Pathogenic variant in NFIA associated with subdural hematomas mimicking nonaccidental trauma

Abstract

Subdural hematoma (SDH) in infants raises the concern for nonaccidental trauma (NAT), especially when presenting with associated injuries. However, isolated SDH could be caused by multiple etiologies. NFIA (MIM# 600727) encodes nuclear factor I A protein (NFI‐A), a transcription factor which plays important roles in gliogenesis. Loss‐of‐function variants in NFIA are associated with autosomal dominant brain malformations with or without urinary tract defects (MIM# 613735). Intracranial hemorrhage of various types besides SDH has been reported in patients with this condition. Here, we report a patient with a heterozygous novel NFIA pathogenic variant affecting splicing who initially presented with SDH concerning for NAT. We also review previous NFIA‐related disorder cases with intracranial hemorrhage. This report emphasizes the importance of genetic evaluation in infants presenting with isolated SDH.

Subdural hemorrhage, macrocephaly, rash, and developmental delay in an infant: A pathogenic variant in NLRP3 causes CINCA/NOMID

“…Another study of injured children found larger subdural depth was associated with rebleeding (Wright et al, 2019). Finally, a previous case report described a child with cerebral atrophy secondary to an NFIA mutation; his SDHs were considered a complication of cerebral atrophy (Wongkittichote et al, 2022). It is plausible that our patient's subdural collections arose from a similar mechanism.…”

Phenotypic Spectrum of NFIA Haploinsufficiency: Two Additional Cases and Review of the Literature

“…Here, we report on two new individuals carrying microdeletions solely affecting NFIA without any other flanking protein-coding sequences. In order to further define the phenotypic effects of NFIA haploinsufficiency, we reviewed the literature and public databases excluding those patients without detailed clinical information or individuals with pathogenic deletions, translocations, inversions, or genetic variants disrupting additional protein-coding sequences [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 23 , 26 , 27 , 28 , 29 ] ( Table S2 ). This careful selection allowed for the identification of a cohort of 24 patients with pathogenic alterations solely involving NFIA .…”

Significant phenotypic variability in a multigenerational family with an NFIA missense mutation: Case series and review of the literature

“…2 Deletion of NFIA often occurs as part of a multigenic microdeletion, although 20 cases resulting from smaller intragenic deletions or point mutations have been reported. [3][4][5][6][7][8][9][10] Clinical manifestations of NFIA-related disorder are highly variable, but almost always include abnormalities, such as hypoplasia, of the corpus callosum. Macrocephaly and nonspecific but distinct facial features have also been reported.…”

“…Truncation or deletion of NFIA causing haploinsufficiency can result in an NFIA ‐related disorder 2 . Deletion of NFIA often occurs as part of a multigenic microdeletion, although 20 cases resulting from smaller intragenic deletions or point mutations have been reported 3–10 …”