Heterozygous inactivating CaSR mutations causing neonatal hyperparathyroidism: function, inheritance and phenotype

Glaudo, Markus; Letz, S; Quinkler, Marcus; Bogner, U.; Elbelt, Ulf; Strasburger, Christian J.; Schnabel, Dirk; Lankes, Erwin; Scheel, Sandra; Feldkamp, Joachim; Haag, Christine; Schulze, Egbert; Frank‐Raue, Karin; Raue, Friedhelm; Mayr, B; Schöfl, Christof

doi:10.1530/eje-16-0223

Cited by 31 publications

(30 citation statements)

References 42 publications

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“…Some centers distinguish between NSHPT and neonatal hyperparathyroidism (NHPT) on the basis of homozygous and heterozygous CaSR mutations, respectively. NHPT may be associated with less marked and symptomatically transient hypercalcemia than NSHPT, with some patients developing symptomless FHH, and therefore not requiring parathyroid surgery . This highlights the value of CASR mutational analysis in distinguishing NSHPT from NHPT.…”

Section: Pth‐dependent Hypercalcemiamentioning

confidence: 93%

Hypercalcemic Disorders in Children

Stokes

Nielsen

Hannan

et al. 2017

Journal of Bone and Mineral Research

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Hypercalcemia is defined as a serum calcium concentration that is greater than two standard deviations above the normal mean, which in children may vary with age and sex, reflecting changes in the normal physiology at each developmental stage. Hypercalcemic disorders in children may present with hypotonia, poor feeding, vomiting, constipation, abdominal pain, lethargy, polyuria, dehydration, failure to thrive, and seizures. In severe cases renal failure, pancreatitis and reduced consciousness may also occur and older children and adolescents may present with psychiatric symptoms. The causes of hypercalcemia in children can be classified as parathyroid hormone (PTH)‐dependent or PTH‐independent, and may be congenital or acquired. PTH‐independent hypercalcemia, ie, hypercalcemia associated with a suppressed PTH, is commoner in children than PTH‐dependent hypercalcemia. Acquired causes of PTH‐independent hypercalcemia in children include hypervitaminosis; granulomatous disorders, and endocrinopathies. Congenital syndromes associated with PTH‐independent hypercalcemia include idiopathic infantile hypercalcemia (IIH), William's syndrome, and inborn errors of metabolism. PTH‐dependent hypercalcemia is usually caused by parathyroid tumors, which may give rise to primary hyperparathyroidism (PHPT) or tertiary hyperparathyroidism, which usually arises in association with chronic renal failure and in the treatment of hypophosphatemic rickets. Acquired causes of PTH‐dependent hypercalcemia in neonates include maternal hypocalcemia and extracorporeal membrane oxygenation. PHPT usually occurs as an isolated nonsyndromic and nonhereditary endocrinopathy, but may also occur as a hereditary hypercalcemic disorder such as familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, and familial isolated primary hyperparathyroidism, and less commonly, as part of inherited complex syndromic disorders such as multiple endocrine neoplasia (MEN). Advances in identifying the genetic causes have resulted in increased understanding of the underlying biological pathways and improvements in diagnosis. The management of symptomatic hypercalcemia includes interventions such as fluids, antiresorptive medications, and parathyroid surgery. This article presents a clinical, biochemical, and genetic approach to investigating the causes of pediatric hypercalcemia. © 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

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Section: Pth‐dependent Hypercalcemiamentioning

confidence: 93%

Hypercalcemic Disorders in Children

Stokes

Nielsen

Hannan

et al. 2017

Journal of Bone and Mineral Research

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“…Mutant sensors in the plasma membrane are major contributors to hyperplasia, which is usually observed in the four glands in NSHPT [17]. The main mutations reported in this condition are compound homozygous or heterozygous inactivating mutations of CASR or sometimes simply de novo occurring heterozygotes [37, 38], such as the R185Q and R227Q mutations, which are the cause of alterations in the MAP-kinase (MAPK) pathway.…”

Section: Genetic Causesmentioning

confidence: 99%

Diseases associated with calcium-sensing receptor

Vahé

Benomar

Espiard

et al. 2017

Orphanet J Rare Dis

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The calcium-sensing receptor (CaSR) plays a pivotal role in systemic calcium metabolism by regulating parathyroid hormone secretion and urinary calcium excretion. The diseases caused by an abnormality of the CaSR are genetically determined or are more rarely acquired. The genetic diseases consist of hyper- or hypocalcemia disorders. Hypercalcaemia disorders are related to inactivating mutations of the CASR gene either heterozygous (autosomal dominant familial benign hypercalcaemia, still named hypocalciuric hypercalcaemia syndrome type 1) or homozygous (severe neonatal hyperparathyroidism). The A986S, R990G and Q1011E variants of the CASR gene are associated with higher serum calcium levels than in the general population, hypercalciuria being also associated with the R990G variant. The differential diagnosis consists in the hypocalciuric hypercalcaemia syndrome, types 2 (involving GNA11 gene) and 3 (involving AP2S1 gene); hyperparathyroidism; abnormalities of vitamin D metabolism, involving CYP24A1 and SLC34A1 genes; and reduced GFR. Hypocalcemia disorders, which are more rare, are related to heterozygous activating mutations of the CASR gene (type 1), consisting of autosomal dominant hypocalcemia disorders, sometimes with a presentation of pseudo-Bartter’s syndrome. The differential diagnosis consists of the hypercalciuric hypocalcaemia syndrome type 2, involving GNA11 gene and other hypoparathyroidism aetiologies. The acquired diseases are related to the presence of anti-CaSR antibodies, which can cause hyper- or especially hypocalcemia disorders (for instance in APECED syndromes), determined by their functionality. Finally, the role of CaSR in digestive, respiratory, cardiovascular and neoplastic diseases is gradually coming to light, providing new therapeutic possibilities. Two types of CaSR modulators are known: CaSR agonists (or activators, still named calcimimetics) and calcilytic antagonists (or inhibitors of the CasR). CaSR agonists, such as cinacalcet, are indicated in secondary and primary hyperparathyroidism. Calcilytics have no efficacy in osteoporosis, but could be useful in the treatment of hypercalciuric hypocalcaemia syndromes.

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“…It was formerly assumed that a dominant negative effect and/or paternal inheritance could have modified the clinical presentation. Recent functional studies, however, have found no evidence for either effect [38] ( Fig. 4 ).…”

Section: Dysmagnesemia Due To Ion Channel/transporter Mutations In Thmentioning

confidence: 83%

Genetics of Magnesium Disorders

Sun

Chen

et al. 2017

Kidney Dis

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Background: Magnesium (Mg²⁺), the second most abundant cation in the cell, is woven into a multitude of cellular functions. Dysmagnesemia is associated with multiple diseases and, when severe, can be life-threatening. Summary: This review discusses Mg²⁺ homeostasis and function with specific focus on renal Mg²⁺ handling. Intrarenal channels and transporters related to Mg²⁺ absorption are discussed. Unraveling the rare genetic diseases with manifestations of dysmagnesemia has greatly increased our understanding of the complex and intricate regulatory network in the kidney, specifically, functions of tight junction proteins including claudin-14, -16, -19, and -10; apical ion channels including: TRPM6, K_v1.1, and ROMK; small regulatory proteins including AC3 and ANK3; and basolateral proteins including EGF receptor, γ-subunit (FXYD2) of Na-K-ATPase, K_ir4.1, CaSR, CNNM2, and SLC41A. Although our understanding of Mg²⁺ handling of the kidney has expanded considerably in the last two decades, many questions remain. Future studies are needed to elucidate a multitude of unknown aspects of Mg²⁺ handling in the kidney. Key Message: Understanding rare and genetic diseases of Mg²⁺ dysregulation has expanded our knowledge and furthers the development of strategies for preventing and managing dysmagnesemia.

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Heterozygous inactivating CaSR mutations causing neonatal hyperparathyroidism: function, inheritance and phenotype

Cited by 31 publications

References 42 publications

Hypercalcemic Disorders in Children

Hypercalcemic Disorders in Children

Diseases associated with calcium-sensing receptor

Genetics of Magnesium Disorders

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