Ahmed Sibtain, Arif Aahan, Abbas Saadia, Khan Muhammad Osama, Kirmani Salman, Khan Aysha Habib
Section of Clinical Chemistry, Department of Pathology and Laboratory Medicine, Aga Khan University, Stadium Road, P.O. Box 3500, Karachi, 74800, Pakistan.
Medical College, Aga Khan University. Stadium Road, P.O. Box 3500, Karachi, 74800, Pakistan.
Ann Med Surg (Lond). 2021 Jan 19;62:154-159. doi: 10.1016/j.amsu.2021.01.041. eCollection 2021 Feb.
Hajdu Cheney Syndrome (HCS) is a rare skeletal disease characterized by severe, progressive focal bone loss with osteoporosis, variable craniofacial, vertebral anomalies and distinctive facial features. It is inherited as an autosomal dominant disease although sporadic cases have been described in literature. Identifying these cases in clinical practice is important for proper diagnosis and management.
We report a case of a 36-year-old male patient presented at metabolic bone disease clinic at the Aga Khan University Hospital with history of multiple fragility fractures and juvenile osteoporosis since childhood. DNA sequence analysis of the NOTCH2 coding sequence revealed a pathogenic variant in NOTCH 2, Exon 34, c.6426_6427insTT (p.Glu2143Leufs*5), consistent with a NOTCH2 related conditions including HCS.
The multitude of presentations associated with HCS are linked to the NOTCH2 gene, as Notch signaling is one of the core signaling pathways that control embryonic development. Hence, mutations in the Notch signaling pathway cause developmental phenotypes that affect various organs including the liver, skeleton, heart, eye, face, kidney, and vasculature.
To the best of our knowledge, nucleotide mutations of c.6933delT, c.6854delA, c.6787C.T, and c.64246427delTCTG were all determined to be novel, with c.6428T > C being the most common mutation found in literature. The c.6426_6427insTT mutation our patient was found to have via gene sequencing too appears to be a novel mutation, which has not previously been reported in literature.
哈伊杜-切尼综合征（HCS）是一种罕见的骨骼疾病，其特征为严重、进行性局灶性骨质流失并伴有骨质疏松症，存在多种颅面、脊柱异常以及独特的面部特征。尽管文献中描述过散发病例，但它以常染色体显性疾病形式遗传。在临床实践中识别这些病例对于正确诊断和管理至关重要。
我们报告一例36岁男性患者，他因自幼患有多发性脆性骨折和青少年骨质疏松症，就诊于阿迦汗大学医院的代谢性骨病门诊。对NOTCH2编码序列进行DNA序列分析，发现NOTCH 2外显子34的c.6426_6427insTT（p.Glu2143Leufs*5）致病性变异，这与包括HCS在内的NOTCH2相关病症一致。
与HCS相关的众多临床表现与NOTCH2基因有关，因为Notch信号通路是控制胚胎发育的核心信号通路之一。因此，Notch信号通路中的突变会导致影响包括肝脏、骨骼、心脏、眼睛、面部、肾脏和脉管系统在内的各个器官的发育表型。
据我们所知，c.6933delT、c.6854delA、c.6787C.T和c.64246427delTCTG的核苷酸突变均被确定为新发现的突变，c.6428T > C是文献中发现的最常见突变。我们的患者通过基因测序发现的c.6426_6427insTT突变似乎也是一种新突变，此前文献中未曾报道过。
