Department of Endocrinology, Genetics and Metabolism, Affiliated Hospital of Jining Medical University, Jining, Shandong, 272029, China.
Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, China.
Orphanet J Rare Dis. 2024 Aug 12;19(1):292. doi: 10.1186/s13023-024-03301-y.
Ankyrin repeat domain containing-protein 11 (ANKRD11), a transcriptional factor predominantly localized in the cell nucleus, plays a crucial role in the expression regulation of key genes by recruiting chromatin remodelers and interacting with specific transcriptional repressors or activators during numerous biological processes. Its pathogenic variants are strongly linked to the pathogenesis and progression of multisystem disorder known as KBG syndrome. With the widespread application of high-throughput DNA sequencing technologies in clinical medicine, numerous pathogenic variants in the ANKRD11 gene have been reported. Patients with KBG syndrome usually exhibit a broad phenotypic spectrum with a variable degree of severity, even if having identical variants. In addition to distinctive dental, craniofacial and neurodevelopmental abnormalities, patients often present with skeletal anomalies, particularly postnatal short stature. The relationship between ANKRD11 variants and short stature is not well-understood, with limited knowledge regarding its occurrence rate or underlying biological mechanism involved. This review aims to provide an updated analysis of the molecular spectrum associated with ANKRD11 variants, investigate the prevalence of the short stature among patients harboring these variants, evaluate the efficacy of recombinant human growth hormone in treating children with short stature and ANKRD11 variants, and explore the biological mechanisms underlying short stature from both scientific and clinical perspectives. Our investigation indicated that frameshift and nonsense were the most frequent types in 583 pathogenic or likely pathogenic variants identified in the ANKRD11 gene. Among the 245 KBGS patients with height data, approximately 50% displayed short stature. Most patients showed a positive response to rhGH therapy, although the number of patients receiving treatment was limited. ANKRD11 deficiency potentially disrupts longitudinal bone growth by affecting the orderly differentiation of growth plate chondrocytes. Our review offers crucial insights into the association between ANKRD11 variants and short stature and provides valuable guidance for precise clinical diagnosis and treatment of patients with KBG syndrome.
锚蛋白重复域蛋白 11（ANKRD11）是一种主要定位于细胞核内的转录因子，在许多生物过程中通过招募染色质重塑因子并与特定的转录抑制子或激活子相互作用，在关键基因的表达调控中发挥着关键作用。其致病性变体与一种称为 KBG 综合征的多系统疾病的发病机制和进展密切相关。随着高通量 DNA 测序技术在临床医学中的广泛应用，ANKRD11 基因中的许多致病性变体已被报道。KBG 综合征患者通常表现出广泛的表型谱，严重程度不同，即使具有相同的变体。除了独特的牙齿、颅面和神经发育异常外，患者还常出现骨骼异常，特别是出生后身材矮小。ANKRD11 变体与身材矮小之间的关系尚未得到很好的理解，其发生率或潜在的生物学机制知之甚少。本综述旨在提供对与 ANKRD11 变体相关的分子谱的最新分析，研究携带这些变体的患者中身材矮小的患病率，评估重组人生长激素治疗患有身材矮小和 ANKRD11 变体的儿童的疗效，并从科学和临床角度探讨身材矮小的潜在生物学机制。我们的研究表明，在 ANKRD11 基因中鉴定出的 583 种致病性或可能致病性变体中，移码和无义突变最为常见。在有身高数据的 245 名 KBG 患者中，约有 50%存在身材矮小。大多数患者对 rhGH 治疗有反应，但接受治疗的患者人数有限。ANKRD11 缺乏可能通过影响生长板软骨细胞的有序分化来破坏纵向骨生长。本综述为 ANKRD11 变体与身材矮小之间的关联提供了重要的见解，并为 KBG 综合征患者的精确临床诊断和治疗提供了有价值的指导。
