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World Journal of Clinical Cases Feb 2020Pseudohypoparathyroidism type Ia (PHP Ia) is a rare hereditary syndrome, and patients with early PHP Ia are generally not diagnosed based on the presentation of...
BACKGROUND
Pseudohypoparathyroidism type Ia (PHP Ia) is a rare hereditary syndrome, and patients with early PHP Ia are generally not diagnosed based on the presentation of cutaneous nodules as the main clinical feature. Here, we describe a Chinese boy with PHP Ia in whom the main clinical feature was cutaneous nodules, and the patient exhibited a novel mutation.
CASE SUMMARY
A 5-year-old boy presented with a 5-year history of cutaneous nodules scattered over his entire body. The patient had a short stature, round face, short neck, and slightly flattened nose; he also had multiple hard papules and cutaneous nodules scattered over his entire body. The patient had a significantly elevated parathyroid hormone level. His serum calcium level was reduced, while his serum phosphorus level was increased and his serum thyroid-stimulating hormone level was elevated. Skin biopsy showed osteoma cutis in subcutaneous tissue. Sanger sequencing revealed a frameshift mutation, c.399delT (p.Ser133Argfs*2) in exon 5 of the gene. The patient was diagnosed with PHP Ia and subclinical hypothyroidism. He was given 1,25-dihydroxyvitamin D, calcium carbonate, and synthetic L-thyroxine. After 3 months of treatment, the patient's parathyroid hormone level decreased, and his serum calcium and serum phosphorus levels were normal. Moreover, his thyroid-stimulating hormone level decreased.
CONCLUSION
These findings can help dermatologists to diagnose PHP Ia in patients with cutaneous nodules as the main early clinical feature.
PubMed: 32110670
DOI: 10.12998/wjcc.v8.i3.587 -
The Journal of International Medical... Nov 2023We report a 15-year-old Chinese girl who presented with intermittent seizure episodes and had been misdiagnosed as having idiopathic epilepsy 5 years previously....
We report a 15-year-old Chinese girl who presented with intermittent seizure episodes and had been misdiagnosed as having idiopathic epilepsy 5 years previously. Laboratory testing revealed hypocalcemia, hyperphosphatemia, and a high parathyroid hormone (PTH) concentration. She was subsequently shown to have pseudohypoparathyroidism type Ib (PHPIb) based on the results of methylation analysis of the gene, which showed a loss of methylation of the differentially methylated regions (DMR) of , , and ; and a gain of methylation of the DMR of the GNAS-NESP55 region. We adjusted the patient's medication by prescribing calcium and calcitriol supplements, and gradually reduced the doses of antiepileptic drugs, until they had been completely discontinued. As a result, the patient did not experience any further seizures or epileptiform symptoms; and had normal plasma calcium, phosphorus, and 25-hydroxyvitamin D concentrations and 24-hour urinary calcium excretion. In addition, her PTH concentration gradually normalized over 12 months, and no urinary stones were found on ultrasonographic examination. In conclusion, the clinical presentation of PHP is complex, and the condition is often misdiagnosed. The diagnosis and follow-up of the present patient have provide valuable insights that should contribute to informed clinical decision-making and the implementation of appropriate treatment strategies.
Topics: Humans; Female; Adolescent; GTP-Binding Protein alpha Subunits, Gs; DNA Methylation; Calcium; Follow-Up Studies; Chromogranins; Pseudohypoparathyroidism; Parathyroid Hormone; Epilepsy; Diagnostic Errors
PubMed: 38017366
DOI: 10.1177/03000605231215202 -
BMC Endocrine Disorders Dec 2019Pseudohypoparathyroidism(PHP) is a heterogeneous group of disorders due to impaired activation of c AMP dependant pathways following binding of parathyroid hormone (PTH)...
BACKGROUND
Pseudohypoparathyroidism(PHP) is a heterogeneous group of disorders due to impaired activation of c AMP dependant pathways following binding of parathyroid hormone (PTH) to its receptor. In PHP end organ resistance to PTH results in hypocalcaemia, hyperphosphataemia and high PTH levels.
CASE PRESENTATION
A 59 year old male presented with a history of progressive impairment of speech and unsteadiness of gait for 1 week and acute onset altered behavior for 1 day and one episode of generalized seizure. His muscle power was grade four according to MRC (medical research council) scale in all limbs and Chovstek's and Trousseau's signs were positive. Urgent non contrast computed tomography scan of the brain revealed extensive bilateral cerebral and cerebellar calcifications. A markedly low ionized calcium level of 0.5 mmol/l, an elevated phosphate level of 9.5 mg/dl (reference range: 2.7-4.5 mg/dl) and an elevated intact PTH of 76.3 pg/l were noted. His renal functions were normal. His hypocalcemia was accentuated by the presence of hypomagnesaemia. His 25 hydroxy vitamin D level was only marginally low which could not account for severe hypocalcaemia. A diagnosis of pseudohypoparathyroidism without phenotypic defects, was made due to hypocalcaemia and increased parathyroid hormone levels with cerebral calcifications. The patient was treated initially with parenteral calcium which was later converted to oral calcium supplements. His coexisting Vitamin D deficiency was corrected with 1αcholecalciferol escalating doses. His hypomagnesaemia was corrected with magnesium sulphate parenteral infusions initially and later with oral preparations. With treatment there was a significant clinical and biochemical response.
CONCLUSION
Pseudohypoparathyroidism can present for the first time in elderly resulting in extensive cerebral calcifications. Identification and early correction of the deficit will result in both symptomatic and biochemical response.
Topics: Calcinosis; Calcium; Humans; Magnesium Deficiency; Magnesium Sulfate; Male; Middle Aged; Parathyroid Hormone; Pseudohypoparathyroidism; Spinal Diseases; Vitamin D; Vitamin D Deficiency
PubMed: 31856822
DOI: 10.1186/s12902-019-0475-z -
Frontiers in Endocrinology 2023The serum calcium (Ca)-to-phosphorus (P) ratio has been proposed to identify patients with primary hyperparathyroidism and chronic hypoparathyroidism (HPT), but it has... (Observational Study)
Observational Study
OBJECTIVE
The serum calcium (Ca)-to-phosphorus (P) ratio has been proposed to identify patients with primary hyperparathyroidism and chronic hypoparathyroidism (HPT), but it has never been tested in pseudohypoparathyroidism (PHP). The aim of this study was to test the performance of Ca/P ratio in PHP diagnosis compared with that in healthy subjects and patients with HPT for differential diagnosis.
DESIGN
A retrospective, cross-sectional, and observational study was carried out.
METHODS
Serum Ca, P, creatinine, parathyroid hormone (PTH), and albumin were collected. Ca and P were expressed in mmol/L. Ca/P diagnostic performance was evaluated by receiver operating characteristic curve, sensitivity, specificity, and accuracy.
RESULTS
A total of 60 patients with PHP, 60 patients with HPT, and 120 controls were enrolled. The Ca/P ratio was lower in patients with PHP and HPT than that in controls (p < 0.0001). The cutoff of 1.78 (2.32 if Ca and P measured in mg/dL) for Ca/P ratio could identify patients with PHP and HPT among the entire cohort (sensitivity and specificity of 76%). No valid cutoff of Ca/P was found to distinguish patients with PHP from patients with HPT; in this case, PTH above 53.0 ng/dL identified patients with PHP (sensitivity and specificity of 100%). The index (Ca/P × PTH) above 116 ng/L recognized patients with PHP from controls (sensitivity of 84.7% and specificity of 87.4%), whereas (Ca/P × PTH) below 34 ng/L recognized patients with HPT from controls (sensitivity of 88.9% and specificity of 90.8%).
CONCLUSIONS
The Ca/P ratio below 1.78 (2.32 CU) is highly accurate to identify patients with PHP and HPT, although it is not reliable to differentiate these two conditions. The index (Ca/P × PTH) is excellent to specifically recognize PHP or HPT from healthy subjects.
Topics: Humans; Calcium; Retrospective Studies; Cross-Sectional Studies; Pseudohypoparathyroidism; Parathyroid Hormone; Hypoparathyroidism; Phosphorus
PubMed: 37854194
DOI: 10.3389/fendo.2023.1268704 -
American Journal of Ophthalmology Case... Dec 2020To describe a case of multiple autoimmune syndrome presenting with type I diabetes, choroidal vitiligo, coeliac disease, pseudohypoparathyroidism, and immune...
PURPOSE
To describe a case of multiple autoimmune syndrome presenting with type I diabetes, choroidal vitiligo, coeliac disease, pseudohypoparathyroidism, and immune thrombocytopenia purpura (ITP), the latter diagnosed seven years after the initial presentation.
OBSERVATIONS
A 26-year-old female presented with bilateral severe diabetic retinopathy. Panretinal photocoagulation (PRP) was initially declined due to poor adherence to treatment. Thirty-three months after the initial presentation, a progression of the retinal disease to bilateral proliferative retinopathy, macular edema, and epiretinal membranes was noted. Additionally, an ischemic branch retinal vein occlusion was diagnosed in the inferior nasal quadrant of the left eye. Over this period visual acuity declined from 6/9 bilaterally to 6/24 and 6/30 in the right and left eyes, respectively. PRP was then performed under subtenons anesthesia. Excessive hemorrhage was noted from the site of the conjunctival wound, and Tranexamic acid was prescribed postoperatively. Investigations did not reveal a primary coagulopathy. Seven years after the initial presentation, the patient was admitted to hospital with a spontaneous right frontal lobe intracerebral hemorrhage, from which a recovery occurred without neurologic deficit. Hematological parameters remained normal for this admission and the cause of the spontaneous hemorrhage remained undiagnosed. Seven months after this episode, the patient was admitted to the Hematology ward after a five-week history of gingival hemorrhage subsequent to a dental procedure. As the platelet count was 16 × 10/L, a diagnosis of ITP was confirmed. However, the platelet count failed to respond to treatment with Prednisone, intravenous Immunoglobulin, Tranexamic acid, Eltrombopag, and Rituximab. A second fatal intracranial hemorrhage occurred two months later.
CONCLUSION AND IMPORTANCE
Multiple autoimmune syndrome may complicate the presentation and management of diabetic retinopathy. In some cases, the manifestations of systemic autoimmune disease may dominate the clinical picture. Management of the more complex disease burden, in this case, became an increasingly perplexing multidisciplinary predicament with each additional autoimmune disorder diagnosed over the treatment course.
PubMed: 33073055
DOI: 10.1016/j.ajoc.2020.100928 -
Genes Jan 2023Pseudohypoparathyroidism (PHP) is a heterogeneous orphan disease characterized by multihormonal resistance and several phenotypic features. In some cases, PHP is caused...
Pseudohypoparathyroidism (PHP) is a heterogeneous orphan disease characterized by multihormonal resistance and several phenotypic features. In some cases, PHP is caused by a mutation in the that encodes the alpha subunit of the G protein, one of the key transmitters of intracellular signals. A correlation between the genotype and phenotype of patients with mutations has not yet been described. This often makes diagnosis, drug prescription, and timely diagnosis difficult. Information about GNAS functioning and the impact of specific mutations on the clinical course of the disease is limited. Establishing of the pathogenicity by newly identified mutations will expand the understanding of this gene functioning in the cAMP signaling pathway and may become the basis for personalized treatment. This paper provides a clinical description of a patient with the Ia PHP phenotype caused by a previously unknown mutation in (NC_000020.11(NM_000516.7)): c.719-29_719-13delinsACCAAAGAGAGCAAAGCCAAG in the heterozygous state. Verification of the pathogenicity of the detected mutation is also described.
Topics: Humans; GTP-Binding Protein alpha Subunits, Gs; Chromogranins; Pseudohypoparathyroidism; Mutation; Phenotype
PubMed: 36833251
DOI: 10.3390/genes14020324 -
The Journal of Clinical Endocrinology... Feb 2022Sporadic pseudohypoparathyroidism type 1B (sporPHP1B) is an imprinting disease without a defined genetic cause, characterized by broad methylation changes in...
CONTEXT
Sporadic pseudohypoparathyroidism type 1B (sporPHP1B) is an imprinting disease without a defined genetic cause, characterized by broad methylation changes in differentially methylated regions (DMRs) of the GNAS gene.
OBJECTIVE
This work aims to provide insights into the causative event leading to the GNAS methylation defects through comprehensive molecular genetic analyses of a pair of female monozygotic twins concordant for sporPHP1B who were conceived naturally, that is, without assisted reproductive techniques.
METHODS
Using the leukocyte genome of the twins and family members, we performed targeted bisulfite sequencing, methylation-sensitive restriction enzyme (MSRE)-quantitative polymerase chain reaction (qPCR), whole-genome sequencing (WGS), high-density single-nucleotide polymorphism (SNP) array, and Sanger sequencing.
RESULTS
Methylation analyses by targeted bisulfite sequencing and MSRE-qPCR revealed almost complete losses of methylation at the GNAS AS, XL, and A/B DMRs and a gain of methylation at the NESP55 DMR in the twins, but not in other family members. Except for the GNAS locus, we did not find apparent methylation defects at other imprinted genome loci of the twins. WGS, SNP array, and Sanger sequencing did not detect the previously described genetic defects associated with familial PHP1B. Sanger sequencing also ruled out any novel genetic alterations in the entire NESP55/AS region. However, the analysis of 28 consecutive SNPs could not exclude the possibility of paternal heterodisomy in a span of 22 kb comprising exon NESP55 and AS exon 5.
CONCLUSION
Our comprehensive analysis of a pair of monozygotic twins with sporPHP1B ruled out all previously described genetic causes. Twin concordance indicates that the causative event was an imprinting error earlier than the timing of monozygotic twinning.
Topics: Adult; Chromogranins; DNA Methylation; Diseases in Twins; Female; GTP-Binding Protein alpha Subunits, Gs; Genomic Imprinting; Humans; Pedigree; Pseudohypoparathyroidism; Twins, Monozygotic; Whole Genome Sequencing
PubMed: 34741517
DOI: 10.1210/clinem/dgab801 -
Italian Journal of Pediatrics Jul 2022Albright's hereditary osteodystrophy (AHO) is an inherited disorder which is caused by an inactivating variant in the GNAS gene. AHO appears associated to either...
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.
Topics: China; Chromogranins; GTP-Binding Protein alpha Subunits, Gs; Hormones; Humans; Phenotype; Pseudohypoparathyroidism
PubMed: 35871092
DOI: 10.1186/s13052-022-01322-6 -
Paternal Uniparental Disomy of the Entire Chromosome 20 in a Child with Beckwith-Wiedemann Syndrome.Genes Jan 2021Epigenetic alterations at imprinted genes on different chromosomes have been linked to several imprinting disorders (IDs) such as Beckwith-Wiedemann syndrome (BWS) and...
Epigenetic alterations at imprinted genes on different chromosomes have been linked to several imprinting disorders (IDs) such as Beckwith-Wiedemann syndrome (BWS) and pseudohypoparathyroidism type 1b (PHP1b). Here, we present a male patient with these two distinct IDs caused by two independent mechanisms-loss of methylation (LOM) at chromosome 11p15.5 associated with multi-locus imprinting disturbances (MLID and paternal uniparental disomy of chromosome 20 (patUPD20). A clinical diagnosis of BWS was made based on the clinical features of macrosomia, macroglossia, and umbilical hernia. The diagnosis of PHP1b was supported by the presence of reduced growth velocity and mild learning disability as well as hypocalcemia and hyperphosphatemia at 14 years of age. Molecular analyses, including genome-wide DNA methylation (Illumina 450k array), bisulfite pyrosequencing, single nucleotide polymorphism (SNP) array and microsatellite analysis, demonstrated loss of methylation (LOM) at IC2 on chromosome 11p15.5, and paternal isodisomy of the entire chromosome 20. In addition, imprinting disturbances were noted at the differentially methylated regions (DMRs) associated with on chromosome 1 and on chromosome 6. This is the first case report of PHP1b due to patUPD20 diagnosed in a BWS patient with LOM at IC2 demonstrating etiologic heterogeneity for multiple imprinting disorders in a single individual.
Topics: Beckwith-Wiedemann Syndrome; Child; Chromosomes, Human, Pair 20; CpG Islands; DNA Methylation; Epigenesis, Genetic; Gene Expression Profiling; Genetic Association Studies; Genetic Predisposition to Disease; Genomic Imprinting; Humans; Loss of Heterozygosity; Male; Microsatellite Repeats; Paternal Inheritance; Pedigree; Polymorphism, Single Nucleotide; Uniparental Disomy
PubMed: 33513760
DOI: 10.3390/genes12020172 -
Medicina (Kaunas, Lithuania) Apr 2024Soft tissue calcifications frequently appear on imaging studies, representing a prevalent but non-specific discovery, varying from a local reaction without clear cause...
Soft tissue calcifications frequently appear on imaging studies, representing a prevalent but non-specific discovery, varying from a local reaction without clear cause to suggesting an underlying systemic condition. Because calcifications like these can arise from various causes, an accurate differential diagnosis is crucial. Differential diagnosis entails a methodical assessment of the patient, encompassing clinical presentation, medical history, radiological and pathological findings, and other pertinent factors. Through scrutiny of the patient's medical and trauma history, we can refine potential causes of calcification to vascular, metabolic, autoimmune, neoplastic, or traumatic origins. Furthermore, routine laboratory assessments, including serum levels of calcium, phosphorus, ionized calcium, vitamin D metabolites, and parathyroid hormone (PTH), aid in identifying metabolic etiologies. We describe a rare occurrence of osteoma cutis in a 15-year-old female patient with a history of pseudohypoparathyroidism (PHP) and Albright's hereditary osteodystrophy (AHO). The patient presented with a painful mass on the lateral side of her left foot. The diagnosis was based on medical history, laboratory tests, and imaging, leading to an excisional biopsy and complete pain relief post-surgery. Understanding such rare occurrences and related conditions is crucial for accurate diagnosis and management.
Topics: Humans; Female; Calcinosis; Pseudohypoparathyroidism; Adolescent; Diagnosis, Differential; Foot; Bone Diseases, Metabolic
PubMed: 38674241
DOI: 10.3390/medicina60040595