Division of Pediatric Endocrinology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.
Division of Medical Genetics, Department of Medical Genetics, Hacettepe University Faculty of Medicine, Ankara, Turkey.
J Pediatr Endocrinol Metab. 2021 Sep 16;34(12):1573-1584. doi: 10.1515/jpem-2021-0387. Print 2021 Dec 20.
Hereditary hypophosphatemic rickets (HR) is conventionally treated with phosphate and calcitriol. Exploring genotype and phenotypic spectrum of X-linked hypophosphatemic rickets (XLHR), focusing on short-term, long-term, and pubertal impact of conventional treatment was aimed.
Sixteen patients from 12 unrelated families with HR were analyzed for phosphate regulating endopeptidase homolog X-linked ( mutation. Initially Sanger sequencing analysis was performed. If mutation was not detected, multiplex ligation-dependent probe amplification (MLPA) was performed. If molecular defect was detected, first-degree relatives were analyzed. Thirteen patients (81%) and five first-degree relatives with XLHR were evaluated for genotype-phenotype or gender-phenotype correlation. Clinical characteristics and response to conventional treatment were determined retrospectively.
Nine different mutations were identified; four splice-site, three point mutations, and two single exon deletions. Four were novel mutations. Despite conventional treatment, median adult height was lower than median height on admission (-3.8 and -2.3 SDS, respectively), metabolic and radiographic recovery were not achieved, adherence was low (30%). Although mean adult height was better in compliant patients than noncompliants (-2.6 vs. -3.7 SDS, respectively), they were still short. Correlation between phenotype and genotype or gender could not be shown. Median phosphate decreased significantly throughout puberty (p=0.014). Median pubertal height was lower than prepubertal height (-4.4 vs. -3.6 SDS; respectively), pubertal growth spurt was not observed. Among five patients with a follow-up longer than five years, three had nephrocalcinosis (60%), two had hyperparathyroidism (40%), 4/6 (33%) required correction osteotomy.
Conventional treatment appears to have limited effect on metabolic, clinical and radiographic recovery in XLHR. Metabolic control and growth worsened during puberty. Although, long-term adverse effects are yet to be seen, introduction of burosumab as first-line treatment may be an alternative after infancy.
遗传性低血磷性佝偻病（HR）通常采用磷酸盐和骨化三醇治疗。本研究旨在探讨 X 连锁低血磷性佝偻病（XLHR）的基因型和表型谱，重点关注常规治疗的短期、长期和青春期影响。
对 12 个无亲缘关系的 HR 患者家系的 16 名患者进行分析，检测磷酸盐调节内皮肽 X 连锁（mutation。首先进行 Sanger 测序分析。如果未检测到mutation，则进行多重连接依赖性探针扩增（MLPA）。如果发现分子缺陷，则分析一级亲属。对 13 名患者（81%）和 5 名 XLHR 一级亲属进行基因型-表型或性别-表型相关性评估。回顾性确定临床特征和对常规治疗的反应。
发现了 9 种不同的mutation，其中 4 种是剪接位点突变，3 种是点突变，2 种是单一外显子缺失。其中 4 种是新突变。尽管接受了常规治疗，但成年后的平均身高仍低于入院时的平均身高（分别为-3.8 和-2.3 SDS），代谢和影像学恢复未达到，依从性低（30%）。尽管依从性好的患者成年后的平均身高好于不依从的患者（分别为-2.6 和-3.7 SDS），但他们仍然偏矮。表型与基因型或性别之间的相关性无法显示。青春期期间磷酸盐中位数明显下降（p=0.014）。青春期身高中位数低于青春期前身高（分别为-4.4 和-3.6 SDS），未观察到青春期生长突增。在随访时间超过 5 年的 5 名患者中，有 3 名患者患有肾钙质沉着症（60%），2 名患者患有甲状旁腺功能亢进症（40%），4/6（33%）需要矫正性截骨术。
常规治疗对 XLHR 的代谢、临床和影像学恢复似乎效果有限。青春期期间代谢控制和生长情况恶化。尽管长期不良影响尚未显现，但在婴儿期后引入布罗索尤单抗作为一线治疗可能是一种替代方法。
