OBJECTIVE: Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia and hyperphosphatemia secondary to hypoparathyroidism. It is classified as type 1, caused by gain-of-function mutations of the calcium-sensing receptor (CASR), and type 2, caused by activating mutations in GNA11, which is a crucial mediator of CASR signaling. What is new? We report a rare pediatric case of ADH type 2.
METHODS: The patient was a 15-year-old girl with short stature. Blood tests demonstrated hypocalcemia and hyperphosphatemia without elevated parathyroid hormone levels. Brain computed tomography revealed calcification in the bilateral basal ganglia. Genetic testing revealed the rare GNA11 mutation, c.1023C>G (p.Phe341Leu). The patient was diagnosed with ADH type 2. She had experienced numbness and tetany in her hands for several years, which improved with alfacalcidol therapy.
CONCLUSIONS: Our patient is the third female and first pediatric reported case of a variant mutation in the GNA11 gene (ADH type 2), c.1023C>G (p.Phe341Leu).

OBJECTIVE: Autosomal dominant hypocalcaemia 1 (ADH1) is a rare autosomal dominant genetic disease, due to the activating mutations of the calcium-sensing receptor (CASR) gene. The current paper presents a severe case of ADH1 with intellectual backwardness, and systematically reviews the reported 17 ADH1 patients in China.
METHODS: A 7 years old boy with recurrent seizures over 1 year was admitted at Yuying children\' hospital, the clinical centre of south province of Zhejiang. Auxiliary examinations demonstrated hypocalcaemia, hyperphosphatemia, hypomagnesemia, hypercalciuria, low parathyroid hormone (PTH), basal ganglia calcifications, normal range of serum creatinine, and 25-hydroxyvitamin D. Wechsler\'s intelligence test result indicated intellectually backward. The patient\'s genotype found a heterozygous variant in CASR gene, c.T416C p. (Ile139Thr). This article also systematically reviews the literatures on ADH1 in China and summarises the clinical characteristics and treatment.
CONCLUSIONS: ADH1 can be a cause of idiopathic hypoparathyroidism. Recognition and rational treatment is important for symptom improvement and reducing high potential adverse effects.

BACKGROUND: Familial hypocalciuric hypercalcemia (FHH) is a rare autosomal dominant disease, which requires differential diagnosis from relatively common primary hyperparathyroidism (PHPT) in order to avoid unnecessary surgery.
METHODS: A 16-year-old female had been followed by the department of psychosomatic medicine at our institution. Throughout the follow-up period, her plasma calcium levels were high, plasma Pi levels were relatively low, and plasma intact PTH was relatively high. She was referred to our department to determine the cause of her hypercalcemia. Her 24 h urinary calcium excretion was as low as 100 mg/day, and calcium creatinine clearance ratio was below 0.01. Moreover, she had a family history of hypercalcemia (proband, her brother, and her father). The genetic testing for her family revealed that she, her brother, and her father were definitively diagnosed with FHH type 1 due to the heterozygous calcium-sensing receptor mutation (NM_00388:4:c.164C > T:p.Pro55Leu).
CONCLUSIONS: We experienced a 16-year-old female with FHH, in whom genetic testing identified the heterozygous calcium-sensing receptor mutation (NM_00388:4:c.164C > T:p.Pro55Leu) as pathogenic, permitting a definitive diagnosis of FHH type 1. The genetic testing for calcium sensing receptor is beneficial to distinguish asymptomatic primary hyperparathyroidism from FHH.

UNASSIGNED: Loss-of-function variants in the calcium-sensing receptor (CASR) gene are known to be involved in a clinical spectrum ranging from asymptomatic familial hypocalciuric hypercalcemia (FHH) to neonatal severe hyperparathyroidism (NSHPT). Homozygous or compound heterozygous variants are usually responsible for severe neonatal forms, whereas heterozygous variants cause benign forms. One recurrent pathogenic variant, p.Arg185Gln, has been reported in both forms, in a heterozygous state. This variant can be a de novo occurrence or can be inherited from a father with FHH.NSHPT leads to global hypotonia, failure to thrive, typical X-ray anomalies (diffuse demineralization, fractures, metaphyseal irregularities), and acute respiratory distress which can be fatal. Phosphocalcic markers show severe hypercalcemia, abnormal urinary calcium resorption, and hyperparathyroidism as major signs.Classical treatment involves calcium restriction, hyperhydration, and bisphosphonates. Unfortunately, the disease often leads to parathyroidectomy. Recently, calcimimetics have been used with variable efficacy. Efficacy in NSHPT seems to be particularly dependent on CASR genotype.
UNASSIGNED: We describe the antenatal presentation of a male with short ribs, initially suspected having skeletal ciliopathy. At birth, he presented with NSHPT linked to the pathogenic heterozygous CASR variant, Arg185Gln, inherited from his father who had FHH. Postnatal therapy with cinacalcet was successful.
UNASSIGNED: An exhaustive literature review permits a comparison with all reported cases of Arg185Gln and to hypothesize that cinacalcet efficacy depends on CASR genotype. This confirms the importance of pedigree and parental history in antenatal short rib presentation and questions the feasibility of phosphocalcic exploration during pregnancy or prenatal CASR gene sequencing in the presence of specific clinical signs. It could in fact enable early calcimimetic treatment which might be effective in the CASR variant Arg185Gln.

We herein report a case of a 60-year-old female receiving hemodialysis who developed severe hyperinsulinemic hypoglycemia and lost her consciousness. A calcimimetic agent had been administered for the secondary hyperparathyroidism. The calcimimetic agent, mimicking the elevation of the extracellular calcium ion concentration, activates calcium-sensing receptors (CaSR) of the parathyroid cells and inhibits the parathyroid hormone secretions. The previous study suggested that the CaSR are also expressed in both human β cells and insulinoma cells, but the reactivity to change in the extracellular calcium ion concentration is different between normal β cells and insulinoma cells. After cessation of the calcimimetic agent, hypoglycemic symptoms disappeared and endogenous insulin secretion dropped to normal levels. However, the result of a prolonged fasting test indicated that she remained hyperinsulinemic even after its cessation, suggesting that she had insulinoma which could not be detected by the imaging examinations. The previous autopsy data showed that there were many cases of the insulinoma without the symptoms of hypoglycemia. We considered the possibility that she had the insulinoma and the pancreatic tumor was too small to promote the insulin secretion and cause hypoglycemia without activation by the calcimimetic agent. We should know that the calcimimetic agent could cause hyperinsulinemic hypoglycemia with the unidentified insulinoma.

Autosomal dominant hypocalcemia, caused by activating mutations of the calcium-sensing receptor (CASR) gene, is characterized by hypocalcemia with an inappropriately low concentration of parathyroid hormone (PTH). In this report, we describe the identification of a novel missense mutation in the CASR gene, in a boy with autosomal dominant hypocalcemia. Polymerase chain reaction (PCR)-single strand and DNA sequencing revealed a heterozygous mutation in CASR gene that causes a leucine substitution for serine at codon 123 (p.Leu123Ser). This mutation was absent in DNA from 50 control patients. In silico studies suggest that the identified variant was likely pathogenic. Sequencing analysis in the mother suggested mosaicism for the same variant, and she was clinically and biochemically unaffected. Clinical manifestations of the index case started with seizures at 14 months of age; cognitive impairment and several neuropsychological disabilities were noted during childhood. Extrapyramidal signs and basal ganglia calcification developed later, namely, hand tremor and rigidity at the age of 7 and 18 years, respectively. Laboratory analysis revealed hypocalcemia, hyperphosphatemia, and low-serum PTH with hypomagnesemia and mild hypercalciuria. After 2 years of treatment with calcium supplements and calcitriol, some brief periods of clinical improvement were reported; as well as an absence of nephrocalcinosis.

Autosomal dominant hypocalcaemia (ADH) is caused by activating variants in the calcium-sensing receptor (CASR) gene, but detailed information on the paediatric phenotype is limited. The current paper presents a case of severe ADH and systematically reviews the literature on ADH in children.
CONCLUSIONS: We found that the severity of clinical neurological symptoms was inversely related to serum calcium levels and a high prevalence of renal calcifications and/or basal ganglia calcifications in children with ADH.