Case Report and Review of the Literature: Congenital Diaphragmatic Hernia and Craniosynostosis, a Coincidence or Common Cause?

Abstract

Congenital diaphragmatic hernia (CDH) is a life-threatening birth defect that presents as either an isolated diaphragm defect or as part of a complex disorder with a wide array of anomalies (complex CDH). Some patients with complex CDH display distinct craniofacial anomalies such as craniofrontonasal dysplasia or craniosynostosis, defined by the premature closure of cranial sutures. Using clinical whole exome sequencing (WES), we found a BCL11B missense variant in a patient with a left-sided congenital diaphragmatic hernia as well as sagittal suture craniosynostosis. We applied targeted sequencing of BCL11B in patients with craniosynostosis or with a combination of craniosynostosis and CDH. This resulted in three additional BCL11B missense mutations in patients with craniosynostosis. The phenotype of the patient with both CDH as well as craniosynostosis was similar to the phenotype of previously reported patients with BCL11B missense mutations. Although these findings imply that both craniosynostosis as well as CDH may be associated with BCL11B mutations, further studies are required to establish whether BCL11B variants are causative mutations for both conditions or if our finding was coincidental.

Case report: A novel truncating variant of BCL11B associated with rare feature of craniosynostosis and global developmental delay

“…In this study, we reviewed the clinical phenotype of the reported patients with craniosynostosis and BCL11B variants ( 9 , 24 ) and our patient (Table1). One de novo missense variant (c.7C > A, p. Arg3Ser) with craniosynostosis in BCL11B gene has been reported ( 9 ).…”

“…Fortunately, the boy was otherwise healthy. Recently, another literature has reported four BCL11B missense mutations (p.Gly667Glu, p.Gly582Ser, p.Pro673Arg, p.Pro422Leu) with craniosynostosis or combined congenital diaphragmatic hernia (CDH) and craniosynostosis ( 24 ). All the BCL11B variants were inherited from their normal parents.…”

“…In this literature, clinical exome sequencing was performed in one patient and targeted sequencing of single gene ( BCL11B ) in other three patients, these sequence methods may miss real pathogenic gene variants. Therefore, the pathogenicity of these inherited missense BCL11B variants in craniosynostosis is questionable as the paper’s title mentioned ( 24 ).…”

Novel BCL11B truncation variant in a patient with developmental delay, distinctive features, and early craniosynostosis

“…Craniosynostosis is a disorder of skull formation caused by premature ossification of cranial sutures, occurring in ~1 in 2250 births 6 . Although the first two reports of BCL11B alterations showed no findings of craniosynostosis, five patients have been reported to show craniosynostosis in association with BCL11B alterations, suggesting a relatively less common manifestation in humans 6,11 .…”

“…The identified variant has not been reported previously and is not registered in any database. The clinical information of this patient is summarized in Table 1 together with previous reports 2,3,[6][7][8][9][10][11][12][13][14][15] .…”