Journal of Neurology

, Volume 266, Issue 5, pp 1167–1181 | Cite as

Dissecting the neurological phenotype in children with callosal agenesis, interhemispheric cysts and malformations of cortical development

  • Sara Uccella
  • Andrea Accogli
  • Domenico Tortora
  • Maria Margherita Mancardi
  • Lino Nobili
  • Bianca Berloco
  • Giovanni Morana
  • Pasquale Striano
  • Valeria Capra
  • Myriam Srour
  • Christine Saint-Martine
  • Andrea Rossi
  • Mariasavina SeverinoEmail author
Original Communication



To describe the neurological phenotype of children with prenatal diagnosis of agenesis of corpus callosum (ACC) and interhemispheric cysts associated with malformations of cortical development (MCD).


We reviewed the neuroimaging, neurologic, EEG, and genetic data of 36 patients (21 males, mean age 7 years) with ACC and interhemispheric cysts. Associations were tested with Chi-squared and Fisher exact tests.


According to the 2001 Barkovich classification, we found 4 type 1c (11.1%), 6 type 2a (16.6%), 18 type 2b (50%, 6/18 girls with Aicardi syndrome), and 9 type 2c cysts (22.2%). EEG showed specific epileptic activity in 27/36 patients (75%). Epilepsy was diagnosed in 16 subjects (16/36, 44.4%), including all Aicardi patients, and was associated with cognitive impairment (p = 0.032). Severe intellectual disability and epilepsy were associated with type 2b cysts, always due to Aicardi patients (p < 0.05). After excluding Aicardi patients, all subjects with type 2b cysts had mild neurological phenotype. Patients with 2a and 2c cysts more frequently had normal cognition (83.3% and 62.5% of cases, respectively). Patients with type 1c cyst mostly had mild/moderate cognitive impairment. Severe neurologic deficits were associated with 1c cysts and 2b cysts with Aicardi syndrome (p < 0.05). Multilobar and/or bilateral MCD were associated with severe neurological and epileptic phenotypes (p < 0.05).


Once excluded Aicardi syndrome, most patients with ACC and interhemispheric cysts have a mild clinical phenotype characterized by borderline/normal cognition and minor neurological signs. Despite the high prevalence of EEG epileptic abnormalities, epilepsy in these cases is infrequent and usually responsive to antiepileptic drugs.


Agenesis of the corpus callosum Interhemispheric cysts Malformations of cortical development Epilepsy Outcome Brain MRI Children 



The authors thank Carola Martinetti, Radiology Unit, University of Genoa, Genoa, Italy. They are also thank the patients and family members, and the ASSACCI (Associazione Anomalie Corpo Calloso Italia) Association.

Compliance with ethical standards

Conflicts of interest

The authors declare that they have no conflict of interest.

Ethical standards

This was a double-center retrospective observational study performed at the Istituto Giannina Gaslini Children’s Hospital (Genoa, Italy) and McGill University (Montreal, Canada). The Ethical Committees of both institutions waived written parental consent due to the retrospective nature of the study. This study has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Supplementary material

415_2019_9247_MOESM1_ESM.xlsx (83 kb)
Supplementary material 1 (XLSX 82 KB)
415_2019_9247_MOESM2_ESM.docx (95 kb)
Supplementary material 2 (DOCX 94 KB)


  1. 1.
    Paul LK, Brown WS, Adolphs R et al (2007) Agenesis of the corpus callosum: genetic, developmental and functional aspects of connectivity. Nat Rev Neurosci 8:287–299. CrossRefGoogle Scholar
  2. 2.
    Edwards TJ, Sherr EH, Barkovich AJ, Richards LJ (2014) Clinical, genetic and imaging findings identify new causes for corpus callosum development syndromes. Brain 137:1579–1613. CrossRefGoogle Scholar
  3. 3.
    Guillem P, Fabre B, Cans C et al (2003) Trends in elective terminations of pregnancy between 1989 and 2000 in a French county (the Isère). Prenat Diagn 23:877–883. CrossRefGoogle Scholar
  4. 4.
    Hetts SW, Sherr EH, Chao S et al (2006) Anomalies of the corpus callosum: an MR analysis of the phenotypic spectrum of associated malformations. AJR Am J Roentgenol 187:1343–1348. CrossRefGoogle Scholar
  5. 5.
    Raybaud C, Girard N (1998) Anatomic MRI study of commissural agenesis and dysplasia of the telencephalon (agenesis of the corpus callosum and related anomalies). Clinical correlations and morphogenetic interpretation. Neurochirurgie 44:38–60Google Scholar
  6. 6.
    Byrd SE, Radkowski MA, Flannery A, McLone DG (1990) The clinical and radiological evaluation of absence of the corpus callosum. Eur J Radiol 10:65–73CrossRefGoogle Scholar
  7. 7.
    Raybaud C (2010) The corpus callosum, the other great forebrain commissures, and the septum pellucidum: anatomy, development, and malformation. Neuroradiology 52:447–477. CrossRefGoogle Scholar
  8. 8.
    Romaniello R, Marelli S, Giorda R et al (2017) Clinical characterization, genetics, and long-term follow-up of a large cohort of patients with agenesis of the corpus callosum. J Child Neurol 32:60–71. CrossRefGoogle Scholar
  9. 9.
    Govil-Dalela T, Kumar A, Agarwal R, Chugani HT (2017) Agenesis of the corpus callosum and aicardi syndrome: a neuroimaging and clinical comparison. Pediatr Neurol 68:44–48.e2. CrossRefGoogle Scholar
  10. 10.
    DAntonio F, Pagani G, Familiari A et al (2016) Outcomes associated with isolated agenesis of the corpus callosum: a meta-analysis. Pediatrics 138:e20160445–e20160445. CrossRefGoogle Scholar
  11. 11.
    Folliot-Le Doussal L, Chadie A, Brasseur-Daudruy M et al (2018) Neurodevelopmental outcome in prenatally diagnosed isolated agenesis of the corpus callosum. Early Hum Dev 116:9–16. CrossRefGoogle Scholar
  12. 12.
    Al-Hashim AH, Blaser S, Raybaud C, MacGregor D (2016) Corpus callosum abnormalities: neuroradiological and clinical correlations. Dev Med Child Neurol 58:475–484. CrossRefGoogle Scholar
  13. 13.
    Yeh H-R, Park H-K, Kim H-J et al (2018) Neurodevelopmental outcomes in children with prenatally diagnosed corpus callosal abnormalities. Brain Dev 40:634–641. CrossRefGoogle Scholar
  14. 14.
    Chadie A, Radi S, Trestard L et al (2008) Neurodevelopmental outcome in prenatally diagnosed isolated agenesis of the corpus callosum. Acta Paediatr 97:420–424. CrossRefGoogle Scholar
  15. 15.
    Barkovich AJ, Simon EM, Walsh CA (2001) Callosal agenesis with cyst: a better understanding and new classification. Neurology 56:220–227CrossRefGoogle Scholar
  16. 16.
    Desikan RS, Barkovich AJ (2016) Malformations of cortical development. Ann Neurol 80:797–810. CrossRefGoogle Scholar
  17. 17.
    Aicardi J, Chevrie JJ, Rousselie F (1969) Spasma-in-flexion syndrome, callosal agenesis, chorioretinal abnormalities. Arch Fr Pediatr 26:1103–1120Google Scholar
  18. 18.
    Aicardi J (2005) Aicardi syndrome. Brain Dev 27:164–171. CrossRefGoogle Scholar
  19. 19.
    Pavone P, Barone R, Baieli S et al (2005) Callosal anomalies with interhemispheric cyst: expanding the phenotype. Acta Paediatr 94:1066–1072. CrossRefGoogle Scholar
  20. 20.
    Griebel ML, Williams JP, Russell SS et al (1995) Clinical and developmental findings in children with giant interhemispheric cysts and dysgenesis of the corpus callosum. Pediatr Neurol 13:119–124CrossRefGoogle Scholar
  21. 21.
    Lena G, van Calenberg F, Genitori L, Choux M (1995) Supratentorial interhemispheric cysts associated with callosal agenesis: surgical treatment and outcome in 16 children. Childs Nerv Syst 11:568–573CrossRefGoogle Scholar
  22. 22.
    Haverkamp F, Heep A, Woelfle J (2002) Psychomotor development in children with early diagnosed giant interhemispheric cysts. Dev Med Child Neurol 44:556–560CrossRefGoogle Scholar
  23. 23.
    Oh KY, Kennedy AM, Selden NR et al (2012) Asymmetric ventriculomegaly, interhemispheric cyst, and dysgenesis of the corpus callosum (AVID): an imaging triad. J Ultrasound Med 31:1811–1820CrossRefGoogle Scholar
  24. 24.
    Moeschler JB, Shevell M, Committee on Genetics (2014) Comprehensive evaluation of the child with intellectual disability or global developmental delays. Pediatrics 134:e903–e918. CrossRefGoogle Scholar
  25. 25.
    Riou EM, Ghosh S, Francoeur E, Shevell MI (2009) Global developmental delay and its relationship to cognitive skills. Dev Med Child Neurol 51:600–606. CrossRefGoogle Scholar
  26. 26.
    Kwan P, Arzimanoglou A, Berg AT et al (2010) Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE commission on therapeutic strategies. Epilepsia 51:1069–1077. CrossRefGoogle Scholar
  27. 27.
    Caldarelli M, Di Rocco C (1996) Surgical options in the treatment of interhemispheric arachnoid cysts. Surg Neurol 46:212–221CrossRefGoogle Scholar
  28. 28.
    Pilu G, Falco P, Perolo A et al (1997) Differential diagnosis and outcome of fetal intracranial hypoechoic lesions: report of 21 cases. Ultrasound Obstet Gynecol 9:229–236. CrossRefGoogle Scholar
  29. 29.
    Bannister C, Russell S, Rimmer S, Mowle D (1999) Fetal arachnoid cysts: their site, progress, prognosis and differential diagnosis. Eur J Pediatr Surg 9:27–28. CrossRefGoogle Scholar
  30. 30.
    Tange Y, Aoki A, Mori K et al (2000) Interhemispheric glioependymal cyst associated with agenesis of the corpus callosum–case report. Neurol Med Chir (Tokyo) 40:536–542CrossRefGoogle Scholar
  31. 31.
    Blaicher W, Prayer D, Kuhle S et al (2001) Combined prenatal ultrasound and magnetic resonance imaging in two fetuses with suspected arachnoid cysts. Ultrasound Obstet Gynecol 18:166–168. CrossRefGoogle Scholar
  32. 32.
    Cinalli G, Peretta P, Spennato P et al (2006) Neuroendoscopic management of interhemispheric cysts in children. J Neurosurg Pediatr 105:194–202. CrossRefGoogle Scholar
  33. 33.
    Murphy A-M, Brenner C, Ann Lynch S (2006) Agenesis of the corpus callosum with interhemispheric cyst, hepatic haemangioma and trisomy 21. Clin Dysmorphol 15:149–151. CrossRefGoogle Scholar
  34. 34.
    Rizk E, Awad AJ, Tubbs RS et al (2013) Dorsal third ventricular cysts revisited. Child’s Nerv Syst 29:2271–2274. CrossRefGoogle Scholar
  35. 35.
    Dall’Asta A, van Oostrum N, Basheer S et al (2018) Etiology and prognosis of severe ventriculomegaly diagnosed at late gestation. Ultraschall der Medizin Eur J Ultrasound. Google Scholar
  36. 36.
    Solt LC, Deck JH, Baim RS, TerBrugge K (1980) Interhemispheric cyst of neuroepithelial origin in association with partial agenesis of the corpus callosum. Case report and review of the literature. J Neurosurg 52:399–403. CrossRefGoogle Scholar
  37. 37.
    Morimoto T, Kaneko M, Nishikawa R et al (1986) Ependymal cyst–case report. No Shinkei Geka 14:351–356Google Scholar
  38. 38.
    Ulu MO, Kafadar AM, Dashti R et al (2010) Treatment of symptomatic interhemispheric arachnoid cysts by cystoperitoneal shunting. J Clin Neurosci 17:700–705. CrossRefGoogle Scholar
  39. 39.
    Fuchs F, Moutard ML, Blin G et al (2008) Prenatal and postnatal follow-up of a fetal interhemispheric arachnoid cyst with partial corpus callosum agenesis, asymmetric ventriculomegaly and localized polymicrogyria. Fetal Diagn Ther 24:385–388. CrossRefGoogle Scholar
  40. 40.
    Uematsu Y, Kubo K, Nishibayashi T et al (2000) Interhemispheric neuroepithelial cyst associated with agenesis of the corpus callosum. Pediatr Neurosurg 33:31–36. CrossRefGoogle Scholar
  41. 41.
    Inagaki H, Kurosaki M, Hori T et al (1992) [Interhemispheric choroidal epithelial cyst associated with partial agenesis of the corpus callosum: case report and review of the literature]. No Shinkei Geka 20:1301–1306Google Scholar
  42. 42.
    Korsic M, Jugović D, Porcnik A (2013) Endoscopic treatment of in utero diagnosed multiloculated interhemispheric cyst in a newborn: case report. Acta Clin Croat 52:119–124Google Scholar
  43. 43.
    Mankotia DS, Sardana H, Sinha S et al (2016) Pediatric interhemispheric arachnoid cyst: an institutional experience. J Pediatr Neurosci 11:29–34. CrossRefGoogle Scholar
  44. 44.
    Fruhman G, Eble TN, Gambhir N et al (2012) Ophthalmologic findings in Aicardi syndrome. J AAPOS 16:238–241. CrossRefGoogle Scholar
  45. 45.
    Laclef C, Anselme I, Besse L et al (2015) The role of primary cilia in corpus callosum formation is mediated by production of the Gli3 repressor. Hum Mol Genet 24:4997–5014. CrossRefGoogle Scholar
  46. 46.
    Putoux A, Baas D, Paschaki M et al (2018) Altered GLI3 and FGF8 signaling underlies Acrocallosal syndrome phenotypes in Kif7 depleted mice. Hum Mol Genet. Google Scholar
  47. 47.
    Wieland I, Jakubiczka S, Muschke P et al (2004) Mutations of the Ephrin-B1 Gene Cause Craniofrontonasal Syndrome. Am J Hum Genet 74:1209–1215. CrossRefGoogle Scholar
  48. 48.
    Utsunomiya H, Yamashita S, Takano K et al (2006) Midline cystic malformations of the brain: imaging diagnosis and classification based on embryologic analysis. Radiat Med 24:471–481. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Pediatric Neuropsychiatry UnitIRCCS Istituto Giannina GasliniGenoaItaly
  2. 2.Neurogenetics UnitIRCCS Istituto Giannina GasliniGenoaItaly
  3. 3.Pediatric Neuroradiology UnitIRCCS Istituto Giannina GasliniGenoaItaly
  4. 4.Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI)University of GenoaGenoaItaly
  5. 5.Pediatric Neurology UnitIRCCS Istituto Giannina GasliniGenoaItaly
  6. 6.Department of Pediatrics, Montreal Children’s HospitalMcGill University Health Center (MUHC)MontrealCanada
  7. 7.Department of Radiology, Montreal Children’s HospitalMcGill University Health Center (MUHC)MontrealCanada

Personalised recommendations