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Endocrine Feb 20242q37 microdeletion syndrome is a rare clinical condition characterized by a series of physical abnormalities. Its Albright hereditary osteodystrophy (AHO)-like...
BACKGROUND
2q37 microdeletion syndrome is a rare clinical condition characterized by a series of physical abnormalities. Its Albright hereditary osteodystrophy (AHO)-like manifestations and possible complication of biochemical abnormalities indicating PTH resistance greatly increased the likelihood of misdiagnosis with classic pseudohypoparathyroidism (PHP) caused by GNAS mutation or methylation alteration, even though there have only been six reports of such clinical occasions.
PURPOSE
to investigate the underlying genetic defect in a male patient presenting hypocalcemia, elevated PTH and with a history of kyphosis.
METHOD
clinical information was collected, while the DNA was extracted from peripheral blood and subjected to methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and exome sequencing.
RESULT
Physical characteristics featuring short stature, obesity, round face, short neck, and shortened 4 metacarpal and laboratory examination of the patient suggested the presence of PTH resistance, which is indicative of PHP. MS-MLPA did not reveal methylation alterations or deletions of GNAS, STX16 or other monogenetic alterations responsible for iPPSDs, but WES revealed a long-range deletion of approximately 4.18 Mb of the 2q37 region that spanned AGAP1 to NDUFA10, indicating that the patient had 2q37 microdeletion syndrome with PTH resistance.
CONCLUSION
After undergoing MS-MLPA and exome sequencing, a novel deletion spanning 4.18 Mb on the 2q37 region was identified in one male patient, clarifying the diagnosis of 2q37 microdeletion syndrome with PTH resistance. The new genetic discovery added to our understanding of the molecular defects that cause inactivating PTH/PTH-related protein signaling disorders (iPPSDs).
PubMed: 38393510
DOI: 10.1007/s12020-024-03740-4 -
Journal of Pediatric Endocrinology &... Mar 2024Pseudohypoparathyroidism type 1A (PHP1A) encompasses the association of resistance to multiple hormones, features of Albright hereditary osteodystrophy and decreased...
OBJECTIVES
Pseudohypoparathyroidism type 1A (PHP1A) encompasses the association of resistance to multiple hormones, features of Albright hereditary osteodystrophy and decreased Gsα activity. Little is known about the early signs of PHP1A, with a delay in diagnosis. We report two PHP1A cases and their clinical and biochemical findings during a 20-year follow-up.
CASE PRESENTATION
Clinical suspicion was based on obesity, TSH resistance and ectopic ossifications which appeared several months before PTH resistance, at almost 3 years of age. Treatment with levothyroxine, calcitriol and calcium was required in both patients. DNA sequencing of GNAS gene detected a heterozygous pathogenic variant within exon 7 (c.569_570delAT) in patient one and a deletion from XLAS to GNAS-exon 5 on the maternal allele in patient 2. In patient 1, ectopic ossifications that required surgical excision were found. Noticeably, patient 2 displayed adult short stature, intracranial calcifications and psychomotor delay. In terms of weight, despite early diagnosis of obesity, dietary measures were established successfully in both cases.
CONCLUSIONS
GNAS mutations should be considered in patients with obesity, ectopic ossifications and TSH resistance presented in early infancy. These cases emphasize the highly heterogeneous clinical picture PHP1A patients may present, especially in terms of final height and cognitive impairment.
Topics: Adult; Humans; GTP-Binding Protein alpha Subunits, Gs; Pseudohypoparathyroidism; Mutation; Obesity; Thyrotropin; Chromogranins
PubMed: 38353264
DOI: 10.1515/jpem-2023-0454 -
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 -
JCI Insight Mar 2024Pseudohypoparathyroidism type 1B (PHP1B) results from aberrant genomic imprinting at the GNAS gene. Defining the underlying genetic cause in new patients is challenging...
Pseudohypoparathyroidism type 1B (PHP1B) results from aberrant genomic imprinting at the GNAS gene. Defining the underlying genetic cause in new patients is challenging because various genetic alterations (e.g., deletions, insertions) within the GNAS genomic region, including the neighboring STX16 gene, can cause PHP1B, and the genotype-epigenotype correlation has not been clearly established. Here, by analyzing patients with PHP1B with a wide variety of genotypes and epigenotypes, we identified a GNAS differentially methylated region (DMR) of distinct diagnostic value. This region, GNAS AS2, was hypomethylated in patients with genetic alterations located centromeric but not telomeric of this DMR. The AS2 methylation status was captured by a single probe of the methylation-sensitive multiplex ligation-dependent probe amplification (MS-MLPA) assay utilized to diagnose PHP1B. In human embryonic stem cells, where NESP55 transcription regulates GNAS methylation status on the maternal allele, AS2 methylation depended on 2 imprinting control regions (STX16-ICR and NESP-ICR) essential for NESP55 transcription. These results suggest that the AS2 methylation status in patients with PHP1B reflects the position at which the genetic alteration affects NESP55 transcription during an early embryonic period. Therefore, AS2 methylation levels can enable mechanistic PHP1B categorization based on genotype-epigenotype correlation and, thus, help identify the underlying molecular defect in patients.
Topics: Humans; GTP-Binding Protein alpha Subunits, Gs; DNA Methylation; Pseudohypoparathyroidism; Genomic Imprinting; Alleles; Chromogranins
PubMed: 38290008
DOI: 10.1172/jci.insight.177190 -
Current Obesity Reports Jun 2024Syndromic obesity refers to obesity occurring with additional clinical findings, such as intellectual disability/developmental delay, dysmorphic features, and congenital... (Review)
Review
Syndromic obesity refers to obesity occurring with additional clinical findings, such as intellectual disability/developmental delay, dysmorphic features, and congenital malformations. PURPOSE OF REVIEW: To present a narrative review regarding the genetic etiology, clinical description, and molecular diagnosis of syndromic obesity, which is a rare condition with high phenotypic variability and genetic heterogeneity. The following syndromes are presented in this review: Prader-Willi, Bardet-Biedl, Pseudohypoparathyroidism, Alström, Smith-Magenis, Cohen, Temple, 1p36 deletion, 16p11.2 microdeletion, Kleefstra, SIM1-related, Börjeson-Forssman-Lehmann, WAGRO, Carpenter, MORM, and MYT1L-related syndromes. RECENT FINDINGS: There are three main groups of mechanisms for syndromic obesity: imprinting, transcriptional activity regulation, and cellular cilia function. For molecular diagnostic, methods of genome-wide investigation should be prioritized over sequencing of panels of syndromic obesity genes. In addition, we present novel syndromic conditions that need further delineation, but evidences suggest they have a higher frequency of obesity. The etiology of syndromic obesity tends to be linked to disrupted neurodevelopment (central) and is associated with a diversity of genes and biological pathways. In the genetic investigation of individuals with syndromic obesity, the possibility that the etiology of the syndromic condition is independent of obesity should be considered. The accurate genetic diagnosis impacts medical management, treatment, and prognosis, and allows proper genetic counseling.
Topics: Humans; Obesity; Intellectual Disability; Syndrome; Phenotype; Bardet-Biedl Syndrome; Prader-Willi Syndrome; Developmental Disabilities; Alstrom Syndrome
PubMed: 38277088
DOI: 10.1007/s13679-023-00543-y -
QJM : Monthly Journal of the... Jun 2024
Topics: Humans; Pseudohypoparathyroidism; Skin Diseases, Genetic; Ossification, Heterotopic; Female; Male; Bone Diseases, Metabolic
PubMed: 38265255
DOI: 10.1093/qjmed/hcae017 -
Nephrology (Carlton, Vic.) May 2024We describe a unique case of 27-year-old male with Gitelman syndrome (GS) co-exist with pseudohypoparathyroidism type 1B (PHP1B). The patient presented with a 5-year...
We describe a unique case of 27-year-old male with Gitelman syndrome (GS) co-exist with pseudohypoparathyroidism type 1B (PHP1B). The patient presented with a 5-year history of seizures, tetany, and numbness of the extremities. Further examinations showed recurrent hypokalemia, inappropriate kaliuresis, hypocalcemia, hyperphosphatemia, and elevated PTH levels. A novel variant of autosomal recessive GS (p.Val287Met SLC12A3) and a novel 492.3Kb deletion containing the whole of STX16, were discovered by a whole-exome sequencing. Following the diagnosis, calcitriol, calcium, and potassium supplements were started. Hematuria calcium and phosphorus levels, as well as blood potassium levels, have recovered and remained within normal ranges after 3 years of follow-up. Our findings have important consequences for supporting the idea that heterozygosity for variants have effects on the patients' clinical performance with autosomal recessive inheritance disorders. Further study is need for the putative effects of the variant. Likewise, further investigation with regards to the gene-gene interaction relations between GS and other electrolyte imbalance disorders is warranted.
Topics: Male; Humans; Adult; Gitelman Syndrome; Hypokalemia; Calcium; Solute Carrier Family 12, Member 3; Pseudohypoparathyroidism; Seizures; Water-Electrolyte Imbalance; Calcium, Dietary; Epigenesis, Genetic; Potassium
PubMed: 38233937
DOI: 10.1111/nep.14270 -
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 -
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 -
Journal of Pediatric Endocrinology &... Jan 2024Pseudohypoparathyroidism (PHP1B) is most commonly caused by epigenetic defects resulting in loss of methylation at the GNAS locus, although deletions of leading to GNAS...
OBJECTIVES
Pseudohypoparathyroidism (PHP1B) is most commonly caused by epigenetic defects resulting in loss of methylation at the GNAS locus, although deletions of leading to GNAS methylation abnormalities have been previously reported. The phenotype of this disorder is variable and can include hormonal resistances and severe infantile obesity with hyperphagia. A possible time relationship between the onset of obesity and endocrinopathies has been previously reported but remains unclear. Understanding of the condition's natural history is limited, partly due to a scarcity of literature, especially in children.
CASE PRESENTATION
We report three siblings with autosomal dominant PHP1B caused by a deletion in who presented with early childhood onset PTH-resistance with normocalcemia with a progressive nature, accompanied by TSH-resistance and severe infantile obesity with hyperphagia in some, not all of the affected individuals.
CONCLUSIONS
PHP1B from a deletion displays intrafamilial phenotypic variation. It is a novel cause of severe infantile obesity, which is not typically included in commercially available gene panels but must be considered in the genetic work-up. Finally, it does not seem to have a clear time relationship between the onset of obesity and hormonal resistance.
Topics: Child; Humans; Child, Preschool; GTP-Binding Protein alpha Subunits, Gs; Siblings; Pediatric Obesity; Chromogranins; Pseudohypoparathyroidism; DNA Methylation; Obesity, Morbid; Phenotype; Hyperphagia; Syntaxin 16
PubMed: 38095637
DOI: 10.1515/jpem-2023-0249