Clinical Diagnosis of Classical Cornelia de Lange Syndrome Made From Postmortem Examination of Second Trimester Fetus With Novel NIPBL Pathogenic Variant

Abstract

Classical Cornelia de Lange syndrome (CdLS) is a rare genetic disorder which is associated with distinctive facial features, growth retardation, significant intellectual disability and global developmental delay, hirsutism, and upper-limb reduction defects. Classical CdLS is associated with pathogenic variants in NIPBL. We present a clinical diagnosis of classical CdLS made in a second trimester male fetus with advanced maceration who had undergone intrauterine death at 15 + 6 weeks gestation. The diagnosis was suspected after multiple congenital anomalies were identified on fetal postmortem examination. These included intrauterine growth retardation, upper limb anomalies, ventricular septal defect and diaphragmatic hernia, and skeletal and genitourinary abnormalities. Related prenatal screening findings included a raised nuchal translucency and low maternal serum pregnancy-associated plasma protein-A. Targeted molecular sequencing of genes associated with CdLS identified a novel de novo frameshift pathogenic variant in NIPBL, which confirmed the diagnosis. This report describes our case and reviews the current literature on prenatal diagnosis of CdLS. In summary, we demonstrate that clinical diagnosis of CdLS in a second trimester fetus, through postmortem examination findings, is possible, with confirmation through molecular testing.

Global interpretation of novel alternative splicing events in human congenital pulmonary airway malformations: A pilot study

“…Besides, NIPBL has been reported to be enriched in the embryonic viscerocranium morphogenesis pathway, and haploid sufficient deletion of NIPBL in mice could cause septal defects in heart development. 33,34 In addition, we found that the KEGG pathway of differentially spliced genes from CPAM-Ⅰ was mainly associated with the PI3K/AKT signaling pathway. Swarr et al performed microarray analysis on lung tissue samples from 58 children with CLMs and found that abnormally expressed genes were enriched in Ras and the PI3K/AKT/mTOR signaling pathways, suggesting that abnormalities in Ras and PI3K/AKT/mTOR signaling pathway may cause defects in epithelial cell development, which may lead to abnormal lung development.…”

“…Hei et al 32 found the NIPBL gene mutations in 15 neonates with complications of multisystem malformations. Besides, NIPBL has been reported to be enriched in the embryonic viscerocranium morphogenesis pathway, and haploid sufficient deletion of NIPBL in mice could cause septal defects in heart development 33,34 …”

Síndrome de Cornelia de Lange, paciente del servicio de neonatología deel Hospital Carlos Andrade Marín en el año 2018.

“…Genitales masculinos, falo pequeño, escroto rugoso con ausencia de testículos, ano permeable. y una prevalencia que oscila entre 1:10.000 a 1:62.000 nacidos vivos (3) . Esto demuestra que es una enfermedad rara.…”

The influence of genetics in congenital diaphragmatic hernia

“…A retrospective review of causes of death with CDLS identified CDH as the cause in 10% of patients 77 . Heterozygous mutations in NIPBL are the cause of CDLS with CDH 78,79 . Denys Drash syndrome [DDS;…”