Neonatal Hypercalcemia due to a Homozygous Mutation in the Calcium-Sensing Receptor: Failure of Cinacalcet

Soblechero, E. García; Castillo, María Teresa Ferrer; Crespo, Belén Jiménez; Quintero, M.L. Domínguez; Fuentes, C.

doi:10.1159/000350540

Cited by 40 publications

(41 citation statements)

References 20 publications

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“…Urgent parathyroidectomy is lifesaving and the treatment of choice, but pamidronate or cinacalcet have been used for treatment while awaiting surgery . Cinacalcet is a positive allosteric modulator of the CaSR and will ameliorate signaling disturbances associated with most loss‐of‐function CaSR mutations; however, if both CASR alleles have mutations whereby the CaSR is not expressed, eg, with a homozygous deletion in exon 5 (c.1392_1404del13), then cinacalcet will be ineffective . Some centers distinguish between NSHPT and neonatal hyperparathyroidism (NHPT) on the basis of homozygous and heterozygous CaSR mutations, respectively.…”

Section: Pth‐dependent Hypercalcemiamentioning

confidence: 99%

“…(118) Cinacalcet is a positive allosteric modulator of the CaSR and will ameliorate signaling disturbances associated with most loss-of-function CaSR mutations; however, if both CASR alleles have mutations whereby the CaSR is not expressed, eg, with a homozygous deletion in exon 5 (c.1392_1404del13), then cinacalcet will be ineffective. (119) 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.…”

Section: Menmentioning

confidence: 99%

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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: 99%

Section: Menmentioning

confidence: 99%

Hypercalcemic Disorders in Children

Stokes

Nielsen

Hannan

et al. 2017

Journal of Bone and Mineral Research

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“…Parathyroidectomy is generally considered the definitive treatment of choice but serum calcium should be lowered prior to surgery. General measures, however, like hydration or forced diuresis and calcitonin do not yield clinically sufficient responses in both variants of neonatal hyperparathyroidism (15,66,67,68,69). Restriction of calcium intake is also mostly ineffective and further aggravates total body calcium deficiency in NSHPT and NHPT patients (70,71,72,73).…”

Section: Casr As a Drug Target For Allosteric Modulatorsmentioning

confidence: 99%

GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts

Mayr¹,

Schnabel²,

Dörr³

et al. 2016

European Journal of Endocrinology

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The calcium-sensing receptor (CASR) is the main calcium sensor in the maintenance of calcium metabolism. Mutations of the CASR, the G protein alpha 11 (GNA11) and the adaptor-related protein complex 2 sigma 1 subunit (AP2S1) genes can shift the set point for calcium sensing causing hyper-or hypo-calcemic disorders. Therapeutic concepts for these rare diseases range from general therapies of hyper-and hypo-calcemic conditions to more pathophysiology oriented approaches such as parathyroid hormone (PTH) substitution and allosteric CASR modulators. Cinacalcet is a calcimimetic that enhances receptor function and has gained approval for the treatment of hyperparathyroidism. Calcilytics in turn attenuate CASR activity and are currently under investigation for the treatment of various diseases. We conducted a literature search for reports about treatment of patients harboring inactivating or activating CASR, GNA11 or AP2S1 mutants and about in vitro effects of allosteric CASR modulators on mutated CASR. The therapeutic concepts for patients with familial hypocalciuric hypercalcemia (FHH), neonatal hyperparathyroidism (NHPT), neonatal severe hyperparathyroidism (NSHPT) and autosomal dominant hypocalcemia (ADH) are reviewed. FHH is usually benign, but symptomatic patients benefit from cinacalcet. In NSHPT patients pamidronate effectively lowers serum calcium, but most patients require parathyroidectomy. In some patients cinacalcet can obviate the need for surgery, particularly in heterozygous NHPT. Symptomatic ADH patients respond to vitamin D and calcium supplementation but this may increase calciuria and renal complications. PTH treatment can reduce relative hypercalciuria. None of the currently available therapies for ADH, however, prevent tissue calcifications and complications, which may become possible with calcilytics that correct the underlying pathophysiologic defect.

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“…In these cases, hypercalcemia with serum calcium levels of around 3 mM was similar to adult patients with the same mutant but only FHH. In contrast, typical patients with neonatal severe hyperparathyroidism (NSHPT) have serum calcium concentrations between 5 and 8 mM (Table 1 and (5,6,7,8)). The milder form of neonatal hyperparathyroidism is therefore more appropriately called NHPT (neonatal hyperparathyroidism).…”

Section: Introductionmentioning

confidence: 99%