A variant in the CASR gene (c.368T>C) causing hypocalcemia refractory to standard medical therapy

Summary Hypoparathyroidism is characterized by low or inappropriately normal parathormone production, hypocalcemia and hyperphosphatemia. Autosomal dominant hypocalcemia (ADH) type 1 is one of the genetic etiologies of hypoparathyroidism caused by heterozygous activating mutations in the calcium-sensing receptor (CASR) gene. Current treatments for ADH type 1 include supplementation with calcium and active vitamin D. We report a case of hypoparathyroidism in an adolescent affected by syncope without prodrome. The genetic testing revealed a variant in the CASR gene. Due to standard therapy ineffectiveness, the patient was treated with recombinant human parathyroid hormone (1–34), magnesium aspartate and calcitriol. He remained asymptomatic and without neurological sequelae until adulthood. Early diagnosis and treatment are important to achieve clinical stability. Learning points Autosomal dominant hypocalcemia (ADH) type 1 is one of the genetic etiologies of hypoparathyroidism caused by heterozygous activating mutations in the calcium-sensing receptor (CASR) gene. The variant c.368T>C (p.Leu123Ser) in heterozygosity in the CASR gene is likely pathogenic and suggests the diagnosis of ADH type 1. Teriparatide (recombinant human parathyroid hormone 1–34) may be a valid treatment option to achieve clinical stability for those individuals whose condition is poorly controlled by current standard therapy.

Effect of Recombinant Human Parathyroid Hormone (1-84) on Resolution of Active Charcot Neuro-osteoarthropathy in Diabetes: A Randomized, Double-Blind, Placebo-Controlled Study

<b>Objectives</b>: Fractures in Charcot neuro-osteoarthropathy (CN) often fail to heal despite prolonged immobilization with below-knee casting. The aim of the study was to assess the efficacy of recombinant human parathyroid hormone (PTH) in reducing time to resolution of CN and healing of fractures. <p><b>Research Design and Methods</b>: People with diabetes and acute (active) Charcot foot were randomized (double-blind) to either full length PTH (1-84) or placebo therapy - both in addition to below-knee casting and Calcium and Vitamin D3 supplementation. The primary outcome was resolution of CN, defined as a skin foot temperature difference below 2°C at two consecutive monthly visits. </p> <p><b>Results:</b> Median time to resolution was 5 months (95% CI 4, 12) in intervention and 6 months (95% CI 2, 9) in control. There was no significant difference in time to resolution between the groups (mixed effects logistic regression; p=0.64). The hazard ratio of resolution was 0.84 (95% CI 0.41, 1.74), p=0.64 and the odds ratio of resolution by 12 months was 1.22 (0.90, 1.67), p=0.20 (intervention versus control). On linear regression analysis, there were no significant differences in the effect of treatment on fracture scores quantitated on magnetic resonance imaging <a>scans </a>(coef= 0.13; 95% CI -0.62, 0.88; p=0.73) and on foot and ankle X-rays (coef= 0.30; 95% CI -0.03, 0.63; p=0.07). </p> <p><b>Conclusions</b>: This double-blind placebo-controlled trial did not reduce time to resolution or enhance fracture healing of CN. There was no added benefit of daily intervention with PTH (1-84) to below-knee casting in achieving earlier resolution of CN. </p>

Effect of Recombinant Human Parathyroid Hormone (1-84) on Resolution of Active Charcot Neuro-osteoarthropathy in Diabetes: A Randomized, Double-Blind, Placebo-Controlled Study

<b>Objectives</b>: Fractures in Charcot neuro-osteoarthropathy (CN) often fail to heal despite prolonged immobilization with below-knee casting. The aim of the study was to assess the efficacy of recombinant human parathyroid hormone (PTH) in reducing time to resolution of CN and healing of fractures. <p><b>Research Design and Methods</b>: People with diabetes and acute (active) Charcot foot were randomized (double-blind) to either full length PTH (1-84) or placebo therapy - both in addition to below-knee casting and Calcium and Vitamin D3 supplementation. The primary outcome was resolution of CN, defined as a skin foot temperature difference below 2°C at two consecutive monthly visits. </p> <p><b>Results:</b> Median time to resolution was 5 months (95% CI 4, 12) in intervention and 6 months (95% CI 2, 9) in control. There was no significant difference in time to resolution between the groups (mixed effects logistic regression; p=0.64). The hazard ratio of resolution was 0.84 (95% CI 0.41, 1.74), p=0.64 and the odds ratio of resolution by 12 months was 1.22 (0.90, 1.67), p=0.20 (intervention versus control). On linear regression analysis, there were no significant differences in the effect of treatment on fracture scores quantitated on magnetic resonance imaging <a>scans </a>(coef= 0.13; 95% CI -0.62, 0.88; p=0.73) and on foot and ankle X-rays (coef= 0.30; 95% CI -0.03, 0.63; p=0.07). </p> <p><b>Conclusions</b>: This double-blind placebo-controlled trial did not reduce time to resolution or enhance fracture healing of CN. There was no added benefit of daily intervention with PTH (1-84) to below-knee casting in achieving earlier resolution of CN. </p>