Cinacalcet Monotherapy in Neonatal Severe Hyperparathyroidism: A Case Study and Review

Gannon, Anthony W.; Monk, Heather M.; Levine, Michael A.

doi:10.1210/jc.2013-2834

Cited by 67 publications

(60 citation statements)

References 28 publications

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“…Cinacalcet was effective in one NSHPT and all four NHPT patients. All four NHPT patients had a heterozygous R185Q mutation and as in FHH patients a rapid fall in PTH preceding the decrease in serum calcium was observed after cinacalcet (15,16). One patient showed a significant but temporary drop of ionized serum calcium by 0.4 mmol/l 12 h after a single dose of 20 mg/m 2 cinacalcet (15) and (Table 3).…”

Section: Casr As a Drug Target For Allosteric Modulatorsmentioning

confidence: 96%

“…There are, however, exceptions from this rule. Homozygous CASR mutations leading to only a mild overall impairment of extracellular calcium sensing may cause a FHH-like phenotype (8,12,13,14), whereas heterozygous CASR mutations causing more pronounced functional impairment can lead to neonatal hyperparathyroidism (NHPT) (15,16,17). Recently it has been found that inactivating mutations in the CASR associated G protein alpha 11 (GNA11) and in the adaptor-related protein complex 2 sigma 1 subunit (AP2S1) can also cause familial hypocalciuric hypercalcemia (FHH types 2 and 3) (18,19,20).…”

Section: Mutations Causing Loss Of Casr Functionmentioning

confidence: 99%

“…The other patients had gradual but constant decreases in total serum calcium after daily doses of 0.4-1 mg/kg per day of cinacalcet (Table 3). In one patient total serum calcium fell to 1.9 mmol/l after 3 days of cinacalcet, which had to be paused to prevent further hypocalcemia (16). None of the four heterozygous NHPT patients treated with cinacalcet required parathyroid surgery (Table 3).…”

Section: Casr As a Drug Target For Allosteric Modulatorsmentioning

confidence: 99%

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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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Section: Casr As a Drug Target For Allosteric Modulatorsmentioning

confidence: 96%

Section: Mutations Causing Loss Of Casr Functionmentioning

confidence: 99%

Section: Casr As a Drug Target For Allosteric Modulatorsmentioning

confidence: 99%

See 1 more Smart Citation

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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“…Calcimimetics increases the sensitivity of CASR; calcium binds to extracellular domain while calcimimetics bind to seven transmembrane domains increasing receptor sensitivity (8). Calcimimetics are reported to be effective in heterozygous mutation causing neonatal hyperparathyroidism (NH-PT); 4 reported cases did not require parathyroidectomy (9,10). Homozygous mutations causing NSHPT are mostly nonresponsive to cinacalcet as mutation affecting the seven transmembrane domains region.…”

Section: Discussionmentioning

confidence: 99%

“…cinacalcet which are reported to be effective in heterozygous cases. Children not responding to medical treatment require an early parathyroidectomy (3,4). In this report, we present a case of a Saudi female baby born to consanguineous parents with neonatal severe hyperparathyroidism presenting in the first month of life; DNA analysis revealed a novel homozygous mutation in the CASR gene.…”

Section: Introductionmentioning

confidence: 94%

Neonatal severe hyperparathyroidism secondary to a novel homozygous CASR gene mutation

Ahmad

Bahasan

Alghamdi

et al. 2017

ccmbm

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SummaryNeonatal severe hyperparathyroidism (NSHPT) is a rare autosomal recessive disease. Children present within the first 6 months of life and more commonly in the first few weeks. Common presentation is poor feeding, polyuria, dehydration, lethargy, failure to thrive, hypotonia, gastrointestinal dysmotility, osteopenia and symptoms of respiratory distress due to a poorly developed chest cage. We present a case of a 2-month old girl with severe hypercalcemia and hyperparathyroidism. She was found to have a novel homozygous mutation in the acceptor splicing site of intron 4 (c.1378 -2A>G) of the calcium sensing receptor gene (CASR). This mutation causes frame shift deletion of exon 5 and insensitivity of CASR to calcium. The patient was treated with intravenous fluids, fruosemide, calcitonin, intravenous pamidronate and oral cinacalcet. She did not respond to medical treatment. Parathyroid gland imaging including ultrasound, MRI and sestamibi nuclear scan were not helpful in localizing the glands. Her symptoms resolved following total parathyroidectomy. She is being treated with alfacalcidiol and calcium supplements to maintain normal serum calcium and phosphate. She achieved her normal developmental milestones.KEY WORDS: neonatal severe hyperparathyroidism; calcium sensing receptor; parathyroidectomy.

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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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Cinacalcet Monotherapy in Neonatal Severe Hyperparathyroidism: A Case Study and Review

Abstract: We describe the first use of cinacalcet as monotherapy for severe hypercalcemia in a newborn with NSHPT. The rapid and durable response to cinacalcet suggests that a trial of calcimimetic therapy should be considered early in the course of NSHPT.

Cited by 67 publications

References 28 publications

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

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

Neonatal severe hyperparathyroidism secondary to a novel homozygous CASR gene mutation

Hypercalcemic Disorders in Children

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