J Pediatr Genet 2023; 12(01): 058-063
DOI: 10.1055/s-0040-1721073
Case-Based Review

Knobloch Syndrome in Siblings with Posterior Fossa Malformations Along with Cerebellar Midline Cleft Abnormality Caused by Biallelic COL18A1 Mutation: Case-Based Review

Siddaramappa J. Patil
1   Division of Medical Genetics, Mazumdar Shaw Medical Center, Narayana Hrudayalaya Hospitals, Bangalore, India
Shruti Pande
2   Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India
Jyoti Matalia
3   Department of Pediatric Ophthalmology and Strabismology, Narayana Nethralaya, Bangalore, India
Venkatraman Bhat
4   Department of Radiology, Mazumdar Shaw Medical Center, Narayana Hrudayalaya Hospitals, Bangalore, India
Minal Kekatpure
5   Division of Pediatric Neurology, Department of Neurology, Mazumdar Shaw Medical Center, Narayana Hrudayalaya Hospitals, Bangalore, India
Katta Mohan Girisha
2   Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India
› Author Affiliations
Funding This study was funded by Indian Council of Medical Research (File No 5/7/1508/2016).


Knobloch syndrome (KS) is an autosomal recessive disorder caused by biallelic pathogenic variants in COL18A1. KS clinically manifests with the typical eye findings (high myopia, vitreoretinal degeneration, retinal detachment, and lens subluxation), variable neurological findings (occipital encephalocele, polymicrogyria, cerebellar malformations, epilepsy, and intellectual disability), and the other uncommon clinical manifestations. Literature review of all KS patients (source PubMed) was done with special reference to cerebellar abnormalities. Here, we report two siblings with typical KS with posterior fossa malformations and novel cerebellar midline cleft abnormality analyzed by whole exome sequencing. Known pathogenic homozygous variant c.2908C > T; (p.Arg970Ter) in exon 26 of COL18A1 was found as a cause for KS. These two siblings presented with early-onset severe ocular manifestations, facial dysmorphism, and variable central nervous system manifestations along with novel cerebellar midline cleft abnormality. The presence or absence of structural brain malformations and genotypes does not absolutely predict cognitive functions in KS patients. However, the presence of posterior fossa abnormality may be predictive for the development of ataxia in later life and needs further studies.

Publication History

Received: 14 September 2020

Accepted: 11 October 2020

Article published online:
10 December 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

  • References

  • 1 Suzuki OT, Sertié AL, Der Kaloustian VM. et al. Molecular analysis of collagen XVIII reveals novel mutations, presence of a third isoform, and possible genetic heterogeneity in Knobloch syndrome. Am J Hum Genet 2002; 71 (06) 1320-1329
  • 2 Kliemann SE, Waetge RT, Suzuki OT, Passos-Bueno MR, Rosemberg S. Evidence of neuronal migration disorders in Knobloch syndrome: clinical and molecular analysis of two novel families. Am J Med Genet A 2003; 119A (01) 15-19
  • 3 Paisán-Ruiz C, Scopes G, Lee P, Houlden H. Homozygosity mapping through whole genome analysis identifies a COL18A1 mutation in an Indian family presenting with an autosomal recessive neurological disorder. Am J Med Genet B Neuropsychiatr Genet 2009; 150B (07) 993-997
  • 4 Khan AO, Aldahmesh MA, Mohamed JY, Al-Mesfer S, Alkuraya FS. The distinct ophthalmic phenotype of Knobloch syndrome in children. Br J Ophthalmol 2012; 96 (06) 890-895
  • 5 Caglayan AO, Baranoski JF, Aktar F. et al. Brain malformations associated with Knobloch syndrome--review of literature, expanding clinical spectrum, and identification of novel mutations. Pediatr Neurol 2014; 51 (06) 806-813.e8
  • 6 Hull S, Arno G, Ku CA. et al. Molecular and clinical findings in patients with Knobloch syndrome. JAMA Ophthalmol 2016; 134 (07) 753-762
  • 7 Corbett MA, Turner SJ, Gardner A. et al. Familial epilepsy with anterior polymicrogyria as a presentation of COL18A1 mutations. Eur J Med Genet 2017; 60 (08) 437-443
  • 8 Sertié AL, Sossi V, Camargo AA, Zatz M, Brahe C, Passos-Bueno MR. Collagen XVIII, containing an endogenous inhibitor of angiogenesis and tumor growth, plays a critical role in the maintenance of retinal structure and in neural tube closure (Knobloch syndrome). Hum Mol Genet 2000; 9 (13) 2051-2058
  • 9 Balikova I, Sanak NS, Fanny D. et al. Three cases of molecularly confirmed Knobloch syndrome. Ophthalmic Genet 2020; 41 (01) 83-87
  • 10 Keren B, Suzuki OT, Gérard-Blanluet M. et al. CNS malformations in Knobloch syndrome with splice mutation in COL18A1 gene. Am J Med Genet A 2007; 143A (13) 1514-1518
  • 11 Suzuki O, Kague E, Bagatini K. et al. Novel pathogenic mutations and skin biopsy analysis in Knobloch syndrome. Mol Vis 2009; 15: 801-809
  • 12 Charsar BA, Goldberg EM. Polymicrogyria and intractable epilepsy in siblings with Knobloch syndrome and homozygous mutation of COL18A1. Pediatr Neurol 2017; 76: 91-92
  • 13 Passos-Bueno MR, Marie SK, Monteiro M. et al. Knobloch syndrome in a large Brazilian consanguineous family: confirmation of autosomal recessive inheritance. Am J Med Genet 1994; 52 (02) 170-173
  • 14 Girisha KM, Shukla A, Trujillano D. et al. A homozygous nonsense variant in IFT52 is associated with a human skeletal ciliopathy. Clin Genet 2016; 90 (06) 536-539
  • 15 Shukla A, Hebbar M, Srivastava A. et al. Homozygous p.(Glu87Lys) variant in ISCA1 is associated with a multiple mitochondrial dysfunctions syndrome. J Hum Genet 2017; 62 (07) 723-727
  • 16 Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 2010; 38 (16) e164
  • 17 Richards S, Aziz N, Bale S. ACMG Laboratory Quality Assurance Committee. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17 (05) 405-424
  • 18 White RJ, Wang Y, Tang P, Montezuma SR. Knobloch syndrome associated with polymicrogyria and early onset of retinal detachment: two case reports. BMC Ophthalmol 2017; 17 (01) 214
  • 19 Carss KJ, Arno G, Erwood M. NIHR-BioResource Rare Diseases Consortium. et al. Comprehensive rare variant analysis via whole-genome sequencing to determine the molecular pathology of inherited retinal disease. Am J Hum Genet 2017; 100 (01) 75-90