119 results on '"Hypocalcemia genetics"'
Search Results
2. Autosomal dominant hypercalciuric hypocalcaemia: the calcium-sensing receptor in renal calcium homeostasis and the impact of renal transplantation.
- Author
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Florance JA, Schollum JBW, Pomeranc A, Endre ZH, and Walker RJ
- Subjects
- Humans, Female, Hypocalcemia genetics, Hypocalcemia etiology, Hypercalciuria genetics, Hypercalcemia genetics, Kidney metabolism, Mutation, Missense, Nephrocalcinosis genetics, Kidney Failure, Chronic surgery, Hypoparathyroidism congenital, Receptors, Calcium-Sensing genetics, Kidney Transplantation, Homeostasis, Calcium metabolism
- Abstract
Calcium-sensing receptors (CaSRs) are G protein-coupled receptors that help maintain Ca
2+ concentrations, modulating calciotropic hormone release (parathyroid hormone (PTH), calcitonin and 1,25-dihydroxyvitamin D) by direct actions in the kidneys, gastrointestinal tract and bone. Variability in population calcium levels has been attributed to single nucleotide polymorphisms in CaSR genes, and several conditions affecting calcium and phosphate homeostasis have been attributed to gain- or loss-of-function mutations. An example is autosomal dominant hypercalciuric hypocalcaemia, because of a missense mutation at codon 128 of chromosome 3, as reported in our specific case and her family. As a consequence of treating symptomatic hypocalcaemia as a child, this female subject slowly developed progressive end-stage kidney failure because of nephrocalcinosis and nephrolithiasis. After kidney transplantation, she remains asymptomatic, with decreased vitamin D and elemental calcium requirements, stable fluid and electrolyte homeostasis during intercurrent illnesses and has normalised urinary calcium and phosphate excretion, reducing the likelihood of hypercalciuria-induced graft impairment. We review the actions of the CaSR, its role in regulating renal Ca2+ homeostasis along with the impact of a proven gain-of-function mutation in the CaSR gene resulting in autosomal dominant hypercalciuric hypocalcaemia before and after kidney transplantation., (© 2024 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)- Published
- 2024
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3. Further delineation of phenotype and genotype of Kenny-Caffey syndrome type 2 (phenotype and genotype of KCS type 2).
- Author
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Chen X and Zou C
- Subjects
- Child, Female, Humans, Male, Constriction, Pathologic, Phenotype, Genotype, Hypocalcemia genetics, Dental Caries, Hypoparathyroidism genetics, Dwarfism, Hyperostosis, Cortical, Congenital
- Abstract
Background: Kenny-Caffey syndrome type 2 (KCS2) is an extremely rare inherited disorder characterized by proportionate short stature, skeletal defects, ocular and dental abnormalities, and transient hypocalcemia. It is caused by variants in FAM111A gene. Diagnosis of KCS2 can be challenging because of its similarities to other syndromes, the absence of clear hallmarks and the deficient number of genetically confirmed cases. Here, we aimed to further delineate and summarize the genotype and phenotype of KCS2, in order to get a better understanding of this rare disorder, and promote early diagnosis and intervention., Methods: We present clinical and genetic characteristics of eight newly affected individuals with KCS2 from six families, including one family with three individuals found to be a father-to-daughter transmission, adding to the limited literature. Furthermore, we performed a review of genetically confirmed KCS2 cases in PubMed, MEDLINE and CNKI databases., Results: There were six females and two males in our cohort. All the patients presented with short stature (100.0%). Clinical manifestations included ocular defects such as hypermetropia (5/8), dental problems such as defective dentition (3/8) and dental caries (3/8), skeletal and brain anomalies such as delayed closure of anterior fontanelle (6/8), cerebral calcification (3/8), cortical thickening (3/8) and medullary stenosis (4/8) of tubular bones. Endocrinologic abnormalities included hypoparathyroidism (5/8) and hypocalcemia (3/8). One male patient had micropenis and microorchidism. All cases harboured missense variants of FAM111A, and nucleotides c.1706 arose as a mutational hotspot, with seven individuals harbouring a c.1706G>A (p.Arg569His) variant, and one child harbouring a c.1531T>C (p.Tyr511His) variant. Literature review yielded a total of 46 patients from 20 papers. Data analysis showed that short stature, hypoparathyroidism and hypocalcemia, ocular and dental defects, skeletal features including cortical thickening and medullary stenosis of tubular bones, and seizures/spasms were present in more than 70% of the reported KCS2 cases., Conclusion: We provide detailed characteristics of the largest KCS2 group in China and present the first genetically confirmed instance of father-to-daughter transmission of KCS2. Our study confirms that Arg569His is the hot spot variant and summarizes the typical phenotypes of KCS2, which would help early diagnosis and intervention., (© 2024 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)
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- 2024
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4. Functional evaluation of a novel nonsense variant of the calcium-sensing receptor gene leading to hypocalcemia.
- Author
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Saglia C, Arruga F, Scolari C, Kalantari S, Albanese S, Bracciamà V, Corso Faini A, Brach Del Prever G, Luca M, Romeo C, Mioli F, Migliorero M, Tessaris D, Carli D, Amoroso A, Vaisitti T, De Sanctis L, and Deaglio S
- Subjects
- Adolescent, Humans, Calcium, HEK293 Cells, Mutation genetics, Receptors, Calcium-Sensing genetics, Hypercalcemia genetics, Hypocalcemia genetics
- Abstract
Objective: The calcium-sensing receptor (CASR) gene encodes a G protein-coupled receptor crucial for calcium homeostasis. Gain-of-function CASR variants result in hypocalcemia, while loss-of-function variants lead to hypercalcemia. This study aims to assess the functional consequences of the novel nonsense CASR variant [c.2897_2898insCTGA, p.(Gln967*) (Q967*)] identified in adolescent patient with chronic hypocalcemia, a phenotype expected for a gain-of-function variants., Design and Methods: To functionally characterize the Q967* mutant receptor, both wild-type (WT) and mutant CASR were transiently transfected into HEK293T cells and calcium-sensing receptor (CaSR) protein expression and functions were comparatively evaluated using multiple read-outs., Results: Western blot analysis revealed that the CaSR mutant protein displayed a lower molecular weight compared with the WT, consistent with the loss of the last 122 amino acids in the intracellular domain. Mitogen-activated protein kinase activation and serum responsive element luciferase assays demonstrated that the mutant receptor had higher baseline activity than the WT. Extracellular-signal-regulated kinase/c-Jun N-terminal kinase phosphorylation, however, remained consistently high in the mutant, without significant modulations following exposure to increasing extracellular calcium (Ca2+o) levels, suggesting that the mutant receptor is more sensitive to Ca2+o compared with the WT., Conclusions: This study provides functional validation of the pathogenicity of a novel nonsense CASR variant, resulting in an abnormally hyperfunctioning protein consistent with the patient's phenotype. Functional analyses indicate that mutant receptor is constitutively active and poorly sensitive to increasing concentrations of extracellular calcium, suggesting that the cytoplasmic tail may contain elements regulating signal transduction., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
- Published
- 2024
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5. A Rare Case of Neonatal Hypomagnesemia with Secondary Hypocalcemia Caused by a Novel Homozygous TRPM6 Gene Variant.
- Author
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Uddin MS, Alradhi AY, Alqathani FMN, Alessa OS, Alshammari ANM, Tripathy R, and Alomari MA
- Subjects
- Infant, Infant, Newborn, Humans, Magnesium, Hypocalcemia genetics, Hypocalcemia complications, Hypocalcemia diagnosis, Sudden Infant Death, Magnesium Deficiency complications, Magnesium Deficiency diagnosis, Magnesium Deficiency genetics, Magnesium Deficiency congenital, TRPM Cation Channels genetics
- Abstract
BACKGROUND Familial hypomagnesemia with secondary hypocalcemia (HSH) is a rare autosomal recessive disorder (OMIM# 602014) caused by mutations in the gene encoding transient receptor potential melastatin 6 (TRPM6)) on chromosome 9q22, a channel involved in epithelial magnesium resorption. While a plethora of studies have delineated various clinical manifestations pertinent to this mutation, the literature is devoid of connections between TRPM6 mutations and bleeding diathesis, or sudden infant death syndrome (SIDS). This report presents a case of familial HSH associated with the novel homozygous TRPM6 gene variant c.5281C>G p. (Arg1761Gly) chr9: 77354845. CASE REPORT This report details a 26-day-old neonate, born full term with optimal Apgar scores, who experienced an abrupt emergence of apnea, cyanosis, bilateral nasal bleeding, and diminished alertness. Despite the neonate's initially unremarkable clinical birth indicators, a meticulous assessment unveiled a pronounced family history of SIDS, including a sibling previously diagnosed with hypomagnesemia. Laboratory examination of the infant demonstrated severe hypomagnesemia and hypocalcemia, conditions which were promptly ameliorated following intravenous administration of magnesium and calcium. Whole-exome sequencing identified a homozygous TRPM6 gene mutation c.5281C>G p. (Arg1761Gly) at chr9: 77354845. This gene is crucial for magnesium regulation. The mutation involves a cytosine-to-guanine shift, resulting in an arginine to glycine amino acid substitution at position 1761 of the TRPM6 protein. CONCLUSIONS This report has highlighted that infantile hypomagnesemia may be associated with symptoms and signs that can mimic infection, or it can present with seizures. Although familial HSH is a rare genetic disorder that can be identified by genetic testing, correction of hypomagnesemia is the most important and immediate clinical management strategy.
- Published
- 2024
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6. Recurrent transient severe hypocalcaemia in two siblings with type 1 Bartter syndrome.
- Author
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Kanda J, Kanda S, Hayashi Y, Nozu K, Ariji S, Shimoda M, Ono M, Kanda S, Yokoyama S, and Takahashi K
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- Humans, Siblings, Parathyroid Hormone, Solute Carrier Family 12, Member 1, Hypocalcemia etiology, Hypocalcemia genetics, Bartter Syndrome complications, Bartter Syndrome diagnosis, Bartter Syndrome genetics
- Abstract
Type 1 Bartter syndrome causes hypokalaemia and metabolic alkalosis owing to mutation in the SLC12A1 gene. Meanwhile, hypocalcaemia is rare in Bartter syndrome, except in type 5 Bartter syndrome. Herein, we describe two siblings with type 1 Bartter syndrome with recurrent transient severe hypocalcaemia. They each visited our hospital several times with chief complaints of numbness in the limbs, shortness of breath and tetany after stresses such as exercise or fever. Severe hypocalcaemia was also observed with a serum calcium level of approximately 6.0 mg/dL at each visit. The clinical symptoms and abnormalities in laboratory findings quickly improved with rest and intravenous treatment. In a steady state, no severe hypocalcaemia was evident, but serum intact parathyroid hormone (PTH) levels were high. In recent years, a large-scale study has revealed that type 1 and type 2 Bartter syndrome have high PTH values. In addition, there are reports that these patients develop hypocalcaemia due to PTH resistance. Therefore, our patient was also in a PTH-resistant state, and hypocalcaemia was thought to be exacerbated by physical stress. It is not well known that Bartter syndrome patients other than those with type 5 suffer from hypocalcaemia. And hypocalcaemia was not detected in normal examinations under steady-state conditions. Therefore, in patients with type 1 and type 2 Bartter syndrome, severe hypocalcaemia may occur, but may go unnoticed. When following up these patients, the attending physician must keep in mind that such patients are in a PTH-resistant state and that physical stress can cause severe hypocalcaemia., (© 2023 The Authors. Nephrology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Nephrology.)
- Published
- 2024
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7. Rare cause of recurrent hypocalcaemia and functional hypoparathyroidism due to hypomagnesaemia caused by TRPM6 gene mutation.
- Author
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Khadse S, Takalikar VS, Ghildiyal R, and Shah N
- Subjects
- Child, Female, Humans, Magnesium therapeutic use, Mutation, Hypocalcemia drug therapy, Hypocalcemia genetics, Hypocalcemia complications, Hypoparathyroidism complications, Hypoparathyroidism drug therapy, Hypoparathyroidism genetics, Magnesium Deficiency complications, Magnesium Deficiency genetics, TRPM Cation Channels genetics
- Abstract
Magnesium is essential for the functioning and release of parathyroid hormone. Therefore, its deficiency can present as functional hypoparathyroidism. This case report describes a rare inherited disorder called congenital hypomagnesaemia with secondary hypocalcaemia due to TRPM6 gene mutation. This disease clinically and biochemically mimics hypoparathyroidism. However, unlike hypoparathyroidism, it can be treated only by long-term oral magnesium supplements. The patient presented to us with recurrent hypocalcaemic convulsions. The laboratory picture in each admission was similar to that of hypoparathyroidism. However, the hypocalcaemia persisted, and it was noticed to be associated with persistent hypomagnesaemia. A defect in the tubular magnesium reabsorption was postulated and a genetic analysis of the patient was done, which revealed a TRPM6 mutation causing hypomagnesaemia by excessive renal excretion of magnesium. The child responded well to oral magnesium supplements and is currently developmentally appropriate for her age and thriving well., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2024
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8. Nanobodies as negative allosteric modulators for human calcium sensing receptor.
- Author
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Cui Q, Wang L, Wang H, Chen X, Han L, Geng T, Kou Y, Zhang W, Dai M, Qiao H, Sun Z, Li L, Lan Z, Xu H, Xu J, Dai Y, and Geng Y
- Subjects
- Humans, Receptors, Calcium-Sensing metabolism, Calcium metabolism, Single-Domain Antibodies, Hypocalcemia genetics, Hypercalcemia genetics
- Abstract
Human calcium sensing receptor (CaSR) senses calcium ion concentrations in vivo and is an important class of drug targets. Mutations in the receptor can lead to disorders of calcium homeostasis, including hypercalcemia and hypocalcemia. Here, 127 CaSR-targeted nanobodies were generated from camels, and four nanobodies with inhibitory function were further identified. Among these nanobodies, NB32 can effectively inhibit the mobilization of intracellular calcium ions (Ca
2+ i ) and suppress the G12/13 and ERK1/2 signaling pathways downstream of CaSR. Moreover, it enhanced the inhibitory effect of the calcilytics as a negative allosteric modulator (NAM). We determined the structure of complex and found NB32 bound to LB2 (Ligand-binding 2) domain of CaSR to prevent the interaction of LB2 domains of two protomers to stabilize the inactive state of CaSR., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)- Published
- 2024
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9. Identification of a Novel Homozygous Missense Mutation in the CLDN16 Gene to Decipher the Ambiguous Clinical Presentation Associated with Autosomal Dominant Hypocalcaemia and Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis in an Indian Family.
- Author
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Thapa R, Roy A, Nayek K, and Basu A
- Subjects
- Humans, Magnesium, Mutation, Missense, Hypercalciuria complications, Hypercalciuria diagnosis, Hypercalciuria genetics, Mutation, Claudins genetics, Nephrocalcinosis complications, Nephrocalcinosis diagnosis, Nephrocalcinosis genetics, Hypocalcemia complications, Hypocalcemia diagnosis, Hypocalcemia genetics, Hypoparathyroidism congenital
- Abstract
Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHNNC) is a rare autosomal recessive renal tubulopathy disorder characterized by excessive urinary loss of calcium and magnesium, polyuria, polydipsia, bilateral nephrocalcinosis, progressive chronic kidney disease, and renal failure. Also, sometimes amelogenesis imperfecta and severe ocular abnormalities are involved. The CLDN-16 and CLDN-19 genes encode the tight junction proteins claudin-16 and claudin-19, respectively, in the thick ascending loop of Henle in the kidney, epithelial cells of the retina, dental enamel, etc. Loss of function of the CLDN-16 and/or CLDN-19 genes leads to FHHNC. We present a case of FHHNC type 1, which was first confused with autosomal dominant hypocalcaemia (ADH) due to the presence of a very low serum parathyroid hormone (PTH) concentration and other similar clinical features before the genetic investigations. After the exome sequencing, FHHNC type 1 was confirmed by uncovering a novel homozygous missense mutation in the CLDN-16 gene (Exon 2, c.374 T > C) which causes, altered protein structure with F55S. Associated clinical, biochemical, and imaging findings also corroborate final diagnosis. Our findings expand the spectrum of the CLDN-16 mutation, which will further help in the genetic diagnosis and management of FHNNC., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2024
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10. Clinical and molecular characteristics of two Italian kindreds with hypoparathyroidism, deafness and renal dysplasia (HDR) syndrome.
- Author
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Dinoi E, Pierotti L, Mazoni L, Citro F, Della Valentina S, Sardella C, Borsari S, Michelucci A, Caligo MA, Marcocci C, and Cetani F
- Subjects
- Male, Humans, Adolescent, Infant, Young Adult, Adult, Italy, Hypocalcemia complications, Hypocalcemia diagnosis, Hypocalcemia genetics, Hypoparathyroidism complications, Hypoparathyroidism diagnosis, Hypoparathyroidism genetics, Deafness complications, Deafness genetics, Hearing Loss, Sensorineural, Nephrosis
- Abstract
Purpose: Hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome, also known as Barakat syndrome, is a rare autosomal dominant disease characterized by the triad of hypoparathyroidism, deafness, and renal abnormalities. The disorder is caused by the haploinsufficiency of the zinc finger transcription factor GATA3 and exhibits a great clinical variability with an age-dependent penetrance of each feature. We report two unrelated kindreds whose probands were referred to our outpatient clinic for further evaluation of hypoparathyroidism., Methods: The proband of family 1, a 17-year-old boy, was referred for severe hypocalcemia (5.9 mg/dL) incidentally detected at routine blood tests. Abdomen ultrasound showed bilateral renal cysts. The audiometric evaluation revealed the presence of bilateral moderate hearing loss although the patient could communicate without any problem. Conversely, the proband of family 2, a 19-year-old man, had severe symptomatic hypocalcemia complicated by epileptic seizure at the age of 14 years; his past medical history was remarkable for right nephrectomy at the age of 4 months due to multicystic renal disease and bilateral hearing loss diagnosed at the age of 18 years., Results: Based on clinical, biochemical, and radiologic data, HDR syndrome was suspected and genetic analysis of the GATA3 gene revealed the presence of two pathogenetic variants in exon 3, c.404dupC and c.431dupG, in the proband of family 1 and 2, respectively., Conclusion: HDR syndrome is a rare cause of hypoparathyroidism and must be excluded in all patients with apparently idiopathic hypoparathyroidism. A correct diagnosis is of great importance for early detection of other HDR-related features and genetic counseling., (© 2023. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)
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- 2024
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11. Hereditary hypomagnesemia with secondary hypocalcemia caused by a novel mutation in TRPM6 gene.
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Dokurel Çetin İ, Betül Gerik-Çelebi H, Demiral M, and Çetin O
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- Male, Infant, Humans, Magnesium, Seizures genetics, Seizures complications, Mutation, TRPM Cation Channels genetics, Hypocalcemia complications, Hypocalcemia genetics, Magnesium Deficiency congenital
- Abstract
Objectives: Hereditary hypomagnesemia with secondary hypocalcemia (HSH), which results from variations in the transient receptor potential melastatin 6 ( TRPM6 ) genes, is a rare hereditary cause of extremely low serum magnesium levels. We describe an infant with triggered seizures due to hypomagnesemia and a novel mutation in TRPM6 gene was identified., Case Presentation: A 10-month-old boy presented with multidrug resistant seizures, and axial hypotonia due to severe hypomagnesemia. Electroencephalography and neuroimaging of the patient was normal. He had a favorable outcome with magnesium supplement. In this study, the patient underwent clinical exome sequencing (CES) which detected a novel homozygous variant in the TRPM6 gene: NM_017662.5: c.5571-3C>G. After replacing his magnesium orally, he was free from seizures and had an encouraging outcome at the twelfth-month follow-up., Conclusions: HSH often presents with developmental issues, treatment-resistant seizures, and increased neuromuscular excitability. Untreated hypomagnesemia can potentially be fatal and severely impair cognitive function. Clinical suspicion is essential for early diagnosis and treatment., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)
- Published
- 2023
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12. Identification of genetic variants and individual genes associated with postpartum hypocalcemia in Holstein cows.
- Author
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Novo LC, Poindexter MB, Rezende FM, Santos JEP, Nelson CD, Hernandez LL, Kirkpatrick BW, and Peñagaricano F
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- Pregnancy, Female, Humans, Cattle, Animals, Male, Calcium metabolism, Postpartum Period genetics, Parturition physiology, Lactation physiology, Milk metabolism, Calcium, Dietary metabolism, Diet veterinary, Hypocalcemia genetics, Hypocalcemia veterinary, Hypocalcemia metabolism, Cattle Diseases, Puerperal Disorders
- Abstract
Periparturient hypocalcemia is a complex metabolic disorder that occurs at the onset of lactation because of a sudden irreversible loss of Ca incorporated into colostrum and milk. Some cows are unable to quickly adapt to this demand and succumb to clinical hypocalcemia, commonly known as milk fever, whereas a larger proportion of cows develop subclinical hypocalcemia. The main goal of this study was to identify causative mutations and candidate genes affecting postpartum blood calcium concentration in Holstein cows. Data consisted of blood calcium concentration measured in 2513 Holstein cows on the first three days after parturition. All cows had genotypic information for 79 k SNP markers. Two consecutive rounds of imputation were performed: first, the 2513 Holstein cows were imputed from 79 k to 312 k SNP markers. This imputation was performed using a reference set of 17,131 proven Holstein bulls with 312 k SNP markers. Then, the 2513 Holstein cows were imputed from 312 k markers to whole-genome sequence data. This second round of imputation used 179 Holstein animals from the 1000 Bulls Genome Project as a reference set. Three alternative phenotypes were evaluated: (1) total calcium concentration in the first 24 h postpartum, (2) total calcium concentration in the first 72 h postpartum calculated as the area under the curve; and (3) the recovery of total calcium concentration calculated as the difference in total calcium concentration between 72 and 24 h. The identification of genetic variants associated with these traits was performed using a two-step mixed model-based approach implemented in the R package MixABEL. The most significant variants were located within or near genes involved in calcium homeostasis and vitamin D transport (GC), calcium and potassium channels (JPH3 and KCNK13), energy and lipid metabolism (CA5A, PRORP, and SREBP1), and immune response (IL12RB2 and CXCL8), among other functions. This work provides the foundation for the development of novel breeding and management tools for reducing the incidence of periparturient hypocalcemia in dairy cattle., (© 2023. The Author(s).)
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- 2023
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13. Intestinal hypomagnesemia in an Iranian patient with a novel TRPM6 variant: a case report and review of the literature.
- Author
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Kamali F, Jamee M, Sayer JA, Sadeghi-Bojd S, Golchehre Z, Dehghanzad R, Keramatipour M, and Mohkam M
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- Female, Humans, Calcium, Diarrhea etiology, Diarrhea complications, Failure to Thrive etiology, Iran, Magnesium, Seizures complications, Aged, Hypocalcemia diagnosis, Hypocalcemia genetics, TRPM Cation Channels genetics
- Abstract
TRPM6 is predominantly expressed in the kidney and colon and encodes a protein containing an ion channel domain and a protein kinase domain. It is crucial for magnesium homeostasis and plays important roles in epithelial magnesium transport and the active magnesium absorption. In this study, we present a 70-day-old Iranian female patient from consanguineous parents with hypomagnesemia and secondary hypocalcemia. She presented with seizures 19 days after birth and refractory watery non-bloody diarrhea. She consequently had failure to thrive. Other features included hypotonia, wide anterior fontanel, ventriculomegaly, and pseudotumor cerebri following administration of nalidixic acid. She had severe hypomagnesemia and hypocalcemia which were treated with magnesium and calcium supplementation. Despite initial unstable response to supplemental magnesium, she eventually improved and the diarrhea discontinued. The patient was discharged by magnesium and calcium therapy. At the last follow-up at age 2.5 years, the patient remained well without any recurrence or complication. Genetic testing by whole-exome sequencing revealed a novel homozygous frameshift insertion-deletion (indel) variant in exon 26 of the TRPM6 gene, c.3693-3699del GCAAGAG ins CTGCTGTTGACATCTGCT, p.L1231Ffs*36. Segregation analysis revealed the TRPM6 heterozygous variant in both parents. Patients with biallelic TRPM6 pathogenic variants typically exhibit hypomagnesemia with secondary hypocalcemia and present with neurologic manifestations including seizures. In some patients, this is also complicated by chronic diarrhea and failure to thrive. Long-term complications are rare and most of the patients show a good prognosis with supplemental magnesium therapy., (© 2023. The Author(s) under exclusive licence to The Japan Society of Nephrology.)
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- 2023
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14. Efficacy and Safety of Encaleret in Autosomal Dominant Hypocalcemia Type 1.
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Gafni RI, Hartley IR, Roszko KL, Nemeth EF, Pozo KA, Lombardi E, Sridhar AV, Roberts MS, Fox JC, and Collins MT
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- Humans, Calcium metabolism, Genes, Dominant genetics, Hypercalciuria drug therapy, Hypercalciuria genetics, Mutation, Treatment Outcome, Hypocalcemia drug therapy, Hypocalcemia genetics, Hypoparathyroidism drug therapy, Hypoparathyroidism genetics, Calcium-Regulating Hormones and Agents therapeutic use
- Published
- 2023
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15. Rare cause of persistent hypocalcaemia in infancy due to PTH gene mutation.
- Author
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Khadse S, Takalikar VS, Ghildiyal R, and Shah N
- Subjects
- Child, Infant, Newborn, Humans, Female, Infant, Calcium, Dietary, Dietary Supplements, Mutation, Hypocalcemia genetics, Hypoparathyroidism complications, Hypoparathyroidism diagnosis, Hypoparathyroidism genetics
- Abstract
Hypocalcaemia is a frequently encountered electrolyte abnormality in neonates and it is mostly transient. However, persistent hypocalcaemia can point towards an endocrine abnormality like hypoparathyroidism, which is usually due to genetic disorders like DiGeorge and Kearns Sayre syndrome or due to mutations of genes like GCM2, CaSR and PTH.Our patient was a female child, who presented with hypocalcaemic convulsions in the neonatal period. On laboratory assessment, serum phosphate levels were noted to be high along with inappropriately low parathyroid hormone (PTH) levels. The child was diagnosed to have hypoparathyroidism and was started on oral calcium and 1,25-dihydroxycholecalciferol supplements to which she responded well. However, the child was lost to follow-up and was readmitted with hypocalcaemic convulsions in infancy. Clinical exome analysis done was diagnostic of homozygous PTH gene mutation. This case demonstrates a rare form of congenital isolated hypoparathyroidism with no other syndromic associations., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2023
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16. 22q11.2 Deletion Syndrome in Taiwan: Clinical Presentation and Immune System Status of Patients.
- Author
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Lee CL, Lin SM, Chen MR, Chuang CK, Chiu HC, Tu YR, Lo YT, Chang YH, Lin HY, and Lin SP
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- Humans, Female, Male, In Situ Hybridization, Fluorescence, Taiwan epidemiology, Cross-Sectional Studies, Comparative Genomic Hybridization, Immune System, Chromosome Deletion, DiGeorge Syndrome genetics, DiGeorge Syndrome diagnosis, Tetralogy of Fallot genetics, Hypocalcemia genetics, Heart Defects, Congenital genetics
- Abstract
Background: 22q11.2 deletion syndrome (22q11.2DS) is a microdeletion syndrome exhibiting significant clinical phenotype variability. This study aimed to investigate the clinical features, immune profiles, and cognitive abilities of 22q11.2DS patients receiving treatment at MacKay Memorial Hospital in Taipei, Taiwan. Methods: This is a cross-sectional analysis between January 2001 and December 2022. We recruited 27 patients with 22q11.2DS using fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (aCGH). Our evaluation included patient history, physical examination, laboratory analysis, and cardiac and cognitive assessment. Results: We included 27 patients with 22q11.2DS, 7 (25.9%) of whom were female. The median age of the patients was 17.9 yr. Ninety-three percent of the patients exhibited the characteristic facial features associated with the syndrome. A family history of 22q11.2DS was found in 11.1% of the patients. Furthermore, 74.1% of the patients had a congenital heart defect, the most common of which was tetralogy of Fallot (40.7%). Hypocalcemia was observed in 40.7% of the patients. A low T-cell count was observed in 66.7% of the patients, whereas 18.5% had low immunoglobulin levels. Cognitive assessments revealed that four out of six evaluated patients (66.7%) had an intellectual disability, as evidenced by intellectual quotient scores less than 70. The remaining two patients (33.3%) had a borderline intellectual function. Conclusion: Tetralogy of Fallot, hypocalcemia, immunologic defects, and cognitive impairment were common among our patients. To address the potential multisystem involvement, we recommend that all affected individuals undergo a comprehensive evaluation by a multidisciplinary care team., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)
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- 2023
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17. An Endocrinological Perspective on 22q11.2 Deletion Syndrome: A Single-center Experience
- Author
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Denkboy Öngen Y, Özemri Sağ Ş, Temel ŞG, and Eren E
- Subjects
- Humans, Calcium, In Situ Hybridization, Fluorescence, Parathyroid Hormone, Chromosome Deletion, Phosphorus, DiGeorge Syndrome complications, DiGeorge Syndrome diagnosis, DiGeorge Syndrome genetics, Hypocalcemia diagnosis, Hypocalcemia genetics, Diabetes Mellitus, Type 2 genetics, Hypoparathyroidism diagnosis, Hypoparathyroidism complications, Dwarfism genetics
- Abstract
Objective: 22q11.2 deletion syndrome (22q11.2 DS) is the most common chromosomal microdeletion disorder. Associated problems in 22q11.2 DS may include cardiac abnormalities, immune dysfunction, facial dysmorphism, with endocrine, genitourinary and gastrointestinal problems, and developmental delay. The aim of this study was to evaluate and present all endocrinological findings of patients with 22q11.2 DS from a single center., Methods: All participants had confirmed 22q11.2 DS by fluorescence in situ hybridization with hypoparathyroidism. Data were retrieved by retrospective review of patient records., Results: A total of 17 patients were reviewed. On physical examination, all patients had similar dysmorphic features. The median age at diagnosis was 45 days (1 day-13 years). Most cases (64.7%, 11/17) were diagnosed with hypoparathyroidism incidentally after routine tests. At the time of diagnosis, mean calcium was 7.04±0.80 mg/dL, phosphorus was 6.2±1.1 mg/dL, and median parathyroid hormone (PTH) was 11.5 (3.7-47.6) ng/L. Transient hypoparathyroidism was detected in five cases (29.4%). There was no significant difference between patients with permanent or transient hypoparathyroidism regarding gender, age at diagnosis, calcium, phosphorus, and PTH levels. However, vitamin D levels were significantly lower in the transient group (p=0.036). During follow-up, short stature, obesity, and type 2 diabetes mellitus were absent. Thyroid autoantibodies were detected in two patients with normal thyroid function tests. Despite there being no pathological short stature, final stature was shorter than the general population (mean height standard deviation score: -0.94±0.83)., Conclusion: Hypocalcemia may be detected during acute illness in some cases where hypocalcemia appears at later ages. There was no significant difference between permanent and transient hypoparathyroidism cases in terms of PTH level. Recognition of the more specific facial findings is important to trigger investigation of genetic variants, additional anomalies, and for follow-up.
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- 2023
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18. GNA11 Variants Identified in Patients with Hypercalcemia or Hypocalcemia.
- Author
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Howles SA, Gorvin CM, Cranston T, Rogers A, Gluck AK, Boon H, Gibson K, Rahman M, Root A, Nesbit MA, Hannan FM, and Thakker RV
- Subjects
- Humans, Calcium metabolism, HEK293 Cells, Mutation genetics, Receptors, Calcium-Sensing genetics, Receptors, Calcium-Sensing metabolism, GTP-Binding Protein alpha Subunits genetics, GTP-Binding Protein alpha Subunits metabolism, Hypocalcemia genetics, Hypocalcemia metabolism, Hypercalcemia genetics
- Abstract
Familial hypocalciuric hypercalcemia type 2 (FHH2) and autosomal dominant hypocalcemia type 2 (ADH2) are due to loss- and gain-of-function mutations, respectively, of the GNA11 gene that encodes the G protein subunit Gα11, a signaling partner of the calcium-sensing receptor (CaSR). To date, four probands with FHH2-associated Gα11 mutations and eight probands with ADH2-associated Gα11 mutations have been reported. In a 10-year period, we identified 37 different germline GNA11 variants in >1200 probands referred for investigation of genetic causes for hypercalcemia or hypocalcemia, comprising 14 synonymous, 12 noncoding, and 11 nonsynonymous variants. The synonymous and noncoding variants were predicted to be benign or likely benign by in silico analysis, with 5 and 3, respectively, occurring in both hypercalcemic and hypocalcemic individuals. Nine of the nonsynonymous variants (Thr54Met, Arg60His, Arg60Leu, Gly66Ser, Arg149His, Arg181Gln, Phe220Ser, Val340Met, Phe341Leu) identified in 13 probands have been reported to be FHH2- or ADH2-causing. Of the remaining nonsynonymous variants, Ala65Thr was predicted to be benign, and Met87Val, identified in a hypercalcemic individual, was predicted to be of uncertain significance. Three-dimensional homology modeling of the Val87 variant suggested it was likely benign, and expression of Val87 variant and wild-type Met87 Gα11 in CaSR-expressing HEK293 cells revealed no differences in intracellular calcium responses to alterations in extracellular calcium concentrations, consistent with Val87 being a benign polymorphism. Two noncoding region variants, a 40bp-5'UTR deletion and a 15bp-intronic deletion, identified only in hypercalcemic individuals, were associated with decreased luciferase expression in vitro but no alterations in GNA11 mRNA or Gα11 protein levels in cells from the patient and no abnormality in splicing of the GNA11 mRNA, respectively, confirming them to be benign polymorphisms. Thus, this study identified likely disease-causing GNA11 variants in <1% of probands with hypercalcemia or hypocalcemia and highlights the occurrence of GNA11 rare variants that are benign polymorphisms. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)
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- 2023
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19. Activating calcium-sensing receptor gene variants in China: a case report of hypocalcaemia and literature review.
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Guo S, Li X, and Shan X
- Subjects
- Male, Child, Humans, Receptors, Calcium-Sensing genetics, Hypercalciuria drug therapy, Hypercalciuria genetics, China, Mutation, Calcium, Hypocalcemia genetics, Hypoparathyroidism
- Abstract
Objectives: Autosomal dominant hypocalcaemia 1 (ADH1) is a rare autosomal dominant genetic disease, due to the activating mutations of the calcium-sensing receptor ( CASR ) gene. The current paper presents a severe case of ADH1 with intellectual backwardness, and systematically reviews the reported 17 ADH1 patients in China., Case Presentation: A 7 years old boy with recurrent seizures over 1 year was admitted at Yuying children' hospital, the clinical centre of south province of Zhejiang. Auxiliary examinations demonstrated hypocalcaemia, hyperphosphatemia, hypomagnesemia, hypercalciuria, low parathyroid hormone (PTH), basal ganglia calcifications, normal range of serum creatinine, and 25-hydroxyvitamin D. Wechsler's intelligence test result indicated intellectually backward. The patient's genotype found a heterozygous variant in CASR gene, c.T416C p. (Ile139Thr). This article also systematically reviews the literatures on ADH1 in China and summarises the clinical characteristics and treatment., Conclusions: ADH1 can be a cause of idiopathic hypoparathyroidism. Recognition and rational treatment is important for symptom improvement and reducing high potential adverse effects., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)
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- 2023
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20. Homozygous Ser-1 to Pro-1 mutation in parathyroid hormone identified in hypocalcemic patients results in secretion of a biologically inactive pro-hormone.
- Author
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Hanna P, Khatri A, Choi S, Brabant S, Gild ML, Piketty ML, Francou B, Prié D, Potts JT Jr, Clifton-Bligh RJ, Linglart A, Gardella TJ, and Jüppner H
- Subjects
- Humans, Parathyroid Hormone genetics, Parathyroid Hormone metabolism, Mutation, Proline genetics, Amino Acids genetics, Hypocalcemia genetics
- Abstract
Like other secreted peptides, nascent parathyroid hormone (PTH) is synthesized with a pre- and a pro-sequence (25 and 6 amino acids, respectively). These precursor segments are sequentially removed in parathyroid cells before packaging into secretory granules. Three patients from two unrelated families who presented during infancy with symptomatic hypocalcemia were found to have a homozygous serine (S) to proline (P) change affecting the first amino acid of the mature PTH. Unexpectedly, biological activity of synthetic [P1]PTH(1-34) was indistinguishable from that of unmodified [S1]PTH(1-34). However, in contrast to conditioned medium from COS-7 cells expressing prepro[S1]PTH(1-84), medium from cells expressing prepro[P1]PTH(1-84) failed to stimulate cAMP production despite similar PTH levels when measured by an intact assay that detects PTH(1-84) and large amino-terminally truncated fragments thereof. Analysis of the secreted, but inactive PTH variant led to the identification of pro[P1]PTH(-6 to +84). Synthetic pro[P1]PTH(-6 to +34) and pro[S1]PTH(-6 to +34) had much less bioactivity than the corresponding PTH(1-34) analogs. Unlike pro[S1]PTH(-6 to +34), pro[P1]PTH(-6 to +34) was resistant to cleavage by furin suggesting that the amino acid variant impairs preproPTH processing. Consistent with this conclusion, plasma of patients with the homozygous P1 mutation had elevated proPTH levels, as determined with an in-house assay specific for pro[P1]PTH(-6 to +84). In fact, a large fraction of PTH detected by the commercial intact assay represented the secreted pro[P1]PTH. In contrast, two commercial biointact assays that use antibodies directed against the first few amino acid residues of PTH(1-84) for capture or detection failed to detect pro[P1]PTH.
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- 2023
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21. The importance of molecular diagnosis in the management of autosomal dominant hypocalcemia type 1 (ADH1): Case report.
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Gómez-Martín JM and Martínez-Vaello V
- Subjects
- Humans, Hypercalciuria, Receptors, Calcium-Sensing, Hypocalcemia etiology, Hypocalcemia genetics, Hypoparathyroidism diagnosis, Hypoparathyroidism genetics
- Published
- 2023
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22. Novel Calcium-Sensing Receptor (CASR) Mutation in a Family with Autosomal Dominant Hypocalcemia Type 1 (ADH1): Genetic Study over Three Generations and Clinical Characteristics.
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Zung A, Barash G, Banne E, and Levine MA
- Subjects
- Humans, Receptors, Calcium-Sensing genetics, Calcium, Hypercalciuria genetics, Creatinine, HEK293 Cells, Mutation, Seizures, Hypocalcemia genetics, Nephrocalcinosis, Nephrolithiasis
- Abstract
Introduction: Activating mutation of the calcium-sensing receptor gene (CASR) reduces parathyroid hormone secretion and renal tubular reabsorption of calcium, defined as autosomal dominant hypocalcemia type 1 (ADH1). Patients with ADH1 may present with hypocalcemia-induced seizures. Calcitriol and calcium supplementation in symptomatic patients may exacerbate hypercalciuria, leading to nephrocalcinosis, nephrolithiasis, and compromised renal function., Methods: We report on a family with seven members over three generations with ADH1 due to a novel heterozygous mutation in exon 4 of CASR: c.416T>C., Results: This mutation leads to substitution of isoleucine with threonine in the ligand-binding domain of CASR. HEK293T cells transfected with wild type or mutant cDNAs demonstrated that p.Ile139Thr substitution led to increased sensitivity of the CASR to activation by extracellular calcium relative to the wild-type CASR (EC50 of 0.88 ± 0.02 m
M vs. 1.1 ± 0.23 mM , respectively, p < 0.005). Clinical characteristics included seizures (2 patients), nephrocalcinosis and nephrolithiasis (3 patients), and early lens opacity (2 patients). In 3 of the patients, serum calcium and urinary calcium-to-creatinine ratio levels obtained simultaneously over 49 patient-years were highly correlated. Using the age-specific maximal-normal levels of calcium-to-creatinine ratio in the correlation equation, we obtained age-adjusted serum calcium levels that are high enough to reduce hypocalcemia-induced seizures and low enough to reduce hypercalciuria., Conclusion: We report on a novel CASR mutation in a three-generation kindred. Comprehensive clinical data enabled us to suggest age-specific upper limit of serum calcium levels, considering the association between serum calcium and renal calcium excretion., (© 2023 The Author(s). Published by S. Karger AG, Basel.)- Published
- 2023
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23. Postoperative Hypocalcemia following Non-Cardiac Surgical Procedures in Children with 22q11.2 Deletion Syndrome.
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Arganbright JM, Tracy M, Feldt M, Narayanan S, Mahadev A, and Noel-MacDonnell J
- Subjects
- Child, Humans, Calcium, Retrospective Studies, Hypocalcemia genetics, Hypocalcemia diagnosis, DiGeorge Syndrome genetics, DiGeorge Syndrome surgery
- Abstract
The guidelines for management of children with 22q11.2 deletion syndrome (22q11DS) highlight the risk for developing hypocalcemia after surgery and recommend monitoring calcium perioperatively. Despite this guidance, little has been published on postoperative hypocalcemia and 22q11DS. Our goals were to evaluate the frequency of perioperative calcium monitoring and examine how often postoperative hypocalcemia was identified. This is a retrospective chart review of patients in our 22q Center's repository. Inclusion criteria were a diagnosis of 22q11DS and a history of a non-cardiac surgical procedure. Data collected included all non-cardiac surgeries and perioperative calcium labs. In total, 68 patients were included and underwent 305 on-cardiac surgeries. Patients in only 17% of these surgeries had postoperative calcium testing, but of those tested, 58% showed hypocalcemia. Patients with history of hypocalcemia at the time of chart review undergoing non-cardiac surgeries were tested postoperatively 40% of the time; however, 67% of these had hypocalcemia. Similarly, for patients without history of hypocalcemia, postoperative testing occurred 60% of the time, with 52% of these having hypocalcemia. This study demonstrates that postoperative hypocalcemia in children with 22q11DS following non-cardiac surgeries is common and affects patients both with and without prior history of hypocalcemia. These data support establishing a protocol for perioperative testing/management of hypocalcemia for patients with 22q11DS.
- Published
- 2022
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24. Autosomal Dominant Hypocalcemia Type 1: A Systematic Review.
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Roszko KL, Stapleton Smith LM, Sridhar AV, Roberts MS, Hartley IR, Gafni RI, Collins MT, Fox JC, and Nemeth EF
- Subjects
- Humans, Hypercalciuria genetics, Hypercalciuria drug therapy, Receptors, Calcium-Sensing genetics, Calcium, Parathyroid Hormone therapeutic use, Vitamin D therapeutic use, Hypocalcemia genetics, Hypocalcemia drug therapy, Nephrocalcinosis genetics, Hypoparathyroidism drug therapy, Hypoparathyroidism genetics, Nephrolithiasis
- Abstract
Autosomal dominant hypocalcemia type 1 (ADH1) is a rare form of hypoparathyroidism due to activating variants of the calcium-sensing receptor gene (CASR). Inherited or de novo activating variants of the CASR alter the set point for extracellular calcium, resulting in inadequate parathyroid hormone (PTH) secretion and inappropriate renal calcium excretion leading to hypocalcemia and hypercalciuria. Conventional therapy includes calcium and activated vitamin D, which can worsen hypercalciuria, resulting in renal complications. A systematic literature review, using published reports from 1994 to 2021, was conducted to catalog CASR variants, to define the ADH1 clinical spectrum, and to determine the effect of treatment on patients with ADH1. There were 113 unique CASR variants reported, with a general lack of genotype/phenotype correlation. Clinical data were available in 191 patients; 27% lacked symptoms, 32% had mild/moderate symptoms, and 41% had severe symptoms. Seizures, the most frequent clinical presentation, occurred in 39% of patients. In patients with blood and urine chemistries available at the time of diagnosis (n = 91), hypocalcemia (99%), hyperphosphatemia (59%), low PTH levels (57%), and hypercalciuria (34%) were observed. Blood calcium levels were significantly lower in patients with severe symptoms compared with asymptomatic patients (6.8 ± 0.7 versus 7.6 ± 0.7 mg/dL [mean ± SD]; p < 0.0001), and the age of presentation was significantly lower in severely symptomatic patients (9.1 ± 15.0 versus 19.3 ± 19.4 years; p < 0.01). Assessments for complications including nephrocalcinosis, nephrolithiasis, renal impairment, and brain calcifications in 57 patients on conventional therapy showed that 75% had at least one complication. Hypercalciuria was associated with nephrocalcinosis, nephrolithiasis, renal impairment, or brain calcifications (odds ratio [OR] = 9.3; 95% confidence interval [CI] 2.4-37.2; p < 0.01). In 27 patients with urine calcium measures before and after starting conventional therapy, the incidence of hypercalciuria increased by 91% (p < 0.05) after therapy initiation. ADH1 is a condition often associated with severe symptomatology at presentation with an increase in the risk of renal complications after initiation of conventional therapy. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)
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- 2022
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25. Autosomal dominant hypocalcemia with a novel CASR mutation: a case study and literature review.
- Author
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Wu Y, Zhang C, Huang X, Cao L, Liu S, and Zhong P
- Subjects
- Calcium, Humans, Hypercalciuria, Mutation, Receptors, Calcium-Sensing genetics, Hypercalcemia, Hypocalcemia genetics, Hypoparathyroidism congenital, Hypoparathyroidism genetics
- Abstract
Autosomal dominant hypocalcemia type 1 (ADH1) is a rare inherited disorder characterized by hypocalcemia with low parathyroid hormone (PTH) levels and high urinary calcium. Its clinical presentation varies from mild asymptomatic to severe hypocalcemia. It is caused by gain-of-function mutations in the calcium-sensing receptor gene ( CASR ) which affect PTH secretion from the parathyroid gland and calcium resorption in the kidney. Here, we describe a case who presented with symptoms of recurrent seizure caused by hypocalcemia with a novel CASR variant. We comprehensively analyzed the phenotypic features of this presentation and reviewed the current literature to better understand clinical manifestations and the genetic spectrum.
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- 2022
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26. FAM111A is dispensable for electrolyte homeostasis in mice.
- Author
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Ilenwabor BP, Schigt H, Kompatscher A, Bos C, Zuidscherwoude M, van der Eerden BCJ, Hoenderop JGJ, and de Baaij JHF
- Subjects
- Animals, Humans, Mice, Calcium metabolism, Electrolytes metabolism, Magnesium metabolism, Mice, Inbred C57BL, Parathyroid Hormone metabolism, Receptors, Virus, Sodium-Phosphate Cotransporter Proteins, Type III metabolism, Water-Electrolyte Balance, Hyperostosis, Cortical, Congenital genetics, Hypocalcemia genetics, Serine Proteases genetics, TRPM Cation Channels metabolism
- Abstract
Autosomal dominant mutations in FAM111A are causative for Kenny-Caffey syndrome type 2. Patients with Kenny-Caffey syndrome suffer from severe growth retardation, skeletal dysplasia, hypoparathyroidism, hypocalcaemia, hyperphosphataemia and hypomagnesaemia. While recent studies have reported FAM111A to function in antiviral response and DNA replication, its role in regulating electrolyte homeostasis remains unknown. In this study, we assessed the role of FAM111A in the regulation of serum electrolyte balance using a Fam111a knockout (Fam111a
-/- ) C57BL/6 N mouse model. Fam111a-/- mice displayed normal weight and serum parathyroid hormone (PTH) concentration and exhibited unaltered magnesium, calcium and phosphate levels in serum and 24-hour urine. Expression of calciotropic (including Cabp28k, Trpv5, Klotho and Cyp24a1), magnesiotropic (including Trpm6, Trpm7, Cnnm2 and Cnnm4) and phosphotropic (Slc20a1, Slc20a2, Slc34a1 and Slc34a3) genes in the kidneys, duodenum and colon were not affected by Fam111a depletion. Only Slc34a2 expression was significantly upregulated in the duodenum, but not in the colon. Analysis of femurs showed unaffected bone morphology and density in Fam111a-/- mice. Kidney and parathyroid histology were also normal in Fam111a-/- mice. In conclusion, our study is the first to characterise the function of FAM111A in vivo and we report that mice lacking FAM111A exhibit normal electrolyte homeostasis on a standard diet., (© 2022. The Author(s).)- Published
- 2022
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27. Late maternal diagnosis of DiGeorge syndrome with congenital hypoparathyroidism following antenatal detection of the same 22q11.2 microdeletion syndrome in the fetus.
- Author
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Liarakos AL, Tran P, Rao R, and Murthy N
- Subjects
- Adult, Chromosomes, Human, Pair 22, Delayed Diagnosis adverse effects, Female, Fetus, Humans, Pregnancy, DiGeorge Syndrome complications, DiGeorge Syndrome diagnosis, DiGeorge Syndrome genetics, Hypocalcemia diagnosis, Hypocalcemia genetics, Hypoparathyroidism complications, Hypoparathyroidism diagnosis, Hypoparathyroidism genetics
- Abstract
Genetic causes of hypocalcaemia can be overlooked in patients who present without apparent syndromic features. One relatively common but under-recognised genetic disorder is DiGeorge syndrome, which is often diagnosed in childhood but rarely in adulthood. Its enigmatic diagnosis can be attributed to its broad heterogeneous clinical presentation, such as the absence of cardiac abnormalities with only subtly abnormal facies. The presence of hypoparathyroidism-related hypocalcaemia may be the first early sign. We describe a young female adult with childhood-onset hypocalcaemia who was diagnosed with DiGeorge syndrome during her pregnancy when the fetus was found to have the same condition on antenatal screening and autopsy. This case reminds clinicians to consider the genetic causes of hypoparathyroidism-induced hypocalcaemia early on in childhood, while acknowledging the possibility of a late diagnosis in adulthood. We also highlight the risks of severe hypocalcaemia in pregnancy and outline a systematic approach to the evaluation of chronic hypocalcaemia., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2022
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28. The Youngest Infant to Be Diagnosed with Autosomal Dominant Hypocalcemia Type 2 Harboring a Novel Variant of GNA11: A Case Study and Literature Review.
- Author
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Kwon EJ, Kim MS, Noh ES, Kim CW, Jang J, Choi JH, Cho SY, and Jin DK
- Subjects
- GTP-Binding Proteins metabolism, Humans, Hypercalciuria genetics, Hypercalciuria metabolism, Infant, GTP-Binding Protein alpha Subunits genetics, GTP-Binding Protein alpha Subunits metabolism, Hypocalcemia diagnosis, Hypocalcemia genetics, Hypocalcemia metabolism, Hypoparathyroidism congenital, Hypoparathyroidism genetics, Hypoparathyroidism metabolism
- Abstract
Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia and inappropriately low PTH concentrations. ADH type 2 (ADH2) is caused by a heterozygous gain-of-function mutation in GNA11 that encodes the subunit of G11, the principal G protein that transduces calcium-sensing receptor signaling in the parathyroid. Clinical features related to hypocalcemia in ADH2 range from asymptomatic to tetany and seizures. We report the clinical and molecular analysis of an infant with ADH2. Exome sequencing identified a de novo heterozygous missense variant, c. G548C (p. Arg183Pro) in GNA11. This is the youngest Korean case to be diagnosed with ADH 2. In addition, we summarized the literature related to eight mutations in GNA11 from 10 families., (© 2022 by the Association of Clinical Scientists, Inc.)
- Published
- 2022
29. Clinical and genetic analysis of pseudohypoparathyroidism complicated by hypokalemia: a case report and review of the literature.
- Author
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Huang S, He Y, Lin X, Sun S, and Zheng F
- Subjects
- Adult, Chromogranins genetics, Female, GTP-Binding Protein alpha Subunits, Gs genetics, Humans, Hypocalcemia genetics, Hypokalemia genetics, Pseudohypoparathyroidism complications, Pseudohypoparathyroidism diagnosis, Pseudohypoparathyroidism genetics, Tetany
- Abstract
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., (© 2022. The Author(s).)
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- 2022
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30. Differential parathyroid and kidney Ca 2+ -sensing receptor activation in autosomal dominant hypocalcemia 1.
- Author
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van Megen WH, Tan RSG, Alexander RT, and Dimke H
- Subjects
- Animals, Calcium metabolism, Canada, HEK293 Cells, Humans, Hypoparathyroidism congenital, Kidney metabolism, Mice, Parathyroid Hormone, Receptors, Calcium-Sensing genetics, Receptors, Calcium-Sensing metabolism, Hypercalciuria genetics, Hypocalcemia genetics
- Abstract
Background: Parathyroid Ca
2+ -sensing receptor (CaSR) activation inhibits parathyroid hormone (PTH) release, while activation of renal CaSRs attenuates Ca2+ transport and increases expression of the pore-blocking claudin-14. Patients with autosomal dominant hypocalcemia 1 (ADH1), due to activating CASR mutations, exhibit hypocalcemia but not always hypercalciuria (elevated Ca2+ in urine). The latter promotes nephrocalcinosis and renal insufficiency. Although CaSRs throughout the body including the kidney harbor activating CASR mutations, it is not understood why only some ADH1 patients display hypercalciuria., Methods: Activation of the CaSR was studied in mouse models and a ADH1 patient. In vitro CaSR activation was studied in HEK293 cells., Findings: Cldn14 showed blood Ca2+ concentration-dependent regulation, which was absent in mice with kidney-specific Casr deletion, indicating Cldn14 is a suitable marker for chronic CaSR activation in the kidney. Mice with a gain-of-function mutation in the Casr (Nuf) were hypocalcemic with low plasma PTH levels. However, renal CaSRs were not activated at baseline but only after normalizing blood Ca2+ levels. Similarly, significant hypercalciuria was not observed in a ADH1 patient until blood Ca2+ was normalized. In vitro experiments indicate that increased CaSR expression in the parathyroid relative to the kidney could contribute to tissue-specific CaSR activation thresholds., Interpretation: Our findings suggest that parathyroid CaSR overactivity can reduce plasma Ca2+ to levels insufficient to activate renal CaSRs, even when an activating mutation is present. These findings identify a conceptually new mechanism of CaSR-dependent Ca2+ balance regulation that aid in explaining the spectrum of hypercalciuria in ADH1 patients., Funding: Erasmus+ 2018/E+/4458087, the Canadian Institutes for Health research, the Novo Nordisk Foundation, the Beckett Foundation, the Carlsberg Foundation and Independent Research Fund Denmark., Competing Interests: Declaration of interests RTA has received consulting fees and a grant from Ardylex Inc to determine the mechanism of action of their drug Tenapanor, which is not related to this work. RTA has received honoraria for Ultragenyx for a lecture on FGF23 lowering therapies. WvM obtained an Erasmus+ grant for a graduate research stay in the lab of H. Dimke. The authors have declared that no conflict of interest exists., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)- Published
- 2022
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31. Hypocalcemia as the Initial Presentation of Type 2 Bartter Syndrome: A Family Report.
- Author
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London S, Levine MA, Li D, Spiegel R, Lebel A, Halevy R, and Tenenbaum-Rakover Y
- Subjects
- Child, Child, Preschool, Female, Humans, Hypercalciuria diagnosis, Hypercalciuria genetics, Male, Phosphates, Pregnancy, Alkalosis complications, Bartter Syndrome complications, Bartter Syndrome diagnosis, Bartter Syndrome genetics, Hypocalcemia etiology, Hypocalcemia genetics, Vitamin D Deficiency complications
- Abstract
Context: Bartter syndrome (BS) is a group of rare autosomal-recessive tubulopathies characterized by hypokalemic, hypochloremic metabolic alkalosis in which the primary defect is a deficiency of transporters involved in sodium chloride reabsorption. Type 2 BS results from a defect in the renal outer medullary potassium channel encoded by the KCNJ1 gene. Type 2 BS presents with polyhydramnios, intrauterine growth retardation, prematurity, failure to thrive, polyuria, hypercalciuria, and life-threatening episodes of dehydration. Hypocalcemia is a very rare presenting symptom of BS, with only a few published cases reporting it as the initial manifestation of type 2 BS., Objective: To describe a child who presented with hypocalcemic seizure at the age of 2.3 years that was first related to vitamin D deficiency and high-phosphate soft drink consumption., Methods: Whole exome sequencing (WES) was used to evaluate the biochemical abnormalities of the proband., Results: We identified a previously described homozygous missense mutation c.212C>T, p.T71M in the KCNJ1 gene associated with type 2 BS. Six additional family members with the same mutation and diagnosed clinically with BS are also reported, 2 presenting with hypocalcemia associated with vitamin D deficiency., Conclusion: This report expands the clinical spectrum associated with KCNJ1 mutations and emphasizes the role of WES in unsolved cases of hypocalcemia when genetic disease is suspected. It also highlights the hazardous effects of phosphate-containing soft drinks on calcium metabolism., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2022
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32. Combination of thrombocytopenia and hypocalcemia may indicate the possibility of Stormorken Syndrome with STIM1 mutation.
- Author
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Wang CH, Liang WC, Lin PC, and Jong YJ
- Subjects
- Blood Platelet Disorders, Dyslexia, Erythrocytes, Abnormal, Humans, Ichthyosis, Migraine Disorders, Miosis genetics, Muscle Fatigue, Mutation, Neoplasm Proteins, Spleen abnormalities, Stromal Interaction Molecule 1 genetics, Hypocalcemia genetics, Thrombocytopenia genetics
- Abstract
Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article.
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- 2022
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33. Homozygous missense variant of PTH (c.166C>T, p.(Arg56Cys)) as the cause of familial isolated hypoparathyroidism in a three-year-old child.
- Author
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Andersen SL, Frederiksen AL, Rasmussen AB, Madsen M, and Christensen AR
- Subjects
- Child, Child, Preschool, Homozygote, Humans, Parathyroid Hormone, Hypocalcemia genetics, Hypoparathyroidism genetics
- Abstract
Objectives: Hypoparathyroidism is a rare disorder which is predominantly of idiopathic or genetic origin in children. The diagnosis is made from the biochemical measurement of parathyroid hormone (PTH), and the key findings include a low PTH in combination with hypocalcemia and hyperphosphatemia. However, the level of PTH encountered in patients with hypoparathyroidism may be dependent on the underlying genetic cause of the disorder as well as the biochemical assay used for assessment of PTH., Case Presentation: A three-year-old child with asymptomatic primary hypoparathyroidism was identified with a homozygous missense variant of PTH . A sudden unexpected high PTH result after a shift from 2nd to 3rd generation PTH assay in the routine laboratory provided a clue on the underlying genetic etiology., Conclusions: Pathogenic variants of PTH as a cause of hypoparathyroidism are rarely described. In this case, the child was asymptomatic, and discordant PTH results were seen with different assays., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)
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- 2022
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34. A functional study for verifying the pathogenicity of a TRPM6 variant of uncertain significance: A novel non-canonical splicing-site variant in primary hypomagnesemia with secondary hypocalcemia.
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Wang P, Qian Y, Gu C, Zhi X, Pu L, Yan D, Shu J, Lv L, and Cai C
- Subjects
- Child, Humans, Pedigree, Virulence, Hypocalcemia genetics, Magnesium Deficiency congenital, Renal Tubular Transport, Inborn Errors, TRPM Cation Channels genetics
- Abstract
Introduction: Primary hypomagnesemia with secondary hypocalcemia (HSH) is a rare autosomal recessive disease caused by biallelic variants in TRPM6 gene., Methods: In this study, we reported a Chinese patient diagnosed with HSH in Tianjin Children's Hospital. Detailed clinical examination and laboratory test were performed and whole exome sequencing (WES) was applied to detect the pathogenic gene in the proband. The suspected compound heterozygous variant in TRPM6 gene was verified by Sanger sequencing and quantitative real-time PCR technology. Minigene assay was performed to verify the function of the variant suspected to affect splicing process., Results: The patient presented with seizure and markedly decreased levels of serum magnesium and calcium. WES combined with functional study diagnosed a pediatric patient with HSH caused by a compound heterozygous variant in TRPM6 gene, containing a novel non-canonical splicing-site variant c.5058-26A > G and a heterozygous deletion in exons 27-33 (chr9q21.13: 77357467-77376734)., Conclusions: The compound heterozygous variant in TRPM6 gene is the pathogenic cause of the proband. The combined application of WES and functional study contribute to validating the effect of an uncertain genetic variant on splicing, improving the pathogenicity evidence and identifying the etiology of the disease. It is helpful for early diagnosis and treatment of HSH., (Copyright © 2021 Elsevier B.V. All rights reserved.)
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- 2021
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35. Parathyroid Hormone Resistance and Autoantibodies to the PTH1 Receptor.
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Mandl A, Burbelo PD, Di Pasquale G, Tay YS, Welch J, Lionakis MS, Rosenzweig SD, Waldman MA, Warner BM, Walitt B, Collins MT, Balow JE, Chiorini JA, Simonds WF, Agarwal SK, Blau JE, and Weinstein LS
- Subjects
- Adult, Aged, DNA Mutational Analysis, Female, Glycopeptides blood, Humans, Hypocalcemia genetics, Immunoglobulin G blood, Immunophenotyping, Kidney Glomerulus pathology, Microscopy, Electron, Mutation, Pseudohypoparathyroidism genetics, Autoantibodies blood, Hypocalcemia etiology, Parathyroid Hormone metabolism, Receptor, Parathyroid Hormone, Type 1 immunology
- Abstract
We describe two cases of acquired parathyroid hormone (PTH) resistance consequent to the development of serum PTH type 1 receptor (PTH1R) autoantibodies, which block PTH binding and signaling. Both cases were associated with other autoimmune manifestations, and one case was associated with atypical membranous glomerulonephritis. In vitro binding and signaling assays identified the presence of PTH1R-blocking IgG autoantibodies, which were not present in serum samples from patients with other renal or autoimmune disorders. (Funded by the Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases and others.)., (Copyright © 2021 Massachusetts Medical Society.)
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- 2021
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36. Novel mutations in TRPM6 gene associated with primary hypomagnesemia with secondary hypocalcemia. Case report.
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Papez J, Starha J, Slaba K, Hubacek JA, Pecl J, Aulicka S, Urik M, Ceylaner S, Vesela P, Slaby O, and Jabandziev P
- Subjects
- Female, Humans, Hypercalciuria, Magnesium, Mutation, Nephrocalcinosis, Renal Tubular Transport, Inborn Errors, Seizures genetics, Hypocalcemia genetics, Magnesium Deficiency congenital, Magnesium Deficiency genetics, TRPM Cation Channels genetics
- Abstract
Background: Primary hypomagnesemia with secondary hypocalcemia (HSH) is a rare genetic disorder. Dysfunctional transient receptor potential melastatin 6 causes impaired intestinal absorption of magnesium, leading to low serum levels accompanied by hypocalcemia. Typical signs at initial manifestation are generalized seizures, tetany, and/or muscle spasms., Case Report: We present a 5 w/o female manifesting tonic-clonic seizures. Laboratory tests detected severe hypomagnesemia and hypocalcemia. The molecular genetic analysis revealed two novel mutations within the TRPM6 gene c.3308dupC (p.Pro1104Thrfs*28) (p.P1104Tfs*28) and c.3958C>T (p.Gln1302*) (p.Q1302*) and the patient was successfully treated with Mg supplementation., Conclusion: Ion disbalance should be taken into account in the differential diagnosis of infantile seizures. Accurate diagnosis of HSH together with appropriate treatment are crucial to prevent irreversible neurological outcomes.
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- 2021
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37. An intricate case of sporadic pseudohypoparathyroidism type 1B with a review of literature.
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Ramalho E Silva JD, da Rocha GFMA, and Oliveira MJM
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- Adult, Female, Humans, Parathyroid Hormone, Pseudohypoparathyroidism, Hypocalcemia genetics, Pseudohypoparathyroidism diagnosis, Pseudohypoparathyroidism genetics, Vitamin D Deficiency
- Abstract
Pseudohypoparathyroidism comprehends an assorted group of genetically rare disorders that share end-organ resistance to parathyroid hormone. Genetic and epigenetic modifications on guanine nucleotide-binding protein alpha-stimulating gene locus are the most common underlying mechanisms associated with pseudohypoparathyroidism. Biochemical and molecular analysis stratify pseudohypoparathyroidism into types 1A, 1B, 1C, and 2. We describe an unusual case of sporadic pseudohypoparathyroidism type 1B. A 34-year-old Caucasian woman was admitted to the emergency department, with persistent asthenia, limb paresthesias, and tactile hyposensitivity. Her physical examination, previous personal and family histories were unsuspicious, except for mild, intermittent and self-limited complaints of paresthesia during her two pregnancies, but no detailed workup was done. No typical features of Albright hereditary osteodystrophy were observed. The initial laboratory investigation showed elevated parathyroid hormone level (311.2 pg/mL), hypocalcemia (albumin-corrected serum calcium 4.3 mg/dL), hypocalciuria, hyperphosphatemia, hypophosphaturia, and vitamin D deficiency. Combined calcium, vitamin D, and magnesium supplementation was commenced, with symptomatic and analytical improvement. Albeit resolution of vitamin D deficiency, the patient relapsed with mild and intermittent lower limb paresthesias. Pseudohypoparathyroidism was confirmed by molecular identification of the 3-kb STX16 deletion. The treatment was readjusted, and one year later, symptomatic remission was attained. Clinical and biochemical features, and their respective course, along with lack of distinctive features of Albright hereditary osteodystrophy pointed to pseudohypoparathyroidism type 1B. A careful follow-up is needed to avoid complications and recurrence. Once correction of hypocalcemia and hyperphosphatemia is achieved, with no reported complications and recurrence, a good prognosis is anticipated, comparable to the general population.
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- 2021
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38. Long-term Clinical Follow-up of Patients with Familial Hypomagnesemia with Secondary Hypocalcemia
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Bayramoğlu E, Keskin M, Aycan Z, Savaş-Erdeve Ş, and Çetinkaya S
- Subjects
- Adolescent, Age Factors, Child, Child Development, Child, Preschool, Female, Follow-Up Studies, Genetic Predisposition to Disease, Humans, Hypocalcemia diagnosis, Hypocalcemia drug therapy, Hypocalcemia metabolism, Infant, Magnesium Compounds therapeutic use, Magnesium Deficiency diagnosis, Magnesium Deficiency drug therapy, Magnesium Deficiency genetics, Magnesium Deficiency metabolism, Male, Phenotype, Retrospective Studies, Time Factors, Treatment Outcome, Young Adult, Hypocalcemia genetics, Magnesium Deficiency congenital, Mutation, TRPM Cation Channels genetics, TRPM Cation Channels metabolism
- Abstract
Objective: Familial hypomagnesemia with secondary hypocalcemia (HSH) is an autosomal recessive disease caused by a mutation in the transient receptor potential melastatin 6 ( TRPM6 ) gene and is characterized by selective magnesium malabsorption. Affected cases are usually diagnosed during infancy and usually present with seizures due to hypocalcemia and hypomagnesemia. Irreversible neurological deficits and arrhythmias can be observed without appropriate treatment. The aim was to evaluate the long-term follow-up of patients with genetically confirmed HSH., Methods: A total of six patients with HSH, two of whom were siblings, were included. Age at diagnosis, clinical, laboratory and follow-up data on admission were recorded. All 39 exons of the TRPM6 gene and flanking exon-intron junctions from genomic DNA were amplified and sequenced in all cases., Results: The median (range) follow-up duration was 12.1 (7.6-21.7) years. All cases were diagnosed in infancy. Four different mutations, three of which had not been previously reported, were detected in the TRPM6 gene. Treatment compliance was good and there were no severe complications in the long-term follow-up of cases. However, mental retardation, specific learning difficulty and attention deficit/hyperactive disorder were observed as comorbidities., Conclusion: Of the four different TRPM6 mutations in this small cohort, three had not been previously reported. The long-term prognosis of HSH appears to be good, given early diagnosis and good treatment compliance. This long-term follow-up and prognostic data and the three novel mutations will contribute to the published evidence concerning this rare condition, HSH, and it is hoped will prevent negative outcomes.
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- 2021
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39. A novel synonymous homozygous variant [c.2538G>A (p.Thr846Thr)] in TRPM6 in a patient with hypomagnesemia with secondary hypocalcemia.
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Acar S, Schlingmann KP, Nalbantoğlu Ö, Köprülü Ö, Arslan G, Özkaya B, and Özkan B
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- Female, Humans, Infant, Magnesium Deficiency genetics, Hypocalcemia genetics, Magnesium Deficiency congenital, Mutation, TRPM Cation Channels genetics
- Abstract
Objectives: Hypomagnesemia 1, intestinal (HOMG1) is characterized by neurological symptoms that occur due to hypocalcemia and hypomagnesemia and caused by mutations in the TRPM6 . Most of the identified variants in TRPM6 lead to premature termination: nonsense, frameshift, deletion, and splice site mutations., Case Presentation: Herein, we report a 1.5 month-old case who presented with convulsion due to hypocalcemia and hypomagnesemia in the early infancy. Sequencing of TRPM6 revealed a novel homozygous synonymous variant [c.2538G > A (p.Thr846Thr)] in the last codon of exon 19, which is most likely to affect the splicing. We report a novel homozygous synonymous variant in the TRPM6 leading to HOMG1, expanding the mutational spectrum., Conclusions: Synonymous mutations that were previously considered as harmless should be evaluated at the nucleotide level, keeping in mind that they may affect splicing and cause to the disease., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)
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- 2021
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40. PTH Infusion for Seizures in Autosomal Dominant Hypocalcemia Type 1.
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Sastre A, Valentino K, Hannan FM, Lines KE, Gluck AK, Stevenson M, Ryalls M, Gorrigan RJ, Pullen D, Buck J, Sankaranarayanan S, Allgrove J, Thakker RV, and Gevers EF
- Subjects
- Calcium blood, Female, Gain of Function Mutation, Genes, Dominant, Humans, Hypocalcemia genetics, Infant, Infusions, Subcutaneous, Male, Receptors, Calcium-Sensing genetics, Young Adult, Hypocalcemia drug therapy, Parathyroid Hormone administration & dosage
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- 2021
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41. Identification of p.Arg205Cys in CASR in an autosomal dominant hypocalcaemia type 1 pedigree: A case report.
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Ji Y, Kang C, Chen J, and Zhang L
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- Calcitriol administration & dosage, Calcium blood, DNA Mutational Analysis, Drug Therapy, Combination methods, Female, Genetic Testing, Heterozygote, Humans, Hydrochlorothiazide administration & dosage, Hypercalciuria blood, Hypercalciuria genetics, Hypocalcemia blood, Hypocalcemia genetics, Hypoparathyroidism blood, Hypoparathyroidism diagnosis, Hypoparathyroidism genetics, Male, Medical History Taking, Middle Aged, Mutation, Missense, Pedigree, Treatment Outcome, Calcium administration & dosage, Hypercalciuria diagnosis, Hypocalcemia diagnosis, Hypoparathyroidism congenital, Receptors, Calcium-Sensing genetics
- Abstract
Rationale: Autosomal dominant hypocalcaemia type 1 (ADH1) is a genetic disease characterized by benign hypocalcemia, inappropriately low parathyroid hormone levels and mostly hypercalciuria. It is caused by the activating mutations of the calcium-sensing receptor gene (CASR), which produces a left-shift in the set point for extracellular calcium., Patient Concerns: A 50-year-old man presenting with muscle spasms was admitted into the hospital. He has a positive familial history for hypocalcemia. Auxiliary examinations demonstrated hypocalcemia, hyperphosphatemia, normal parathyroid hormone level and nephrolithiasis. A missense heterozygous variant in CASR, c 613C > T (p. Arg205Cys) which has been reported in a familial hypocalciuric hypercalcemia type 1 patient was found in the patient's genotype. It is the first time that this variant is found associating with ADH1. The variant is predicted vicious by softwares and cosegregates with ADH1 in this pedigree. CASR Arg205Cys was deduced to be the genetic cause of ADH1 in the family., Diagnosis: The patient was diagnosed with ADH1 clinically and genetically., Interventions: Oral calcitriol, calcium and hydrochlorothiazide were prescribed to the patient., Outcomes: After the treatments for 1 week, the patient's symptom was improved and the re-examination revealed serum calcium in the normal range. A 3-month follow-up showed his symptom was mostly relieved., Lessons: The variant of CASR Arg205Cys, responsible for ADH1 in this family, broadened the genetic spectrum of ADH1. Further and more studies are required to evaluate the correlation between genotype and phenotype in ADH1 patients., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)
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- 2021
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42. Report of a novel variant in the FAM111A gene in a fetus with multiple anomalies including gracile bones, hypoplastic spleen, and hypomineralized skull.
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Müller R, Steffensen T, Krstić N, and Cain MA
- Subjects
- Abnormalities, Multiple diagnostic imaging, Abnormalities, Multiple pathology, Bone Diseases, Developmental diagnosis, Bone Diseases, Developmental diagnostic imaging, Bone Diseases, Developmental pathology, Cardiovascular Abnormalities diagnosis, Cardiovascular Abnormalities genetics, Cardiovascular Abnormalities pathology, Craniofacial Abnormalities diagnosis, Craniofacial Abnormalities diagnostic imaging, Craniofacial Abnormalities pathology, Dwarfism diagnosis, Dwarfism diagnostic imaging, Dwarfism pathology, Facial Bones abnormalities, Facial Bones pathology, Female, Fetus, Genetic Predisposition to Disease, Heterozygote, Humans, Hyperostosis, Cortical, Congenital diagnosis, Hyperostosis, Cortical, Congenital diagnostic imaging, Hyperostosis, Cortical, Congenital pathology, Hypocalcemia diagnosis, Hypocalcemia diagnostic imaging, Hypocalcemia pathology, Male, Mutation genetics, Pregnancy, Skull abnormalities, Skull pathology, Spleen abnormalities, Spleen diagnostic imaging, Exome Sequencing, Abnormalities, Multiple genetics, Bone Diseases, Developmental genetics, Craniofacial Abnormalities genetics, Dwarfism genetics, Hyperostosis, Cortical, Congenital genetics, Hypocalcemia genetics, Receptors, Virus genetics
- Abstract
Kenny-Caffey syndrome type 2 (KCS2) and osteocraniostenosis (OCS) are allelic disorders caused by heterozygous pathogenic variants in the FAM111A gene. Both conditions are characterized by gracile bones, characteristic facial features, hypomineralized skull with delayed closure of fontanelles and hypoparathyroidism. OCS and KCS2 are often referred to as FAM111A-related syndromes as a group; although OCS presents with a more severe, perinatal lethal phenotype. We report a novel FAM111A mutation in a fetus with poorly ossified skull, proportionate long extremities with thin diaphysis, and hypoplastic spleen consistent with FAM111A-related syndromes. Trio whole exome sequencing identified a p.Y562S de novo missense variant in the FAM111A gene. The variant shows significant similarity to other reported pathogenic mutations fitting proposed pathophysiologic mechanism which provide sufficient evidence for classification as likely pathogenic. Our report contributed a novel variant to the handful of OCS and KCS2 cases reported with pathogenic variants., (© 2021 Wiley Periodicals LLC.)
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- 2021
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43. The Calcium-Sensing Receptor Is Essential for Calcium and Bicarbonate Sensitivity in Human Spermatozoa.
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Boisen IM, Rehfeld A, Mos I, Poulsen NN, Nielsen JE, Schwarz P, Rejnmark L, Dissing S, Bach-Mortensen P, Juul A, Bräuner-Osborne H, Lanske B, and Blomberg Jensen M
- Subjects
- Acrosome Reaction drug effects, Acrosome Reaction genetics, Adult, Bicarbonates pharmacology, Calcium pharmacology, Calcium Signaling drug effects, Calcium Signaling genetics, Case-Control Studies, Female, Humans, Hypercalcemia congenital, Hypercalcemia genetics, Hypercalcemia metabolism, Hypercalcemia pathology, Hypercalciuria genetics, Hypercalciuria metabolism, Hypercalciuria pathology, Hypocalcemia genetics, Hypocalcemia metabolism, Hypocalcemia pathology, Hypoparathyroidism congenital, Hypoparathyroidism genetics, Hypoparathyroidism metabolism, Hypoparathyroidism pathology, Kidney metabolism, Kidney pathology, Magnesium metabolism, Magnesium pharmacology, Male, Mutation, Receptors, Calcium-Sensing genetics, Sperm Motility drug effects, Sperm Motility genetics, Spermatozoa drug effects, Spermatozoa physiology, Testicular Neoplasms genetics, Testicular Neoplasms metabolism, Testicular Neoplasms pathology, Bicarbonates metabolism, Calcium metabolism, Receptors, Calcium-Sensing physiology, Spermatozoa metabolism
- Abstract
Context: The calcium-sensing receptor (CaSR) is essential to maintain a stable calcium concentration in serum. Spermatozoa are exposed to immense changes in concentrations of CaSR ligands such as calcium, magnesium, and spermine during epididymal maturation, in the ejaculate, and in the female reproductive environment. However, the role of CaSR in human spermatozoa is unknown., Objective: This work aimed to investigate the role of CaSR in human spermatozoa., Methods: We identified CaSR in human spermatozoa and characterized the response to CaSR agonists on intracellular calcium, acrosome reaction, and 3',5'-cyclic adenosine 5'-monophosphate (cAMP) in spermatozoa from men with either loss-of-function or gain-of-function mutations in CASR and healthy donors., Results: CaSR is expressed in human spermatozoa and is essential for sensing extracellular free ionized calcium (Ca2+) and Mg2+. Activators of CaSR augmented the effect of sperm-activating signals such as the response to HCO3- and the acrosome reaction, whereas spermatozoa from men with a loss-of-function mutation in CASR had a diminished response to HCO3-, lower progesterone-mediated calcium influx, and were less likely to undergo the acrosome reaction in response to progesterone or Ca2+. CaSR activation increased cAMP through soluble adenylyl cyclase (sAC) activity and increased calcium influx through CatSper. Moreover, external Ca2+ or Mg2+ was indispensable for HCO3- activation of sAC. Two male patients with a CASR loss-of-function mutation in exon 3 presented with normal sperm counts and motility, whereas a patient with a loss-of-function mutation in exon 7 had low sperm count, motility, and morphology., Conclusion: CaSR is important for the sensing of Ca2+, Mg2+, and HCO3- in spermatozoa, and loss-of-function may impair male sperm function., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2021
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44. Rare diseases caused by abnormal calcium sensing and signalling.
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Tőke J, Czirják G, Enyedi P, and Tóth M
- Subjects
- Calcium, Humans, Infant, Newborn, Mutation, Rare Diseases, Receptors, Calcium-Sensing genetics, Hypercalcemia genetics, Hypocalcemia genetics
- Abstract
The calcium-sensing receptor (CaSR) provides the major mechanism for the detection of extracellular calcium concentration in several cell types, via the induction of G-protein-coupled signalling. Accordingly, CaSR plays a pivotal role in calcium homeostasis, and the CaSR gene defects are related to diseases characterized by serum calcium level changes. Activating mutations of the CaSR gene cause enhanced sensitivity to extracellular calcium concentration resulting in autosomal dominant hypocalcemia or Bartter-syndrome type V. Inactivating CaSR gene mutations lead to resistance to extracellular calcium. In these cases, familial hypocalciuric hypercalcaemia (FHH1) or neonatal severe hyperparathyroidism (NSHPT) can develop. FHH2 and FHH3 are associated with mutations of genes of partner proteins of calcium signal transduction. The common polymorphisms of the CaSR gene have been reported not to affect the calcium homeostasis itself; however, they may be associated with the increased risk of malignancies.
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- 2021
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45. Five patients with disorders of calcium metabolism presented with GCM2 gene variants.
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García-Castaño A, Madariaga L, Gómez-Conde S, Cordo CLR, López-Iglesias M, Garcia-Fernández Y, Martín A, González P, Goicolea I, de Nanclares GP, De la Hoz AB, Aguayo A, de LaPiscina IM, Martínez R, Saso L, Urrutia I, Velasco O, Castaño L, and Gaztambide S
- Subjects
- Adolescent, Adult, Aged, Calcium blood, Calcium Signaling genetics, Cohort Studies, DNA Mutational Analysis, Female, Germ-Line Mutation, Heterozygote, High-Throughput Nucleotide Sequencing, Humans, Hyperparathyroidism, Primary blood, Hyperparathyroidism, Primary diagnosis, Hypocalcemia blood, Hypocalcemia diagnosis, Hypoparathyroidism blood, Hypoparathyroidism diagnosis, Infant, Male, Middle Aged, Nuclear Proteins metabolism, Parathyroid Glands, Parathyroid Hormone blood, Parathyroid Hormone metabolism, Transcription Factors metabolism, Calcium metabolism, Hyperparathyroidism, Primary genetics, Hypocalcemia genetics, Hypoparathyroidism genetics, Nuclear Proteins genetics, Transcription Factors genetics
- Abstract
The GCM2 gene encodes a transcription factor predominantly expressed in parathyroid cells that is known to be critical for development, proliferation and maintenance of the parathyroid cells. A cohort of 127 Spanish patients with a disorder of calcium metabolism were screened for mutations by Next-Generation Sequencing (NGS). A targeted panel for disorders of calcium and phosphorus metabolism was designed to include 65 genes associated with these disorders. We observed two variants of uncertain significance (p.(Ser487Phe) and p.Asn315Asp), one likely pathogenic (p.Val382Met) and one benign variant (p.Ala393_Gln395dup) in the GCM2 gene in the heterozygous state in five families (two index cases had hypocalcemia and hypoparathyroidism, respectively, and three index cases had primary hyperparathyroidism). Our study shows the utility of NGS in unravelling the genetic origin of some disorders of the calcium and phosphorus metabolism, and confirms the GCM2 gene as an important element for the maintenance of calcium homeostasis. Importantly, a novel variant in the GCM2 gene (p.(Ser487Phe)) has been found in a patient with hypocalcemia.
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- 2021
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46. Adult Chinese twins with Kenny-Caffey syndrome type 2: A potential age-dependent phenotype and review of literature.
- Author
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Cheng SSW, Chan PKJ, Luk HM, Mok MT, and Lo IFM
- Subjects
- Abnormalities, Multiple diagnosis, Abnormalities, Multiple epidemiology, Abnormalities, Multiple physiopathology, Adult, China epidemiology, Dwarfism diagnosis, Dwarfism epidemiology, Dwarfism physiopathology, Eye Abnormalities diagnosis, Eye Abnormalities epidemiology, Eye Abnormalities physiopathology, Female, Humans, Hyperostosis, Cortical, Congenital diagnosis, Hyperostosis, Cortical, Congenital epidemiology, Hyperostosis, Cortical, Congenital physiopathology, Hypocalcemia diagnosis, Hypocalcemia epidemiology, Hypocalcemia physiopathology, Male, Middle Aged, Phenotype, Twins genetics, Abnormalities, Multiple genetics, Dwarfism genetics, Eye Abnormalities genetics, Hyperostosis, Cortical, Congenital genetics, Hypocalcemia genetics, Receptors, Virus genetics
- Abstract
Kenny-Caffey syndrome (KCS) type 2 (OMIM 127000) is a rare syndromic cause of hypoparathyroidism which is characterized by proportionate short stature, long bone abnormalities, delayed closure of anterior fontanelle, eye abnormalities, and normal intelligence. It is caused by variants in FAM111A (NM_001942519.1). In this review, we reported the first Chinese patients, a pair of monozygotic twins, with genetically confirmed KCS type 2 with over 20 years follow-up. We summarized the clinical features of 14 previously reported and genetically confirmed KCS type 2 patients; our twin patients exhibited a unique spinal manifestation which could be an important age-dependent feature of KCS type 2. In this review, over 60% KCS type 2 patients had dental problem and over 80% suffered from refractive errors or structural eye abnormalities. Therefore, early dental, ophthalmological, and orthopedic assessments are warranted for KCS type 2 patients. Micro-orchidism, previously reported in KCS type 2 patients, was also detected in our patients. The possibility of subfertility should be considered in male KCS type 2 patients. A multidisciplinary management approach for this rare syndrome is recommended., (© 2020 Wiley Periodicals LLC.)
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- 2021
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47. Changes in mRNA of immune factors expressed by milk somatic cells of Holstein cows with hypocalcemia after calving.
- Author
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Ohtsuka H, Ohsawa M, Murakami K, Murata R, Kato T, and Tajima M
- Subjects
- Animals, Cattle, Cattle Diseases genetics, Female, Hypocalcemia genetics, Hypocalcemia immunology, Postpartum Period, RNA, Messenger genetics, Cattle Diseases immunology, Gene Expression Regulation immunology, Hypocalcemia veterinary, Immunologic Factors metabolism, Milk cytology, RNA, Messenger metabolism
- Abstract
Changes in immune factors expressed by milk somatic cells from Holstein cows with hypocalcemia after calving were investigated in this study. Fourteen multiparous Holstein cows after their 3rd or 4th calving in one farm were used. The cows were divided into 2 groups: 7 cows needing treatment due to onset of hypocalcemia (hypocalcemia group; age = 5.53 ± 0.27 years, parity = 3.14 ± 0.14) and 7 cows without health problems (control group; age = 5.88 ± 0.31 years, parity = 3.57 ± 0.26). Milk samples were collected aseptically using a cannula and mRNA of immune factors expressed by milk somatic cells were analyzed. Milk samples (50 mL) were collected from the right rear mammary gland of cows before milking at day 1 and weeks 1, 2, 4, and 8 after calving. All milk samples showed a negative reaction to the California Mastitis Test. Levels of relative interleukin (IL)-6 and cathelicidin in the hypocalcemia group were lower than those in the control group in weeks 1 to 8. A significant difference in relative IL-6 levels was found in week 4 ( P < 0.05). These results suggest that levels of IL-6 expressed by milk somatic cells may be affected by hypocalcemia in dairy cows., (Copyright and/or publishing rights held by the Canadian Veterinary Medical Association.)
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- 2021
48. Overlapping phenotype comprising Kenny-Caffey type 2 and Sanjad-Sakati syndromes: The first case report.
- Author
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Cavole TR, Perrone E, de Faria Soares MF, Dias da Silva MR, Maeda SS, Lazaretti-Castro M, and Alvarez Perez AB
- Subjects
- Abnormalities, Multiple genetics, Adolescent, Dwarfism complications, Dwarfism genetics, Growth Disorders complications, Growth Disorders genetics, Humans, Hyperostosis, Cortical, Congenital complications, Hyperostosis, Cortical, Congenital genetics, Hypocalcemia complications, Hypocalcemia genetics, Hypoparathyroidism complications, Hypoparathyroidism genetics, Intellectual Disability complications, Intellectual Disability genetics, Male, Osteochondrodysplasias complications, Osteochondrodysplasias genetics, Seizures complications, Seizures genetics, Abnormalities, Multiple pathology, Dwarfism pathology, Growth Disorders pathology, Hyperostosis, Cortical, Congenital pathology, Hypocalcemia pathology, Hypoparathyroidism pathology, Intellectual Disability pathology, Mutation, Osteochondrodysplasias pathology, Phenotype, Receptors, Virus genetics, Seizures pathology
- Abstract
Kenny-Caffey syndrome (KCS) is a rare hereditary skeletal disorder involving hypoparathyroidism. The autosomal dominant form (KCS2), caused by heterozygous pathogenic variants in the FAM111A gene, is distinguished from the autosomal recessive form (KCS1) and Sanjad-Sakati syndrome (SSS), both caused by pathogenic variants in the tubulin folding cofactor E (TBCE) gene, by the absence of microcephaly and intellectual disability. We present a patient with KCS2 caused by a de novo pathogenic variant c.1706G>A (p.Arg569His) in FAM111A gene, presenting intellectual disability and microcephaly, which are considered to be typical signs of SSS. We suggest that KCS1, KCS2, and SSS may not represent mutually exclusive clinical entities, but possibly an overlapping spectrum., (© 2020 Wiley Periodicals LLC.)
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- 2020
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49. [Clinical and genetic characteristics of primary hypoparathyroidism in children].
- Author
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Song FY, Du M, Dong Q, Yin H, Gao K, and Chen XB
- Subjects
- Child, DNA Copy Number Variations, Female, Humans, Male, Retrospective Studies, Hypocalcemia diagnosis, Hypocalcemia genetics, Hypoparathyroidism diagnosis, Hypoparathyroidism genetics, Urogenital Abnormalities
- Abstract
Objective: To analyze the clinical and genetic characteristics of primary hypoparathyroidism in children. Methods: The clinical data including age, symptoms, laboratory examination and cranial CT of 13 children with primary hypoparathyroidism diagnosed in the Capital Institute of Pediatrics from May 2017 to December 2019 were collected and analyzed retrospectively. These children and their parents also had gene detected by whole exome sequencing and (or) copy number variation sequencing. Results: Among the 13 patients, 7 were male and 6 female. The onset age was 3 years (1 day-12 years) old. The time from onset to confirmed diagnosis was 2 months (2 days-10 years). The clinical manifestations included convulsion (9 cases), tetany (2 cases), muscle pain (1 case), mental retardation (5 cases), deafness (1 case), and initially misdiagnosed epilepsy (5 cases). The lab examination showed average blood calcium level of (1.7±0.3) mmol/L, blood phosphorus of (2.8±0.4) mmol/L, and parathyroid hormone of 8.2 (3.9-28.7)ng/L. Head CT found 7 cases of ectopic calcification. Among the 7 cases who had genetic abnormalities according to the gene detection, 5 had heterozygous deletion of 22q11.2 region, and only one of whom was diagnosed with typical DiGeorge syndrome. As for the rest 2 cases, one had autosomal dominant hypocalcemia caused by novel heterozygous variation of CaSR gene c.2495T>G (p.F832C), and the other was hypoparathyroidism-deafness-renal dysplasia syndrome caused by GATA3 c.708dupC (p.S237Qfs*66) novel heterozygous variation. Conclusions: Primary hypoparathyroidism in children is mainly characterized by hypocalcemia and usually accompanied with diverse symptoms which may indicate genetic disorders. The detection of large fragment deletion should be considered to exclude 22q11.2 deletion syndrome.
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- 2020
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50. A nonsense variant in Rap Guanine Nucleotide Exchange Factor 5 (RAPGEF5) is associated with equine familial isolated hypoparathyroidism in Thoroughbred foals.
- Author
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Rivas VN, Magdesian KG, Fagan S, Slovis NM, Luethy D, Javsicas LH, Caserto BG, Miller AD, Dahlgren AR, Peterson J, Hales EN, Peng S, Watson KD, Khokha MK, and Finno CJ
- Subjects
- Animals, Embryo, Nonmammalian, Female, Homozygote, Horse Diseases etiology, Horses, Hypocalcemia genetics, Hypocalcemia pathology, Hypoparathyroidism genetics, Hypoparathyroidism pathology, Male, Pedigree, Whole Genome Sequencing, Xenopus embryology, ras Guanine Nucleotide Exchange Factors chemistry, Codon, Nonsense, Horse Diseases genetics, Hypocalcemia veterinary, Hypoparathyroidism veterinary, ras Guanine Nucleotide Exchange Factors genetics, ras Guanine Nucleotide Exchange Factors metabolism
- Abstract
Idiopathic hypocalcemia in Thoroughbred (TB) foals causes tetany and seizures and is invariably fatal. Based upon the similarity of this disease with human familial hypoparathyroidism and occurrence only in the TB breed, we conducted a genetic investigation on two affected TB foals. Familial hypoparathyroidism was identified, and pedigree analysis suggested an autosomal recessive (AR) mode of inheritance. We performed whole-genome sequencing of the two foals, their unaffected dams and four unaffected, unrelated TB horses. Both homozygosity mapping and an association analysis were used to prioritize potential genetic variants. Of the 2,808 variants that significantly associated with the phenotype using an AR mode of inheritance (P<0.02) and located within a region of homozygosity, 1,507 (54%) were located in a 9.7 Mb region on chr4 (44.9-54.6 Mb). Within this region, a nonsense variant (RAPGEF5 c.2624C>A,p.Ser875*) was significantly associated with the hypoparathyroid phenotype (Pallelic = 0.008). Affected foals were homozygous for the variant, with two additional affected foals subsequently confirmed in 2019. Necropsies of all affected foals failed to identify any histologically normal parathyroid glands. Because the nonsense mutation in RAPGEF5 was near the C-terminal end of the protein, the impact on protein function was unclear. Therefore, we tested the variant in our Xenopus overexpression model and demonstrated RAPGEF5 loss-of-function. This RAPGEF5 variant represents the first genetic variant for hypoparathyroidism identified in any domestic animal species., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2020
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