The Fetus with Ganglionic Eminence Abnormality: Head Size and Extracranial Sonographic Findings Predict Genetic Diagnoses and Postnatal Outcomes

Abstract

Background and purpose: Ganglionic eminence abnormalities on fetal MR imaging are associated with cerebral malformations. Their presumed genetic basis and associated postnatal outcomes remain largely unknown. We aimed to elucidate these through a multicenter study.

Materials and methods: Between January 2010 and June 2020, seven hospitals in 2 countries performing fetal MR imaging examinations identified fetal MR imaging studies demonstrating ganglionic eminence enlargement, cavitation, or both. Cases with no genetic diagnosis, no whole exome sequencing, or no outcome of a liveborn child were excluded. Head size was classified as large (fronto-occipital diameter > 95th centile), small (fronto-occipital diameter <5th centile), or normal.

Results: Twenty-two fetuses with ganglionic eminence abnormalities were identified. Of 8 with large heads, 2 were diagnosed with MTOR mutations; 1 with PIK3CA mutation-producing megalencephaly, polymicrogyria, polydactyly, hydrocephalus (MPPH) syndrome; 3 with TSC mutations; 1 with megalencephaly capillary malformation syndrome; and 1 with hemimegalencephaly. Cardiac rhabdomyoma was present prenatally in all cases of TSC; mutation postaxial polydactyly accompanied megalencephaly capillary malformation and MPPH. Of 12 fetuses with small heads, 7 had TUBA1A mutations, 1 had a TUBB3 mutation, 2 had cobblestone lissencephaly postnatally with no genetic diagnosis, 1 had a PDHA1 mutation, and 1 had a fetal akinesia dyskinesia sequence with no pathogenic mutation on trio whole exome sequencing. One of the fetuses with a normal head size had an OPHN1 mutation with postnatal febrile seizures, and the other had peri-Sylvian polymicrogyria, seizures, and severe developmental delay but no explanatory mutation on whole exome sequencing.

Conclusions: Fetal head size and extracranial prenatal sonographic findings can refine the phenotype and facilitate genetic diagnosis when ganglionic eminence abnormality is diagnosed with MR imaging.

FIG 1.

PIK3CA pathogenic variant. Case 2 at 31 weeks 3 days' gestation. Megalencephaly, polymicrogyria, polydactyly hydrocephalus syndrome due to a PIK3CA heterozygous pathogenic variant. The fronto-occipital diameter is >6 SDs above the mean for gestation. Enlarged bilateral ganglionic eminences (arrows, A) are seen on T2-weighted single-shot FSE and DWI (A and B). Diffusion-weighted b = 0 image (C) and T2*-weighted EPI (D) confirm the absence of hemorrhage as the cause for ganglionic eminence enlargement. Abnormal opercularization is present with Sylvian fissures lined by peri-Sylvian polymicrogyria (E). Postaxial polydactyly is seen on sonography with arrow indicating a rudimentary sixth digit medial to the fifth digit of the hand (F).

FIG 2.

MTOR/PROS pathway mutations. Smith-Kingsmore syndrome (case 5) at 25 weeks' gestation demonstrates enlarged GEs on DWI and T2-weighted single-shot FSE. There is bilateral underopercularization and left peri-Sylvian polymicrogyria (arrow). The right hemisphere is mildly overgrown.

FIG 3.

Tuberous sclerosis complex (A and B). Case 1. Dichorionic diamniotic twin at 22 weeks 5 days' gestation. T2-weighted single-shot FSE image demonstrates hemimegalencephaly and marked enlargement of the ipsilateral GE, which merges with a hypointense masslike lesion in the enlarged right cerebral hemisphere. The fetus had left ventricular cardiac rhabdomyoma on prenatal sonography (arrow, B); the findings likely represent tuberous sclerosis complex with an associated hemispheric malformation or, less likely, coexistent subependymal giant cell astrocytoma. No postmortem data or confirmatory genetic testing was available. Case 8. T2 single-shot FSE at 25 weeks gestation (C) and T2 FSE at 1-week postnatal imaging (D) demonstrate mild enlargement of the right GE, ipsilateral and mild ventriculomegaly on fetal MR imaging, and typical changes of tuberous sclerosis complex postnatally. The fetus' father also had tuberous sclerosis complex.

FIG 4.

TUBA1A mutations (A–C). Case 18. T2-weighted single-shot FSE at 24 weeks 4 days' gestation. TUBA1A pathogenic heterozygous variant. The bilateral GEs are enlarged. The fronto-occipital diameter is 2.5, standard deviations below the mean. The corpus callosum and cerebellum are severely hypogenetic/hypoplastic. Underopercularization, severe ventriculomegaly, a thin kinked brainstem (A), a ventral pontine cleft suggestive of a Walker-Warburg phenotype, and apparent diencephalic-mesencephalic fusion or dysplasia (C) are also noted. D, Case 19 at 33 weeks. TUBA1A mutation with enlarged, cavitated GEs and abnormal persistence of hemispheric lamination.

FIG 5.

PDHA1 and OPHN1 mutations. A and B, PDHA1 mutation. Case 20 at 23 weeks 3 days' gestation. PDHA1 mutation. Agenesis of the corpus callosum with the anterior commissure present (short arrow), cavitated enlarged GEs, and anterior temporal pole subependymal pseudocysts (germinolytic cysts) (long arrows). C and D, Case 21 at 29 weeks. OPHN1 mutation with mild ventriculomegaly (11 mm) and bilaterally enlarged GEs.