Prenatal diagnosis of diencephalic‐mesencephalic junction dysplasia: Fetal magnetic resonance imaging phenotypes, genetic diagnoses, and outcomes

Abstract

Objective Report a single‐center 12‐year experience in the fetal diagnosis of diencephalic‐mesencephalic junction dysplasia (DMJD) to expand the phenotype with Magnetic resonance imaging (MRI)‐based classification, evaluate genetic etiologies, and ascertain outcomes. Methods Retrospective medical record and imaging review of all fetal MRI exams with DMJD were performed at our institution. Results Thirty‐three pregnancies with fetal MRI findings of DMJD at 24 (18–37) weeks gestational age were studied; 70% were referred for fetal hydrocephalus. Three fetal MRI patterns were recognized. Type A (butterfly/hypothalamus‐midbrain union) was seen in two cases (6%), Type B (partial thalamus‐midbrain union) in 22 fetuses (70%), and Type C (complete/near complete midbrain‐thalamic continuity) in nine fetuses (24%). L1CAM mutations were identified in four cases, and biallelic VRK1 variants in another. Among 14 live‐born cases, 11 survived infancy, and 10 underwent postnatal brain MRI which confirmed the fetal MRI diagnosis in all but one case. Development was delayed in all surviving infants, most with additional neurological sequelae. Conclusions DMJD may be identified by prenatal MRI as early as 18 weeks gestation. We propose three distinct phenotypic forms of DMJD, Types A–C. Next‐generation sequencing provides an underlying molecular diagnosis in some patients, but further studies on associated genetic diagnoses and clinical outcomes are indicated.

L1CAM variants cause two distinct imaging phenotypes on fetal MRI

“…These features were confirmed on post‐mortem MRI. Remarkably, thalamic–mesencephalic fusion on sagittal planes should be reassessed after birth, since this might be over‐estimated on fetal MRI due to its limited spatial resolution, as shown by Lawrence et al 11 . It is noteworthy that pathological data of roughly 100 fetal cases of genetically confirmed L1 syndrome have been reported yet none of them described in detail the DMJ 18 .…”

“…These features were confirmed on post-mortem MRI. Remarkably, thalamic-mesencephalic fusion on sagittal planes should be reassessed after birth, since this might be over-estimated on fetal MRI due to its limited spatial resolution, as shown by Lawrence et al 11 It is noteworthy that pathological data of roughly 100 fetal cases of genetically confirmed L1 syndrome have been reported yet none of them described in detail the DMJ. 18 This is likely because the vast majority of these cases were identified prior to the recognition of DMJD as a distinct neuroradiological sign, thereby suggesting that the occurrence of DMJD might be underestimated in L1 fetuses.…”

“…Of note, data on additional brainstem anomalies were only provided in one fetus. 11 Here, we describe 10 fetal cases harboring 9 L1CAM pathogenic variants, providing evidence that deleterious variants in this gene may cause a recognizable brainstem malformation variably associated with diencephalosynapsis, ventriculomegaly, and CCA.…”

“…We previously suggested that these DMJD cases were potentially linked to L1CAM mutations, yet no genetic testing was performed at that time 10 . Recently, the largest series of fetal DMJD has been reported, unveiling the contribution of L1CAM mutations in four out of seven subjects tested for this gene 11 . Interestingly, different patterns of DMJD were associated with L1CAM variants, including a new subtype overlapping with type‐B DMJD, characterized by complete thalamic–midbrain fusion on the sagittal plane.…”

“…Interestingly, different patterns of DMJD were associated with L1CAM variants, including a new subtype overlapping with type‐B DMJD, characterized by complete thalamic–midbrain fusion on the sagittal plane. Of note, data on additional brainstem anomalies were only provided in one fetus 11 …”