenous group of disorders, characterized by parathyroid hormone (PTH) resistance caused by mutations in the GNAS gene or other upstream targets. Here, we investigate the characteristics of a female patient diagnosed with PHP complicated with hypokalemia, and her family members. CASE PRESENTATION AND GENE ANALYSIS: A 27-year-old female patient occasionally exhibited asymptomatic hypocalcemia and hypokalemia during her pregnancy 1 year ago. Seven months after delivery, she experienced tetany and dysphonia with diarrhea. Tetany symptoms were relieved after intravenous calcium gluconate supplementation and she was then transferred to our Hospital. Laboratory assessments of the patient revealed hypokalemia, hypocalcemia and hyperphosphatemia despite elevated PTH levels. CT scanning of the brain revealed globus pallidus calcification. Possible mutations in GNAS and hypokalemia related genes were identified using WES, exon copies of STX16 were analized by MLPA and the methylation status of GNAS in three differential methylated regions (DMRs) was analyzed by methylation-specific polymerase chain reaction, followed by confirmation with gene sequencing. The patient was clinically diagnosed with PHP-1b. Loss of methylation in the A/B region and hypermethylation in the NESP55 region were detected. No other mutations in GNAS or hypokalemia related genes and no deletions of STX16 exons were detected. A negative family history and abnormal DMRs in GNAS led to a diagnosis of sporadic PHP-1b of the patient. CONCLUSIONS: Hypokalemia is a rare disorder associated with PHP-1b. Analysis of genetic and epigenetic mutations can aid in the diagnosis and accurate subtyping of PHP.


Assuntos
Hipocalcemia , Hipopotassemia , Pseudo-Hipoparatireoidismo , Tetania , Adulto , Cromograninas/genética , Feminino , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Humanos , Hipocalcemia/genética , Hipopotassemia/genética , Pseudo-Hipoparatireoidismo/complicações , Pseudo-Hipoparatireoidismo/diagnóstico , Pseudo-Hipoparatireoidismo/genética
20.
BMC Endocr Disord ; 22(1): 70, 2022 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-35296306

RESUMO

BACKGROUND: The GNAS gene on chromosome 20q13.3, encodes the alpha-subunit of the stimulatory G protein, which is expressed in most tissues and regulated through reciprocal genomic imprinting. Disorders of GNAS inactivation produce several different clinical phenotypes including pseudohypoparathyroidism (PHP), pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC). The clinical and biochemical characteristics overlap of PHP subtypes and other related disorders presents challenges for differential diagnosis. METHODS: We enrolled a total of 11 Chinese children with PHP in our study and analyzed their clinical characteristics, laboratory results, and genetic mutations. RESULTS: Among these 11 patients, nine of them (9/11) presented with resistance to parathyroid hormone (PTH); and nine (9/11) presented with an Albright's hereditary osteodystrophy (AHO) phenotype. GNAS abnormalities were detected in all 11 patients, including nine cases with GNAS gene variations and two cases with GNAS methylation defects. These GNAS variations included an intronic mutation (c.212 + 3_212 + 6delAAGT), three missense mutations (c.314C > T, c.308 T > C, c.1123G > T), two deletion mutations (c.565_568delGACT*2, c.74delA), and two splicing mutations (c.721 + 1G > A, c.432 + 1G > A). Three of these mutations, namely, c.314C > T, c.1123G > T, and c.721 + 1G > A, were found to be novel. This data was then used to assign a GNAS subtype to each of these patients with six cases diagnosed as PHP1a, two cases as PHP1b, one as PPHP, and two as POH. CONCLUSIONS: Evaluating patients with PTH resistance and AHO phenotype improved the genetic diagnosis of GNAS mutations significantly. In addition, our results suggest that when GNAS gene sequencing is negative, GNAS methylation study should be performed. Early genetic detection is required for the differential diagnosis of GNAS disorders and is critical to the clinician's ability to distinguish between heterotopic ossification in the POH and AHO phenotype.


Assuntos
Doenças Ósseas Metabólicas , Cromograninas/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Ossificação Heterotópica , Pseudo-Hipoparatireoidismo , Dermatopatias Genéticas , Adolescente , Doenças Ósseas Metabólicas/diagnóstico , Doenças Ósseas Metabólicas/genética , Doenças Ósseas Metabólicas/patologia , Criança , Pré-Escolar , China , Feminino , Humanos , Lactente , Masculino , Ossificação Heterotópica/diagnóstico , Ossificação Heterotópica/genética , Ossificação Heterotópica/patologia , Pseudo-Hipoparatireoidismo/diagnóstico , Pseudo-Hipoparatireoidismo/genética , Pseudo-Hipoparatireoidismo/patologia , Pseudopseudo-Hipoparatireoidismo/diagnóstico , Pseudopseudo-Hipoparatireoidismo/genética , Pseudopseudo-Hipoparatireoidismo/patologia , Dermatopatias Genéticas/diagnóstico , Dermatopatias Genéticas/genética , Dermatopatias Genéticas/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...