A Homozygous<i>CaSR</i>Mutation Causing a FHH Phenotype Completely Masked by Vitamin D Deficiency Presenting as Rickets

Szczawinska, D; Schnabel, Dirk; Letz, S; Schöfl, Christof

doi:10.1210/jc.2013-3593

Cited by 18 publications

(15 citation statements)

References 36 publications

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“…Inactivating mutations of the CASR lead to a right-shifted dose-response curve for extracellular calcium with a higher 'setpoint' resulting in hypercalcemic diseases (6,7,8). The phenotype depends on the degree of overall functional impairment of extracellular calcium sensing by CASRdependent mechanisms.…”

Section: Mutations Causing Loss Of Casr Functionmentioning

confidence: 99%

“…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%

“…As FHH may be confused with primary hyperparathyroidism, it is of prime clinical concern to correctly diagnose FHH in order to avoid futile parathyroid surgery. Correct diagnosis, however, may be masked by severe vitamin D deficiency (8). In any case the presence of a CASR, GNA11, or AP2S1 mutation confirmed by sequencing of the respective gene and with proven functional impairment is required for making a definitive diagnosis (57,58).…”

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: Mutations Causing Loss Of Casr Functionmentioning

confidence: 99%

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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“…FHH is characterized biochemically by lifelong modest elevation of the serum calcium concentration with a relatively mismatched hypocalciuria and normal or mildly elevated circulating parathyroid hormone (PTH) level that is not suppressed by the hypercalcemia. 1,2 Individuals with FHH are usually asymptomatic, and the disorder is considered benign. FHH is associated with heterogeneous inactivating mutations in the calcium-sensing receptor ( CaSR ) gene.…”

Section: Introductionmentioning

confidence: 99%

“…A recent report described a patient who developed severe adolescent rickets due to vitamin D deficiency. 2 Another report considered that vitamin D deficiency modulates the severity of FHH. 3 …”

Section: Introductionmentioning

confidence: 99%

Atypical skeletal manifestations of rickets in a familial hypocalciuric hypercalcemia patient

Wang

Jiang

et al. 2017

Bone Res

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Familial hypocalciuric hypercalcemia (FHH) is caused by inactivating mutations in the calcium-sensing receptor (CaSR) gene. The loss of function of CaSR presents with rickets as the predominant skeletal abnormality in mice, but is rarely reported in humans. Here we report a case of a 16-year-old boy with FHH who presented with skeletal manifestations of rickets. To identify the possible pathogenic mutation, the patient was evaluated clinically, biochemically, and radiographically. The patient and his family members were screened for genetic mutations. Physical examination revealed a pigeon breast deformity and X-ray examinations showed epiphyseal broadening, both of which indicate rickets. Biochemical tests also showed increased parathyroid hormone (PTH), 1,25-dihydroxyvitamin D, and elevated ionized calcium. Based on these results, a diagnosis of FHH was suspected. Sequence analysis of the patient’s CaSR gene revealed a new missense mutation (c.2279T>A) in exon 7, leading to the damaging amino change (p.I760N) in the mature CaSR protein, confirming the diagnosis of FHH. Moreover, the skeletal abnormities may be related to but not limited to vitamin D abnormity. Elevated PTH levels and a rapid skeletal growth period in adolescence may have also contributed. Our study revealed that rickets-like features have a tendency to present atypically in FHH patients who have a mild vitamin D deficiency, and that CaSR mutations may have a partial role in the pathogenesis of skeletal deformities.

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Genotype–Phenotype Correlations in Asian Indian Children and Adolescents with Primary Hyperparathyroidism

et al. 2022

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A HomozygousCaSRMutation Causing a FHH Phenotype Completely Masked by Vitamin D Deficiency Presenting as Rickets

Abstract: CaSR mutations causing mild functional impairment can lead to FHH, even in homozygous patients. The skeletal deformities in the index case were mainly due to severe vitamin D deficiency, and the CaSR mutation did not appear to have played a major independent role in the skeletal phenotype.

Cited by 18 publications

References 36 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

Atypical skeletal manifestations of rickets in a familial hypocalciuric hypercalcemia patient

Genotype–Phenotype Correlations in Asian Indian Children and Adolescents with Primary Hyperparathyroidism

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