Prenatal Diagnosis of VLDLR-associated Cerebellar Hypoplasia via Fetal MRI

A 26-year-old G1P0 female presented for prenatal care after normal cell-free DNA screening and fetal ultrasound in Japan. Routine ultrasound at 35 weeks revealed posterior fossa abnormalities, characterized as a small cerebellum and splaying of cerebellar hemispheres.

Fetal MRI at 35 weeks demonstrated a hypoplastic cerebellar vermis lacking foliation and fissures, resulting in a smooth cerebellar surface, consistent with the “small featureless cerebellum” phenotype ([Fig. 1A, B]). Additionally, imaging showed cerebral simplified gyral pattern with reduced sulcation for age ([Fig. 2]), suggestive of a Reelin pathway disorder.

Fig. 1 Fetal MRI at 35 weeks. (A) Sagittal and (B) coronal T2-weighted images showing a hypoplastic cerebellar vermis with absent folia and fissures and a smooth cerebellar contour (white arrows), consistent with the “featureless cerebellum” phenotype of VLDLR mutation. (A) Inset shows a representative sagittal T2-weighted image of a normal cerebellar vermis at the same gestational age for comparison, demonstrating well-formed folia, sharply delineated fissures, particularly the primary fissure (arrow), and a lobulated hemispheric contour indicative of advanced cerebellar maturation.

Fig. 2 (A) Axial and (B) coronal T2-weighted images at the level of the cerebral hemispheres showing simplified gyral pattern with decreased sulcation, consistent with extensive malformation of cortical development.

Trio exome sequencing identified compound heterozygous likely pathogenic variants in the VLDLR gene: a paternally inherited nonsense variant (c.1378G > T pGlu460*) and a maternally inherited deletion (chr9:2629280–2652591). These findings support a diagnosis of VLDLR-associated cerebellar hypoplasia.

VLDLR encodes a receptor in the Reelin signaling cascade.[1] Variants in VLDLR or RELN disrupt cortical neuron and Purkinje cell migration, causing cortical and cerebellar malformations. Postnatal features include cerebellar ataxia and intellectual disability.[1] [2] [3] Differential comprises DAB1 variants and MAB21L1-related cerebellar, ocular, craniofacial, and genital (COFG) syndrome, in which comparable cerebellar imaging findings have been described.[4] [5]

Prenatal recognition of cerebellar hypoplasia with absent fissures and cortical simplification should prompt consideration of Reelin pathway defects and genetic testing, enabling accurate counseling on prognosis and recurrence risk.

Publication History

Received: 08 September 2025

Accepted: 30 October 2025

Article published online:
10 November 2025

• References

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