Abstract
Isolated cleft lip and/or palate (ICLP) is one of the most common congenital birth defects in the USA, affecting roughly 1 in 600 births annually. Along with the facial deformity, this population has been found to have abnormal neurodevelopment and gross structural abnormalities in the brain, particularly within the cerebellum. The current study examined cerebellar structure within the two primary subtypes of ICLP: cleft lip with/without cleft palate (CL/P) and cleft palate alone (CPO). A large sample of 107 subjects aged 7 to 27 years with ICLP was compared to 127 healthy controls. Samples were separated by sex. Brain structure was obtained via magnetic resonance imaging. For males, after controlling for intracranial volume, cerebellum volume was significantly lower in the ICLP group (F = 12.351, p = 0.001). Regionally in the cerebellum, males with ICLP had proportionally larger anterior lobes (F = 4.022, p = 0.047) and smaller superior posterior lobes (F = 5.686, p = 0.019). CL/P males showed only a reduction in overall cerebellum volume, with no regional changes. CPO males showed only regional changes, with no reduction in overall volume. Females with ICLP showed no overall or regional cerebellar abnormalities. However, females with CPO did have significantly lower cerebellum volumes than controls. The results reveal both global and regional cerebellar abnormalities within subjects with ICLP. They also establish the existence of abnormal cerebellar morphologies that are dependent on cleft subtype as well as sex. This lends further support to the claim that CL/P and CPO are distinct conditions.
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References
Canfield MA, Honein MA, Yuskiv N, Xing J, Mai CT, Collins JS, et al. National estimates and race/ethnic-specific variation of selected birth defects in the United States, 1999–2001. Birth Defects Res A Clin Mol Teratol. 2006;76(11):747–56.
Jones MC. Etiology of facial clefts: prospective evaluation of 428 patients. Cleft Palate J. 1988;25(1):16–20.
Stanier P, Moore GE. Genetics of cleft lip and palate: syndromic genes contribute to the incidence of non-syndromic clefts. Hum Mol Genet. 2004;13(Spec No 1):R73–81.
Jones MC. Facial clefting. Etiology and developmental pathogenesis. Clin Plast Surg. 1993;20(4):599–606.
Fraser FC. The genetics of cleft lip and cleft palate. Am J Hum Genet. 1970;22(3):336–52.
Wilkie AO, Morriss-Kay GM. Genetics of craniofacial development and malformation. Nature Review Genetics. 2001;2(6):458–68.
Hagberg C, Larson O, Milerad J. Incidence of cleft lip and palate and risks of additional malformations. Cleft Palate Craniofac J. 1998;35(1):40–5.
Vanderas AP. Incidence of cleft lip, cleft palate, and cleft lip and palate among races: a review. Cleft Palate J. 1987;24(3):216–25.
Derijcke A, Eerens A, Carels C. The incidence of oral clefts: a review. Br J Oral Maxillofac Surg. 1996;34(6):488–94.
Speltz ML, Endriga MC, Hill S, Maris CL, Jones K, Omnell ML. Cognitive and psychomotor development of infants with orofacial clefts. J Pediatr Psychol. 2000;25(3):185–90.
Conrad AL, Richman L, Nopoulos P, Dailey S. Neuropsychological functioning in children with non-syndromic cleft of the lip and/or palate. Child Neuropsychol. 2009;15(5):471–84.
Nopoulos P, Berg S, VanDemark D, Richman L, Canady J, Andreasen NC. Cognitive dysfunction in adult males with non-syndromic clefts of the lip and/or palate. Neuropsychologia. 2002;40(12):2178–84.
Richman LC, Eliason MJ, Lindgren SD. Reading disability in children with clefts. Cleft Palate J. 1988;25(1):21–5.
Broder HL, Richman LC, Matheson PB. Learning disability, school achievement, and grade retention among children with cleft: a two-center study. Cleft Palate Craniofac J. 1998;35(2):127–31.
Hunt O, Burden D, Hepper P, Johnston C. The psychosocial effects of cleft lip and palate: a systematic review. Eur J Orthod. 2005;27(3):274–85.
Richman LC. Cognitive patterns and learning disabilities of cleft palate children with verbal deficits. J Speech Hear Res. 1980;23(2):447–56.
Richman LC, Eliason M. Type of reading disability related to cleft type and neuropsychological patterns. Cleft Palate J. 1984;21(1):1–6.
Millard T, Richman LC. Different cleft conditions, facial appearance, and speech: relationship to psychological variables. Cleft Palate Craniofac J. 2001;38(1):68–75.
Kjaer I. Human prenatal craniofacial development related to brain development under normal and pathologic conditions. Acta Odontol Scand. 1995;53(3):135–43.
Nopoulos P, Langbehn DR, Canady J, Magnotta V, Richman L. Abnormal brain structure in children with isolated clefts of the lip or palate. Arch Pediatr Adolesc Med. 2007;161(8):753–8.
Nopoulos P, Choe I, Berg S, Van Demark D, Canady J, Richman L. Ventral frontal cortex morphology in adult males with isolated orofacial clefts: relationship to abnormalities in social function. Cleft Palate Craniofac J. 2005;42(2):138–44.
Shriver AS, Canady J, Richman L, Andreasen NC, Nopoulos P. Structure and function of the superior temporal plane in adult males with cleft lip and palate: pathologic enlargement with no relationship to childhood hearing deficits. J Child Psychol Psychiatry. 2006;47(10):994–1002.
Nopoulos P, Berg S, Canady J, Richman L, Van Demark D, Andreasen NC. Structural brain abnormalities in adult males with clefts of the lip and/or palate. Genet Med. 2002;4(1):1–9.
Conrad AL, Dailey S, Richman L, Canady J, Karnell MP, Axelson E, et al. Cerebellum structure differences and relationship to speech in boys and girls with nonsyndromic cleft of the lip and/or palate. Cleft Palate Craniofac J. 2010;47(5):469–75.
Tiemeier H, Lenroot RK, Greenstein DK, Tran L, Pierson R, Giedd JN. Cerebellum development during childhood and adolescence: a longitudinal morphometric MRI study. Neuroimage. 2010;49(1):63–70.
Hollingshead AB. Four factor index of social status. Unpublished manuscript. Yale University, New Haven, CT; 1975
Andreasen NC, Nopoulos P, Magnotta V, Pierson R, Ziebell S, Ho BC. Progressive brain change in schizophrenia: a prospective longitudinal study of first-episode schizophrenia. Biol Psychiatry. 2011;70(7):672–9.
Harris G, Andreasen NC, Cizadlo T, Bailey JM, Bockholt HJ, Magnotta VA, et al. Improving tissue classification in MRI: a three-dimensional multispectral discriminant analysis method with automated training class selection. J Comput Assist Tomogr. 1999;23(1):144–54.
Andreasen NC, Cohen G, Harris G, Cizadlo T, Parkkinen J, Rezai K, et al. Image processing for the study of brain structure and function: problems and programs. J Neuropsychiatry Clin Neurosci. 1992;4(2):125–33.
Cohen G, Andreasen NC, Alliger R, Arndt S, Kuan J, Yuh WT, et al. Segmentation techniques for the classification of brain tissue using magnetic resonance imaging. Psychiatry Res. 1992;45(1):33–51.
Andreasen NC, Cizadlo T, Harris G, Swayze 2nd V, O'Leary DS, Cohen G, et al. Voxel processing techniques for the antemortem study of neuroanatomy and neuropathology using magnetic resonance imaging. J Neuropsychiatry Clin Neurosci. 1993;5(2):121–30.
Andreasen NC, Nopoulos P, Schultz S, Miller D, Gupta S, Swayze V, et al. Positive and negative symptoms of schizophrenia: past, present, and future. Acta Psychiatr Scand Suppl. 1994;384:51–9.
Magnotta VA, Harris G, Andreasen NC, O'Leary DS, Yuh WT, Heckel D. Structural MR image processing using the BRAINS2 toolbox. Comput Med Imaging Graph. 2002;26(4):251–64.
Talairaich J, Tournoux P. Co-planar stereotaxic atlas of the human brain. New York: Thieme Medical Publishers; 1988.
Pierson R, Corson PW, Sears LL, Alicata D, Magnotta V, Oleary D, et al. Manual and semiautomated measurement of cerebellar subregions on MR images. Neuroimage. 2002;17(1):61–76.
Fan L, Tang Y, Sun B, Gong G, Chen ZJ, Lin X, et al. Sexual dimorphism and asymmetry in human cerebellum: an MRI-based morphometric study. Brain Res. 2010;1353:60–73.
Huang Y, Wu J, Ma J, Beaty TH, Sull JW, Zhu L, Huang Y, Wu J, Ma J, Beaty TH, Sull JW, Zhu L, et al. Association between IRF6 SNPs and oral clefts in West China. J Dent Res. 2009;88(8):715–8.
Giedd JN, Raznahan A, Mills K, Lenroot RK. Review: magnetic resonance imaging of male/female differences in human adolescent brain anatomy. Biol Sex Differ. 2012;3(1):19.
Gur RC, Turetsky BI, Matsui M, Yan M, Bilker W, Hughett P, et al. Sex differences in brain gray and white matter in healthy young adults: correlations with cognitive performance. J Neurosci. 1999;19(10):4065–72.
Cosgrove KP, Mazure CM, Staley JK. Evolving knowledge of sex differences in brain structure, function, and chemistry. Biol Psychiatry. 2007;62(8):847–55.
Abel KM, Drake R, Goldstein JM. Sex differences in schizophrenia. Int Rev Psychiatry. 2010;22(5):417–28.
Beacher FD, Minati L, Baron-Cohen S, Lombardo MV, Lai MC, Gray MA, et al. Autism attenuates sex differences in brain structure: a combined voxel-based morphometry and diffusion tensor imaging study. AJNR Am J Neuroradiol. 2012;33(1):83–9.
Hafner H. Gender differences in schizophrenia. Psychoneuroendocrinology. 2003;28 Suppl 2:17–54.
Rinehart NJ, Cornish KM, Tonge BJ. Gender differences in neurodevelopmental disorders: autism and fragile X syndrome. Curr Top Behav Neurosci. 2011;8:209–29.
Wing L. Sex ratios in early childhood autism and related conditions. Psychiatry Res. 1981;5(2):129–37.
Sparks BF, Friedman SD, Shaw DW, Aylward EH, Echelard D, Artru AA, et al. Brain structural abnormalities in young children with autism spectrum disorder. Neurology. 2002;59(2):184–92.
Nopoulos P, Berg S, VanDemark D, Richman L, Canady J, Andreasen NC. Increased incidence of a midline brain anomaly in patients with nonsyndromic clefts of the lip and/or palate. J Neuroimaging. 2001;11(4):418–24.
Boes AD, Murko V, Wood JL, Langbehn DR, Canady J, Richman L, et al. Social function in boys with cleft lip and palate: relationship to ventral frontal cortex morphology. Behav Brain Res. 2007;181(2):224–31.
Schmahmann JD. Disorders of the cerebellum: ataxia, dysmetria of thought, and the cerebellar cognitive affective syndrome. J Neuropsychiatry Clin Neurosci. 2004;16(3):367–78.
Rapoport M, van Reekum R, Mayberg H. The role of the cerebellum in cognition and behavior: a selective review. J Neuropsychiatry Clin Neurosci. 2000;12(2):193–8.
Andreasen NC, Paradiso S, O'Leary DS. “Cognitive dysmetria” as an integrative theory of schizophrenia: a dysfunction in cortical-subcortical-cerebellar circuitry? Schizophr Bull. 1998;24(2):203–18.
Richman LC, Ryan SM. Do the reading disabilities of children with cleft fit into current models of developmental dyslexia? Cleft Palate Craniofac J. 2003;40(2):154–7.
Richman LC, Wilgenbusch T, Hall T. Spontaneous verbal labeling: visual memory and reading ability in children with cleft. Cleft Palate Craniofac J. 2005;42(5):565–9.
Acknowledgments
This project is funded by 5 R01 DE014399-05, a grant from the National Institutes of Dental and Craniofacial Research (NIDCR).
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The authors have no conflicts of interest associated with this manuscript.
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DeVolder, I., Richman, L., Conrad, A.L. et al. Abnormal Cerebellar Structure Is Dependent on Phenotype of Isolated Cleft of the Lip and/or Palate. Cerebellum 12, 236–244 (2013). https://doi.org/10.1007/s12311-012-0418-y
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DOI: https://doi.org/10.1007/s12311-012-0418-y
Keywords
- Isolated cleft
- Cleft lip with/without cleft palate
- Cleft palate alone
- Cerebellum
- Magnetic resonance imaging
- Brain structure