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American Journal of Medical Genetics.... Feb 2018Pseudohypoparathyroidism 1A (PHP1A) is a rare, genetic disorder. Most patients with PHP1A have cognitive impairment but this has not been systematically studied. We...
Pseudohypoparathyroidism 1A (PHP1A) is a rare, genetic disorder. Most patients with PHP1A have cognitive impairment but this has not been systematically studied. We hypothesized that children with PHP1A would have lower intelligent quotient (IQ) scores than controls. To evaluate cognition and behavior, we prospectively enrolled children with PHP1A, one unaffected sibling (when available) and controls matched on BMI/age/gender/race. Evaluations included cognitive and executive function testing. Parents completed questionnaires on behavior and executive function. We enrolled 16 patients with PHP1A, 8 unaffected siblings, and 15 controls. Results are presented as mean (SD). The PHP1A group had a composite IQ of 85.9 (17.2); 25% had a composite IQ < -2 SD. The PHP1A group had significantly lower IQs than matched controls (composite IQ -17.3, 95%CI -28.1 to -6.5, p < 0.01) and unaffected siblings (composite IQ -21.5, 95%CI -33.9 to -9.1, p < 0.01). Special education services were utilized for 93% of the patients with PHP1A. Deficits were observed in executive function and parents reported delayed adaptive behavior skills and increased rates of attention deficit hyperactivity disorder. In conclusion, children with PHP1A have lower intelligence quotient scores, poorer executive function, delayed adaptive behavior skills, and increased behavior problems.
Topics: Adolescent; Alleles; Case-Control Studies; Child; Child Behavior; Child, Preschool; Cognition; Cognitive Dysfunction; Female; Genetic Predisposition to Disease; Genotype; Humans; Intelligence Tests; Male; Phenotype; Pseudohypoparathyroidism; Risk Factors; Severity of Illness Index; Siblings
PubMed: 29193623
DOI: 10.1002/ajmg.a.38534 -
BMC Medical Genetics Mar 2018Pseudohypoparathyroidism (PHP) is a rare disease whose phenotypic features are rather difficult to identify in some cases. Thus, although these patients may present with...
BACKGROUND
Pseudohypoparathyroidism (PHP) is a rare disease whose phenotypic features are rather difficult to identify in some cases. Thus, although these patients may present with the Albright's hereditary osteodystrophy (AHO) phenotype, which is characterized by small stature, obesity with a rounded face, subcutaneous ossifications, mental retardation and brachydactyly, its manifestations are somewhat variable. Indeed, some of them present with a complete phenotype, whereas others show only subtle manifestations. In addition, the features of the AHO phenotype are not specific to it and a similar phenotype is also commonly observed in other syndromes. Brachydactyly type E (BDE) is the most specific and objective feature of the AHO phenotype, and several genes have been associated with syndromic BDE in the past few years. Moreover, these syndromes have a skeletal and endocrinological phenotype that overlaps with AHO/PHP. In light of the above, we have developed an algorithm to aid in genetic testing of patients with clinical features of AHO but with no causative molecular defect at the GNAS locus. Starting with the feature of brachydactyly, this algorithm allows the differential diagnosis to be broadened and, with the addition of other clinical features, can guide genetic testing.
METHODS
We reviewed our series of patients (n = 23) with a clinical diagnosis of AHO and with brachydactyly type E or similar pattern, who were negative for GNAS anomalies, and classify them according to the diagnosis algorithm to finally propose and analyse the most probable gene(s) in each case.
RESULTS
A review of the clinical data for our series of patients, and subsequent analysis of the candidate gene(s), allowed detection of the underlying molecular defect in 12 out of 23 patients: five patients harboured a mutation in PRKAR1A, one in PDE4D, four in TRPS1 and two in PTHLH.
CONCLUSIONS
This study confirmed that the screening of other genes implicated in syndromes with BDE and AHO or a similar phenotype is very helpful for establishing a correct genetic diagnosis for those patients who have been misdiagnosed with "AHO-like phenotype" with an unknown genetic cause, and also for better describing the characteristic and differential features of these less common syndromes.
Topics: Adolescent; Adult; Brachydactyly; Child; Child, Preschool; Chromogranins; Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; Cyclic Nucleotide Phosphodiesterases, Type 4; DNA-Binding Proteins; Diagnosis, Differential; Female; GTP-Binding Protein alpha Subunits, Gs; Gene Dosage; Genetic Loci; Genetic Testing; Humans; Infant; Male; Mutation; Parathyroid Hormone-Related Protein; Phenotype; Pseudohypoparathyroidism; Repressor Proteins; Transcription Factors
PubMed: 29499646
DOI: 10.1186/s12881-018-0530-z -
Frontiers in Neurology 2023Fahr's disease, or primary familial brain calcification (PFBC), is a rare genetic neurologic disease characterized by abnormal calcification of the basal ganglia,...
Fahr's disease, or primary familial brain calcification (PFBC), is a rare genetic neurologic disease characterized by abnormal calcification of the basal ganglia, subcortical white matter and cerebellum. Common clinical features include parkinsonism, neuropsychiatric symptoms, and cognitive decline. Genes implicated in Fahr's disease include , , , , , and . We present the case of a 51-year-old woman who developed subacute cognitive and behavioral changes primarily affecting frontal-subcortical pathways and parkinsonism in association with extensive bilateral calcifications within the basal ganglia, subcortical white matter, and cerebellum on neuroimaging. Relevant family history included a paternal aunt with parkinsonism at age 50. Normal parathyroid hormone and calcium levels in the patient's serum ruled out hypoparathyroidism or pseudohypoparathyroidism as causes for the intracranial calcifications. Genetic panel sequencing revealed a variant of unknown significance in the gene resulting in a p.Arg919Gln substitution in the tyrosine kinase domain of PDGFRB protein. To our knowledge this is the first report of a p.Arg919Gln variant in the gene associated with PFBC. Although co-segregation studies were not possible in this family, the location of the variant is within the tyrosine kinase domain of PDGFRB and pathogenicity calculators predict it is likely to be pathogenic. This report adds to the list of genetic variants that warrant functional analysis and could underlie the development of PFBC, which may help to further our understanding of its pathogenesis and the development of targeted therapies for this disorder.
PubMed: 37780723
DOI: 10.3389/fneur.2023.1235909 -
Medical Archives (Sarajevo, Bosnia and... Feb 2023Hypothyroidism is a manifestation of multi-hormonal resistance in pseudohypoparathyroidism type Ia (PHP Ia). (Review)
Review
BACKGROUND
Hypothyroidism is a manifestation of multi-hormonal resistance in pseudohypoparathyroidism type Ia (PHP Ia).
OBJECTIVE
The aim of this article was to present 9 months old male patient as case of congenital hypothyroidism.
CASE REPORT
We describe a 9 months old male diagnosed with congenital hypothyroidism at age 1.5 month, who developed later (at age 5 months) cyanotic attack associated with hypocalcaemia, hyperphosphatemia, and hyperparathyroidism, patient had typical characters of AHO, so the diagnosis of Pseudohypoparathyroidism 1a associated with resistance (TSH) was established.
CONCLUSION
Children diagnosed with PHP 1a should be further evaluated for associated resistance endocrinopathies. The literature on pseudohypoparathyroidism is reviewed with special emphasis on the misdiagnosis with congenital hypothyroidism.
Topics: Humans; Infant; Male; Chromogranins; Congenital Hypothyroidism; Diagnostic Errors; GTP-Binding Protein alpha Subunits, Gs; Pseudohypoparathyroidism
PubMed: 36923733
DOI: 10.5455/medarh.2023.77.70-73 -
Journal of Bone and Mineral Research :... Oct 2022Loss 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...
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).
Topics: Humans; Retroelements; Chromogranins; Comparative Genomic Hybridization; Pseudohypoparathyroidism; GTP-Binding Protein alpha Subunits, Gs; RNA, Messenger; Parathyroid Hormone; DNA-Directed RNA Polymerases; DNA Methylation
PubMed: 35859320
DOI: 10.1002/jbmr.4652 -
Clinical Epigenetics May 2022Beckwith-Wiedemann syndrome (BWS) and Pseudohypoparathyroidism type 1B (PHP1B) are imprinting disorders (ID) caused by deregulation of the imprinted gene clusters...
Novel genetic variants of KHDC3L and other members of the subcortical maternal complex associated with Beckwith-Wiedemann syndrome or Pseudohypoparathyroidism 1B and multi-locus imprinting disturbances.
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.
Topics: Beckwith-Wiedemann Syndrome; DNA Methylation; Genomic Imprinting; Humans; Proteins; Pseudohypoparathyroidism
PubMed: 35643636
DOI: 10.1186/s13148-022-01292-w -
The Journal of Clinical Endocrinology... Nov 2018Pseudohypoparathyroidism (PHP) is a rare genetic disorder characterized by early-onset obesity and multihormone resistance. To treat abnormal weight gain and prevent...
CONTEXT
Pseudohypoparathyroidism (PHP) is a rare genetic disorder characterized by early-onset obesity and multihormone resistance. To treat abnormal weight gain and prevent complications such as diabetes, we must understand energy balance and glucose homeostasis in PHP types 1A and 1B.
OBJECTIVE
The aim of this study was to evaluate food intake, energy expenditure, and glucose homeostasis in children with PHP.
DESIGN
Assessments included resting energy expenditure (REE), physical activity, food intake, sucrose preference, questionnaires, endocrine status, and auxological status. All patients underwent an oral glucose tolerance test (OGTT).
SETTING
Vanderbilt University Medical Center.
PATIENTS
We assessed 16 children with PHP1A, three with PHP1B, and 15 healthy controls.
MAIN OUTCOME MEASURES
Food intake during an ad lib buffet meal and glucose at five time points during OGTT.
RESULTS
PHP1A and control groups were well matched. Participants with PHP1A had significantly lower REE without concomitant change in food intake or physical activity. At baseline, participants with PHP1A had significantly lower fasting glucose and insulin resistance. During OGTT, participants with PHP1A had significantly delayed peak glucose and a slower rate of glucose decline despite similar oral glucose insulin sensitivity. Participants with PHP1A had 0.46% lower HbA1c levels than controls from a clinic database after adjustment for OGTT 2-hour glucose. The PHP1B group was similar to the PHP1A group.
CONCLUSIONS
In contrast to other monogenic obesity syndromes, our results support reduced energy expenditure, not severe hyperphagia, as the primary cause of abnormal weight gain in PHP. Patients with PHP are at high risk for dysglycemia without reduced insulin sensitivity.
Topics: Adolescent; Blood Glucose; Child; Chromogranins; Cross-Sectional Studies; Energy Metabolism; Feeding Behavior; Female; GTP-Binding Protein alpha Subunits, Gs; Genetic Testing; Glucose Tolerance Test; Homeostasis; Humans; Hyperphagia; Insulin Resistance; Male; Prospective Studies; Pseudohypoparathyroidism; Severity of Illness Index; Weight Gain
PubMed: 30085125
DOI: 10.1210/jc.2018-01067 -
Anales de Pediatria Feb 2019Since Albright and co-workers described pseudohypoparathyroidism in 1942 as the combined presence of hypocalcaemia and hyperphosphataemia associated with the existence...
Since Albright and co-workers described pseudohypoparathyroidism in 1942 as the combined presence of hypocalcaemia and hyperphosphataemia associated with the existence of tissue resistance to parathyroid hormone (PTH) action upon normal renal function, great advances have been made in the clinical and genetic profile of patients affected by this condition. Furthermore, not only have genetic bases of pseudohypoparathyroidism been unravelled, but also variants in other genes involved in the PTH/PTHrP signalling pathway through Gsα, have been identified as the cause of diseases that share clinical features with pseudohypoparathyroidism. In the paediatric setting, the first symptoms suggesting the impairment of this signalling pathway are the presence of subcutaneous ossifications, brachydactyly and/or early onset obesity, followed by the possible development of PTH resistance. This clinical suspicion should be confirmed by an accurate molecular diagnosis to allow for coordinated multidisciplinary clinical management. Among the features of this group of disorders, physicians should pay attention to evaluation of PTH and/or thyrotropin (TSH) resistance at diagnosis and throughout follow-up, as well as growth hormone deficiency, hypogonadism, skeletal deformities, dental impairment, obesity, insulin resistance, impaired glucose tolerance or type2 diabetes mellitus and hypertension, as well as ectopic ossifications (either subcutaneous or affecting deeper tissues) and impairment of neurocognitive development.
Topics: Child; Diagnosis, Differential; Genetic Markers; Humans; Pediatrics; Pseudohypoparathyroidism
PubMed: 30591400
DOI: 10.1016/j.anpedi.2018.11.014 -
Frontiers in Physiology 2018Dental aberrations have been mentioned in relation to non-surgical hypoparathyroidism (Ns-HypoPT) and pseudohypoparathyroidism (PHP). However, a systematic review of...
Dental aberrations have been mentioned in relation to non-surgical hypoparathyroidism (Ns-HypoPT) and pseudohypoparathyroidism (PHP). However, a systematic review of dental characteristics have not been performed. The present systematic review describes the dental findings in patients with Ns-HypoPT and PHP. Studies on Ns-HypoPT and PHP reporting dental features were eligible. A systematic literature search was conducted using four bibliographic databases (Web of Science, Scopus, Pubmed, and Embase) and was limited to studies written in English. Reviews, meta-analyses and letters were excluded. Both the research and reporting of results were based on PRISMA (preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines. Of 88 studies included, nine were cross-sectional, one was a prospective cohort study, 26 were case series, and 52 were case reports. The most frequently reported findings in patients with Ns-HypoPT were enamel opacities, enamel hypoplasia, hypodontia, and eruption disturbances. In patients with PHP, enamel hypoplasia, eruption disturbance, and deviation of the root morphology were the most frequently reported findings. An association between enamel hypoplasia and Ns-HypoPT and PHP is likely. The results should, however, be interpreted cautiously due to the limited number of high-quality studies. The present review confirms the need of further well-designed studies, such as large-scale studies, e.g., multicenter studies, to conclude on the reported associations between Ns-HypoPT/PHP and enamel hypoplasia.
PubMed: 29971010
DOI: 10.3389/fphys.2018.00701 -
Mutation Research. Reviews in Mutation... 2024GNAS (guanine nucleotide-binding protein, alpha stimulating) is an imprinted gene that encodes Gα, the α subunit of the heterotrimeric stimulatory G protein. This... (Review)
Review
BACKGROUND
GNAS (guanine nucleotide-binding protein, alpha stimulating) is an imprinted gene that encodes Gα, the α subunit of the heterotrimeric stimulatory G protein. This subunit mediates the signalling of a diverse array of G protein-coupled receptors (GPCRs), including the melanocortin 4 receptor (MC4R) that serves a pivotal role in regulating food intake, energy homoeostasis, and body weight. Genetic or epigenetic alterations in GNAS are known to cause pseudohypoparathyroidism in its different subtypes and have been recently associated with isolated, early-onset, severe obesity. Given the diverse biological functions that Gα serves, multiple molecular mechanisms involving various GPCRs, such as MC4R, β- and β-adrenoceptors, and corticotropin-releasing hormone receptor, have been implicated in the pathophysiology of severe, early-onset obesity that results from genetic or epigenetic GNAS changes.
SCOPE OF REVIEW
This review examines the structure and function of GNAS and provides an overview of the disorders that are caused by defects in this gene and may feature early-onset obesity. Moreover, it elucidates the potential molecular mechanisms underlying Gα deficiency-induced early-onset obesity, highlighting some of their implications for the diagnosis, management, and treatment of this complex condition.
MAJOR CONCLUSIONS
Gα deficiency is an underappreciated cause of early-onset, severe obesity. Therefore, screening children with unexplained, severe obesity for GNAS defects is recommended, to enhance the molecular diagnosis and management of this condition.
Topics: Humans; GTP-Binding Protein alpha Subunits, Gs; Chromogranins; Epigenesis, Genetic; Obesity; Animals; Pseudohypoparathyroidism; Mutation; Receptor, Melanocortin, Type 4; Age of Onset
PubMed: 38103632
DOI: 10.1016/j.mrrev.2023.108487