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Cognitive and behavioral phenotype of children with pseudohypoparathyroidism type 1A.

ABSTRACT: 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?

SUBMITTER: Perez KM

PROVIDER: S-EPMC5942181 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Cognitive and behavioral phenotype of children with pseudohypoparathyroidism type 1A.

Perez Katia M KM Lee Evon B EB Kahanda Sachini S Duis Jessica J Reyes Monica M Jüppner Harald H Shoemaker Ashley H AH

American journal of medical genetics. Part A 20171128 2

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. P ...[more]

PMID: 29193623

Similar Datasets

Energy expenditure in obese children with pseudohypoparathyroidism type 1a.

Project description:ContextPatients with pseudohypoparathyroidism type 1a (PHP-1a) develop early-onset obesity. The abnormality in energy expenditure and/or energy intake responsible for this weight gain is unknown.ObjectiveThe aim of this study was to evaluate energy expenditure in children with PHP-1a compared with obese controls.PatientsWe studied 6 obese females with PHP-1a and 17 obese female controls. Patients were recruited from a single academic center.MeasurementsResting energy expenditure (REE) and thermogenic effect of a high fat meal were measured using whole room indirect calorimetry. Body composition was assessed using whole body dual energy x-ray absorptiometry. Fasting glucose, insulin, and hemoglobin A1C were measured.ResultsChildren with PHP-1a had decreased REE compared with obese controls (P<0.01). After adjustment for fat-free mass, the PHP-1a group's REE was 346.4 kcals day(-1) less than obese controls (95% CI (-585.5--106.9), P<0.01). The thermogenic effect of food (TEF), expressed as percent increase in postprandial energy expenditure over REE, was lower in PHP-1a patients than obese controls, but did not reach statistical significance (absolute reduction of 5.9%, 95% CI (-12.2-0.3%), P=0.06).ConclusionsOur data indicate that children with PHP-1a have decreased REE compared with the obese controls, and that may contribute to the development of obesity in these children. These patients may also have abnormal diet-induced thermogenesis in response to a high-fat meal. Understanding the causes of obesity in PHP-1a may allow for targeted nutritional or pharmacologic treatments in the future.

| S-EPMC3610772 | biostudies-literature

Resting Energy Expenditure Is Decreased in Pseudohypoparathyroidism Type 1A.

Project description:ContextPseudohypoparathyroidism type 1A (PHP1A) is caused by loss-of-function mutations on the maternally inherited GNAS allele and is associated with early-onset obesity, neurocognitive defects, and resistance to multiple hormones. The role of energy intake vs central regulation of energy expenditure in the pathophysiology of obesity remains unclear.ObjectiveThe aim of this study was to evaluate resting energy expenditure (REE) in participants with PHP1A.DesignWe assessed REE, biochemical, endocrine, and auxological status of 12 participants with PHP1A who had normal or elevated body mass index; controls were a cohort of 156 obese participants.SettingThis study took place at Children's Hospital in Philadelphia and Sick Children's Hospital in Toronto.Main outcome measuresREE as a percent of predicted REE was the outcome measure.ResultsPHP1A participants had normal endocrine status while receiving appropriate hormone replacement therapy, but had significantly decreased REE as a percent of predicted REE (using the modified Schofield equation).ConclusionOur results are consistent with REE being the principal cause of obesity in PHP1A rather than it being caused by excessive energy intake or endocrine dysfunction.

| S-EPMC4803160 | biostudies-literature

GNAS mutations in Pseudohypoparathyroidism type 1a and related disorders.

Project description:Pseudohypoparathyroidism type 1a (PHP1a) is characterized by hypocalcaemia and hyperphosphatemia due to parathyroid hormone resistance, in association with the features of Albright's hereditary osteodystrophy (AHO). PHP1a is caused by maternally inherited inactivating mutations of Gs-alpha, which is encoded by a complex imprinted locus termed GNAS. Paternally inherited mutations can lead either to pseudopseudohypoparathyroidism (PPHP) characterized by AHO alone, or to progressive osseous heteroplasia (POH), characterized by severe heterotopic ossification. The clinical aspects and molecular genetics of PHP1a and its related disorders are reviewed together with the 343 kindreds with Gs-alpha germline mutations reported so far in the literature. These 343 (176 different) mutations are scattered throughout the 13 exons that encode Gs-alpha and consist of 44.9% frameshift, 28.0% missense, 14.0% nonsense, and 9.0% splice-site mutations, 3.2% in-frame deletions or insertions, and 0.9% whole or partial gene deletions. Frameshift and other highly disruptive mutations were more frequent in the reported 37 POH kindreds than in PHP1a/PPHP kindreds (97.3% vs. 68.7%, P < 0.0001). This mutation update and respective genotype-phenotype data may be of use for diagnostic and research purposes and contribute to a better understanding of these complex disorders.

| S-EPMC4309471 | biostudies-literature

Delayed diagnosis of pseudohypoparathyroidism type 1a with rare hypothyroidism since childhood.

Project description:Pseudohypoparathyroidism (PHP) is a rare disorder that associates with resistance to parathyroid hormone (PTH). A 21-year old man visited outpatient clinic to treat previously diagnosed hypothyroidism and vitamin D deficiency. Despite daily 150 mcg of levothyroxine supplement, thyroid-stimulating hormone level was elevated, but thyroid autoantibodies were not detected. He showed features of Albright Hereditary Osteodystrophy and elevated serum PTH level with normal albumin-corrected calcium and phosphorus level. The Ellsworth-Howard test proved the blunted response of urinary phosphorus and cyclic adenosine monophosphate after the infusion of the exogenous PTH, suggesting PTH resistance. DNA analysis revealed a heterozygous mutation in the GNAS gene (c.478C > T). Herein, we report a case of PHP type 1a confirmed by clinical, biochemical and molecular analyses. Establishing correct diagnosis of PHP is necessary for efficient therapeutic management.

| S-EPMC9389559 | biostudies-literature

Pseudohypoparathyroidism type 1a due to a novel mutation in the GNAS gene.

Project description: Not available

| S-EPMC4950054 | biostudies-literature

Identification of a novel GNAS mutation in a case of pseudohypoparathyroidism type 1A with normocalcemia.

Project description:BackgroundPseudohypoparathyroidism type 1A (PHP1A) is a rare genetic disease primarily characterized by resistance to parathyroid hormone along with hormonal resistance and other features of Albright hereditary osteodystrophy (AHO). It is caused by heterozygous inactivating mutations in the maternal allele of the GNAS gene, which encodes the stimulatory G-protein alpha subunit (Gsα) and regulates production of the second messenger cyclic AMP (cAMP). Herein, we report a case of of PHP1A with atypical clinical manifestations (oligomenorrhea, subclinical hypothyroidism, and normocalcemia) and explore the underlying genetic cause in this patient.MethodsBlood samples were collected from the patient, her family members, and 100 healthy controls. The 13 exons and flanking splice sites of the GNAS gene were amplified by PCR and sequenced. To further assess whether the novel mutation resulted in gain or loss of function of Gsα, we examined the level of cAMP activity associated with this mutation through in vitro functional studies by introducing the target mutation into a human GNAS plasmid.ResultsA novel heterozygous c.715A > G (p.N239D) mutation in exon 9 of the GNAS gene was identified in the patient. This mutation was also found in her mother, who was diagnosed with pseudopseudohypoparathyroidism. An in vitro cAMP assay showed a significant decrease in PTH-induced cAMP production in cells transfected with the mutant plasmid, compared to that in the wild-type control cells (P < 0.01), which was consistent with loss of Gsa activity.ConclusionWe identified a novel GNAS mutation that altered Gsα function, which furthers our understanding of the pathogenesis of this disease. Screening for GNAS mutations should be considered in suspected cases of PHP1A even if the classical signs are not present.

| S-EPMC6065144 | biostudies-literature

(Epi)genotype-Phenotype Analysis in 69 Japanese Patients With Pseudohypoparathyroidism Type I.

Project description:Pseudohypoparathyroidism type I (PHP-I) is divided into PHP-Ia with Albright hereditary osteodystrophy and PHP-Ib, which usually shows no Albright hereditary osteodystrophy features. Although PHP-Ia and PHP-Ib are typically caused by genetic defects involving ? subunit of the stimulatory G protein (Gs?)-coding GNAS exons and methylation defects of the GNAS differentially methylated regions (DMRs) on the maternal allele, respectively, detailed phenotypic characteristics still remains to be examined.To clarify phenotypic characteristics according to underlying (epi)genetic causes.We performed (epi)genotype-phenotype analysis in 69 Japanese patients with PHP-I; that is, 28 patients with genetic defects involving Gs?-coding GNAS exons (group 1) consisting of 12 patients with missense variants (subgroup A) and 16 patients with null variants (subgroup B), as well as 41 patients with methylation defects (group 2) consisting of 21 patients with broad methylation defects of the GNAS-DMRs (subgroup C) and 20 patients with an isolated A/B-DMR methylation defect accompanied by the common STX16 microdeletion (subgroup D).Although (epi)genotype-phenotype findings were grossly similar to those reported previously, several important findings were identified, including younger age at hypocalcemic symptoms and higher frequencies of hyperphosphatemia in subgroup C than in subgroup D, development of brachydactyly in four patients of subgroup C, predominant manifestation of subcutaneous ossification in subgroup B, higher frequency of thyrotropin resistance in group 1 than in group 2, and relatively low thyrotropin values in four patients with low T4 values and relatively low luteinizing hormone/follicle-stimulating hormone values in five adult females with ovarian dysfunction.The results imply the presence of clinical findings characteristic of each underlying cause and provide useful information on the imprinting status of Gs?.

| S-EPMC5779104 | biostudies-literature

Intragenic GNAS deletion involving exon A/B in pseudohypoparathyroidism type 1A resulting in an apparent loss of exon A/B methylation: potential for misdiagnosis of pseudohypoparathyroidism type 1B.

Project description:ContextSeveral endocrine diseases that share resistance to PTH are grouped under the term pseudohypoparathyroidism (PHP). Patients with PHP type Ia show additional hormone resistance, defective erythrocyte G(s)alpha activity, and dysmorphic features termed Albright's hereditary osteodystrophy (AHO). Patients with PHP-Ib show less diverse hormone resistance and normal G(s)alpha activity; AHO features are typically absent in PHP-Ib. Mutations affecting G(s)alpha coding exons of GNAS and epigenetic alterations in the same gene are associated with PHP-Ia and -Ib, respectively. The epigenetic GNAS changes in familial PHP-Ib are caused by microdeletions near or within GNAS but without involving G(s)alpha coding exons.ObjectiveWe sought to identify the molecular defect in a patient who was diagnosed with PHP-Ia based on clinical presentation (hormone resistance and AHO) but displayed the molecular features typically associated with PHP-Ib (loss of methylation at exon A/B) without previously described genetic mutations.MethodsMicrosatellite typing, comparative genome hybridization, and allelic dosage were performed for proband and her parents.ResultsComparative genome hybridization revealed a deletion of 30,431 bp extending from the intronic region between exons XL and A/B to intron 5. The same mutation was also demonstrated, by PCR, in the patient's mother, but polymorphism and allele dosage analyses indicated that she had this mutation in a mosaic manner.ConclusionWe discovered a novel multiexonic GNAS deletion transmitted to our patient from her mother who is mosaic for this mutation. The deletion led to different phenotypic manifestations in the two generation and appeared, in the patient, as loss of GNAS imprinting.

| S-EPMC2840867 | biostudies-literature

Mutations in pseudohypoparathyroidism 1a and pseudopseudohypoparathyroidism in ethnic Chinese.

Project description:An inactivating mutation in the GNAS gene causes either pseudohypoparathyroidism 1a (PHP1A) when it is maternally inherited or pseudopseudohypoparathyroidism (PPHP) when it is paternally inherited. We investigated clinical manifestations and mutations of the GNAS gene in ethnic Chinese patients with PHP1A or PPHP. Seven patients from 5 families including 4 girls and 2 boys with PHP1A and 1 girl with PPHP were studied. All PHP1A patients had mental retardation. They were treated with calcitriol and CaCO3 with regular monitoring of serum Ca levels, urinary Ca/Cr ratios, and renal sonography. Among them, 5 patients also had primary hypothyroidism suggesting TSH resistance. One female patient had a renal stone which was treated with extracorporeal shockwave lithotripsy. She had an increased urinary Ca/Cr ratio of 0.481 mg/mg when the stone was detected. We detected mutations using PCR and sequencing as well as analysed a splice acceptor site mutation using RT-PCR, sequencing, and minigene construct. We detected 5 mutations: c.85C>T (Q29*), c.103C>T (Q35*), c.840-2A>G (R280Sfs*21), c.1027_1028delGA (D343*), and c.1174G>A (E392K). Mutations c.840-2A>G and c.1027_1028delGA were novel. The c.840-2A>G mutation at the splice acceptor site of intron 10 caused retention of intron 10 in the minigene construct but skipping of exon 11 in the peripheral blood cells. The latter was the most probable mechanism which caused a frameshift, changing Arg to Ser at residue 280 and invoking a premature termination of translation at codon 300 (R280Sfs*21). Five GNAS mutations in ethnic Chinese with PHP1A and PPHP were reported. Two of them were novel. Mutation c.840-2A>G destroyed a spice acceptor site and caused exon skipping. Regular monitoring and adjustment in therapy are mandatory to achieve optimal therapeutic effects and avoid nephrolithiasis in patients with PHP1A.

| S-EPMC3961212 | biostudies-literature

Unrecognized Pseudohypoparathyroidism Type 1A as a Cause of Hypocalcemia and Seizures in a 64-Year-Old Woman.

Project description:Pseudohypoparathyroidism type 1A (PHP1A) is usually diagnosed in childhood or early adulthood. We describe the case of a 64-year-old woman admitted to the Neurological Unit for recurrent episodes of loss of consciousness and seizures. Glycemia and ECG were normal, while hypocalcemia was noted. Clinical history revealed carpo-pedal spasm since the age of 30 years, cognitive impairment, hypothyroidism since early adulthood, and menopause at 30 years. She was taking oral calcium and cholecalciferol for chronic hypocalcemia. Physical features suggested Albright's osteodystrophy. Blood calcium was confirmed low, with increased parathyroid hormone, moderate 25OH-vitamin D deficiency, and normal creatinine. Brain CT scan revealed calcifications of the basal ganglia, cortical and subcortical white matter, and cerebellum. Therapy was switched to oral calcitriol, with normalization of calcium levels; levetiracetam was started and no further seizures occurred. The clinical diagnosis of PHP1A was confirmed by molecular analysis, which demonstrated the heterozygous c.568_571del mutation of the GNAS gene. Our report illustrates the natural history of a patient with PHP1A, which went undiagnosed until the age of 64 years, with multi-hormonal resistance and clinical sequelae evolving throughout life, and underlines the importance of diagnosing this rare disease, which has a great impact on patients and their family life.

| S-EPMC6343178 | biostudies-literature

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