A Novel NOTCH3 Variant Leading to Lateral Meningocele Syndrome: Prenatal Diagnosis and Possible Expansion of the Phenotype

Abstract

Introduction: NOTCH3, one of the four mammalian Notch receptors, acts as a transcriptional activator in a variety of tissues. Variants in NOTCH3 lead to distinct phenotypes, depending on variant type and location. Truncating variants in the last exon generate a protein lacking the PEST domain, responsible for degradation, leading to a gain-of-function effect and causing Lateral Meningoceles syndrome (LMS), characterized by dysmorphisms and variable cardiac, skeletal, and connective tissue abnormalities; motor delay may occur, but the cognitive function is usually normal.

Case presentation: We report the first case of prenatal molecular diagnosis of LMS, which was made using prenatal exome sequencing after an ultrasound with findings of fetal cystic hygroma, mild bilateral ventriculomegaly, and facial dysmorphisms. After birth, magnetic resonance imaging confirmed the presence of lateral meningoceles. A complete clinical evaluation was performed and unexpected biliary anomalies were found.

Conclusion: The occurrence of biliary anomalies has not been previously reported in LMS but may have biological plausibility. Expression of NOTCH3 has been demonstrated in biliary development and is thought to play a role in the differentiation of hepatoblasts into biliary epithelial cells, and also in liver regeneration and repair. We hypothesize that the findings reported here might expand the phenotype of LMS.

Keywords: Clinical Genetics; Dysmorphology; Fetal exome sequencing; Neurology; Prenatal Diagnosis.

Fig. 1.

Dysmorphisms. a At birth presenting with webbed neck, micrognathia, low set and posteriorly rotated ears. b At age 1 year and 1 month, requiring tracheostomy, showing ocular hypertelorism, arched eyebrows, a frontal hemangioma, long smooth philtrum, and low set ears.

Fig. 2.

a Neuroaxis MR performed at 1 month, showing multiple lateral meningoceles (coronal T2-weighted image, arrows). b Ultrasound performed in the neonatal period, the arrow indicates a longitudinal view of the gallbladder, with intrahepatic positioning and a small irregular shape. c The arrow indicates the intrahepatic gallbladder; the arrowhead indicates an enlarged portal vein; the asterisk indicates ectasia of the main intrahepatic bile ducts. d Ultrasound performed at months, showing disturbed blood flow as a sign of the partial portosystemic shunt (abernethy type 2). MR, magnetic resonance.