Hirschsprung disease [Hirschsprung, 1888] HSCR, OMIM 142623) is a genetically heterogenous condition. It is observed in isolation due to mutations in several different genes or as part of complex genetic syndromes such as Waardenburg and Down syndromes [Parisi and Kapur, 2000]. The association of HSCR, microcephaly, and mental retardation was® rst described in a pair of sibs by Goldberg and Shprintzen [1981]. Because of parental consanguinity [Hurst et al., 1988] and sib recurrence in three families [Goldberg and Shprintzen, 1981; Kumasaka and Clarren, 1988; Yomo et al., 1991] autosomal recessive inheritance has been proposed. In 1998, Mowat et al. reported 6 sporadic patients® ve with HSCR, one with constipation) who shared the same distinctive facial appearance, microcephaly, and mental retardation, different from the original patients described by Goldberg and Shprintzen [Mowat et al., 1998]. They recognized the same facial appearance in three previously published patients [Hurst et al., 1988, case 3; Tanaka et al., 1993; Lurie et al., 1994]. The characteristic facial anomalies described included deep set, large eyes, broad nasal bridge, rounded nasal tip, prominent columella, open mouthed expression, triangular jaw, prominent chin, and large uplifted ear lobes.