Department of Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
Department of Molecular Oncology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
Front Endocrinol (Lausanne). 2024 Oct 7;15:1415639. doi: 10.3389/fendo.2024.1415639. eCollection 2024.
So far, only 11 mutations have been described as causes of familial isolated hypoparathyroidism (FIH). In this report, we describe a family with FIH but with significant elevation of functionally inactive PTH due to a mutation. We also show a positive therapeutic outcome of recombinant human PTH (teriparatide) therapy in one of the siblings who was not well controlled on large doses of calcitriol and calcium replacement therapy.
The proband is a 34-year-old woman who has a history of chronic severe hypocalcemia (HypoCa) since birth. She and her three brothers (33-year-old male twins, and a 21-year-old male) were diagnosed with pseudohypoparathyroidism type 1b (PHPT 1b) based on the presence of chronic HypoCa (serum Ca 1.6-1.85 mmol/l) since birth associated with significantly elevated plasma PTH levels in the range of 310-564 pg/dl (normal range 10-65) and absence of signs of Albright hereditary osteodystrophy.
WES showed no pathogenic, likely pathogenic or variants of unknown significance in any known calcium-associated genetic disorder but a bi-allelic variant in the itself ((NM_000315.4:c.128G>A, p.Gly43Glu). This was confirmed by Sanger sequencing in the patient and her affected brothers.
Because the patient's HypoCa was not controlled on large doses of calcitriol and calcium carbonate, a trial of teriparatide 20 mcg SC daily was started and resulted in normalization of calcium, decline in PTH levels and significant improvement in her general wellbeing.
High PTH in the presence of congenital hypocalcemia is not always due to receptor or post-receptor defect and can be due to a biologically inactive mutated PTH. In such cases, treatment with teriparatide may result in stabilization of biochemical profile and improvement in quality of life.
迄今为止，仅有 11 种突变被描述为家族性孤立性甲状旁腺功能减退症（FIH）的病因。在本报告中，我们描述了一个家族，该家族患有 FIH，但由于 突变，导致功能无活性的 PTH 显著升高。我们还展示了其中一位兄弟姐妹的治疗结果，该患者对大剂量骨化三醇和钙替代治疗的反应不佳，但使用重组人甲状旁腺激素（特立帕肽）治疗后病情得到了改善。
先证者是一位 34 岁女性，自出生以来一直患有慢性严重低钙血症（HypoCa）。她和她的三个兄弟（33 岁的双胞胎男性和 21 岁的男性）均被诊断为 1b 型假性甲状旁腺功能减退症（PHPT 1b），其依据是出生后即存在慢性 HypoCa（血清 Ca 为 1.6-1.85 mmol/l），同时伴有 310-564 pg/dl 范围内显著升高的血浆 PTH 水平（正常范围为 10-65），并且无 Albright 遗传性骨营养不良的迹象。
WES 显示在任何已知的钙相关遗传疾病中均未发现致病性、可能致病性或意义不明的变异，但在 基因中存在双等位基因变异（NM_000315.4：c.128G>A，p.Gly43Glu）。该结果通过对患者及其受影响的兄弟进行 Sanger 测序得到了证实。
由于患者的 HypoCa 对大剂量骨化三醇和碳酸钙的治疗反应不佳，因此开始使用特立帕肽 20 mcg SC 每日进行治疗，结果导致钙水平正常化，PTH 水平下降，并且整体健康状况得到了显著改善。
先天性低钙血症时高 PTH 并不总是由于受体或受体后缺陷引起，也可能是由于生物无活性的突变 PTH 引起。在这种情况下，使用特立帕肽治疗可能会稳定生化谱并改善生活质量。
