Cerebellar Hypoperfusion in Two Patients with Cornelia de Lange Syndrome with Novel NIPBL Variants.

Introduction: Cornelia de Lange syndrome (CdLS) is a rare congenital malformation characterized by distinctive facial features, short stature, and limb defects. In addition, half of the patients with CdLS exhibit repetitive self-injurious behaviors (SIBs) related to intellectual disability with autistic traits. CdLS is caused by pathogenic variants of genes encoding the cohesin complex pathway, with 70% of these variants identified in the nipped-B-like (NIPBL) gene.

Case presentation: We report 2 patients with CdLS who exhibited repetitive SIBs. Patient 1, a 40-year-old male, carried a novel heterozygous duplication variant, c.1458dup, p.(Glu487*), in exon 9 of the NIPBL gene. Patient 2, a 49-year-old female, carried a novel heterozygous insertion variant, c.1751_1752ins[A;1652_1751], p.(Asp584Glufs*8), in exon 10 of the NIPBL gene. These variants were predicted to confer loss of function to the protein because of a premature stop codon. In both patients, single-photon emission computed tomography using N-isopropyl-p-[123I] iodoamphetamine (IMP-SPECT) revealed diffuse hypoperfusion in the cerebellum.

Discussion: This report identified 2 novel pathogenic variants in the NIPBL gene and the relationship between SIBs and cerebellar hypoperfusion in patients with CdLS. The cerebellar hypoperfusion might have been caused by the dysfunction of the cohesin complex via the downregulation of the NIPBL gene products. Further studies should be conducted to elucidate the contribution of the NIPBL gene to the development of the cerebello-cerebral cortical circuits associated with behavioral disorders.