Distinguishing 3 classes of corpus callosal abnormalities in consanguineous families

Abstract

Objective: We sought to create a classification system for pediatric corpus callosal abnormalities (CCA) based upon midline sagittal brain MRI. We used the term CCA for patients with structural variants of the corpus callosum, excluding patients with interhemispheric cyst variant or pure dysplasia without hypoplasia. Currently, no system exists for nonsyndromic forms of CCA, and attempts to create such a system have been hampered by highly variable morphology in patients with sporadic CCA. We reasoned that any useful strategy should classify affected family members within the same type, and that phenotypic variability should be minimized in patients with recessive disease.

Methods: We focused recruitment toward multiplex consanguineous families, ascertained 30 patients from 19 consanguineous families, and analyzed clinical features together with brain imaging.

Results: We identified 3 major CCA classes, including hypoplasia, hypoplasia with dysplasia, and complete agenesis. Affected individuals within a given multiplex family usually displayed the same variant of the class of abnormality and they always displayed the same class of abnormality within each family, or they displayed complete agenesis. The system was validated among a second cohort of 10 sporadic patients with CCA.

Conclusions: The data suggest that complete agenesis may be a common end-phenotype, and implicate multiple overlapping pathways in the etiology of CCA.

Figure 1. Classification of morphologic spectrum of midline sagittal MRI appearance of the corpus callosum (CC)

Schematics depict the appearance of CC on midline sagittal MRI. Appearance of normal CC showing rostrum, genu, corpus, and splenium. CC abnormalities were divided into principal classes: HYPOPLASIA, DYSPLASIA WITHOUT HYPOPLASIA, HYPOPLASIA WITH DYSPLASIA, and COMPLETE AGENESIS. There are 3 subtypes of HYPOPLASIA: hypoplasia without dysplasia, apple core corpus callosal abnormalities (CCA), and anterior remnant CCA, based upon the physical appearance. DYSPLASIA WITHOUT HYPOPLASIA encompasses cases in which the CC is morphologically abnormal but has no evidence of hypoplasia, and is represented by a case with hump-shaped CC. In HYPOPLASIA WITH DYSPLASIA CCA, there are 2 subtypes, stripe CCA and kinked CCA. COMPLETE AGENESIS is characterized by absence of an evident CC at the level of MRI.

Figure 2. Midline sagittal MRI representing the spectrum of corpus callosum (CC) abnormalities in 30 patients with corpus callosal abnormalities (CCA)

(A) Normal CC. (B–D) HYPOPLASIA class of CCA. (B) Hypoplasia without dysplasia CCA, (C) apple core CCA, (D) Anterior remnant CCA (black arrow). (E, F) HYPOPLASIA WITH DYSPLASIA class of CCA. (E) Stripe CCA, (F) kinked CCA. (G) COMPLETE AGENESIS. (H) Example of Probst bundles. Number of patients with each class of CCA, and each subtype of CCA, from a cohort of 29 patients.

Figure 3. Imaging spectrum of HYPOPLASIA class

(Top row) CCA-184: Affected children have multiple epiphyseal dysplasia, mild mental retardation, developmental delay, prominent ventricles, and corpus callosal abnormalities (CCA). (A, B) HYPOPLASIA, hypoplasia without dysplasia CCA. (D) HYPOPLASIA, apple core CCA subtype. (C) COMPLETE AGENESIS. CCA-385: Affected children have GnRH deficiency, respiratory abnormalities, septo-optic dysplasia, bilateral optic colobomas, pituitary hypoplasia, cerebellar vermis hypoplasia, mild polymicrogyria, and CCA. (E, F) Hypoplasia without dysplasia CCA. (Bottom row) CCA-542: Affected children have epilepsy, hypotonia and hyporeflexia, perisylvian polymicrogyria, and CCA. (G) HYPOPLASIA, apple core CCA. (H) HYPOPLASIA, Hypoplasia without dysplasia CCA. (I) COMPLETE AGENESIS. CCA-557: Affected children have cerebellar vermis hypoplasia and CCA. (J) Apple core CCA. (K) COMPLETE AGENESIS.

Figure 4. Imaging spectrum of HYPOPLASIA WITH DYSPLASIA class

(Top row) CCA-405: Affected children have mental retardation, dysmorphic features, and corpus callosal abnormalities (CCA). (A, B) Stripe CCA. CCA-636: Affected children have spasticity, ataxia, white matter hypoplasia, cerebellar hypoplasia, and CCA. (C, D) Stripe CCA. (Bottom row) CCA-523: Affected children have spasticity, epilepsy, and CCA. (E, F) Kinked CCA. CCA-531: Affected children have cerebellar vermis hypoplasia, spasticity, and CCA. (G) Kinked CCA. (H) COMPLETE AGENESIS.