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An unusual presentation of Kabuki syndrome: Clinical overlap with CHARGE syndrome
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European Journal of Medical Genetics xxx (2014) 1e3
Contents lists available at ScienceDirect
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Clinical report
An unusual presentation of Kabuki syndrome: Clinical overlap with CHARGE syndrome Q2
Judith M.A. Verhagen a, Wilma Oostdijk b, Cecilia E.J. Terwisscha van Scheltinga c, Nicoline E. Schalij-Delfos d, Yolande van Bever a, * a
Department of Clinical Genetics, Erasmus Medical Center Rotterdam, The Netherlands Department of Pediatrics, Leiden University Medical Center, The Netherlands Department of Pediatric Surgery, Erasmus Medical Center Rotterdam, The Netherlands d Department of Ophthalmology, Leiden University Medical Center, The Netherlands b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 November 2013 Accepted 15 May 2014 Available online xxx
Kabuki syndrome is a rare genetic disorder characterized by intellectual disability and multiple congenital anomalies, including short stature, peculiar facial appearance, skeletal anomalies, a variety of visceral malformations and abnormal dermatoglyphic patterns. We describe a case of Kabuki syndrome presenting with atypical features, consisting of bilateral microphthalmia, coloboma, anal atresia and panhypopituitarism, showing considerable phenotypic overlap with CHARGE syndrome. This report demonstrates that clinical follow-up and molecular genetic testing can be useful for establishing the correct diagnosis. Ó 2014 Published by Elsevier Masson SAS.
Keywords: Kabuki syndrome Microphthalmia Coloboma Anal atresia Panhypopituitarism
1. Introduction Kabuki syndrome (KS, OMIM 147820) was first described in 1981 by Niikawa and Kuroki. Since then, several hundreds of patients have been reported. Characteristic features include mild to moderate intellectual disability, postnatal growth retardation, minor skeletal anomalies, persistent fetal fingerpads, and distinctive facial features with long palpebral fissures, everted lateral lower eyelids, arched eyebrows, short columella with depressed nasal tip and prominent ears [Adam and Hudgins, 2005]. Congenital heart defects, predominantly left-sided obstructions and septal defects, are present in 45e50% of patients with Kabuki syndrome. Urogenital malformations are reported in approximately 40% of patients. The most common findings include horseshoe kidney, renal dysplasia, hydronephrosis, cryptorchidism and hypospadias. Other frequently observed features include feeding problems (82%), joint laxity (84%), abnormal dentition (58%), cleft lip/palate (37%), ptosis (42%), strabismus (33%), recurrent infections (61%) and premature thelarche (29%) [Bögershausen and Wollnik, 2013; Makrythanasis et al., 2013].
* Corresponding author. Department of Clinical Genetics, Erasmus Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. Tel.: þ31 10 7036915. E-mail address: [email protected] (Y. van Bever).
Recently, mutations in the genes KMT2D and KDM6A, encoding proteins involved in histone modification, were identified in patients with Kabuki syndrome [Lederer et al., 2012; Ng et al., 2010]. KMT2D is the major causative gene accounting for approximately 67% of cases [Bögershausen and Wollnik, 2013]. KDM6A mutations account for another 10% of cases [Miyake et al., 2013]. In about one-quarter of patients with suspected Kabuki syndrome the underlying genetic cause remains unknown. We describe a KMT2D positive case of Kabuki syndrome with atypical features and discuss the clinical overlap with CHARGE syndrome. 2. Clinical report A newborn male was admitted to our pediatric department because of mild respiratory distress and multiple congenital anomalies. He was the second child of healthy, nonconsanguineous parents of Caucasian origin. The family history was unremarkable. He was born at 41 þ 2 weeks of gestation by vaginal delivery after an uneventful pregnancy. His birth weight was 3290 g (25e50th percentile) and head circumference 34.5 cm (10e25th percentile). Apgar scores were 4, 4 and 7 at 1, 5, and 10 min, respectively. He had transient neonatal hypoglycemia. On physical examination he displayed abnormal eyes, retrognathia, dysplastic ears, micropenis, retractile testicles, anal atresia with
http://dx.doi.org/10.1016/j.ejmg.2014.05.005 1769-7212/Ó 2014 Published by Elsevier Masson SAS.
Please cite this article in press as: Verhagen JMA, et al., An unusual presentation of Kabuki syndrome: Clinical overlap with CHARGE syndrome, European Journal of Medical Genetics (2014), http://dx.doi.org/10.1016/j.ejmg.2014.05.005
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rectoscrotal fistula and rocker bottom deformity of the right foot (Fig. 1AeB). Surgical correction of the anorectal malformation was performed on day 2. Laboratory investigations showed hypoglycemia, central hypothyroidism, hypocortisolism and low levels of insulin-like growth factor-I (IGF-I), indicative of panhypopituitarism. Magnetic resonance imaging (MRI) of the brain subsequently revealed an ectopic pituitary gland. The inner ears appeared normal. Spinal X-ray showed multiple segmentation defects in the sacral region. A renal ultrasound was normal. Ophthalmological examination revealed severe bilateral microphthalmia with iris and retinochoroidal coloboma. At the age of 6 weeks he developed nystagmus. Cardiologic examination demonstrated a bicuspid aortic valve with mild aortic insufficiency. He failed the neonatal hearing screening. Brainstem evoked response audiometry (BERA) revealed moderate bilateral hearing loss (range 50e70 dB). Hormone supplements (i.e. hydrocortisone, levothyroxine and growth hormone) and hearing aids were prescribed. Because of feeding problems he received nasogastric tube feeding until age 9 months. Our initial list of differential diagnoses included CHARGE syndrome, cat eye syndrome, 22q11.2 deletion syndrome, Pallistere Hall syndrome and syndromic microphthalmia. Microarray analysis (Affymetrix GeneChip 260k) showed a normal male profile. Multiplex ligation-dependent probe amplification (MLPA) analysis using the SALSA P250-A1 probemix showed no copy number variation of the 22q11.2 region. Mutation analysis of CHD7 revealed a paternally inherited unclassified variant c.1397C>T (p.Ser466Leu) in exon 2. This variant is now classified as a polymorphism (CDH7
database: www.chd7.org). Mutation analysis of GLI3 and SOX2 was normal. Hence, no definitive diagnosis could be made at this time. On re-evaluation at the age of 2 years 1 month he had evident developmental delay. He was able to pull himself up and walk with support. Speech was absent. His visual acuity corresponded to the age of 3 months. He had frequent temper tantrums en recurrent infections. His length was 79 cm (<3rd percentile) and weight 9.78 kg (10e25th percentile). He was noted to have a long left palpebral fissure, everted lateral lower eyelids, hypodontia and fetal fingerpads (Fig. 1CeD). His facial features led us to a clinical suspicion of Kabuki syndrome. This diagnosis was confirmed by mutation analysis of KMT2D, which revealed a de novo pathogenic deletion c.12986_13010del25 resulting in a premature stop codon (p.Gln4329Leufs*47). On follow-up visits, he did not show catch-up growth in height despite proper growth hormone dosages. Because of persisting feeding problems a percutaneous endoscopic gastrostomy (PEG) tube was placed at the age of 2 years 8 months. 3. Discussion The clinical phenotype of Kabuki syndrome is often well recognizable. However, Kabuki syndrome is rarely diagnosed in the newborn period. The characteristic facial features, in particular the striking elongation of palpebral fissures, tend to become more pronounced with age [Vaux et al., 2005]. Other less specific features are usually present from birth. Our case report underscores the importance of clinical follow-up, although we acknowledge that distinctive facial dysmorphisms were already evident in the neonatal period on retrospective evaluation (Fig. 1AeB). The diagnosis was further complicated by the presence of several atypical features, including bilateral microphthalmia, coloboma, anal atresia and panhypopituitarism. Any of these features are known but infrequent manifestations of Kabuki syndrome, with an estimated prevalence of less than 5% [Ito et al., 2013; Ming et al., 2003]. The phenotypic variability of Kabuki syndrome might at least partially be explained by the effect of modifier genes. However, we cannot exclude the possibility that our patient carries another mutation in a different gene that is responsible for the unusual features. The application of new sequencing technologies might lead to the identification of more patients with atypical clinical presentations of Kabuki syndrome who would otherwise have remained undiagnosed. These findings might further broaden the phenotypic spectrum of Kabuki syndrome. However, it will be a huge challenge to determine whether observed variants are truly disease-causing and explain all features. Kabuki syndrome shows many similarities with CHARGE syndrome (OMIM 214800), as illustrated by several previous published cases [Genevieve et al., 2004; Ming et al., 2003]. The major criteria Table 1 Clinical features of Kabuki and CHARGE syndrome compared to our patient.
Fig. 1. Facial features of the patient at age 1 day (AeB) and 2 years 1 month (CeD): frontal bossing, bilateral microphthalmia with iris coloboma, long left palpebral fissure, eversion of the lateral lower eyelids, prominent dysplastic ears, and retrognathia.
Feature
Kabuki syndromea
CHARGE syndromeb
Present case
Developmental delay Growth retardation Cleft lip and/or palate Choanal atresia Ocular coloboma Congenital heart defects Urogenital malformations Anorectal malformations
99% 70% 37% NR NR* 46% 44% NR*
99% 37% 48% 55% 81% 76% 81% NR
þ þ þ þ þ þ
NR ¼ not reported (* frequency <5% in previous studies, see main text). a MLL2 positive cohort from meta-analysis by Bögershausen and Wollnik [2013]. b CDH7 positive cohort (n ¼ 280) described by Bergman et al. [2011].
Please cite this article in press as: Verhagen JMA, et al., An unusual presentation of Kabuki syndrome: Clinical overlap with CHARGE syndrome, European Journal of Medical Genetics (2014), http://dx.doi.org/10.1016/j.ejmg.2014.05.005
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of CHARGE syndrome are coloboma, choanal atresia, semicircular canal defects and cranial nerve dysfunction [Bergman et al., 2011]. Clinical features shared with Kabuki syndrome include developmental delay, intellectual disability, postnatal growth retardation, cleft lip/palate, congenital heart defects and urogenital malformations. Regarding the combination of coloboma (C), heart defect (H), growth retardation (R), genital hypoplasia (G) and hearing loss (E), CHARGE syndrome was initially considered a likely diagnosis in our patient (Table 1). However, he fulfilled only one major criterion and therefore could not be clinically diagnosed as having CHARGE syndrome. Since the identification of the major genes underlying Kabuki syndrome and CHARGE syndrome, molecular genetic testing can help to establish the correct diagnosis. Our report illustrates that Kabuki syndrome should be considered in patients with features of CHARGE syndrome without CDH7 mutation. Conflict of interest The authors declare no conflict of interest. Acknowledgements
3
References Adam MP, Hudgins L. Kabuki syndrome: a review. Clin Genet 2005;67:209e19. Bergman JE, Janssen N, Hoefsloot LH, Jongmans MC, Hofstra RM, van RavenswaaijArts CM. CHD7 mutations and CHARGE syndrome: the clinical implications of an expanding phenotype. J Med Genet 2011;48:334e42. Bögershausen N, Wollnik B. Unmasking Kabuki syndrome. Clin Genet 2013;83:201e 11. Genevieve D, Amiel J, Viot G, Le Merrer M, Sanlaville D, Urtizberea A, et al. Atypical findings in Kabuki syndrome: report of 8 patients in a series of 20 and review of the literature. Am J Med Genet A 2004;129A:64e8. Ito N, Ihara K, Tsutsumi Y, Miyake N, Matsumoto N, Hara T. Hypothalamic pituitary complications in Kabuki syndrome. Pituitary 2013;16:133e8. Lederer D, Grisart B, Digilio MC, Benoit V, Crespin M, Ghariani SC, et al. Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome. Am J Hum Genet 2012;90:119e24. Makrythanasis P, van Bon B, Steehouwer M, Rodriguez-Santiago B, Simpson M, Dias P, et al. MLL2 mutation detection in 86 patients with Kabuki syndrome: a genotype-phenotype study. Clin Genet 2013. Q1 Ming JE, Russell KL, Bason L, McDonald-McGinn DM, Zackai EH. Coloboma and other ophthalmologic anomalies in Kabuki syndrome: distinction from charge association. Am J Med Genet A 2003;123A:249e52. Miyake N, Mizuno S, Okamoto N, Ohashi H, Shiina M, Ogata K, et al. KDM6A point mutations cause Kabuki syndrome. Hum Mutat 2013;34:108e10. Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ, Gildersleeve HI, et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet 2010;42:790e3. Vaux KK, Hudgins L, Bird LM, Roeder E, Curry CJ, Jones M, et al. Neonatal phenotype in Kabuki syndrome. Am J Med Genet A 2005;132A:244e7.
We are grateful to the family for participating in this study. We wish to thank T. de Vries Lentsch for his assistance with the illustrations.
Please cite this article in press as: Verhagen JMA, et al., An unusual presentation of Kabuki syndrome: Clinical overlap with CHARGE syndrome, European Journal of Medical Genetics (2014), http://dx.doi.org/10.1016/j.ejmg.2014.05.005
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European Journal of Medical Genetics xxx (2014) 1e3
Contents lists available at ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Clinical report
An unusual presentation of Kabuki syndrome: Clinical overlap with CHARGE syndrome Q2
Judith M.A. Verhagen a, Wilma Oostdijk b, Cecilia E.J. Terwisscha van Scheltinga c, Nicoline E. Schalij-Delfos d, Yolande van Bever a, * a
Department of Clinical Genetics, Erasmus Medical Center Rotterdam, The Netherlands Department of Pediatrics, Leiden University Medical Center, The Netherlands Department of Pediatric Surgery, Erasmus Medical Center Rotterdam, The Netherlands d Department of Ophthalmology, Leiden University Medical Center, The Netherlands b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 November 2013 Accepted 15 May 2014 Available online xxx
Kabuki syndrome is a rare genetic disorder characterized by intellectual disability and multiple congenital anomalies, including short stature, peculiar facial appearance, skeletal anomalies, a variety of visceral malformations and abnormal dermatoglyphic patterns. We describe a case of Kabuki syndrome presenting with atypical features, consisting of bilateral microphthalmia, coloboma, anal atresia and panhypopituitarism, showing considerable phenotypic overlap with CHARGE syndrome. This report demonstrates that clinical follow-up and molecular genetic testing can be useful for establishing the correct diagnosis. Ó 2014 Published by Elsevier Masson SAS.
Keywords: Kabuki syndrome Microphthalmia Coloboma Anal atresia Panhypopituitarism
1. Introduction Kabuki syndrome (KS, OMIM 147820) was first described in 1981 by Niikawa and Kuroki. Since then, several hundreds of patients have been reported. Characteristic features include mild to moderate intellectual disability, postnatal growth retardation, minor skeletal anomalies, persistent fetal fingerpads, and distinctive facial features with long palpebral fissures, everted lateral lower eyelids, arched eyebrows, short columella with depressed nasal tip and prominent ears [Adam and Hudgins, 2005]. Congenital heart defects, predominantly left-sided obstructions and septal defects, are present in 45e50% of patients with Kabuki syndrome. Urogenital malformations are reported in approximately 40% of patients. The most common findings include horseshoe kidney, renal dysplasia, hydronephrosis, cryptorchidism and hypospadias. Other frequently observed features include feeding problems (82%), joint laxity (84%), abnormal dentition (58%), cleft lip/palate (37%), ptosis (42%), strabismus (33%), recurrent infections (61%) and premature thelarche (29%) [Bögershausen and Wollnik, 2013; Makrythanasis et al., 2013].
* Corresponding author. Department of Clinical Genetics, Erasmus Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. Tel.: þ31 10 7036915. E-mail address: [email protected] (Y. van Bever).
Recently, mutations in the genes KMT2D and KDM6A, encoding proteins involved in histone modification, were identified in patients with Kabuki syndrome [Lederer et al., 2012; Ng et al., 2010]. KMT2D is the major causative gene accounting for approximately 67% of cases [Bögershausen and Wollnik, 2013]. KDM6A mutations account for another 10% of cases [Miyake et al., 2013]. In about one-quarter of patients with suspected Kabuki syndrome the underlying genetic cause remains unknown. We describe a KMT2D positive case of Kabuki syndrome with atypical features and discuss the clinical overlap with CHARGE syndrome. 2. Clinical report A newborn male was admitted to our pediatric department because of mild respiratory distress and multiple congenital anomalies. He was the second child of healthy, nonconsanguineous parents of Caucasian origin. The family history was unremarkable. He was born at 41 þ 2 weeks of gestation by vaginal delivery after an uneventful pregnancy. His birth weight was 3290 g (25e50th percentile) and head circumference 34.5 cm (10e25th percentile). Apgar scores were 4, 4 and 7 at 1, 5, and 10 min, respectively. He had transient neonatal hypoglycemia. On physical examination he displayed abnormal eyes, retrognathia, dysplastic ears, micropenis, retractile testicles, anal atresia with
http://dx.doi.org/10.1016/j.ejmg.2014.05.005 1769-7212/Ó 2014 Published by Elsevier Masson SAS.
Please cite this article in press as: Verhagen JMA, et al., An unusual presentation of Kabuki syndrome: Clinical overlap with CHARGE syndrome, European Journal of Medical Genetics (2014), http://dx.doi.org/10.1016/j.ejmg.2014.05.005
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rectoscrotal fistula and rocker bottom deformity of the right foot (Fig. 1AeB). Surgical correction of the anorectal malformation was performed on day 2. Laboratory investigations showed hypoglycemia, central hypothyroidism, hypocortisolism and low levels of insulin-like growth factor-I (IGF-I), indicative of panhypopituitarism. Magnetic resonance imaging (MRI) of the brain subsequently revealed an ectopic pituitary gland. The inner ears appeared normal. Spinal X-ray showed multiple segmentation defects in the sacral region. A renal ultrasound was normal. Ophthalmological examination revealed severe bilateral microphthalmia with iris and retinochoroidal coloboma. At the age of 6 weeks he developed nystagmus. Cardiologic examination demonstrated a bicuspid aortic valve with mild aortic insufficiency. He failed the neonatal hearing screening. Brainstem evoked response audiometry (BERA) revealed moderate bilateral hearing loss (range 50e70 dB). Hormone supplements (i.e. hydrocortisone, levothyroxine and growth hormone) and hearing aids were prescribed. Because of feeding problems he received nasogastric tube feeding until age 9 months. Our initial list of differential diagnoses included CHARGE syndrome, cat eye syndrome, 22q11.2 deletion syndrome, Pallistere Hall syndrome and syndromic microphthalmia. Microarray analysis (Affymetrix GeneChip 260k) showed a normal male profile. Multiplex ligation-dependent probe amplification (MLPA) analysis using the SALSA P250-A1 probemix showed no copy number variation of the 22q11.2 region. Mutation analysis of CHD7 revealed a paternally inherited unclassified variant c.1397C>T (p.Ser466Leu) in exon 2. This variant is now classified as a polymorphism (CDH7
database: www.chd7.org). Mutation analysis of GLI3 and SOX2 was normal. Hence, no definitive diagnosis could be made at this time. On re-evaluation at the age of 2 years 1 month he had evident developmental delay. He was able to pull himself up and walk with support. Speech was absent. His visual acuity corresponded to the age of 3 months. He had frequent temper tantrums en recurrent infections. His length was 79 cm (<3rd percentile) and weight 9.78 kg (10e25th percentile). He was noted to have a long left palpebral fissure, everted lateral lower eyelids, hypodontia and fetal fingerpads (Fig. 1CeD). His facial features led us to a clinical suspicion of Kabuki syndrome. This diagnosis was confirmed by mutation analysis of KMT2D, which revealed a de novo pathogenic deletion c.12986_13010del25 resulting in a premature stop codon (p.Gln4329Leufs*47). On follow-up visits, he did not show catch-up growth in height despite proper growth hormone dosages. Because of persisting feeding problems a percutaneous endoscopic gastrostomy (PEG) tube was placed at the age of 2 years 8 months. 3. Discussion The clinical phenotype of Kabuki syndrome is often well recognizable. However, Kabuki syndrome is rarely diagnosed in the newborn period. The characteristic facial features, in particular the striking elongation of palpebral fissures, tend to become more pronounced with age [Vaux et al., 2005]. Other less specific features are usually present from birth. Our case report underscores the importance of clinical follow-up, although we acknowledge that distinctive facial dysmorphisms were already evident in the neonatal period on retrospective evaluation (Fig. 1AeB). The diagnosis was further complicated by the presence of several atypical features, including bilateral microphthalmia, coloboma, anal atresia and panhypopituitarism. Any of these features are known but infrequent manifestations of Kabuki syndrome, with an estimated prevalence of less than 5% [Ito et al., 2013; Ming et al., 2003]. The phenotypic variability of Kabuki syndrome might at least partially be explained by the effect of modifier genes. However, we cannot exclude the possibility that our patient carries another mutation in a different gene that is responsible for the unusual features. The application of new sequencing technologies might lead to the identification of more patients with atypical clinical presentations of Kabuki syndrome who would otherwise have remained undiagnosed. These findings might further broaden the phenotypic spectrum of Kabuki syndrome. However, it will be a huge challenge to determine whether observed variants are truly disease-causing and explain all features. Kabuki syndrome shows many similarities with CHARGE syndrome (OMIM 214800), as illustrated by several previous published cases [Genevieve et al., 2004; Ming et al., 2003]. The major criteria Table 1 Clinical features of Kabuki and CHARGE syndrome compared to our patient.
Fig. 1. Facial features of the patient at age 1 day (AeB) and 2 years 1 month (CeD): frontal bossing, bilateral microphthalmia with iris coloboma, long left palpebral fissure, eversion of the lateral lower eyelids, prominent dysplastic ears, and retrognathia.
Feature
Kabuki syndromea
CHARGE syndromeb
Present case
Developmental delay Growth retardation Cleft lip and/or palate Choanal atresia Ocular coloboma Congenital heart defects Urogenital malformations Anorectal malformations
99% 70% 37% NR NR* 46% 44% NR*
99% 37% 48% 55% 81% 76% 81% NR
þ þ þ þ þ þ
NR ¼ not reported (* frequency <5% in previous studies, see main text). a MLL2 positive cohort from meta-analysis by Bögershausen and Wollnik [2013]. b CDH7 positive cohort (n ¼ 280) described by Bergman et al. [2011].
Please cite this article in press as: Verhagen JMA, et al., An unusual presentation of Kabuki syndrome: Clinical overlap with CHARGE syndrome, European Journal of Medical Genetics (2014), http://dx.doi.org/10.1016/j.ejmg.2014.05.005
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of CHARGE syndrome are coloboma, choanal atresia, semicircular canal defects and cranial nerve dysfunction [Bergman et al., 2011]. Clinical features shared with Kabuki syndrome include developmental delay, intellectual disability, postnatal growth retardation, cleft lip/palate, congenital heart defects and urogenital malformations. Regarding the combination of coloboma (C), heart defect (H), growth retardation (R), genital hypoplasia (G) and hearing loss (E), CHARGE syndrome was initially considered a likely diagnosis in our patient (Table 1). However, he fulfilled only one major criterion and therefore could not be clinically diagnosed as having CHARGE syndrome. Since the identification of the major genes underlying Kabuki syndrome and CHARGE syndrome, molecular genetic testing can help to establish the correct diagnosis. Our report illustrates that Kabuki syndrome should be considered in patients with features of CHARGE syndrome without CDH7 mutation. Conflict of interest The authors declare no conflict of interest. Acknowledgements
3
References Adam MP, Hudgins L. Kabuki syndrome: a review. Clin Genet 2005;67:209e19. Bergman JE, Janssen N, Hoefsloot LH, Jongmans MC, Hofstra RM, van RavenswaaijArts CM. CHD7 mutations and CHARGE syndrome: the clinical implications of an expanding phenotype. J Med Genet 2011;48:334e42. Bögershausen N, Wollnik B. Unmasking Kabuki syndrome. Clin Genet 2013;83:201e 11. Genevieve D, Amiel J, Viot G, Le Merrer M, Sanlaville D, Urtizberea A, et al. Atypical findings in Kabuki syndrome: report of 8 patients in a series of 20 and review of the literature. Am J Med Genet A 2004;129A:64e8. Ito N, Ihara K, Tsutsumi Y, Miyake N, Matsumoto N, Hara T. Hypothalamic pituitary complications in Kabuki syndrome. Pituitary 2013;16:133e8. Lederer D, Grisart B, Digilio MC, Benoit V, Crespin M, Ghariani SC, et al. Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome. Am J Hum Genet 2012;90:119e24. Makrythanasis P, van Bon B, Steehouwer M, Rodriguez-Santiago B, Simpson M, Dias P, et al. MLL2 mutation detection in 86 patients with Kabuki syndrome: a genotype-phenotype study. Clin Genet 2013. Q1 Ming JE, Russell KL, Bason L, McDonald-McGinn DM, Zackai EH. Coloboma and other ophthalmologic anomalies in Kabuki syndrome: distinction from charge association. Am J Med Genet A 2003;123A:249e52. Miyake N, Mizuno S, Okamoto N, Ohashi H, Shiina M, Ogata K, et al. KDM6A point mutations cause Kabuki syndrome. Hum Mutat 2013;34:108e10. Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ, Gildersleeve HI, et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet 2010;42:790e3. Vaux KK, Hudgins L, Bird LM, Roeder E, Curry CJ, Jones M, et al. Neonatal phenotype in Kabuki syndrome. Am J Med Genet A 2005;132A:244e7.
We are grateful to the family for participating in this study. We wish to thank T. de Vries Lentsch for his assistance with the illustrations.
Please cite this article in press as: Verhagen JMA, et al., An unusual presentation of Kabuki syndrome: Clinical overlap with CHARGE syndrome, European Journal of Medical Genetics (2014), http://dx.doi.org/10.1016/j.ejmg.2014.05.005
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