Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.
Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.
Clin Endocrinol (Oxf). 2019 Nov;91(5):683-690. doi: 10.1111/cen.14078. Epub 2019 Sep 9.
Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominantly inherited disorder with overlapping biochemistry profile with primary hyperparathyroidism (PHPT), making the correct diagnosis a challenge. The objective of the study was to evaluate the results of the clinical work-up of a large group of hypercalcemic individuals.
Cross-sectional study.
Patients undergoing clinical work-up of hypercalcemia.
Molecular genetic analysis of the CASR gene and exon 2 of the AP2S1 gene. Plasma levels of ionized calcium and PTH as well as calcium creatinine clearance ratio (CCCR).
A rare CASR variant was identified in 38 of 624 index patients (6.1%). A total of 18 CASR variants identified in this study were novel. No variants were identified in exon 2 of the AP2S1 gene. The majority of the variants (N = 16) were classified as likely pathogenic. The level of plasma calcium, plasma PTH and the CCCR was not affected by the type of variant (ie nonsense vs missense) (all P-values >.05). The CCCR was found to be significantly lower for variants in the transmembrane domain compared with variants located in the extracellular domain (P < .05). Plasma levels of calcium and PTH were not associated with the location of the variant (P > .05).
We expanded the spectrum of CASR variants in hypercalcemia with 18 novel variants, and suggest that the location of the CASR variant may affect calcium excretion as determined by the CCCR.
家族性低钙性高钙血症（FHH）是一种常染色体显性遗传疾病，其生化特征与原发性甲状旁腺功能亢进症（PHPT）重叠，使得正确诊断具有挑战性。本研究的目的是评估一大群高钙血症患者的临床检查结果。
横断面研究。
接受高钙血症临床检查的患者。
CASR 基因和 AP2S1 基因外显子 2 的分子遗传分析。离子钙和 PTH 以及钙肌酐清除率比（CCCR）的血浆水平。
在 624 名索引患者中的 38 名（6.1%）中鉴定出罕见的 CASR 变体。本研究共鉴定出 18 种新的 CASR 变体。在 AP2S1 基因的外显子 2 中未发现变体。大多数变体（N=16）被归类为可能致病。变体的类型（无意义 vs 错义）（所有 P 值>.05）不影响血浆钙、血浆 PTH 和 CCCR 的水平。与位于细胞外域的变体相比，跨膜域中的变体的 CCCR 明显较低（P<.05）。血浆钙和 PTH 水平与变体的位置无关（P>.05）。
我们在高钙血症中扩展了 CASR 变体谱，增加了 18 种新变体，并表明 CASR 变体的位置可能会影响 CCCR 确定的钙排泄。
