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.

Prenatal MR Imaging Phenotype of Fetuses with Tuberous Sclerosis: An Institutional Case Series and Literature Review

“…Four additional cases were identified following an audit of our institutional iuMR data base (Figs 2-4), 2 of which were included in a prior publication on imaging of fetal GE abnormalities, 8 with a total of 51 cases (Fig 1). Details of included and excluded studies with full citations are provided in the Online Supplemental Data.…”

“…5 However, fetal cranial manifestations of TSC are not confined to these 2 abnormalities despite their acknowledged importance as primary diagnostic criteria. 8 Improved understanding of the range of abnormal fetal brain phenotypes in TSC and their variation with gestational age may help identify potentially affected fetuses earlier; triage pregnancies appropriately for more efficient and cost-effective genetic testing and prenatal surveillance with cardiac sonography when cardiac tumors are not present; and initiate intrauterine rapamycin treatment earlier when this treatment becomes more mainstream.…”

Second trimester fetal MRI of the brain: Through the ground glass

“…A strong association between MTOR-PIK3CA (PROS) AKT pathway mutations, including tuberous sclerosis, and fetal head size greater than the 97th centile has been found in patients with GE abnormalities; conversely, TUBA1A mutations were the dominant cause in cases where the frontal-occipital circumference was below the third centile. 25 The main imaging findings in both types of malformations include restricted diffusion on the DWI sequences in the affected areas, consistent with increased cellular density. The main differential diagnosis includes ischemic and hemorrhagic changes, which give a completely different prognosis to the fetus.…”

“…The changes can be bilateral (more commonly) or unilateral and are central to a range of neurodevelopmental abnormalities that encompass abnormal neuroblast proliferation, differentiation, and migration processes, leading to generalized or local abnormal neuronal organization. A strong association between MTOR‐PIK3CA (PROS) AKT pathway mutations, including tuberous sclerosis, and fetal head size greater than the 97th centile has been found in patients with GE abnormalities; conversely, TUBA1A mutations were the dominant cause in cases where the frontal‐occipital circumference was below the third centile 25 …”

“…The main differential diagnosis includes ischemic and hemorrhagic changes, which give a completely different prognosis to the fetus. In cases of germinal matrix hemorrhage, there will be a signal drop in the T2*/SWI sequences, and the surrounding structures will have a close to normal appearance, in comparison to GE anomalies where they are disorganized and nodular 24,25 …”