IFT74致病性变异相关的窒息性胸廓发育不良：一例病例报告

文献信息

中文摘要

背景： 窒息性胸廓发育不良（ATD）是一种罕见的骨骼纤毛病，其特征为胸廓狭窄、肋骨短小和肺发育不良。虽然通常与IFT80或DYNC2H1的致病性变异相关，但近期基因组学进展已发现IFT74双等位基因变异是短肋胸廓发育不良20型（SRTD20）的病因。由于其罕见性，IFT74相关ATD的临床进展和表型谱仍知之甚少。
病例介绍： 我们报告一例足月男婴，出生时表现为严重呼吸窘迫、大头畸形和窄胸伴漏斗胸。初始放射学骨骼检查对典型发育不良无结论。尽管接受了强化新生儿监护，患儿仍出现持续性呼吸衰竭、反复肺不张和严重轴性肌张力低下。磁共振成像（MRI）未显示结构异常。全外显子组测序（WES）发现IFT74基因纯合致病性拷贝数缺失。临床过程并发严重口咽吞咽困难和反复吸入性肺炎。尽管放置了胃造瘘并给予最大支持治疗，患儿仍在四个月龄时发生致命性心肺骤停。
结论： 本病例突出了IFT74相关SRTD20的一种致死性新生儿表型，强化了IFT74在纤毛组装和轴突导向中的关键作用。早期WES对于诊断遗传异质性骨骼发育不良、提供准确的预后咨询以及在严重胸廓功能不全病例中指导临终讨论至关重要。

英文摘要

BACKGROUND: Asphyxiating Thoracic Dystrophy (ATD) is a rare skeletal ciliopathy characterized by a constricted thoracic cage, short ribs, and pulmonary hypoplasia. While typically linked to pathogenic variants in IFT80 or DYNC2H1, recent genomic advancements have identified biallelic variants in IFT74 as a cause of short-rib thoracic dysplasia type 20 (SRTD20). Due to its rarity, the clinical progression and phenotypic spectrum of IFT74-related ATD remain poorly understood.
CASE PRESENTATION: We report the case of a term male infant presenting at birth with severe respiratory distress, macrocephaly, and a narrow chest with pectus excavatum. Initial radiographic skeletal surveys were inconclusive for classic dysplasia. Despite intensive neonatal care, the patient experienced persistent respiratory failure, recurrent atelectasis, and profound axial hypotonia. Magnetic resonance imaging (MRI) revealed no structural abnormalities. Whole exome sequencing (WES) identified a homozygous pathogenic copy number loss in the IFT74 gene. The clinical course was complicated by severe oropharyngeal dysphagia and recurrent aspiration pneumonia. Despite gastrostomy placement and maximal supportive care, the infant suffered a fatal cardiopulmonary arrest at four months of age.
CONCLUSIONS: This case highlights a lethal neonatal phenotype of IFT74-related SRTD20, reinforcing the critical role of IFT74 in ciliary assembly and axonal guidance. Early WES is essential for diagnosing genetically heterogeneous skeletal dysplasias, providing accurate prognostic counseling, and guiding end-of-life discussions in cases of severe thoracic insufficiency.