Abstract A case of a female diagnosed with Kabuki syndrome at 4 years old, with global developmental delay, distinctive facial features, and congenital anomalies. Her physical examination and past medical history were consistent with characteristic features of the rare, Kabuki syndrome. She was found to have a novel gene mutation in the MLL2 gene. The mutation was a truncating alternation in exon 48. Novel MLL2 mutation in a 4 year old patient with Kabuki Syndrome Candace Gamble, MD UTHSC-Houston, Combined Pediatrics and Medical Genetics, PGY-3 Results Cytogenetics: Chromosomal Microarray- Normal female Molecular Genetics: MLL2 Sequencing- Heterozygous for the c.15585C>T, p.Q5195X alteration in exon 48. Introduction Kabuki syndrome is a rare, multiple congenital anomaly disorder characterized by typical facial features, minor skeletal anomalies, congenital heart defects, mild to moderate intellectual disability, and post natal growth deficiency. The distinctive facial features include long palpebral fissures with eversion of the lower lid, arched eyebrows with sparseness of the lateral third, depressed nasal tip, and prominent ears. It was originally described in 1981 by Japanese scientists, Yoshikazu Kuroki and Norio Niikawa [Kuroki et al., 1981]. Although, seen across multiple ethnicities, the name is derived from resemblance to the make-up laden, Japanese kabuki theater characters. MLL2 is the only known gene in which mutations cause Kabuki syndrome [Bokinni, 2012 and Ng et al, 2010]. The MLL2 gene encodes a large protein important in epigenetic control of active chromatin states. There are currently 210 reported mutations in the Human Genetic Database and about 400 cases reported worldwide, with almost half being missense or nonsense mutations [Ng et al, 2010]. Of the few genotype-phenotype correlations studies, Kabuki patients with MLL2 mutations have a higher rate of renal anomalies, and those with nonsense or missense mutations were more severely affected [Markythanasis, 2013]. Kabuki syndrome is inherited in an autosomal dominant pattern, with estimated high but unknown de novo mutation rate. Although rare with an incidence of 1 in 30,000-86,000, Kabuki is a readily identifiable genetic syndrome, and serves as an important part of the pediatrician’s knowledge base to ensure appropriate referrals, surveillance, and medical care [Adam, 2011]. We present a 4 year old female with multiple medical problems commonly seen in the pediatric population, who we diagnosed with Kabuki syndrome, after initial medical genetics evaluation. Clinical Report The female patient was born to 34 year old G5P4 and 40 year old male. Prenatal history was normal with routine care. The patient’s mother recalls that fetal movement began later and was less active than her previous pregnancies. The patient was born at 38 weeks gestation, via SVD. Birth weight was 3945 grams (75-90%), length 52 cm (25-50%), and FOC 33.5 cm (50-75%). Physical exam at birth was remarkable for a sacral dimple, cleft palate, and dysmorphic features. Karyotype at birth showed normal female. Her neonatal course was complicated by hypoglycemia and she was discharged home at 14 days of life. The patient presented at 4 years of age to Medical Genetics with global developmental delay and joint laxity. Past medical history was significant for feeding difficulties, cleft palate repair at 11 months, strabismus correction at 12 months, PE tubes placed at 11 months, 3 years and 4 years. She also had recently begun having seizure-like activities, described as head drops by her parents. Development was delayed in gross, fine motor, and speech. She walked at 2 years of age and first words were at 4 years and used an assisted technology device for communication. She received speech, occupational, and physical therapy once weekly. On examination, the weight was 18.6 kg (25%), height cm (5%), and FOC 50.5 cm (25-50%). The patient was normocephalic with large, prominent and slightly cupped ears (Figure 1). The right ear was significant for a tubercle on the mid-helix (Figure 2). There were long palpebral fissures and eversion of the lower eyelids. The eyebrows were arched with sparseness in the lateral third. There was a broad nasal tip and dental crowding was present. A well healed surgical scar was noted to the mid-palate extending to the uvula. Persistent fetal fingertip pads bilaterally (Figure 3) and persistent fetal toe pads on the great toes were noted. There was 5 th finger brachydactyly with broad great toes bilaterally. The elbow and knee joints were hyperextensible bilaterally. Tone and gross motor were intact, but speech was unintelligible. Conclusions Kabuki syndrome is associated with multiple congenital anomalies, developmental delay, and dymorphisms that should heighten the clinician’s awareness for an underlying genetic condition. Early diagnosis is important in order to initiate early intervention for developmental delay and intellectual disabilities seen in greater than 90% of cases [Bokinni, 2012]. It is also important in screening for structural anomalies including cardiac, genitourinary, gastrointestinal, musculoskeletal, and ophthalmic. Physiological differences include seizures, hearing loss, feeding difficulties, and increased susceptibility to infections [Adam, 2011]. This case also highlights some of the rare manifestations of Kabuki syndrome including neonatal hypoglycemia, seen in 7-8% of cases [Zarate, 2012]. A novel mutation in MLL2 was identified in our patient. The mutation c.15585C>T, p.Q5195X, has never been reported in the literature and is not listed in the Human Genetic Mutation Database. It is a nonsense mutation, thus confirming the diagnosis. Interestingly, the mutation was found in exon 48, which has a high frequency of known mutations, along with exon 39. The mechanism behind the increased frequency of mutations in exon 48 remains unknown [Hannibal et al, 2011]. However, it does elicit an area for further research to analyze genotype-phenotype correlations, diagnostic testing strategies, and possible gene therapy targets. Lastly our case highlights the importance of molecular diagnosis. Although the facial features of Kabuki are very distinctive, the additional clinical manifestations may overlap with other genetic syndromes including CHARGE, 22q11 deletion, and X-chromosome abnormalities [Adam, 2011]. A chromosomal microarray to evaluate for microduplication and microdeletion sydromes is indicated along with MLL2 sequencing analysis to confirm the diagnosis. Molecular diagnosis gives the opportunity to accurately provide families with recurrence risk, prognosis, and definitive answers for those who have endured a long diagnostic odyssey. References 1. Kuroki K, Yasuki S, Chyo H, Hata A, Matsui I A new malformation syndrome of long palpebral fissures, large ears, depressed nasal tip, and skeletal anomalies associated with postnatal dwarfism and mental retardation. The Journal of Pediatrics 99(4): Bokinni, Y. Kabuki syndrome revisited Journal of Human Genetics 55: Ng et al Exome sequencing identifies MLL2 muations as cause of Kabuki syndrome. Nat Genet 42(9): Makrythanasis P et al MLL2 mutation detection in 86 patients with Kabuki syndrome: a genotype-phenotype study. Clinical Genetics. 5. Adam M, Hudgins L, Hannibal M Kabuki syndrome. (Updated 1 September 2011). Kabuki Syndrome. In GeneReviews at GeneTests Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle Available at Accessed 26 April Zarate YA, Zhan H, Jones JR Infrequent manifestations of labuki syndrome in a patient with novel MLL2 mutation. Mol Syndromology 3: Hannibal et al, Spectrum of MLL2(ALR) mutations in 110 case of Kabuki syndrome. Am J Med Genet A 155(7): Texas Pediatric Society Electronic Poster Contest Figure 2 Figure 1 Figure 3