Fetal for Thursday, April 10th, 2025

History

• 33 y/o woman, G2P1
• Abnormal ultrasound
• Gestational age: 20 wks 1 day

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Question

What is the most likely explanation?

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Correct answer

Tubulinopathy

Discussion

In the presented case, the patient's diagnosis of a tubulinopathy  (TUBB3), specifically involving the TUBB3 gene, is supported by both prenatal ultrasound and subsequent MRI findings. The ultrasound demonstrated and the MRI show callosal agenesis. Furthermore, the MRI shows a diffuse abnormality in sulcation/gyration, with shallow appearance of many large sulci. The sagittal images also show an atypical appearance of the brain stem, which appears "kinked". These findings are characteristic of tubulinopathies and highlight the pivotal role of TUBB3 in neuronal migration, commissural formation, and cortical folding. 

Tubulinopathies constitute a complex group of neurological disorders characterized by specific structural brain anomalies, notably cerebellar hypoplasia (78%), dysmorphic basal ganglia (75%), and callosal dysgenesis (40%). These disorders highlight the critical role of tubulin proteins in axonal pathfinding and brain development, particularly evident in the severe phenotypes of fetal tubulinopathies. While postnatally the dysmorphic appearance of the basal ganglia constitutes a salient feature, this is difficult to identify prenatally. 

Genetic analysis has revealed that mutations in TUBB1A, TUBB2B, and TUBB3 account for the majority of cerebral malformations associated with these conditions, over 90% in fact. In contrast, TUBB4A mutations, while causing hypomyelination, do not typically lead to brain malformations. 

TUBB3 mutations are associated with a wide range of manifestations, from Congenital Fibrosis of the Extraocular Muscles (CFEOM) to  Malformations of Cortical Development (MCD). The phenotypic variability in cortical abnormalities and associated features (ventriculomegaly, cerebellar hypoplasia, callosal dysgenesis) underscores the necessity for high quality imaging that captures as many malformative features as possible, to differentiate from other causes. 

Differential diagnosis

• Congenital Infection – TORCH can cause brain malformations (e.g: polymicrogyria), ventriculomegaly, calcifications, and white matter abnormalities. They often present with additional findings like intracranial calcifications and cortical destruction. Callosal dysgenesis is inconsistent with this finding. 
• Isolated Callosal Agenesis –  Isolated agenesis lacks the associated cortical malformations,  abnormal basal ganglia, and cerebellar hypoplasia.
• Pyruvate Dehydrogenase Deficiency – A metabolic disorder that leads to lactic acidosis and structural brain abnormalities, including ventricular enlargement and corpus callosum hypoplasia. In fetuses, it typically presents with cystic necrosis of the ganglionic eminences. 

References

• Bahi-Buisson N, Poirier K, Fourniol F, Saillour Y, Valence S, Lebrun N, Hully M, Bianco CF, Boddaert N, Elie C, Lascelles K, Souville I; LIS-Tubulinopathies Consortium; Beldjord C, Chelly J. The wide spectrum of tubulinopathies: what are the key features for the diagnosis? Brain. 2014 Jun;137(Pt 6):1676-700. doi: 10.1093/brain/awu082. PMID: 24860126.
• Gonçalves FG, Freddi TAL, Taranath A, Lakshmanan R, Goetti R, Feltrin FS, Mankad K, Teixeira SR, Hanagandi PB, Arrigoni F. Tubulinopathies. Top Magn Reson Imaging. 2018 Dec;27(6):395-408. doi: 10.1097/RMR.0000000000000188. PMID: 30516692.