Seefried Lothar, Jakob Franz
Orthopädisches Zentrum für Muskuloskeletale Forschung, Universität Würzburg, Brettreichstr. 11, 97074, Würzburg, Deutschland.
Internist (Berl). 2021 May;62(5):486-495. doi: 10.1007/s00108-021-00995-1. Epub 2021 Mar 29.
Delineating the genetic background and the underlying pathophysiology of rare skeletal dysplasias enables a broader understanding of these disorders as well as novel perspectives regarding differential diagnosis and targeted development of therapeutic approaches. Hypophosphatasia (HPP) due to genetically determined Alkaline Phosphatase deficiency exemplifies this development. While an enzyme replacement therapy could be established for severe HPP with the prevailing bone manifestation, the clinical impact of not immediately bone-related manifestations just being successively understood. Correspondingly, the elucidation of the pathophysiology underlying renal phosphate wasting expanded our knowledge regarding phosphate metabolism and bone health and facilitated the development of an anti-FGF-23 Antibody for targeted treatment of X‑linked Hypophosphatemia (XLH). Evolutions regarding the nosology of osteogenesis imperfecta (OI) along with the identification of further causative genes also detected in the context of genetically determined osteoporosis illustrate the pathophysiologic interrelation between monogenetic bone dysplasias and multifactorial osteoporosis. While current therapeutic strategies for OI follow osteoporosis treatment, the expanding knowledge about OI forms the fundament for establishing improved treatment strategies-for both OI and osteoporosis. Similar developments are emerging regarding rare skeletal disorders like Achondroplasia, Fibrodysplasia ossificans progressive and Morbus Morquio (Mukopolysaccharidosis Type IV).
明确罕见骨骼发育异常的遗传背景和潜在病理生理学,有助于更广泛地理解这些疾病,并为鉴别诊断和靶向治疗方法的开发提供新的视角。由基因决定的碱性磷酸酶缺乏引起的低磷血症(HPP)就是这一进展的例证。虽然可以为以骨骼表现为主的严重HPP建立酶替代疗法,但与骨骼无直接关联的表现的临床影响只是逐渐被认识。相应地,对肾性磷酸盐消耗潜在病理生理学的阐明扩展了我们对磷酸盐代谢和骨骼健康的认识,并促进了用于靶向治疗X连锁低磷血症(XLH)的抗FGF-23抗体的开发。成骨不全(OI)分类学的进展以及在基因决定的骨质疏松症背景下也发现的其他致病基因的鉴定,说明了单基因骨发育异常与多因素骨质疏松症之间的病理生理相互关系。虽然目前OI的治疗策略遵循骨质疏松症的治疗方法,但对OI不断扩展的认识为建立针对OI和骨质疏松症的改进治疗策略奠定了基础。对于软骨发育不全、进行性骨化性纤维发育不良和莫尔基奥氏病(IV型粘多糖贮积症)等罕见骨骼疾病,也正在出现类似的进展。