CASE REPORT Lower Lip Pits: Van der Woude or Kabuki Syndrome? Ferri P. David-Paloyo, M.D., Xuecai Yang, M.D., Ju-Li Lin, M.D., Fen-Hwa Wong, Ph.D., Yah-Huei Wu-Chou, Ph.D., Lun-Jou Lo, M.D. Kabuki syndrome (KS) is a multiple congenital anomaly/mental retardation syndrome with characteristic facial features. Despite more than 350 documented cases and recent correlation of MLL2 mutations as a genetic cause, its full clinical spectrum is still being defined. This report describes two patients who were initially diagnosed with Van der Woude syndrome (VWS) based on the presence of lower lip pits. However, this finding can occur with KS, albeit infrequently. For patients with lower lip pits, a thorough evaluation should be made to distinguish between VWS and KS, as there are differences in long-term prognosis. KEY WORDS: Kabuki syndrome, lower lip pits, Van der Woude syndrome INTRODUCTION The Kabuki syndrome (KS, also Kabuki make-up syndrome or Niikawa-Kuroki syndrome, OMIM 147920) is a multiple congenital anomaly/mental retardation syndrome concurrently described in 1981 by the groups of Niikawa and Kuroki in Japan (Kuroki et al., 1981; Niikawa et al., 1981). More than 350 patients of diverse ethnic backgrounds have been documented since. Its incidence in the Japanese population is about 1 in 32,000, and it is presumed that this approximates the incidence in other populations as well (Niikawa et al., 1988; Schrander- Stumpel et al., 1994; Wessels et al., 2001; Adam and Hudgins, 2004; Armstrong et al., 2005). Among the cardinal manifestations that have been described, the distinctive facial features are present in 100% of patients. Other craniofacial manifestations have been noted with varying frequencies. One such feature that has been inconsistently reported is the lower lip pits (Matsumoto and Niikawa, 2003; Adam and Hudgins, 2004; Armstrong et al., 2005). Classically, lip pits are more frequently associated with Van der Woude syndrome (VWS). VWS is usually limited to the presence of the lip pits with some combination of cleft lip and palate. Patients with VWS generally progress along a normal developmental course (Jones, 2006; McMillan et al., 2006). In contrast, diagnosis of KS is rarely established in the neonatal period owing to the inconspicuous presentation of the facial features in younger patients (Burke and Jones, 1995; Vaux et al., 2005). The presence of lower lip pits can introduce diagnostic confusion, as VWS becomes the presumptive diagnosis. Although the recent identification of mutations in the MLL2 gene in patients with KS has provided a molecular means to confirm the clinical diagnosis (Ng et al., 2010; Adam et al., 2011; Hannibal et al., 2011; Li et al., 2011; Micale et al., 2011; Paulussen et al., 2011), the cost and limited availability of such testing remain prohibitive in many circumstances. Thus, for the most part, diagnosis of KS remains clinical. This report presents two patients whose initial consulta- tion for lower lip pits and cleft palate led to a diagnosis of VWS; however, as they developed, they exhibited features more consistent with KS. Reviewing their clinical features and courses, these two cases underscore the need for careful evaluation of patients who present with lip pits and to heighten the awareness about this particular differential diagnosis. MATERIALS AND METHODS Two patients whose initial presentation with cleft palate and lower lip pits led to a diagnosis of VWS are discussed. Informed written consent was secured from the respective Dr. David-Paloyo, Section of Plastic and Reconstructive Surgery, Department of Surgery, Manila Doctors Hospital, Manila, Philip- pines. Dr. Yang, Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Medical College, Qingdao University, Qingdao, Shandong, China. Dr. Lin, Division of Pediatric Genetics, Department of Pediatrics, Chang Gung Children Hospital, Chang Gung University, Taoyuan, Taiwan. Dr. Wong, Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan. Dr. Wu-Chou, Department of Medical Research, Chang Gung Craniofacial Research Center, Chang Gung Memorial Hospital; Graduate Institute of Clinical Medical Scienc- es, Chang Gung University, Taoyuan, Taiwan. Dr. Lo, Department of Plastic and Reconstructive Surgery, Chang Gung Craniofacial Research Center, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan. Submitted October 2012; Revised March 2013, June 2013; Accepted August 2013. Address correspondence to: Dr. Lun-Jou Lo, Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, 5 Fu- Hsin Street, Guei-Shan, Taoyuan (333) Taiwan. E-mail lunjoulo@ cgmh.org.tw. Dr. Yah-Huei Wu-Chou, Department of Medical Research, Chang Gung Memorial Hospital, 5 Fu-Hsin Street, Guei- Shan, Taoyuan (333) Taiwan. E-mail yhwc8876@gmail.com. DOI: 10.1597/12-258 0 The Cleft Palate-Craniofacial Journal 00(00) pp. 000–000 Month 2013 Ó Copyright 2013 American Cleft Palate-Craniofacial Association