Endocrine, Bone Diseases and Genetics Unit, Reference Centre for Rare Diseases of Calcium and Phosphate Metabolism, OSCAR Network, ERN BOND, Children's Hospital, Toulouse University Hospital; RESTORE, INSERM U1301, Paul Sabatier University; Toulouse, France.
AP-HP, Paris Saclay University, INSERM; Centre de Référence des Maladies Rares du Calcium et du Phosphore, Service d'Endocrinologie et diabète de l'enfant, Filières Santé Maladies Rares OSCAR, ERN endoRARE et BOND, Hôpital Bicêtre Paris-Saclay; U1185 physiologie et physiopathologie endocrinienne; Le Kremlin Bicêtre, France.
Arch Pediatr. 2024 Sep;31(4S1):4S27-4S32. doi: 10.1016/S0929-693X(24)00154-4.
Autosomal recessive hypophosphatemic rickets type 2 (ARHR2; MIM #613312) is a very rare disorder caused by biallelic loss-of-function mutations in the ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) gene. ENPP1 deficiency encompasses a spectrum of phenotypes that includes, in addition to ARHR2, generalized arterial calcification of infancy (GACI), ossification of the posterior longitudinal ligament (OPLL), and pseudoxanthoma elasticum. ARHR2 can be found in GACI survivors, but it may also be the first manifestation of ENPP1 deficiency. Although the precise mechanisms are not fully elucidated, patients with GACI and ARHR2 have elevated serum FGF23 levels, leading to renal phosphate wasting and hypophosphatemia. As a result, the clinical and radiological phenotype of ARHR2 patients is very similar to that of patients affected with other forms of hypophosphatemic rickets, such as X-linked hypophosphatemia. Patients show signs of rickets (abnormal mineralization of growth plates in children) and osteomalacia (abnormal bone mineralization in children and adults) of varying severity. Clinical manifestations specific to ENPP1 loss-of-function mutations and common to GACI, such as ectopic calcifications (valvular, arterial, or periarticular), deafness, OPLL, and PXE, may also be found. Genetic confirmation of the disease is important so as to ensure that patients receive the appropriate treatment or have the opportunity to participate in clinical trials to evaluate the safety and efficacy of novel and promising recombinant enzyme therapies.
常染色体隐性低血磷性佝偻病 2 型（ARHR2；MIM#613312）是一种非常罕见的疾病，由 ENPP1（核苷酸外切磷酸二酯酶 1）基因的双等位基因功能丧失突变引起。ENPP1 缺乏症包括多种表型，除 ARHR2 外，还包括婴儿期全身动脉钙化（GACI）、后纵韧带骨化（OPLL）和假性黄色瘤弹性组织变性。ARHR2 可在 GACI 幸存者中发现，但也可能是 ENPP1 缺乏症的首发表现。尽管确切的机制尚未完全阐明，但 GACI 和 ARHR2 患者的血清 FGF23 水平升高，导致肾脏磷酸盐丢失和低磷血症。因此，ARHR2 患者的临床和影像学表型与其他低血磷性佝偻病患者（如 X 连锁低血磷症）非常相似。患者表现出不同严重程度的佝偻病（儿童生长板矿化异常）和骨软化症（儿童和成人骨矿化异常）的迹象。常见于 GACI 的与 ENPP1 功能丧失突变相关的特异性临床表现，如异位钙化（瓣膜、动脉或关节周围）、耳聋、OPLL 和 PXE，也可能存在。疾病的遗传确认非常重要，以便确保患者接受适当的治疗或有机会参加临床试验，评估新型有前途的重组酶治疗的安全性和有效性。
