Author Proof A American Journal of Medical Genetics 9999:1±9 (2002) Craniofacial Phenotypes in Segmentally Trisomic Mouse Models for Down Syndrome Joan T. Richtsmeier, 1,2 * Ann Zumwalt, 3 Elaine J. Carlson, 4 Charles J. Epstein, 4 and Roger H. Reeves 5 1 Department of Anthropology, Pennsylvania State University, University Park, Pennsylvania 2 Center for Craniofacial Development and Disorders, Johns Hopkins Hospital, Baltimore, Maryland 3 Department of Cell Biology and Anatomy, Johns Hopkins University School of Medicine, Baltimore, Maryland 4 Department of Pediatrics, University of California, San Francisco, California, 5 Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland Trisomy for chromosome 21 (Chr 21) has profound effects on development that result in a constellation of phenotypes known as Down syndrome (DS). Distinctive cranio- facial manifestations are among the few features common to all individuals with DS. The characteristic face of a person with DS results primarily from maldevelopment of the underlying craniofacial skeleton and mandible. The Ts65Dn mouse, which has segmental trisomy 16, producing a dosage imbalance for about half the genes found on human Chr 21, exhibits speci®c skeletal malformations corresponding directly to the craniofacial dysmorphogenesis in DS. Here we demonstrate that Ts1Cje mice, which are at dosage imbalance for about 3 4 of the genes triplicated in Ts65Dn, demon- strate a very similar pattern of anomalies in the craniofacial skeleton. However, one character of Ts65Dn mice, a broadening of the cranial vault contributing to brachy- cephaly, is not seen in Ts1Cje mice. These observations independently con®rm that a dosage imbalance for mouse genes ortholo- gous to those on human Chr 21 has corre- sponding effects in both species. The subtle differences in the craniofacial phenotypes of Ts1Cje and Ts65Dn mice have implica- tions for elucidation of the mechanisms by which this aneuploidy disrupts develop- ment. ß 2002 Wiley-Liss, Inc. KEY WORDS: Down syndrome; trisomy; aneuploidy; Ts1Cje; Ts65Dn; mouse models; skull; mor- phometrics INTRODUCTION Trisomy 21 (Ts21) produces the clinical entity known as Down syndrome (DS) (MIM 190685) [LeJeune et al., 1959]. DS is characterized by a number of features that distinguish individuals with three rather than two copies of chromosome 21 (Chr 21). Although the overall pattern of abnormalities is quite characteristic, only a subset of the features are present in any individual with Ts21, and only a few features are present in all individuals with DS [Epstein, 1986]. Among these, the distinctive craniofacial appearance is a constant and immediately recognizable phenotype of DS. Several quantitative studies (primarily using roentgencephalo- metric methods) have shown that these features re¯ect, in part, developmental anomalies of the craniofacial skeleton. Features that have been de®ned qualitatively and quantitatively in humans with DS include overall reduction in skull size, determined by a generalized reduction in all measures taken on a lateral cephalo- gram; a ¯attened occiput, noted on observation and re¯ected in a reduction in cranial length; brachyce- phaly, measured as an increase in the cranial breadth/ length ratio; a small midface, re¯ected in measures that traverse the nasomaxillary complex; a reduced maxilla, re¯ected in measures of the palate and alveolar segments; reduced interorbital distance; and a reduced mandible, as measured on the ramus [Kisling, 1966; Fink et al., 1975; Farkas et al., 1985] (Fig. 1). Although craniofacial effects are an invariant aspect of DS, a great amount of individual metric variation in these craniofacial features and in other metric phenotypes has been reported among DS individuals [Kisling, 1966; Thelander and Pryor, 1966; Frostad et al., 1971; Cronk and Reed, 1981]. Two mouse strains with segmental trisomy 16 have been studied as genetic models of DS. Ts65Dn mice, AJMG-01-0337 Grant sponsor: Public Health Service; Grant numbers: 1F33DE/HD05706, HD 34198, HD38384, HD24605. *Correspondence to: Joan T. Richtsmeier, Department of Anthropology, 320 Carpenter Bldg., Pennsylvania State Univer- sity, University Park, PA 16802. E-mail: jta10@psu.edu Received 21 May 2001; Accepted 5 October 2001 Published online 00 Month 2001; DOI 10.1002/ajmg.10175 ß 2002 Wiley-Liss, Inc.