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European Journal of Medical Genetics xxx (2014) 1e3

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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 (

An unusual presentation of Kabuki syndrome: clinical overlap with CHARGE syndrome.

Kabuki syndrome is a rare genetic disorder characterized by intellectual disability and multiple congenital anomalies, including short stature, peculi...
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