CASR基因新发变异致新生儿重症甲状旁腺功能亢进症1例报告

doi:10.12372/jcp.2022.21e1090

摘要/Abstract

摘要：

新生儿重症甲状旁腺功能亢进症是一种罕见的危及生命的疾病,在新生儿期表现为严重的高钙血症、甲状旁腺功能亢进和骨质减少。患儿,女,14日龄,生后4天起病,表现为高胆红素血症、纳差、反应差、肌张力低下,严重的高钙血症和甲状旁腺功能亢进。基因检测显示,CASR基因存在未报道过的c.888C > A (p.Ser296Arg)（来源于父亲）、c.1576G > T (p.Glu526Ter)（来源于母亲）复合杂合变异。患儿经多次唑来膦酸静脉滴注,吸吮力、反应及肌张力有好转,血钙开始明显下降但一周后又升高。生后54天患儿行一侧甲状旁腺切除术,血钙有所下降,于生后64天出院。生后17月随访,患儿体格和神经发育迟缓。NSHPT由CASR基因失活变异引起,表现为严重的高钙血症和甲状旁腺功能亢进,伴生长发育迟缓。甲状旁腺全切除术是首选治疗手段,双膦酸盐可能具有一定的疗效。

关键词: 甲状旁腺功能亢进症, CASR基因, 高钙血症, 新生儿

Abstract:

To improve the understanding of neonatal severe hyperparathyroidism (NSHPT). The clinical data, gene test result, treatment and prognosis of a child with NSHPT were retrospectively analyzed. A 14-day-old female infant presented with hyperbilirubinemia, poor feeding, lethargy, hypotonia, severe hypercalcemia and hyperparathyroidism 4 days after birth. She was found to carry novel compound heterozygous mutations of c.888C > A (p. Ser296Arg) (from father) and c.1576G > T (p. Glu526Ter) (from mother) in the CASR gene. The infant received multiple-dose intravenous zoledronate. After the drug treatment, symptoms improved including sucking, reaction and muscle tension. Serum calcium decreased obviously at first, but increased again after one week. Unilateral parathyroidectomy was performed 54 days after birth. Postoperative serum calcium reduced and the patient was discharged 64 days after birth. At 17 months of follow-up, the patient showed delayed growth and neurodevelopmental retardation. NSHPT is caused by an inactivation variation of the CASR gene and is characterized by severe hypercalcemia and hyperparathyroidism with growth retardation. Total parathyroidectomy is the first choice of treatment, bisphosphonates may have a certain effect.

Key words: neonate, hyperparathyroidism, CASR gene, hypercalcemia

王盈灿, 谭金童, 陈妍, 黄琦, 夏红萍. CASR基因新发变异致新生儿重症甲状旁腺功能亢进症1例报告[J]. 临床儿科杂志, 2022, 40(6): 442-445.

WANG Yingcan, TAN Jintong, CHEN Yan, HUANG Qi, XIA Hongping. Neonatal severe hyperparathyroidism caused by novel variation in CASR gene: a case report[J]. Journal of Clinical Pediatrics, 2022, 40(6): 442-445.

图/表 3

表1

图1

图2

参考文献 20

[1]	García Soblechero E, Ferrer Castillo MT, Jiménez Crespo B, et al. Neonatal hypercalcemia due to a homozygous mutation in the calcium-sensing receptor: failure of cinacalcet[J]. Neonatology, 2013, 104(2): 104-108. doi: 10.1159/000350540 pmid: 23817301
[2]	Hannan FM, Kallay E, Chang W, et al. The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases[J]. Nat Rev Endocrinol, 2018, 15(1): 33-51. doi: 10.1038/s41574-018-0115-0 pmid: 30443043
[3]	Diao J, DeBono A, Josephs TM, et al. Therapeutic opportunities of targeting allosteric binding sites on the calcium-sensing receptor[J]. ACS Pharmacol Transl Sci, 2021, 4(2): 666-679. doi: 10.1021/acsptsci.1c00046
[4]	Vahe C, Benomar K, Espiard S, et al. Diseases associated with calcium-sensing receptor[J]. Orphanet J Rare Dis, 2017, 12(1): 19. doi: 10.1186/s13023-017-0570-z pmid: 28122587
[5]	Lee JY, Shoback DM. Familial hypocalciuric hypercalcemia and related disorders[J]. Best Pract Res Clin Endocrinol Metab, 2018, 32(5): 609-619. doi: 10.1016/j.beem.2018.05.004
[6]	Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5): 405-424. doi: 10.1038/gim.2015.30 pmid: 25741868
[7]	Simonds WF, James-Newton LA, Agarwal SK, et al. Familial isolated hyperparathyroidism: clinical and genetic characteristics of 36 kindreds[J]. Medicine (Baltimore), 2002, 81(1): 1-26. doi: 10.1097/00005792-200201000-00001
[8]	Gorvin CM, Frost M, Malinauskas T, et al. Calcium-sensing receptor residues with loss- and gain-of-function mutations are located in regions of conformational change and cause signalling bias[J]. Hum Mol Genet, 2018, 27(21): 3720-3733. doi: 10.1093/hmg/ddy263
[9]	董倩, 宋福英, 杜牧, 等. 一例新生儿严重甲状旁腺功能亢进症患儿的临床及基因变异分析[J]. 中华医学遗传学杂志, 2020, 37(11): 1247-1249.
[10]	Hannan FM, Babinsky VN, Thakker RV. Disorders of the calcium-sensing receptor and partner proteins: insights into the molecular basis of calcium homeostasis[J]. J Mol Endocrinol, 2016, 57(3): 127-142. doi: 10.1530/JME-16-0124 pmid: 27647839
[11]	Ahmad S, Kuraganti G, Steenkamp D. Hypercalcemic crisis: a clinical review[J]. Am J Med, 2015, 128(3): 239-245. doi: 10.1016/j.amjmed.2014.09.030
[12]	Garcia-Garcia E, Dominguez-Pascual I, Requena-Diaz M, et al. Intraoperative parathyroid hormone monitoring in neonatal severe primary hyperparathyroidism[J]. Pediatrics, 2014, 134(4): e1203-e1205.
[13]	Brachet C, Boros E, Tenoutasse S, et al. Association of parathyroid adenoma and familial hypocalciuric hypercalcaemia in a teenager[J]. Eur J Endocrinol, 2009, 161(1): 207-210. doi: 10.1530/EJE-09-0257 pmid: 19423559
[14]	Marx SJ. Calcimimetic use in familial hypocalciuric hypercalcemia-a perspective in endocrinology[J]. J Clin Endocrinol Metab, 2017, 102(11): 3933-3936. doi: 10.1210/jc.2017-01606
[15]	Murphy H, Patrick J, Báez-Irizarry E, et al. Neonatal severe hyperparathyroidism caused by homozygous mutation in CASR: A rare cause of life-threatening hypercalcemia[J]. Eur J Med Genet, 2016, 59(4): 227-231. doi: 10.1016/j.ejmg.2016.02.001 pmid: 26855056
[16]	Hannan FM, Olesen MK, Thakker RV. Calcimimetic and calcilytic therapies for inherited disorders of the calcium-sensing receptor signalling pathway[J]. Br J Pharmacol, 2018, 175(21): 4083-4094. doi: 10.1111/bph.14086
[17]	Wilhelm-Bals A, Parvex P, Magdelaine C, et al. Successful use of bisphosphonate and calcimimetic in neonatal severe primary hyperparathyroidism[J]. Pediatrics, 2012, 129(3): e812-e816.
[18]	Sun X, Huang L, Wu J, et al. Novel homozygous inactivating mutation of the calcium-sensing receptor gene in neonatal severe hyperparathyroidism responding to cinacalcet therapy: A case report and literature review[J]. Medicine (Baltimore), 2018, 97(45): e13128. doi: 10.1097/MD.0000000000013128
[19]	Gulcan-Kersin S, Kirkgoz T, Eltan M, et al. Cinacalcet as a first-line treatment in neonatal severe hyper-parathyroidism secondary to calcium sensing receptor (CaSR) mutation[J]. Horm Res Paediatr, 2020, 93(5): 313-321. doi: 10.1159/000510623
[20]	Leunbach TL, Hansen AT, Madsen M, et al. A novel case of neonatal severe hyperparathyroidism successfully treated with a type II calcimimetic drug[J]. Bone Rep, 2021, 14: 100761.

时间	事件
4日龄	出现首发症状：吸吮无力、精神反应差
14~21、26~54日龄	鲑降钙素 3 IU/kg 皮下注射 q12h
15、30、37、44日龄	唑来磷酸 0.025 mg/kg 静脉滴注
43日龄	明确诊断,基因检测结果：患儿CASR基因存在c.888C>A (p.Ser296Arg)和c.1576G>T (p.Glu526Ter)复合杂合变异,其父携带c.888C > A杂合变异,其母携带c.1576G > T杂合变异
54日龄	左侧甲状旁腺切除术
64日龄	出院：血钙和PTH有所下降,但仍偏高,患儿生命体征平稳,吸吮、反应及肌张力好转
3月龄	家长自行停止一切药物治疗
17月龄	当地医院随访：身高70 cm（P₃）,体质量7.5 kg（P₃）,头围46 cm（P₅₀）,肌张力偏低,可独坐,不能扶站,不会叫爸爸妈妈