scholarly journals A Novel Variant in the CASR Gene c.368T>Cp.(Leu123Ser) in a Case of Hypocalcemia Refractory to Standard Medical Therapy

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A694-A694
Author(s):  
Diana Festas da Silva ◽  
Adriana De Sousa Lages ◽  
Joana Serra Caetano ◽  
Rita Cardoso ◽  
Isabel Dinis ◽  
...  
Keyword(s):  
Standard Therapy ◽  
Cranial Computed Tomography ◽  
Renal Ultrasound ◽  
Mineral Density ◽  
Left Femur ◽  
Casr Gene ◽  
Standard Medical Therapy ◽  
Medullary Nephrocalcinosis ◽  
Novel Variant

Abstract Introduction: Hypoparathyroidism is characterized by low or inappropriately normal PTH production, hypocalcemia and hyperphosphatemia. Autosomal dominant hypocalcemia (ADH) type 1 is one of the genetic etiologies of this, caused by heterozygous activating mutations in the CASR gene. Some individuals fail to meet treatment goals despite standard therapy. Clinical Case: A 13-year-old male patient was admitted in the emergency department due to syncope during physical activity. There was no reference to seizures or other complaints. Standard screening for metabolic diseases revealed no changes at the 7th day of life and family history was unremarkable. There was a history of febrile seizures up to 5 years of age with several hospitalizations for diagnosis investigation that were inconclusive. Physical examination showed a positive Chvostek signal, without other changes. A basic workup revealed hypocalcemia 1.67mmol/L (NR: 2.19-2.66), hyperphosphatemia 3.06mmol/L (NR: 0.95-1.75), hypomagnesemia 0.62mmol/L (NR: 0.7-1.0), low 25Hydroxyvitamin D 8.7ng/mL (NR: >30ng/mL) and inappropriately low PTH 4.0pg/mL (NR: 16.0-87.0). Cranial computed tomography scan showed bilateral calcifications of the basal ganglia. Dual-energy x-ray absorptiometry revealed bone mineral density z-scores increased 15% in spine lumbar and decreased 7% in left femur. Cardiac ultrasound and electrocardiography were normal. The patient started therapy with intravenous calcium gluconate. During this treatment, he developed significant calcification of the peripheral veins at the site of administration, leading to intravenous therapy suspension. The dose of oral calcium, calcitriol and magnesium was gradually increased and sevelamer started to control hyperphosphatemia. Despite the optimization, the patient maintained hypocalcemia refractory to standard therapy. As a last resource strategy in therapeutic optimization, the patient started on rhPTH (1-34). Ever since, the patient has been clinically asymptomatic with biochemical stability and with a reasonable quality of life. At age 18, renal ultrasound revealed diffuse medullary nephrocalcinosis. The genetic testing revealed a novel variant c.368T>C p.(Leu123Ser) likely pathogenic in heterozygosity in the CASR gene, suggesting the diagnosis of ADH type 1. The patient′s mother did not give her consent for genetic study and patient’s father had already died with a diagnosis of acute leukemia. Conclusion: This case can be explained by the presence of a likely pathogenic variant in heterozygosity in the CASR gene that has been described in the medical literature that has not been identified in gnomAD population database, suggesting the diagnosis of ADH type 1. rhPTH (1-34) may be a treatment option for those individuals who are not well controlled on standard therapy, but long-term follow-up studies are needed to reinforce its safety.

scholarly journals Novel Heterozygous Calcium Sensing Receptor (CASR) Genetic Variant in Child with Unique Phenotype: Hypocalcemia, Mandibular Hypoplasia, Renal Cysts and Type E Brachydactyly

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A703-A703
Author(s):  
Nicole Legro ◽  
Deborah Kees-Folts ◽  
Roger Ladda ◽  
Lina Huerta-Saenz
Keyword(s):  
Genetic Testing ◽  
Gene Mutation ◽  
Renal Cysts ◽  
Laboratory Evaluation ◽  
Renal Ultrasound ◽  
Calcium Sensing Receptor ◽  
Mandibular Hypoplasia ◽  
Casr Gene ◽  
Calcium Sensing ◽  
Medullary Nephrocalcinosis

Abstract Background: There are over 230 disease-causing variants in the calcium-sensing receptor gene (CaSR). Gain-of-function missense mutations in CaSR cause Autosomal Dominant Hypocalcemia (ADH) characterized by hypocalcemia (hCa), hypoparathyroidism (hPTH), and hypercalciuria. Patients with ADH are sensitive to fluctuations in serum calcium (Ca); and supplementation with Ca and vitamin D can cause inappropriate renal calcium retention leading to hypercalcemic events and long-term renal complications. Clinical Case: A 15-year-old adopted (at age 18 months) Korean female was initially diagnosed with hPTH and chronic hCa after presenting with hCa seizures. Laboratory values showed hCa (7.7 mg/dL), hyperphosphatemia (7.6 mg/dL) and hPTH (< 3 pg/mL.) Initially, she was treated with Ca supplementation (20 mg/kg/day elemental Ca), and calcitriol (0.01 mcg/kg/day). She presented at age 4 with hematuria and was found to have obstructive nephrolithiasis requiring operative intervention. Renal ultrasound (US) showed bilateral medullary nephrocalcinosis. She continued treatment with Ca and calcitriol. At age 6, a thiazide diuretic and potassium citrate supplement were added due to hypercalciuria. She had recurrent nephrolithiasis and persistent nephrocalcinosis. Follow-up renal US also showed bilateral renal cysts. Biweekly laboratory evaluation demonstrated an exuberant response to calcium supplementation. Serum Ca levels oscillated between 7.0 -10 mg/dL, but she showed minimal symptoms of hCa. At age 14, she was also recognized to have submandibular hypoplasia and brachydactyly of the 4th and 5th metacarpals and metatarsals bilaterally and genetic testing for CaSR gene mutation was requested. Sshe developed acute kidney injury and hypercalcemia, possibly precipitated by viral illness. However, 3 weeks before, calcitriol dose was increased to 1.25 mcg twice a day (0.07 mcg/kg/day). At admission, serum Ca was 12.7 mg/dL, iPTH 5.2 mg/dL, phosphorus 4.5 mg/dL, BUN 36 mg/dL, creatinine 1.85 mg/dL. Symptoms included headache, muscle spasm and throat spasm. She received intravenous fluids and recovered, but had an extended hospital stay. Targeted genetic analysis of the CaSR gene was completed, and identified a heterozygous variant (c.2506G>T, p.V836L) which is predicted to be likely pathogenic and cause ADH. After CaSR gene mutation identification, the calcitriol and also elemental Ca dosing were decreased to achieve a low Ca level (~7 mg/dL) with normal urine Ca/creatinine ratio. Patient remains asymptomatic. Conclusion: This is the first case of a novel mutation in the CaSR (c.2506G>T, p.V836L) associated with ADH, brachydactyly, renal cysts, and mandibular hypoplasia. Timely genetic testing for ADH in patients with newly diagnosed hPTH can lead to changes in therapy and improved prognosis.

THE NUCLEAR FACTOR OF HEPATOCYTES 1β (HNF1β)–ASSOCIATED DISEASE. CLINIC, DIAGNOSTIC, TREATMENT (LITERATURE REVIEW AND CLINICAL OBSERVATION)

2019 ◽  
Vol 23 (2) ◽  
pp. 100-108
Author(s):  
S. V. Papizh ◽  
O. R. Piruzieva
Keyword(s):  
Sanger Sequencing ◽  
Clinical Observation ◽  
Liver Enzymes ◽  
Renal Ultrasound ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Renal Hypoplasia ◽  
Unilateral Renal Agenesis ◽  
Elevated Liver Enzymes ◽  
Medullary Nephrocalcinosis

Hepatocyte nuclear factor 1β (HNF1β)-associated disease is a rare autosomal dominant disease caused by various mutations in the HNF1β gene coding the hepatocyte nuclear factor 1β. HNF1β is a transcription factor that is critical for the development of kidney urogenital tract, pancreas, liver, brain, and parathyroid gland. Renal phenotype or HNF1β- nephropathy appeared to be extremely heterogenic: multicystic renal dysplasia, renal hypoplasia, unilateral renal agenesis, horseshoe kidney, atypical familial juvenile hyperuricemic nephropathy, urinary tract malformations and tubular dysfunction. Extrarenal phenotype of HNF1β-associated disease could be maturity-onset diabetes of the young (MODY), pancreatic atrophy and exocrine pancreatic dysfunction, elevated liver enzymes, neonatal cholestasis, congenital abnormalities of the genital tract, hyperparathyroidism, neurological symptoms. The multisystem phenotype makes clinical verification of the diagnosis extremely difficult. In this article, we present a clinical observation of a child with HNF1β – associated disease. The first clinical presentation of HNF1β-associated disease was ultrasound changes in the kidneys (hyperechogenic kidneys?), which were detected by prenatal ultrasonography in pregnancy. Renal ultrasound revealed polycystic kidney disease in the first days of life and bilateral medullary nephrocalcinosis by the age of three. The clinical examination showed a reduced renal function and developed Fanconi syndrome (glycosuria, low molecular proteinuria, hypophosphatemia, aminoaciduria, hyperuricosuria) in the first year of life. Also the child had a non-constant asymptomatic elevation of liver enzymes, hyperparathyroidism, osteoporosis. The diagnosis was confirmed by the results of next generation sequencing which revealed novel heterozygous mutation in exon 4 of the HNF1b gene (chr17: 36091813C>T), p.Cys273Tyr (c.818G>A). The identified mutation was validated by Sanger sequencing. Validation by Sanger sequencing did not reveal a chr17: 36091813C>T mutation in parents, which suggested the appearance of a mutation in the child de novo.

scholarly journals Topical co‐administration of zoledronate with recombinant human bone morphogenetic protein-2 can induce and maintain bone formation in the bone marrow environment

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Hideki Ueyama ◽  
Yoichi Ohta ◽  
Yuuki Imai ◽  
Akinobu Suzuki ◽  
Ryo Sugama ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Formation ◽  
Bone Structure ◽  
Precursor Cells ◽  
The Other ◽  
Bone Morphogenetic Protein 2 ◽  
New Bone Formation ◽  
Micro Computed Tomography ◽  
Mineral Density ◽  
Left Femur

Abstract Background Bone morphogenetic proteins (BMPs) induce osteogenesis in various environments. However, when BMPs are used alone in the bone marrow environment, the maintenance of new bone formation is difficult owing to vigorous bone resorption. This is because BMPs stimulate the differentiation of not only osteoblast precursor cells but also osteoclast precursor cells. The present study aimed to induce and maintain new bone formation using the topical co-administration of recombinant human BMP-2 (rh-BMP-2) and zoledronate (ZOL) on beta-tricalcium phosphate (β-TCP) composite. Methods β-TCP columns were impregnated with both rh-BMP-2 (30 µg) and ZOL (5 µg), rh-BMP-2 alone, or ZOL alone, and implanted into the left femur canal of New Zealand white rabbits (n = 56). The implanted β-TCP columns were harvested and evaluated at 3 and 6 weeks after implantation. These harvested β-TCP columns were evaluated radiologically using plane radiograph, and histologically using haematoxylin/eosin (H&E) and Masson’s trichrome (MT) staining. In addition, micro-computed tomography (CT) was performed for qualitative analysis of bone formation in each group (n = 7). Results Tissue sections stained with H&E and MT dyes revealed that new bone formation inside the β-TCP composite was significantly greater in those impregnated with both rh-BMP-2 and ZOL than in those from the other experimental groups at 3 and 6 weeks after implantations (p < 0.05). Micro-CT data also demonstrated that the bone volume and the bone mineral density inside the β-TCP columns were significantly greater in those impregnated with both rh-BMP-2 and ZOL than in those from the other experimental groups at 3 and 6 weeks after implantations (p < 0.05). Conclusions The topical co-administration of both rh-BMP-2 and ZOL on β-TCP composite promoted and maintained newly formed bone structure in the bone marrow environment.

scholarly journals MECHANISMS IN ENDOCRINOLOGY: Mechanisms and evaluation of bone fragility in type 1 diabetes mellitus

2016 ◽  
Vol 174 (4) ◽  
pp. R127-R138 ◽  
Author(s):  
F S Hough ◽  
D D Pierroz ◽  
C Cooper ◽  
S L Ferrari ◽  
_ _
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Type 1 Diabetes Mellitus ◽  
Bone Fragility ◽  
Mineral Density ◽  
Good Glycaemic Control ◽  
Marrow Adiposity ◽  
Igf1 Deficiency

Subjects with type 1 diabetes mellitus (T1DM) have decreased bone mineral density and an up to sixfold increase in fracture risk. Yet bone fragility is not commonly regarded as another unique complication of diabetes. Both animals with experimentally induced insulin deficiency syndromes and patients with T1DM have impaired osteoblastic bone formation, with or without increased bone resorption. Insulin/IGF1 deficiency appears to be a major pathogenetic mechanism involved, along with glucose toxicity, marrow adiposity, inflammation, adipokine and other metabolic alterations that may all play a role on altering bone turnover. In turn, increasing physical activity in children with diabetes as well as good glycaemic control appears to provide some improvement of bone parameters, although robust clinical studies are still lacking. In this context, the role of osteoporosis drugs remains unknown.

scholarly journals Bone mineral density predictors in long-standing type 1 and type 2 diabetes mellitus

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Stefana Catalina Bilha ◽  
Letitia Leustean ◽  
Cristina Preda ◽  
Dumitru D. Branisteanu ◽  
Laura Mihalache ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Bone Mineral Density ◽  
Lumbar Spine ◽  
Femoral Neck ◽  
Bone Mineral ◽  
Mineral Density ◽  
Cross Sectional ◽  
The Impact

Abstract Background Despite the increased fracture risk, bone mineral density (BMD) is variable in type 1 (T1D) and type 2 (T2D) diabetes mellitus. We aimed at comparing independent BMD predictors in T1D, T2D and control subjects, respectively. Methods Cross-sectional case-control study enrolling 30 T1D, 39 T2D and 69 age, sex and body mass index (BMI) – matched controls that underwent clinical examination, dual-energy X-ray absorptiometry (BMD at the lumbar spine and femoral neck) and serum determination of HbA1c and parameters of calcium and phosphate metabolism. Results T2D patients had similar BMD compared to T1D individuals (after adjusting for age, BMI and disease duration) and to matched controls, respectively. In multiple regression analysis, diabetes duration – but not HbA1c- negatively predicted femoral neck BMD in T1D (β= -0.39, p = 0.014), while BMI was a positive predictor for lumbar spine (β = 0.46, p = 0.006) and femoral neck BMD (β = 0.44, p = 0.007) in T2D, besides gender influence. Age negatively predicted BMD in controls, but not in patients with diabetes. Conclusions Long-standing diabetes and female gender particularly increase the risk for low bone mass in T1D. An increased body weight partially hinders BMD loss in T2D. The impact of age appears to be surpassed by that of other bone regulating factors in both T1D and T2D patients.

(deleted)

2021 ◽  
Author(s):  
MV Osikov ◽  
EV Davydova ◽  
KS Abramov
Keyword(s):  
Bone Healing ◽  
Standard Therapy ◽  
Type I Collagen ◽  
Femoral Shaft ◽  
Control Group ◽  
Blood Levels ◽  
Type I ◽  
Mineral Density ◽  
Fracture Consolidation ◽  
To Receive

Efferent physical therapy holds promise as an adjunct to the combination treatment of femoral fractures in young, working-age individuals. The aim of the study was to investigate the dynamics of bone turnover markers at different stages of femoral fracture consolidation in patients undergoing ozone therapy. The study enrolled 20 men (group 2, 47.8 ± 3.5 years) with a femoral shaft fracture (AO/ASIF 32А, 32В). The control group (group 1, 46.8 ± 3.7 years) comprised 10 healthy males. Subgroup 2a (n = 10) was assigned to receive standard therapy; subgroup 2b (n = 10) was assigned to receive standard therapy complemented by minor autohemotherapy (MAHT) at 20 mg/L ozone concentrations. On days 7, 30 and 90, fracture consolidation was assessed on the RUST scale and blood levels of С-terminal telopeptides of type I collagen (bCTx, pg/ml) and procollagen type I carboxy-terminal propeptide (PICP, ng/ml) were measured. On day 7, the total RUST score in subgroups 2a and 2b was 4 points; on day 30, it was 6.5 and 8.7 points, respectively, and on day 90, it reached 10 and 11.5 points, respectively. Bone mineral density was as high as 90% in the MAHT subgroup vs. 78% in subgroup 2а, indicating faster bone healing. On day 30, bCTx levels in subgroup 2b were higher than in subgroup 2a (2289.4 [2145.3; 2365.4] vs. 1894.6 [1745.3; 2098.2], respectively. On day 7, PICP was significantly elevated in subgroup 2b in comparison with subgroup 2a; its levels peaked on days 30 and 90 (day 30: 268.3 [231.2; 286.3] vs. 183.2 [174.6; 195.6]; day 90: 584.6 [512.3; 589.3] vs. 351.2 [312.3; 369.4]. Thus, MAHT produces a positive effect on the quality and intensity of bone healing in men with isolated closed femoral shaft fractures.

scholarly journals Dietary n-3 PUFA content as a modulator of the femur properties in growing pigs

2019 ◽  
Vol 121 (5) ◽  
pp. 508-518
Author(s):  
Monika Sobol ◽  
Grzegorz Skiba ◽  
Stanisława Raj
Keyword(s):  
Linolenic Acid ◽  
Bone Mineral ◽  
Linseed Oil ◽  
Control Diet ◽  
Biomechanical Properties ◽  
Growing Pigs ◽  
Mineral Density ◽  
Pufa Content ◽  
Left Femur ◽  
Pufa Ratio

AbstractThe relationships between both dietary and empty body fatty acid composition and the morphometry, densitometry, geometry and biomechanical properties of the femur of growing pigs were analysed. A total of thirty-two pigs aged 115 d were divided into four groups (n 8 per group). The pigs were fed either a control diet (group C) or a diet supplemented with linseed oil (rich in α-linolenic acid (C18 : 3n-3), group L), fish oil (rich in EPA (C20 : 5n-3) and DHA (C22 : 6n-3), group F) and beef tallow (rich in SFA, group T). The diets differed in n-3 PUFA contents (0·63–18·52 g/kg) and n-6:n-3 PUFA ratios (0·91–14·51). At 165 d of age, the pigs were slaughtered and the fatty acids in the empty body were determined. Moreover, the left femur was dissected. The cortical wall thickness, cross-sectional area, cortical index, bone mineral content, bone mineral density, maximum elastic strength and maximum strength were lower (P<0·05) in the femurs of pigs from groups C and T than in those from groups F and L. Significant positive correlations were found between the densitometry, geometry and biomechanical properties of the femur and both dietary and empty body n-3 PUFA content, whereas significant negative correlations were observed between the same properties and both dietary and empty body n-6:n-3 PUFA ratio. The results of the present study suggest that in growing pigs α-linolenic acid has a similar positive effect on bone health to that of EPA and DHA.

Sign in / Sign up

Export Citation Format

Share Document