(Received for Publication: October 22, 2015) Key words Kabuki syndrome, cleft palate, anorectal malformation, diaphragmatic hernia

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1 303 Case Report J. St. Marianna Univ. Vol. 6, pp , 2015 Kabuki Syndrome with Multiple Associated Surgical Anomalies (Cleft Palate, Anorectal Anomaly and Diaphragmatic Hernia): Case Report and Literature Review Shigeyuki Furuta 1, Hideaki Sato 1, Shiho Tsuji 1, Shutaro Manabe 1, Hiroshi Masaki 2, and Hiroaki Kitagawa 3 (Received for Publication: October 22, 2015) Abstract We report our experience with a case of Kabuki syndrome complicated by multiple anomalies requiring surgery. The patient was a male infant born at 41 weeks 5 days gestation, weighing 4,468 g, who presented with an imperforate anus and cleft palate. A radical operation was performed under a diagnosis of low imperforate anus without fistula. However, an anastomotic leakage occurred, requiring a colostomy. Despite the presence of an asymptomatic concomitant Morgagni hernia, the patient was placed under follow-up observation. Eight months after the infant s birth, the stoma was closed. Eleven months after birth, Kabuki syndrome was suspected because of the characteristic facial features, and a mutation in MLL2 was diagnosed. Key words Kabuki syndrome, cleft palate, anorectal malformation, diaphragmatic hernia Introduction In 1981, Niikawa et al. and Kuroki et al. reported a malformation syndrome in individuals presenting with facial features that resemble the makeup of Kabuki actors 1)2). The five cardinal features of this syndrome include the characteristic facial features, skeletal anomalies, short stature, mental retardation, and characteristic dermatoglyphic patterns. Because of the characteristic facial features, the syndrome has been named Kabuki syndrome (KS). It is an autosomal dominant disorder, and the responsible gene, MLL2 has been reported to be associated with methylation of histones located in region 12 of the long arm of chromosome 12 3). We encountered a patient in whom KS was associated with an MLL2 mutation and complicated by a cleft palate, an anorectal malformation, and a diaphragmatic hernia. We report the details of this case and discuss the associated malformations. Case Report The case is that of a male who was tranferred to our hospital with a cleft plate and an imperforate anus. He had a 39-year-old father, a 28-year-old mother, and two brothers, aged 5 and 3 years. His parents were Chinese citizens. The infant was born at 41 weeks 5 days gestational age, weighing 4,468 g (+3.8 standard deviation [SD]). Cyanosis was noted immediately after birth and oxygen was immediately administered, which resolved the cyanosis. The Apgar scores were 7 at 1 minute and 8 at 5 minutes after birth. Physical examination on admission showed the following: height, 54.5 cm (+2.6 SD); head circumference, 36.0 cm; body temperature, 36.1 C; respiratory rate, 55 breaths per minute; pulse rate, 140 beats per minute and regular; blood pressure, 76/31 mmhg; 1 Department of Pediatric Surgery, St. Marianna University Yokohama- City Seibu Hospital, Yokohama, Japan 2 Department of Neonatology, St. Marianna University Yokohama- City Seibu Hospital, Yokohama, Japan 3 Department of Pediatric Surgery, St. Marianna University School of Medicine, Kawasaki, Japan 201

2 304 Furuta S Sato H et al and percutaneous arterial oxygen saturation, 90% to 94% (oxygen 40% via face mask). The infant was of clear consciousness, and his body posture was normal. His muscle tone and movement of his upper and lower limbs were good. Peripheral cyanosis was noted, and congestion of the face was marked. Despite a flat anterior fontanel and large pinnae, the infant s face did not appear to be characteristic of KS. Although neither labial nor nasal malformation was observed, cleft palate was noted. No thoracic deformity was observed, and no heart murmur was detected. Breath sounds were reduced in the right lung, and transient tachypnea was noted. The abdomen was flat and soft, and no anomaly was observed in the genitalia. An imperforate anus was diagnosed. On the invertogram taken 24 hours after birth, the distance from the blind end of the rectum to the skin was 8 mm, and there was no fistula; thus, a low-type imperforate anus without fistula was diagnosed (Figure 1). We then performed chest radiography and computed tomography. A mass shadow with a well-defined margin was detected in the medial segment of the right lower lung field (Figure 2 1). Because the liver protruded from the right posterior aspect of the sternum into the thoracic cavity, Morgagni hernia was diagnosed (Figure 2 2). Neither electrocardiography nor echocardiography revealed any abnormalities. On the basis of these findings, a radical perineal operation for the imperforate anus was performed on day 1. Anastomotic leakage occurred on day 7, and a stoma was constructed from the sigmoid colon. The Figure 1. Invertogram at 24 hours after birth. The distance from the rectal blind pouch to skin was 8 mm. respiratory symptoms had resolved by 24 days, and oxygen administration was discontinued. The infant was discharged at 65 days of age. Although the infant presented with macrosomia (defined as height >2.6 SD and weight >3.8 SD above the mean at birth), postnatal growth deficiency was observed. By 13 months of age, both height and weight were within the normal range. Motor development was delayed. He was able to sit alone at 10 months, to crawl and to stand while holding onto furniture at 13 months, and to walk alone at 17 months. Figure 2. ( 1) Chest roentgenogram at birth. A mass shadow with a well-defined margin negative for the silhouette sign was detected in the medial segment of the right lower lung field. (2) Enhanced CT at birth. The liver protruded from the right posterior aspect of the sternum into the thoracic cavity. A Morgagni hernia was diagnosed. 202

3 Kabuki Syndrome with surgical anomalies 305 At 24 months of age, he was only making sounds and was not able to make clear speech. The stoma was closed at 8 months after infant s birth. At 11 months after birth, he was diagnosed as having KS because of his peculiar facial features (characterized by long palpebral fissures with eversion of the lateral third of the lower eyelids, a broad and depressed nasal tip, arched eyebrows, strabismus of the left eye, and large prominent earlobes) (MLL2 mutation: c.3532c>t). He currently defecates easily without the use of laxatives or enemas. Imaging studies show no worsening of the Morgagni hernia, and he does not currently have any clinical symptoms. Thus, he has been placed under follow-up observation. Discussion Although approximately 400 cases of KS have been reported in Japan and overseas 3)4), the prevalence is estimated to be 1/32,000 5). Most are isolated cases, and there are only a few reports of familial occurrence 6). The gene identified as responsible are MLL2 3) and KDM6A 3), and a molecular genetic test for MLL2 is clinically available. The MLL2 gene mutation has been found in 61.7% and the KDM6A gene mutation in 6.2% of patients clinically diagnosed as having KS 7). Because MLL2 and KDM6A are histone methyltransferases for H3K4 and H3K27, respectively, KS appears to be related to aberrant histone methylation. In our case, a MLL2 abnormality was noted due to the characteristic facial features, which lead to a definitive diagnosis 11 months after birth. The five cardinal features of KS and their frequencies are as follows: (1) characteristic facial features (observed in up to 100%of patients), which include long palpebral fissures with eversion of the lateral third of the lower eyelids (in almost 100%), arched eyebrows, of which the lateral half is sparse, a broad and depressed nasal tip, short nasal septum, and large prominent earlobes; (2) skeletal abnormalities (observed in up to 92%) including brachydactyly (especially shortening of the little finger and the middle phalanx), scoliosis, sagittal cleft of the vertebral bodies, and rib anomalies; (3) specific dermatoglyphic patterns (observed in up to 90%); (4) mental retardation (observed in up to 92%); and (5) short stature (postnatal growth deficiency) (observed in up to 88%) 4)5). The diagnosis is initially made on the basis of clinical findings, although first KS is suspected because of the characteristic facial features. The malformations associated with KS that have been reported including congenital heart defects; renal and genitourinary anomalies; cleft lip and/or cleft palate; digestive tract defects including anorectal malformation, blepharoptosis and strabismus; widely spaced teeth, and dental hypoplasia. Functional abnormalities include susceptibility to infection, autoimmune disease, convulsions, endocrine abnormalities (including early breast development in girls), eating problems, and hearing impairment. The associated malformations observed in our case were cleft palate, anorectal malformation, and diaphragmatic hernia (i.e., Morgagni hernia). The prevalence of a combination of KS and cleft palate is high, at 35% among the patients with KS 4), half of those with this combination present with an MLL2 gene mutation 7). A combination of KS and anorectal malformation has been reported in 9 patients 8 12) including ours, as shown in Table 1, and the prevalence of this combination is reported to range from 5% to 25% 4)13)14). Interestingly, all of these patients except ours were girls, all of whom had a vestibular fistula and many of whom had a cleft palate (6/9). Postoperative bowel function appears to be good in them. A combination of KS and diaphragmatic hernia has been reported in 8 cases including ours, as shown in Table 2 12)15 18). Half of them appear to be characterized by Morgagni hernia. Moreover, the diaphragmatic hernia in 2 other cases was located on the right side. Although a combination of KS and diaphragmatic hernia has been considered rare, the prevalence of this combination might be higher than we expect. When we focused on a combination of KS and other diaphragm diseases in addition to diaphragmatic hernia, we unexpectedly found more cases with concomitant diaphragmatic eventration. One report even noted an incidence of such cases of 25% 13). From the literature review, we identified 12 cases 9)13)19 26). Diaphragmatic eventration occurred on the right side in 78% (7/9) and on both sides with right-side predominance in 22% (2/9). In addition, among the 8 cases involving a diaphragmatic hernia Table 2, 6 lesions were located on the right side, including the 4 Morgagni hernias; the location was unknown in 2 cases (cases 5 and 7). The overwhelming predominance on the right side is interesting. Moreover, all patients with concomitant diaphragmtic anomalies survived, so the combination of KS and diaphragmatic defect does not appear to determine prognosis. The reason for the presence of multiple associated malformations, as seen in our case, remains unknown. However, because KS is complicated by vari 203

4 Furuta S Sato H et al 306 Table 1. Kabuki Syndrome Associated with Anorectal Anomalies Table 2. Kabuki Syndrome Associated with Diaphragmatic Defects ous malformations, the MLL2 mutation is assumed to affect multiple genes in multiple organs. In addition, the KS complicated by cleft palate, anorectal malfor mation, and diaphragmatic hernia in our patient did not appear to be a life-threatening problem. References 1) Niikawa N, Matsuura N, Fukushima Y, Ohsawa T, Kajii T. Kabuki make-up syndrome: A syn drome of mental retardation, unusual facies, large and protruding ears, and postnatal growth deficiency. J Pediatr 1981; 99: ) Kuroki Y, Suzuki Y, Chyo H, Hata A, Matsui I. A new malformation syndrome of long palpe Conflict of Interest The authors declare that they have no conflicts of interest. 204

5 Kabuki Syndrome with surgical anomalies 307 bral fissures, large ears, depressed nasal tip and skeletal anomalies associated with postnatal dwarfism and mental retardation. J Pediatr 1981; 99: ) Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ, Gildersleeve HI, Beck AE, Tabor HK, Cooper GM, Mefford HC, Lee C, Turner EH, Smith JD, Rieder MJ, Yoshiura K, Matsumoto N, Ohta T, Niikawa N, Nickerson DA, Bamshad MJ, Shendure J. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet 2010; 42: ) Matsumoto N, and Niikawa N. Kabuki make-up syndrome: A review. Am J Med Genet C Semin Med Genet 2003; 117C: ) Niikawa N, Kuroki Y, Kajii T, Matsuura N, Ishikiriyama S, Tonoki H, Ishikawa N, Yamada Y, Fujita M, Umemoto H, et al. Kabuki make-up (Nikawa-Kuroki) syndrome: a study of 62 patients. Am J Med Genet 1988; 31: ) Courtens W, Rassart A, Stene JJ, Vamos E. Further evidence for autosomal dominant inheritance and ectodermal abnormalities in Kabuki syndrome. Am J Med Genet 2000; 93: ) Miyake N, Koshimizu E, Okamoto N, Mizuno S, Ogata T, Nagai T, Kosho T, Ohashi H, Kato M, Sasaki G, Mabe H, Watanabe Y, Yoshino M, Matsuishi T, Takanashi J, Shotelersuk V, Tekin M, Ochi N, Kubota M, Ito N, Ihara K, Hara T, Tonoki H, Ohta T, Saito K, Matsuo M, Urano M, Enokizono T, Sato A, Tanaka H, Ogawa A, Fujita T, Hiraki Y, Kitanaka S, Matsubara Y, Makita T, Taguri M, Nakashima M, Tsurusaki Y, Saitsu H, Yoshiura K, Matsumoto N, Niikawa N. MLL2 and KDM6A mutations in patients with Kabuki syndrome. Am J Med Genet A A: ) Matsumura M, Yamada R, Kitani Y, Nishi T, Yamamoto H, Oahama Y, Kuroki Y. Anorectal anomalies associated with Kabuki make-up syndrome. J Pediatr Surg 1992; 27: ) Philip N, Meinecke P, David A, Dean J, Ayme S, Clark R, Gross-Kieselstein E, Hosenfeld D, Moncla A, Muller D. Kabuki make-up (Nikawa- Kuroki) syndrome: a study of 16 non-japanese cases. Clin Dysmorphol 1992; 1: ) Kokitsu-Nakata NM, Vendramini S, Guion-Almeida ML. Lower lip pits and anorectal anomalies in Kabuki syndrome. Am J Med Genet 1999; 86: ) Selicorni A, Colombo C, Bonato S, Milani D, Giunta AM, Bedeschi MF. Biliary atresia and Kabuki syndrome: another case with long-term follow-up. Am J Med Genet 2001; 100: ) Abdel-Salam GM, Afifi HH, Eid MM, el-badry TH, Kholoussi NM. Anorectal anomalies, Diaphragmatic defect, Cleft palate, Lower lop pits, Hypopigmentation and Hypogammaglobulinemia a in Kabuki syndrome: A rare combination. Genet Couns 2008; 19: ) Vaux KK, Hudgins L, Bird LM, Roeder E, Curry CJ, Jones M, Jones KL. Neonatal phenotype in Kabuki syndrome. Am J Med Genet 2005; 132A: ) Dentici ML, Di Pede A, Lepri FR, Gnazzo M, Lombardi MH, Auriti C, Petrocchi S, Pisaneschi E, Bellacchio E, Capolino R, Braguglia A, Angioni A, Dotta A, Digilio MC, Dallapiccola B. Kabuki syndrome: clinical and molecular diagnosis in the first year of life. Arch Dis Child 2015; 100: ) Tsukahara M, Kuroki Y, Imaizumi K, Miyazawa Y, Matsuo K. Dominant inheritance of Kabuki make-up syndrome. Am J Med Genet 1997; 73: ) Donadio A, Garavelli L, Banchini G, Neri G. Kabuki syndrome and Diaphragmatic Defects: A frequent association in non-asian patients? Am J Med Genet 2000; 91: ) van Haelst MM, Brooks AS, Hoogeboom J, Wessels MW, Tibboel D, de Jongste JC, den Hollander JC, Bongers-Schokking JJ, Niermeijer MF, Willems PJ. Unexpected life-threatening complications in Kabuki syndrome. Am J Med Genet 2000; 94: ) Geneviève D, Amiel J, Viot G, Le Merrer M, Sanlaville D, Urtizberea A, Gérard M, Munnich A, Cormier-Daire V, Lyonnet S. Atypical findings in Kabuki syndrome: report of 8 patients in a series of 20 and review of the literature. Am J Med Genet 2004; 129A: ) Halal F, Gledhill R, Dudkiewicz A. Autosomal dominant inheritance of the Kabuki make-up (Niikawa-Kuroki) syndrome. Am J Med Genet 1989; 33: ) McGaughran J, Aftimos S, Jefferies C, Winship I. Clinical phenotypes of nine cases of Kabuki syndrome from New Zealand. Clin Dysmorphol 2001; 10: ) Scherer S, Theile U, Beyer V, Ferrari R, Kreck C, Rister M. Patient with Kabuki syndrome and acute leukemia. Am J Med Genet 2003; 122A: 205

6 308 Furuta S Sato H et al ) David G, Sillence D, Hardwick R, Opitz JM. A case of Kabuki (Niikawa-Kuroki) syndrome associated with manifestations resembling C-trigonocephaly syndrome. Am J Med Genet 2004; 130A: ) Shalev SA, Clarke LA, Koehn D, Langlois S, Zackai EH, Hall JG, McDonald McGinn DM. Long-term follow-up of three individuals with Kabuki syndrome. Am J Med Genet 2004; 125A: ) Sethi SK, Faridi MM. Kabuki syndrome and diaphragmatic defect. Indian Pediatr 2006; 43; ) Chaudhry IA, Shamsi FA, Alkuraya HS, Al- Sharif A. Ocular manifestations in Kabuki syndrome: the first report from Saudi Arabia. Int Ophthalmol 2008; 28: ) Zarate YA, Zhan H, Jones JR. Infrequent manifestations of Kabuki syndrome in a patient with novel MLL2 mutation. Mol Syndromol 2012; 3: