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Annals of Medicine and Surgery (2012) Feb 2024Fahr's syndrome is primarily familial, autosomal dominant, and genetically diverse. Basal ganglia calcification that is bilaterally symmetrical is a hallmark of this...
INTRODUCTION AND IMPORTANCE
Fahr's syndrome is primarily familial, autosomal dominant, and genetically diverse. Basal ganglia calcification that is bilaterally symmetrical is a hallmark of this illness. Although the specific origins of this illness are unknown, it may be brought on by problems with calcium metabolism, infections, toxins, hereditary factors, hypoparathyroidism, and pseudohypoparathyroidism. The prevalence of this syndrome is less than 0.5%.
CASE PRESENTATION
An 11-year-old female comes to the Emergency Department with her parents complaining of high-grade fever and convulsions for 1 week. Convulsion, which is a generalized tonic-clonic seizure, duration was ~5 min and associated with urinary incontinence and biting tongue. On examination, the patient was confused and irritable. Vital signs were normal; there is weakness in the right arm and right leg, associated with irregular movement. There was alternation in her level of consciousness, slurring of speech, and psychiatric symptoms. Another aspect of the neurological examination and systems was normal, and there was no meningeal irritation.
CLINICAL DISCUSSION
The pathogenesis of Fahr's syndrome is not completely known. The calcification is caused by flaws in the transport of radioactive particles and tissue damage caused by free radicals. Bilateral calcification found on a computed tomography (CT) scan of the brain, autosomal dominant inheritance, the absence of any infection, drugs, or toxins, the absence of mitochondrial dysfunction, and the presence of progressive neurological dysfunction is the clinical criteria for diagnosing Fahr's syndrome.
CONCLUSION
Basal ganglia calcification that is bilaterally symmetrical is a hallmark of Fahr's syndrome. CT scans are the gold standard for conclusively diagnosing Fahr's syndrome.
PubMed: 38333236
DOI: 10.1097/MS9.0000000000001586 -
Endocrine Dec 2022The application of the third-generation parathyroid hormone (PTH) assay [PTH(1-84) assay] for evaluating PTH levels in patients with pseudohypoparathyroidism type-1...
Full-length versus intact PTH concentrations in pseudohypoparathyroidism type 1 and primary hyperparathyroidism: clinical evaluation of immunoassays in individuals from China.
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 (3/2 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) (r = 0.9661, 0.7733, and 0.9575, respectively). No significant differences were noted in 3/2 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.
Topics: Humans; Hyperparathyroidism, Primary; Parathyroid Hormone; Immunoassay; Pseudohypoparathyroidism; Linear Models; Calcium
PubMed: 36220966
DOI: 10.1007/s12020-022-03204-7 -
Journal of Clinical Medicine Dec 2023Hypercalcitoninaemia has been described in patients with pseudohypoparathyroidism (PHP) type 1A and 1B. Elevated calcitonin levels are thought to result from impaired... (Review)
Review
C-Cell Hyperplasia and Cystic Papillary Thyroid Carcinoma in a Patient with Type 1B Pseudohypoparathyroidism and Hypercalcitoninaemia: Case Report and Review of the Literature.
Hypercalcitoninaemia has been described in patients with pseudohypoparathyroidism (PHP) type 1A and 1B. Elevated calcitonin levels are thought to result from impaired Gsα receptor signaling, leading to multiple hormone resistance. Evidence on the risk of medullary thyroid carcinoma (MTC) or C-cell hyperplasia in PHP patients with hypercalcitoninaemia is lacking. A 43-year-old Caucasian man was referred to our endocrinology clinic for chronic hypocalcemia associated with elevated serum parathormone levels and a single cystic thyroid nodule. The patient did not show skeletal deformities, and screening for concomitant hormone resistances was negative, except for the presence of elevated serum calcitonin levels. The workup led to a molecular diagnosis of sporadic PHP1B. Fine needle aspiration of the thyroid nodule was not diagnostic. The calcium stimulation test yielded an abnormal calcitonin response. Given the scarcity of data on the risk of thyroid malignancy in PHP and calcium stimulation test results, total thyroidectomy was performed. Histological examination revealed cystic papillary thyroid cancer in a background of diffuse C-cell hyperplasia. To our knowledge, we are the first to describe a rare form of thyroid cancer combined with C-cell hyperplasia in a patient with PHP and hypercalcitoninaemia. In the present case, a mere receptor resistance might not fully explain the elevated calcitonin levels, suggesting that hypercalcitoninaemia should be carefully evaluated in PHP patients, especially in the case of concomitant thyroid nodules. Further studies on larger cohorts are needed to elucidate this topic.
PubMed: 38137593
DOI: 10.3390/jcm12247525 -
Bone Reports Jun 2022Pseudohypoparathyroidism type 1a (PHP1a) is a genetic disorder caused by heterozygous loss-of-function mutations on the maternal allele of the gene. Patients with PHP1a...
Pseudohypoparathyroidism type 1a (PHP1a) is a genetic disorder caused by heterozygous loss-of-function mutations on the maternal allele of the gene. Patients with PHP1a predominantly exhibit parathyroid hormone (PTH) resistance and physical features of Albright's hereditary osteodystrophy. We report two unrelated cases with PHP1a who developed tertiary hyperparathyroidism (HPT). Molecular analyses of the gene identified a previously known heterozygous 4-bp deletion (c. 565_568delGACT) in exon 7 in case 1 and a novel heterozygous missense mutation (p.Lys233Glu) in exon 9 in case 2. Both patients developed tertiary HPT associated with hyperfunctioning parathyroid glands during long-term treatment of hypocalcemia. Case 1 had severe osteoporosis and underwent parathyroidectomy. Case 2 was asymptomatic with no evidence of bone diseases associated with tertiary HPT. PHP1a patients are at risk of developing tertiary HPT and should be treated with sufficient doses of calcium and vitamin D to achieve serum PTH levels within the mid - normal to double the upper limit of the normal range, regardless of serum calcium levels.
PubMed: 35497370
DOI: 10.1016/j.bonr.2022.101569 -
The Journal of Clinical Endocrinology... May 2022Parathyroid hormone (PTH) gene mutations represent a rare cause of familial isolated hypoparathyroidism (FIH). These defects can cause hypoparathyroidism with increased...
CONTEXT
Parathyroid hormone (PTH) gene mutations represent a rare cause of familial isolated hypoparathyroidism (FIH). These defects can cause hypoparathyroidism with increased or decreased serum levels of PTH through 1) impaired PTH synthesis; 2) induction of parathyroid cell apoptosis; or 3) secretion of bioinactive PTH molecules. Eight pathogenic mutations of this gene have been described previously.
OBJECTIVE
Through describing 2 novel mutations of the PTH gene, we aim to extend the molecular basis for FIH and further refine the proposed mechanisms by which PTH mutations cause hypoparathyroidism.
METHODS
Proband case reports were compiled with extended family analysis. The probands in both kindreds presented before age 10 days with hypocalcemia and elevated phosphate levels. Proband A had low PTH levels, whereas these levels were elevated in Proband B. Proband B was initially diagnosed with pseudohypoparathyroidism. Methylation analysis was performed of CpG dinucleotides within 3 GNAS differentially methylated regions; whole-genome sequencing; and PTH infusion with analysis of nephrogenous 3',5'-cyclic adenosine 5'-monophosphate.
RESULTS
Proband A had a novel heterozygous sequence change in exon 2 of the PTH gene, c.46_47delinsAA (p.Ala16Lys), and proband B had a novel homozygous nucleotide transition in PTH exon 3 (c.128G > A; p.G43E) that led to replacement of glycine by glutamic acid at position 12 of PTH 1-84. PTH 1-34 infusion demonstrated that renal responsiveness to PTH was intact and not antagonized by circulating bioinactive PTH.
CONCLUSION
PTH gene mutations are uncommon causes of hypoparathyroidism, but can be misdiagnosed as disorders of gland development or receptor function if PTH levels are decreased or elevated, respectively. Genetic testing should be considered early in the diagnostic approach to these presentations.
Topics: Child; Cyclic AMP; Humans; Hypocalcemia; Hypoparathyroidism; Mutation; Parathyroid Hormone; Pseudohypoparathyroidism
PubMed: 35165722
DOI: 10.1210/clinem/dgac086 -
European Journal of Endocrinology Jul 2023Maternal inactivating GNAS mutations lead to pseudohypoparathyroidism 1A (PHP1A), newly classified as inactivating parathyroid hormone (PTH)/PTHrP-signaling disorder... (Observational Study)
Observational Study
BACKGROUND
Maternal inactivating GNAS mutations lead to pseudohypoparathyroidism 1A (PHP1A), newly classified as inactivating parathyroid hormone (PTH)/PTHrP-signaling disorder type 2 of maternal inheritance (iPPSD2). Patients present with resistance to PTH and other hormones, subcutaneous ossifications, brachydactyly, short stature, and early-onset obesity. They can be born small for gestational age (SGA) and may present with growth hormone (GH) deficiency. The use of recombinant human GH (rhGH) therapy has been sporadically reported, yet we lack data on the long-term efficacy and safety of rhGH, as well as on adult height.
OBJECTIVE
Our multicenter, retrospective, observational study describes growth in patients treated with rhGH in comparison with untreated iPPSD2/PHP1A controls.
METHODS
We included 190 patients, of whom 26 received rhGH. Height, weight, body mass index at various time points, and adult height were documented. We analyzed the effect of rhGH on adult height by using linear mixed models.
RESULTS
Adult height was available for 11/26 rhGH-treated individuals and for 69/164 controls. Patients treated with rhGH showed a gain in height of 0.7 standard deviation scores (SDS) after 1 year (CI +0.5 to +0.8, P < .001) and of 1.5 SDS after 3 years (CI +1.0 to +2.0, P < .001). Additionally, there was a clear beneficial impact of rhGH on adult height when compared with untreated controls, with a difference of 1.9 SDS (CI +1.1 to +2.7, P < .001). Body mass index SDS did not vary significantly upon rhGH therapy.
CONCLUSION
Recombinant human growth hormone treatment of iPPSD2/PHP1A patients with short stature improves growth and adult height. More studies are needed to confirm long-term efficacy and safety.
Topics: Humans; Adult; Growth Hormone; Retrospective Studies; Human Growth Hormone; Pseudohypoparathyroidism; Dwarfism, Pituitary; Hypopituitarism; Mutation; Body Height; Recombinant Proteins; Growth Disorders; Chromogranins; GTP-Binding Protein alpha Subunits, Gs
PubMed: 37440712
DOI: 10.1093/ejendo/lvad085 -
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 Endocrine Disorders Apr 2022Pseudohypoparathyroidism (PHP) encompasses a highly heterogenous group of disorders, characterized by parathyroid hormone (PTH) resistance caused by mutations in the... (Review)
Review
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.
Topics: Adult; Chromogranins; Female; GTP-Binding Protein alpha Subunits, Gs; Humans; Hypocalcemia; Hypokalemia; Pseudohypoparathyroidism; Tetany
PubMed: 35410271
DOI: 10.1186/s12902-022-01011-9 -
Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... Oct 2022Pseudohypoparayhyroidism (PHP) is a rare autosomal dominant or recessive genetic disorder characterized by low calcium, high phosphorus, and target organ resistance to...
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 () 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 in the 4 patients. There were phenotype overlap among the various subtypes of PHP. Detection of gene methylation in patients with clinical suspicion of Type Ib PHP is helpful for the diagnosis and treatment of PHP.
Topics: Humans; Chromogranins; GTP-Binding Protein alpha Subunits, Gs; Hypokalemia; Calcium; Pseudohypoparathyroidism; Phosphorus
PubMed: 36411698
DOI: 10.11817/j.issn.1672-7347.2022.220029 -
AACE Clinical Case Reports 2020Acrodysostosis is a rare skeletal dysplasia with one gene mutation associated with pseudohypoparathyroidism. We describe a 15-year-old male patient with genetic...
OBJECTIVE
Acrodysostosis is a rare skeletal dysplasia with one gene mutation associated with pseudohypoparathyroidism. We describe a 15-year-old male patient with genetic acrodysostosis who presented with hyperparathyroidism.
METHODS
Laboratory testing, including genetic testing for acrodysostosis and biochemical evaluation for hypercalcemia, were obtained. For evaluation of the source of hyperparathyroidism, parathyroid imaging including technetium (99mTc) sestamibi (MIBI) scan, ultrasound, and 4-dimensional computed tomography scans were performed.
RESULTS
The initial calcium level of 11.7 mg/dL (reference range is 8.4 to 10.2 mg/dL), phosphorus of 2.6 mg/dL (reference range is 2.9 to 5.0 mg/dL), and parathyroid hormone (PTH) of 177 pg/mL (reference range is 15 to 65 pg/mL) were suspicious for hyperparathyroidism. Magnesium, albumin, creatinine, and PTH-related peptide levels were normal. His calcium/creatinine ratio was 0.15, calcium/creatinine clearance ratio was 0.008, and the fractional excretion of phosphorus was 34%. Our patient had no symptoms other than long-standing bone pain. Thyroid ultrasound then MIBI scan did not show a parathyroid adenoma or parathyroid gland hyperplasia. Familial hypocalciuric hypercalcemic syndrome was entertained, but without a family history and documented normal calcium levels throughout childhood, it was considered unlikely. On subsequent testing, his calcium and PTH levels increased. Subsequent imaging including repeat thyroid ultrasound, MIBI scan, and computed tomography did not find a definitive cause. Multiple endocrine neoplasia type 1 genetic testing was negative. Without an adenoma seen to remove surgically, we performed a trial of cinacalcet with successful reduction in PTH and normalization of his calcium and phosphorus levels.
CONCLUSION
Pseudohypoparathyroidism and hypocalcemia are well reported in acrodysostosis. To the best of our knowledge, this is the first reported case of hypercalcemia caused by hyperparathyroidism in a patient with acrodysostosis.
PubMed: 33244495
DOI: 10.4158/ACCR-2020-0103