The presence of multiple dysmorphic features in some children with autism spectrum disorder (ASD) might identify distinct ASD phenotypes and serve as potential markers for understanding causes and prognoses. To evaluate dysmorphology in ASD, children aged 3–6 years with ASD and non-ASD population controls (POP) from the Study to Explore Early Development were evaluated using a novel, systematic dysmorphology review approach. Separate analyses were conducted for non-Hispanic White, non-Hispanic Black, and Hispanic children. In each racial/ethnic group, ~ 17% of ASD cases were Dysmorphic compared with ~ 5% of POP controls. The ASD–POP differential was not explained by known genetic disorders or birth defects. In future epidemiologic studies, subgrouping ASD cases as Dysmorphic vs. Non-dysmorphic might help delineate risk factors for ASD.
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Aase, J. M. (1990). The physical examination in dysmorphology. In J. M Aase (Ed.), Diagnostic dysmorphology (pp. 33–42). New York: Plenum Medical Book Co.
Abrahams, B. S., & Geschwind, D. H. (2008). Advances in autism genetics: On the threshold of a new neurobiology. Nature Reviews Genetics, 9(5), 341–355.
Allanson, J. E. (1989). Time and natural history: The changing face. Journal of Craniofacial Genetics and Developmental Biology, 9(1), 21–28.
Allanson, J. E., Cunniff, C., Hoyme, H. E., McGaughran, J., Muenke, M., & Neri, G. (2009). Elements of morphology: Standard terminology for the head and face. American Journal of Medical Genetics Part A, 149A(1), 6–28.
American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington: American Psychiatric Publishing.
Amiet, C., Gourfinkel-An, I., Bouzamondo, A., Tordjman, S., Baulac, M., Lechat, P., … Cohen, D. (2008). Epilepsy in autism is associated with intellectual disability and gender: Evidence from a meta-analysis. Biological Psychiatry, 64, 577–582.
Angkustsiri, K., Krakowiak, P., Moghaddam, B., Wardinsky, T., Gardner, J., Kalamkarian, N., … Hansen, R. L. (2011). Minor physical anomalies in children with autism spectrum disorders. Autism, 15(6), 746–760.
Baio, J., Wiggins, L., Christensen, D. L., Maenner, M. J., Daniels, J., Warren, Z., … Dowling, N. F. (2018). Prevalence of autism spectrum disorder among children aged 8 years—Autism and Developmental Disabilities Monitoring Network. Morbidity and Mortality Weekly Report Surveillance Summaries, 67(6), 1–23.
Biesecker, L. G., Aase, J. M., Clericuzio, C., Gurrieri, F., Temple, I. K., & Toriello, H. (2009). Elements of morphology: Standard terminology for the hands and feet. American Journal of Medical Genetics Part A, 149A(1), 93–127.
Bill, B. R., & Geschwind, D. H. (2009). Genetic advances in autism: Heterogeneity and convergence on shared pathways. Current Opinion in Genetics & Development, 19(3), 271–278.
Braddock, S. R., Henley, K. M., & Maria, B. L. (2007). The face of Joubert syndrome: A study of dysmorphology and anthropometry. American Journal of Medical Genetics Part A, 143A(24), 3235–3242.
Bradley, C. B., Browne, E. N., Alexander, A. A., Collins, J., Dahm, J. L., DiGuiseppi, C. G., … Daniels, J. L. (2018). Demographic and operational factors predicting study completion in a multisite case-control study of preschool children. American Journal of Epidemiology, 187(3), 592–603.
Bushby, K. M., Cole, T., Matthews, J. N., & Goodship, J. A. (1992). Centiles for adult head circumference. Archives of Disease in Childhood, 67(10), 1286–1287.
Campbell, M., Geller, B., Small, A. M., Petti, T. A., & Ferris, S. H. (1978). Minor physical anomalies in young psychotic children. American Journal of Psychiatry, 135(5), 573–575.
Carey, J. C., Cohen, M. M. Jr., Curry, C. J. R., Devriendt, K., Holmes, L. B., & Verloes, A. (2009). Elements of morphology: Standard terminology for the lips, mouth, and oral region. American Journal of Medical Genetics Part A, 149A(1), 77–92.
Centers for Disease Control and Prevention. (2008). Update on overall prevalence of major birth defects—Atlanta, Georgia, 1978–2005. Morbidity and Mortality Weekly Report, 57(1), 1–5.
Cole, T. R., & Hughes, H. E. (1994). Sotos syndrome: A study of the diagnostic criteria and natural history. Journal of Medical Genetics, 31(1), 20–32.
Cung, W., Freedman, L. A., Khan, N. E., Romberg, E., Gardner, P. J., Bassim, C. W., … Stewart, D. R. (2015). Cephalometry in adults and children with neurofibromatosis type 1: Implications for the pathogenesis of sphenoid wing dysplasia and the “NF1 facies”. European Journal of Medical Genetics, 58(11), 584–590.
DiGuiseppi, C. G., Daniels, J. L., Fallin, D. M., Rosenberg, S. A., Schieve, L. A., Thomas, K. C., … Schendel, D. E. (2016). Demographic profile of families and children in the Study to Explore Early Development (SEED): Case-control study of autism spectrum disorder. Disability and Health Journal, 9(3), 544–551.
Duvekot, J., van der Ende, J., Verhulst, F. C., Slappendel, G., van Daalen, E., Maras, A., & Greaves-Lord, K. (2017). Factors influencing the probability of a diagnosis of autism spectrum disorder in girls versus boys. Autism, 21(6), 646–658.
Eaves, L. C., & Ho, H. H. (2008). Young adult outcome of autism spectrum disorders. Journal of Autism and Developmental Disorders, 38, 739–747.
Egbe, A. C. (2015). Birth defects in the newborn population: Race and ethnicity. Pediatric Neonatology, 56(3), 183–188.
Feingold, M., & Bossert, W. H. (1974). Normal values for selected physical parameters: An aid to syndrome delineation. Birth Defects: Original Articles Series, 10(13), 1–16.
Flor, J., Bellando, J., Lopez, M., & Shul, A. (2017). Developmental functioning and medical co-morbidity profile of children with complex and essential autism. Autism Research, 10(8), 1344–1352.
Goldfarb, W., & Botstein, A. (1956). Physical stigmata in schizophrenic children. Unpublished manuscript. Brooklyn, NY: Henry Ittleson Center for Child Research.
Gualtieri, C. T., Adams, A., Shen, C. D., & Loiselle, D. (1982). Minor physical anomalies in alcoholic and schizophrenic adults with hyperactive and autistic children. American Journal of Psychiatry, 139(5), 640–643.
Hall, B. D., Graham, J. M. Jr., Cassidy, S. B., & Opitz, J. M. (2009). Elements of morphology: Standard terminology for the periorbital region. American Journal of Medical Genetics Part A, 149A(1), 29–39.
Hennekam, R. C., Biesecker, L. G., Allanson, L. G., Hall, J. G., Opitz, J. M., Temple, I. K. … Elements of Morphology Consortium. (2013). Elements of morphology: General terms for congenital anomalies. American Journal of Medical Genetics Part A. 161A(11), 2726–2733.
Hennekam, R. C., Cormier-Daire, V., Hall, J. G., Mèhes, K., Patton, M., & Stevenson, R. E. (2009). Elements of morphology: Standard terminology for the nose and philtrum. American Journal of Medical Genetics Part A, 149A(1), 61–76.
Hook, E. B. (1971). Some general considerations concerning monitoring: Application to utility of minor defects as markers. In E. B. Hook. D. T. Janerich. I. H. Porter (Eds.), Monitoring, birth defects, and environment (pp. 177–197). New York: Academic Press.
Howden, L. M., & Meyer, J. A. (2011). Age and sex composition: 2010. 2010 census briefs. Washington, DC: U.S. Department of Commerce, Economics and Statistics Administration, U.S. Census Bureau.
Hunter, A., Frias, J. L., Gillesen-Kaesbach, G., Hughes, H., Jones, K. L., & Wilson, L. (2009). Elements of morphology: Standard terminology for the ear. American Journal of Medical Genetics Part A, 149A(1), 40–60.
Karimi, P., Kamali, E., Mousavi, S. M., & Karahmadi, M. (2017). Environmental factors influencing the risk of autism. Journal of Research in Medical Sciences, 22, 27.
Leppig, K. A., Werler, M. M., Cann, C. I., Cook, C. A., & Holmes, L. B. (1987). Predictive value of minor anomalies. I. Association with major malformations. Journal of Pediatrics, 110(4), 531–537.
Links, P. S. (1980). Minor physical anomalies in childhood autism. Part II. Their relationship to maternal age. Journal of Autism and Developmental Disorders, 10(3), 287–292.
Links, P. S., Stockwell, M., Abichandani, F., & Simeon, J. (1980). Minor physical anomalies in childhood autism. Part I. Their relationship to pre- and perinatal complications. Journal of Autism and Developmental Disorders, 10(3), 273–285.
Little, R. J. A., & Rubin, D. B. (1987). Statistical analysis with missing data (p. 278). New York: Wiley.
Liu, Y., & De, A. (2015). Multiple imputation by fully conditional specification for dealing with missing data in a large epidemiologic study. International Journal of Statistics in Medical Research, 4(3), 287–295.
Marden, P. M., Smith, D. W., & McDonald, M. J. (1964). Congenital anomalies in the newborn infant, including minor variations. Journal of Pediatrics, 64, 357–371.
Méhes, K. (1983). General characterization of minor malformations: Epidemiology in the newborn populations. In K. Méhes (Ed.), Minor malformations in the neonate (pp. 17–20). Budapest: Akadémiai Kiadó.
Merks, J. H., van Karnebeek, C. D., Caron, H. N., & Hennekam, R. C. (2003). Phenotypic abnormalities: Terminology and classification. American Journal of Medical Genetics Part A, 123A(3), 211–230.
Merlob, P., Papier, C. M., Klingberg, M. A., & Reisner, S. H. (1985). Incidence of congenital malformations in the newborn, particularly minor abnormalities. Progress in Clinical and Biological Research, 163C, 51–55.
Miles, J. H., & Hillman, R. E. (2000). Value of a clinical morphology examination in autism. American Journal of Medical Genetics, 91(4), 245–253.
Miles, J. H., Takahashi, T. N., Bagby, S., Sahota, P. K., Vaslow, D. F., Wang, R. E., … Farmer, J. E. (2005). Essential versus complex autism: Definition of fundamental prognostic subtypes. American Journal of Medical Genetics Part A, 135A(2), 171–180.
Miles, J. H., Takahashi, T. N., Hong, J., Munden, N., Flournoy, N., Braddock, S. R., … Farmer, J. E. (2008). Development and validation of a measure of dysmorphology: Useful for autism subgroup classification. American Journal of Medical Genetics Part A, 146A(9), 1101–1116.
Miller, M. T., Strömland, K., Ventura, L., Johansson, M., Bandim, J. M., & Gillberg, C. (2005). Autism associated with conditions characterized by developmental errors in early embryogenesis: A mini review. International Journal of Developmental Neuroscience, 23(2–3), 201–219.
Mnukhin, S. S., & Isaev, D. N. (1975). On the organic nature of some forms of schizoid or autistic psychopathy. Journal of Autism and Childhood Schizophrenia, 5(2), 99–108.
Muhle, R., Trentacoste, S. V., & Rapin, I. (2004). The genetics of autism. Pediatrics, 113(5), e472–e486.
Raghunathan, T. E., Lepkowski, J. M., Van Hoewyk, J., & Solenberger, P. (2001). A multivariate technique for multiply imputing missing values using a sequence of regression models. Survey Methodology, 27(1), 85–95.
Reich, R., Cloninger, C. R., & Guze, S. B. (1975). The multifactorial model of disease transmission: I. Description of the model and its use in psychiatry. British Journal of Psychiatry, 127, 1–10.
Robert, C., Pasquier, L., Cohen, D., Fradin, M., Canitano, R., Damaj, L., … Tordjman, S. (2017). Role of genetics in the etiology of autistic spectrum disorder: Towards a hierarchical diagnostic strategy. International Journal of Molecular Sciences. 18(3), e618.
Ronald, A., & Hoekstra, R. A. (2011). Autism spectrum disorders and autistic traits: A decade of new twin studies. American Journal of Medical Genetics Part B, Neuropsychiatric Genetics, 156B(3), 255–274.
Rosti, R. O., Sadek, A. A., Vaux, K. K., & Gleeson, J. G. (2014). The genetic landscape of autism spectrum disorders. Developmental Medicine & Child Neurology, 56(1), 12–18.
Rubin, D. B. (1987). Multiple imputation for nonresponse in surveys (p. 258). New York: Wiley.
Sandin, S., Lichtenstein, P., Kuja-Halkola, R., Larsson, H., Hultman, C. M., & Reichenberg, A. (2014). The familial risk of autism. Journal of the American Medical Association, 311(17), 1770–1777.
Schendel, D. E., Diguiseppi, C., Croen, L. A., Fallin, M. D., Reed, P. L., Schieve, L. A., … Yeargin-Allsopp, M. (2012). The Study to Explore Early Development (SEED): A multisite epidemiologic study of autism by the Centers for Autism and Developmental Disabilities Research and Epidemiology (CADDRE) network. Journal of Autism and Developmental Disorders, 42(10), 2121–2140.
Steg, J. P., & Rapoport, J. L. (1975). Minor physical anomalies in normal, neurotic, learning disabled, and severely disturbed children. Journal of Autism and Childhood Schizophrenia, 5(4), 299–307.
Stoelb, M., Yarnal, R., Miles, J., Takahashi, T. N., Farmer, J. E., & McCathren, R. B. (2004). Predicting responsiveness to treatment of children with autism: A retrospective study of the importance of physical dysmorphology. Focus on Autism and Other Developmental Disabilities, 19(2), 66–77.
Tammimies, K., Marshall, C. R., Walker, S., Kaur, G., Thiruvahindrapuram, B., & Lionel, A. C. (2015). Molecular diagnostic yield of chromosomal microarray analysis and whole-exome sequencing in children with autism spectrum disorder. Journal of the American Medical Association, 314(9), 895–903.
Thomas, I. T., Gaitantzis, Y. A., & Frias, J. L. (1987). Palpebral fissure length from 29 weeks gestation to 14 years. Journal of Pediatrics, 111(2), 267–268.
Van Buuren, S. (2007). Multiple imputation of discrete and continuous data by fully conditional specification. Statistical Methods in Medical Research, 16(3), 219–242.
Waldrop, M. F., Pederson, F. A., & Bell, R. Q. (1968). Minor physical anomalies and behavior in preschool children. Child Development, 39(2), 391–400.
Walker, H. A. (1977). Incidence of minor physical anomaly in autism. Journal of Autism and Childhood Schizophrenia, 7(4), 165–176.
Werling, D. M., & Geschwind, D. H. (2013). Understanding sex bias in autism spectrum disorder. Proceedings of the National Academy of Sciences of the United States of America, 110(13), 4868–4869.
Wong, V. C. N., Fung, C. K. Y., & Wong, P. T. Y. (2014). Use of dysmorphology for subgroup classification on autism spectrum disorder in Chinese children. Journal of Autism and Developmental Disorders, 44(1), 9–18.
Yuan, Y. C. (2000). Multiple imputation for missing data: Concepts and new developments, SAS technical report no. P267-25 (p. 11). Rockville, MD: SAS Institute, Inc.
Zachariah, S. M., Oomen, S. P., Padankatti, C. S., Grace, H., & Glory, L. (2017). Dysmorphism in non-syndromic autism: A cross-sectional study. Indian Pediatrics, 54(7), 560–562.
Zankl, A., & Molinari, L. (2003). Abase—A tool for the rapid assessment of anthropometric measurements on handheld computers. American Journal of Medical Genetics Part A, 121A(2), 146–150.
The authors thank the participating families and the many staff and scientists from all sites who contribute to the Study to Explore Early Development (SEED). Specifically, the authors would like to acknowledge the following study staff from SEED who assisted in the data collection for the dysmorphology assessment: from CA SEED, Ms. Katherine Chau, Dr. Arthur Grix, Ms. Vickie Hefferman, Ms. Lucy Murillo, Dr. Jean Sakimura, Dr. Khin Win, and Dr. Dana Won; from CO SEED, Ms. Kristina Hightshoe, Ms. Mary Murphy, Dr. Ann Reynolds, Ms. Ann Ribe, Ms. Katie Szalewski, and Ms. Gabriella Yates; from GA SEED, Ms. Basudha Chaudhuri, Ms. Karen Clay, Ms. Phyllis Cook-Stillwell, Ms. Tracy Johnson, Ms. Ashleigh McCraw, Ms. Charmaine McKenzie, Ms. Julia Richardson, Ms. Robin Tate-Sparks, and Ms. Shawanna Taylor; from MD SEED, Ms. Martyna Galazka, Ms. Pam Gillin, Ms. Ashley Graham, Ms. Katie Lewis, Dr. Deepa Mennon, Ms. Julie Rusyniak, and Ms. Katie Voss; from NC SEED, Mr. Craig Clement, Ms. Betsy Glaser, Mr. Matt Herr, Mr. Eric Johnson, and Ms. Karina Yelin; and from PA SEED, Ms. Tina Almadinejad, Ms. Jessica Beauvais, Ms. Megan Carolan, Mr. Christopher Colameco, Ms. Casara Ferretti, Ms. Kathleen Lesko, Dr. Susan Levy, Ms. Rita Mack, Ms. Elizabeth McCaffrey, Ms. Donna McDonald-McGinn, Ms. Megan Ott, Ms. Michelle Petrongolo, Ms. Saba Qasmieh, Ms. Sarah Woldoff, and Ms. Jordana Woodford. The authors acknowledge Dr. Arthur Grix for developing and testing the Dysmorphology Review Form for dysmorphology assessment of the mouth, lips, and teeth. The authors acknowledge the following SEED study staff who assisted with data entry of dysmorphology reviews: Mr. Christopher Colameco, Ms. Vickie Hefferman, Mr. Joel Rothwell, and Ms. Gabriella Yates. The authors acknowledge the following SEED study staff from the SEED Data Coordinating Center for developing the data-entry interfaces for dysmorphology assessment: Mr. Michael Babcock, Mr. Patrick Thompson, Mr. Alex Walworth, and Mr. Maurice Wong. This research is supported by the Centers for Disease Control and Prevention, Centers for Autism and Developmental Disabilities Research, through six cooperative agreements (COs): CO# U10DD000180, Colorado Department of Public Health/University of Colorado School of Medicine; CO# U10DD000181, Kaiser Foundation Research Institute (CA); CO# U10DD000182, University of Pennsylvania; CO# U10DD000183, Johns Hopkins University; CO# U10DD000184, University of North Carolina at Chapel Hill; and CO# U10DD000498, Michigan State University. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
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Shapira, S.K., Tian, L.H., Aylsworth, A.S. et al. A Novel Approach to Dysmorphology to Enhance the Phenotypic Classification of Autism Spectrum Disorder in the Study to Explore Early Development. J Autism Dev Disord 49, 2184–2202 (2019). https://doi.org/10.1007/s10803-019-03899-0
- Autism spectrum disorder
- Birth defects
- Dysmorphic features
- Genetic disorders
- Morphologic anomalies
- Phenotypic classification