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      Successful treatment of neonatal severe hyperparathyroidism with cinacalcet in two patients


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          Neonatal severe hyperparathyroidism (NSHPT) is a rare disorder caused by inactivating calcium-sensing receptor (CASR) mutations that result in life-threatening hypercalcemia and metabolic bone disease. Until recently, therapy has been surgical parathyroidectomy. Three previous case reports have shown successful medical management of NSHPT with cinacalcet. Here we present the detailed description of two unrelated patients with NSHPT due to heterozygous R185Q CASR mutations. Patient 1 was diagnosed at 11 months of age and had developmental delays, dysphagia, bell-shaped chest, and periosteal bone reactions. Patient 2 was diagnosed at 1 month of age and had failure to thrive, osteopenia, and multiple rib fractures. Cinacalcet was initiated at 13 months of age in patient 1, and at 4 months of age in patient 2. We have successfully normalized their parathyroid hormone and alkaline phosphatase levels. Despite the continuance of mild hypercalcemia (11–12 mg/dl), both patients showed no hypercalcemic symptoms. Importantly, patient 1 had improved neurodevelopment and patient 2 never experienced any developmental delays after starting cinacalcet. Neither experienced fractures after starting cinacalcet. Both have been successfully managed long-term without any significant adverse events. These cases expand the current literature of cinacalcet use in NSHPT to five successful reported cases. We propose that cinacalcet may be considered as an option for treating the severe hypercalcemia and metabolic bone disease found in infants and children with inactivating CASR disorders.

          Learning points

          • NSHPT due to mutations in the CASR gene occurs with hypercalcemia and metabolic bone disease, but not always with severe critical illness in infancy.

          • NSHPT should be considered in the differential diagnosis for a newborn with a bell-shaped chest, osteopenia, and periosteal reactions.

          • Neurodevelopmental consequences may occur in children with hypercalcemia and may improve during treatment.

          • Calcimimetics can be used to successfully treat the pathophysiology of NSHPT directly to control serum calcium levels.

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          Most cited references15

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          Identification of 70 calcium-sensing receptor mutations in hyper- and hypo-calcaemic patients: evidence for clustering of extracellular domain mutations at calcium-binding sites.

          The calcium-sensing receptor (CaSR) is a G-protein-coupled receptor that has an extracellular bilobed venus flytrap domain (VFTD) predicted to contain five calcium (Ca(2+))-binding sites. To elucidate the structure-function relationships of the VFTD, we investigated 294 unrelated probands with familial hypocalciuric hypercalcaemia (FHH), neonatal severe primary hyperparathyroidism (NSHPT) or autosomal dominant hypocalcaemic hypercalciuria (ADHH) for CaSR mutations and performed in vitro functional expression studies and three-dimensional modelling of mutations involving the VFTD. A total of 70 different CaSR mutations were identified: 35 in FHH, 10 in NSHPT and 25 in ADHH patients. Furthermore, a CaSR variant (Glu250Lys) was identified in FHH and ADHH probands and demonstrated to represent a functionally neutral polymorphism. NSHPT was associated with a large proportion of truncating CaSR mutations that occurred in the homozygous or compound heterozygous state. Thirty-four VFTD missense mutations were identified, and 18 mutations were located within 10 Å of one or more of the predicted Ca(2+)-binding sites, particularly at the VFTD cleft, which is the principal site of Ca(2+) binding. Mutations of residues 173 and 221, which are located at the entrance to the VFTD cleft binding site, were associated with both receptor activation (Leu173Phe and Pro221Leu) and inactivation (Leu173Pro and Pro221Gln), thereby highlighting the importance of these residues for entry and binding of Ca(2+) by the CaSR. Thus, these studies of disease-associated CaSR mutations have further elucidated the role of the VFTD cleft region in Ca(2+) binding and the function of the CaSR.
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            Primary hyperparathyroidism in children and adolescents.

            Primary hyperparathyroidism (PHPT) is a common endocrine disorder in adults in whom the typical presentation is incidentally discovered as asymptomatic hypercalcemia. PHPT is much less common in children and adolescents, but has greater morbidity in this age group, as most young patients with PHPT will have symptomatic hypercalcemia or complications such as kidney stones, abdominal pain, and skeletal fragility. An important feature of PHPT in younger patients is the relatively high prevalence of germline inactivating mutations of the CASR gene, which encodes the calcium-sensing receptor. Biallelic CASR mutations cause neonatal severe hyperparathyroidism, a life-threatening condition that presents within days of life with marked hypercalcemia, respiratory distress, failure to thrive, and skeletal demineralization. By contrast, more common heterozygous CASR mutations are generally associated with a benign variant of PHPT termed familial hypocalciuric hypercalcemia. Appropriate management of PHPT in children and adolescents requires distinction between familial hypocalciuric hypercalcemia, which generally requires no specific treatment, and other forms of PHPT that are best treated by parathyroidectomy. 2012 Published by Elsevier B.V
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              Cinacalcet monotherapy in neonatal severe hyperparathyroidism: a case study and review.

              Neonatal severe hyperparathyroidism (NSHPT) is a severe form of familial hypocalciuric hypercalcemia characterized by severe hypercalcemia and skeletal demineralization. In most cases, NSHPT is due to biallelic loss-of-function mutations in the CASR gene encoding the calcium-sensing receptor (CaSR), but some patients have heterozygous mutations. Conventional treatment consists of iv saline, bisphosphonates, and parathyroidectomy.

                Author and article information

                Endocrinol Diabetes Metab Case Rep
                Endocrinol Diabetes Metab Case Rep
                EDM Case Reports
                Endocrinology, Diabetes & Metabolism Case Reports
                Bioscientifica Ltd (Bristol )
                18 June 2015
                : 2015
                : 150040
                [1 ]Division of Pediatric Endocrinology, Department of Pediatrics, Riley Hospital for Children, Indiana University School of Medicine , 705 Riley Hospital Drive, Room 5960, Indianapolis, Indiana, 46220, USA
                [2 ]Division of Pediatric Endocrinology, Department of Pediatrics, Medical College of Wisconsin, Children's Hospital of Wisconsin , 9000 W. Wisconsin Avenue, PO Box 1997, Milwaukee, Wisconsin, 53201, USA
                [3 ]Division of Endocrinology, Department of Medicine, Indiana University School of Medicine , 541 North Clinical Drive, Indianapolis, Indiana, 46202, USA
                Author notes
                Correspondence should be addressed to M M Fisher Email: mamfishe@ 123456iu.edu
                © 2015 The authors

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.

                : 18 May 2015
                : 18 June 2015
                Novel Treatment


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