Department of Endocrinology, Seth GS Medical College and KEM Hospital, Parel, Mumbai, 400012, India.
Department of Endocrinology, Vydehi Institute of Medical Sciences and Research Centre, Bengaluru, 560066, India.
Calcif Tissue Int. 2022 Sep;111(3):229-241. doi: 10.1007/s00223-022-00985-x. Epub 2022 May 14.
Childhood and adolescent primary hyperparathyroidism (PHPT) is a very rare disease. Data on its molecular genetics are scarce. We performed a retrospective analysis (January 2000-January 2021) to determine the deleterious germline variants and genotype-phenotype correlations in children and adolescents < 20 years diagnosed with PHPT from a single referral center. Clinical features, biochemistry, imaging, management, and genetics (clinical exome analyzed for 11 PHPT and 7 pancreatitis-associated genes, MLPA for CDC73) were recorded. Thirty-six patients (20 males; median age 17 years) were classified into those with familial and/or syndromic (F/S) or apparently sporadic (AS) presentation. Sixteen (44.4%) harbored pathogenic/likely pathogenic germline variants in PHPT-associated genes. The genetic yield in F/S group was 90% (MEN1:8/10; CDC73:1/10), and AS group was 26.9% (CDC73:4/26; CASR:3/26). F/S group had frequent asymptomatic presentation (60% vs none; P < 0.001), lower serum PTH (237.5 vs 1369.1 pg/mL; P = 0.001), and maximum parathyroid dimension (0.9 vs 2.2 cm; P = 0.01) than AS group. Among the AS group, renal involvement was higher in those with molecular diagnoses (71.4% vs 10.5%; P = 0.01). All those with novel CASR variants (including one homozygous) had hypercalciuria and histology-proven parathyroid adenoma/carcinoma. A missense CTRC VUS occurred in one patient with chronic pancreatitis. In summary, Asian Indian children and adolescents with PHPT have high genetic yield, even with apparently sporadic presentation. The phenotypic spectrum of CASR variants is expanded to include childhood/adolescent PHPT with hypercalciuria and single gland neoplasia. The proposed roles for renal involvement to predict molecular diagnosis among those with apparently sporadic presentation require further elucidation.
儿童和青少年原发性甲状旁腺功能亢进症（PHPT）是一种非常罕见的疾病。关于其分子遗传学的数据很少。我们进行了一项回顾性分析（2000 年 1 月至 2021 年 1 月），以确定从单一转诊中心诊断为 PHPT 的儿童和青少年 <20 岁的有害种系变异和基因型-表型相关性。记录了临床特征、生化、影像学、治疗和遗传学（对 11 个 PHPT 和 7 个胰腺炎相关基因进行临床外显子组分析，对 CDC73 进行 MLPA）。36 名患者（20 名男性；中位年龄 17 岁）分为家族性和/或综合征性（F/S）或明显散发性（AS）表现。16 名（44.4%）携带 PHPT 相关基因的致病性/可能致病性种系变异。F/S 组的遗传检出率为 90%（MEN1：8/10；CDC73：1/10），AS 组为 26.9%（CDC73：4/26；CASR：3/26）。F/S 组无症状表现更为常见（60% vs 无；P<0.001），血清 PTH 水平更低（237.5 vs 1369.1 pg/mL；P=0.001），甲状旁腺最大尺寸更小（0.9 vs 2.2 cm；P=0.01）。在 AS 组中，有分子诊断的患者肾脏受累更高（71.4% vs 10.5%；P=0.01）。所有具有新型 CASR 变异的患者（包括一个纯合子）均有高钙尿症和组织学证实的甲状旁腺腺瘤/癌。一名慢性胰腺炎患者的 CTRC VUS 出现错义突变。总之，亚洲印度儿童和青少年 PHPT 的遗传检出率很高，即使表现为明显的散发性。CASR 变异的表型谱扩展到包括儿童/青少年 PHPT 伴高钙尿症和单个腺体肿瘤。在表现为明显散发性的患者中，肾脏受累预测分子诊断的作用有待进一步阐明。
