Novel homozygous inactivating mutation of the calcium-sensing receptor gene (CASR) in neonatal severe hyperparathyroidism—lack of effect of cinacalcet

Atay, Zeynep; Bereket, Abdullah; Haliloğlu, Belma; Abali, Saygın; Ozdogan, Tutku; Altuncu, Emel; Canaff, Lucie; Vilaça, Tatiane; Wong, Betty; Cole, David E. C.; Hendy, Geoffrey N.; Turan, Serap

doi:10.1016/j.bone.2014.04.010

Cited by 32 publications

(42 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cinacalcet, which is a CaSR‐positive allosteric modulator, has been successfully used to manage life‐threatening hypercalcemia in some NSHPT probands . However, the effectiveness of cinacalcet for NSHPT will depend on the underlying CaSR mutation, and patients harboring biallelic truncating CaSR mutations will be unlikely to respond to this calcimimetic agent . Parathyroidectomy remains the treatment of choice for children with primary hyperparathyroidism or NSHPT because it represents a curative procedure for these disorders .…”

Section: Management Of Hypercalcemiamentioning

confidence: 99%

“…(142) However, the effectiveness of cinacalcet for NSHPT will depend on the underlying CaSR mutation, and patients harboring biallelic truncating CaSR mutations will be unlikely to respond to this calcimimetic agent. (143) Parathyroidectomy remains the treatment of choice for children with primary hyperparathyroidism or NSHPT because it represents a curative procedure for these disorders. (144) Hypocalcemia due to hungry bone syndrome or postsurgical hypoparathyroidism represents the most common complication of parathyroidectomy, and close monitoring of serum calcium concentrations is required following surgery.…”

Section: Management Of Hypercalcemiamentioning

confidence: 99%

See 1 more Smart Citation

Hypercalcemic Disorders in Children

Stokes

Nielsen

Hannan

et al. 2017

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

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.

show abstract

Section: Management Of Hypercalcemiamentioning

confidence: 99%

Section: Management Of Hypercalcemiamentioning

confidence: 99%

Hypercalcemic Disorders in Children

Stokes

Nielsen

Hannan

et al. 2017

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

“…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%