慢性低磷血症促成由ENPP1新型致病变异所致的常染色体隐性低磷性佝偻病2型的诊断

文献信息

中文摘要

常染色体隐性低磷性佝偻病2型（ARHR2）是一种罕见的代谢性骨病，由ENPP1双等位基因功能丧失变异引起；ENPP1编码外核苷酸焦磷酸酶/磷酸二酯酶1（ENPP1），该酶是生成细胞外焦磷酸所必需的，而细胞外焦磷酸是异位钙化的关键内源性抑制剂。ENPP1缺乏症的临床谱差异很大，由于表型异质性以及与更常见的代谢性骨病和甲状旁腺疾病重叠，成年期识别具有挑战性。我们描述了两名40岁末的兄弟，携带一种新型纯合ENPP1剪接位点致病变异（c.1437+1G>C），表现为慢性低磷血症、血清PTH升高、骨骼外钙化，以及高分辨率外周定量计算机断层扫描（HR-pQCT）显示明显异常的骨微结构。兄弟1表现为长期低磷血症、后纵韧带骨化、传导性听力损失、先天性髋关节发育不良和主动脉瓣钙化。兄弟2表现为进行性脊髓病和椎管狭窄，并因推测为正常血钙性原发性甲状旁腺功能亢进而接受甲状旁腺切除术。术后甲状旁腺功能减退导致开始使用骨化三醇和钙补充剂，随后出现肾结石。两名患者均显示FGF23介导的肾磷酸盐消耗、1,25-二羟维生素D低正常水平、甲状旁腺激素升高和血钙正常，倾向于代表继发性而非原发性甲状旁腺功能亢进，并且HR-pQCT显示皮质骨和松质骨参数显著异常。这些病例突出了成人起病ARHR2的诊断陷阱，包括对FGF23介导的磷酸盐消耗识别延迟以及误诊为原发性甲状旁腺功能亢进。准确的遗传学诊断至关重要，因为ARHR2在临床上模仿X连锁低磷血症，强调需要早期识别以指导安全有效的治疗。

英文摘要

Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) is a rare metabolic bone disorder caused by biallelic loss-of-function variants in ENPP1, the gene encoding for Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), an enzyme essential for generating extracellular pyrophosphate, a key endogenous inhibitor of ectopic calcification. The clinical spectrum of ENPP1 deficiency varies widely, and recognition in adulthood is challenging due to phenotypic heterogeneity and overlap with more common metabolic bone and parathyroid disorders. We describe two brothers in their late 40s with a novel homozygous ENPP1 splice-site pathogenic variant (c.1437 + 1G > C) presenting with chronic hypophosphatemia, elevated serum PTH, extra-skeletal calcifications, and markedly abnormal bone microarchitecture on high-resolution peripheral quantitative computed tomography (HR-pQCT). Brother 1 exhibited long-standing hypophosphatemia, ossification of the posterior longitudinal ligament, conductive hearing loss, congenital hip dysplasia, and aortic valve calcification. Brother 2 presented with progressive myelopathy and spinal stenosis, and underwent parathyroidectomy for presumed normocalcemic primary hyperparathyroidism. Postoperative hypoparathyroidism led to initiation of calcitriol and calcium supplementation, and subsequent nephrolithiasis. Both patients demonstrated FGF23-mediated renal phosphate wasting, low-normal 1,25-dihydroxyvitamin D, elevated parathyroid hormone and normocalcemia, favored to represent secondary rather than primary hyperparathyroidism, and significant abnormalities in cortical and trabecular bone parameters by HR-pQCT. These cases highlight diagnostic pitfalls in adult-onset ARHR2, including delayed recognition of FGF23-mediated phosphate wasting and misdiagnosis as primary hyperparathyroidism. Accurate genetic diagnosis is essential because ARHR2 clinically mimics X-linked hypophosphatemia, underscoring the need for early recognition to guide safe and effective treatment.