CASE REPORT Pediatrics DOI: 10.3346/jkms.2010.25.12.1821 • J Korean Med Sci 2010; 25: 1821-1823 Cornelia de Lange Syndrome with NIPBL Gene Mutation: A Case Report Kyung-Hee Park1, Seung-Tae Lee2, Cornelia de Lange Syndrome (CdLS) is a multiple congenital anomaly characterized by Chang-Seok Ki2, and Shin-Yun Byun3 distinctive facial features, upper limb malformations, growth and cognitive retardation. The diagnosis of the syndrome is based on the distinctive clinical features. The etiology is Department of Pediatrics1, Pusan National University Hospital, Busan; Department of still not clear. Mutations in the sister chromatid cohesion factor genes NIPBL, SMC1A (also Laboratory Medicine2, Samsung Medical Center, called SMC1L1) and SMC3 have been suggested as probable cause of this syndrome. We Sungkyunkwan University, Seoul; Department of experienced a case of newborn with CdLS showing bushy eyebrows and synophrys, long Pediatrics3, Pusan National University Yangsan curly eyelashes, long philtrum, downturned angles of the mouth and thin upper lips, cleft Hospital, Yangsan, Korea palate, micrognathia, excessive body hair, micromelia of both hands, flexion contracture Received: 24 March 2010 of elbows and hypertonicity. We detected a NIPBL gene mutation in a present neonate Accepted: 24 May 2010 with CdLS, the first report in Korea. Address for Correspondence: Shin-Yun Byun, M.D. Key Words: De Lange Syndrome; Genes; NIPBL Department of Pediatrics, Pusan National University Yangsan Hospital, Beomeo-ri, Mulgeum-eup, Yangsan 626-770, Korea Tel: +82.55-360-2180, Fax: +82.55-360-2181 E-mail: [email protected] INTRODUCTION ficulty requiring continuous positive airway pressure. No evi- dence of respiratory distress syndrome was noted on a chest ra- Cornelia de Lange Syndrome (CdLS) is a multiple congenital diograph. A laryngeal anomaly and large tongue base were evi- anomaly characterized by distinctive facial features, upper limb dent, which nearly obstructed the vocal cord. A physical exami- malformations, growth and cognitive retardation (1, 2). The syn- nation revealed bushy eyebrows and synophrys, long curly eye- drome has unknown genetic and molecular pathogenesis. Di- lashes, long philtrum, downturned angles of the mouth and thin agnosis is based on the distinctive clinical features and lack of a upper lips, cleft palate, micrognathia, excessive body hair, micro- definitive laboratory marker. Most cases are sporadic, although melia of both hands, flexion contracture of elbows and hyper- autosomal dominant inheritance mutations in Nipped-B ho- tonicity (Figs. 1, 2). molog (NIPBL), which is located at 5p13, have been suggested The patient had no relevant family history. The patient has (3, 4). Since CdLS was first described in Korea in 1967, several two siblings born of a different father. They are healthy, morpho- cases have been reported (5). The majority of these previous re- logically normal children. ports concerned the accompanying anomaly associated with A brain sonogram revealed increased periventricular echo- CdLS. These included a case of CdLS with imperforate anus and genicity. Computed tomography (CT) of the neck revealed no a case of CdLS with entropion, which was reported by a pedia- abnormality in upper airway except micrognathia. However, the trician and ophthalmologist respectively (6, 7). However, there patient had suffered from upper airway obstruction due to secre- is no report regarding the genetic analysis of CdLS in the Kore- tion from 1 month of age, which led to tracheostomy at 3 months an population. The present report is the first description of a of age. The patient exhibited feeding intolerance. Abdominal NIPBL gene mutation in a neonate with CdLS in Korea. ultrasonography and upper GI series showed gastroesophageal reflux but no other abnormalities. Chromosome analysis showed CASE REPORT a normal karyotype, 46, XY. The parents rejected their gene anal- ysis. The patient had been hospitalized for 5 months due to re- A 1,840 g male was delivered via normal vaginal delivery in our current sepsis and respiratory problems. At 5 months of age, the hospital at 32 weeks gestational age at May 2009. His mother patient was discharged and did not visit for 5 months after dis- was 40-yr-old, and had gestational diabetes mellitus and poly- charge. hydramnios. Apgar scores were 2 and 4 at 1 and 5 min, respec- To analyze gene mutation, peripheral blood samples were tively. The patient presented with cyanosis and respiratory dif- obtained from the patient with the informed consent of the fam- © 2010 The Korean Academy of Medical Sciences. pISSN 1011-8934 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. eISSN 1598-6357 Park K-H, et al. • Cornelia de Lange Syndrome with NIPBL Gene Mutation ily. Genomic DNA was isolated from peripheral blood leuko- el mutation that has not reported elsewhere. cytes using the Wizard Genomic DNA purification kit according to the manufacturer’s instructions (Promega, Madison, WI, USA). DISCUSSION Polymerase chain reaction (PCR) was performed using a Model 9600 thermal cycler (Applied Biosystems, Foster City, CA, USA), CdLS formerly described a child with similar features at autop- and direct sequencing of all coding exons and their flanking se- sy in 1916, was first reported in 1933 by Cornelia de Lange (8). quences of the NIPBL gene was accomplished using author-de- This syndrome is a multiple congenital anomaly characterized signed primer pairs (sequences available upon request) in an by distinctive facial features, hirsutism, upper limb malforma- ABI Prism 3100 Genetic Analyzer with a BigDye Terminator Cy- tions, gastroesophageal dysfunction, growth retardation, and cle Sequencing Ready Reaction kit (Applied Biosystems). Se- neurodevelopmental delay. The facial features are characteris- quence variations were analyzed with reference to the wild type tic and easily recognizable, with microcephaly, bushy eyebrows sequence (GenBank accession No. NM_002529) using the Se- and synophrys, long and curly eyelashes, anteverted nares, long quencher program (Gene Codes, Ann Arbor, MI, USA). philtrum, thin lips, downturned angles of mouth, and microgna- Sequence analysis of the NIPBL gene revealed a heterozygous thia. C→G transversion at nucleotide number 7178, which substitut- The feature of CdLS is expressed by a variable phenotype and ed the 2393rd serine to form a stop codon (Fig. 3). This is a nov- ranges from mild to severe. Van Allen et al. (9) proposed a classi- fication system based on the clinical variability. Type I or classic CdLS patients have the characteristic facial and skeletal chang- es. Type II or mild CdLS patients have similar facial features but minor skeletal abnormalities to those seen in Type I. Type III or phenoscopy CdLS have phenotypic manifestations of CdLS that are causally related to chromosomal aneuploidies or teratogen- ic exposures. Our patient exhibited characteristic facial features and severe skeletal symptoms as abscent forearm, which is com- patable with Type I. The incidence of CdLS is reported to be one in 10,000-100,000 births, although the exact incidence is unknown (10, 11). The etiology of CdLS is still not clear. Recently, heterozygous muta- tions in cohesin regulator and cohesin structural components have been linked to CdLS (3, 4, 12-15). Cohesin regulates sister Fig. 1. General appea­ rance shows distinctive chromatid cohesion during the mitotic cell cycle and is a multi- facial features, excessive subunit protein complex (12). In 2004, two independent groups body hair, micromelia of reported that CdLS is caused by mutations in the NIPBL gene both hands, flexion con­ tracture of elbows, and located on 5p13.2 (3, 4). The NIPBL gene is the human homo- hypertonicity. logue of the Drosophila Nipped-B gene and belongs to the fam- ily of chromosomal adherins involved in chromatid cohesion processes and enhancer-promoter communications (13, 14). In addition, X-linked CdLS can arise from mutations in the SMC1A gene that encodes a subunit of the cohesion complex (15). Approximately 60% of the probands with CdLS have hetero- zygous mutations in the NIPBL gene, while a smaller percent of Fig. 2. Facial exami­ nation shows bushy eyebrows and syno­ phrys, long curly eye­ lashes, long philtrum, downturned angles of c.7178C>G; p.Ser2393X the mouth and thin upper lips, cleft palate, Fig. 3. Sequence analysis of the NIPBL gene identified a heterozygous nonsense mu­ micrognathia. tation generating a premature stop codon (c.7178C>G; p.Ser2393X). 1822 http://jkms.org DOI: 10.3346/jkms.2010.25.12.1821 Park K-H, et al. • Cornelia de Lange Syndrome with NIPBL Gene Mutation cases exhibit mutations in the SMC1A or SMC3 cohesin subunit Nipped-B, is mutated in Cornelia de Lange syndrome. Nat Genet 2004; genes (3). There has been concern about genotype-phenotype 36: 636-41. correlation. Gillis et al. reported a significant differences between 5. Mun YR, Ahn SI, Yang KS. De Lange syndrome. J Korean Med Assoc 1967; subjects with and without mutations in terms of the degree of 10: 455-60. growth retardation and developmental delay (16). 6. Lee SH, Jang JW, Kim IS, Kim WD, Lee SG. A case of Cornelia de Lange syndrome with imperforate anus. J Korean Soc Neonatol 2007; 14: 253-7. It has been demonstrated that mutations in NIPBL cause both 7. Kim IT, Park JW, Choi WC. A Korean case of Cornelia de Lange syndrome. mild and severe forms (9, 17). SMC1A and SMC3 mutations con- Korean J Ophthalmol 2005; 19: 153-5. tribute to 5% of cases of CdLS and result in a consistently mild 8. Braddock SR, Lachman RS, Stoppenhagen CC, Carey JC, Ireland M, phenotype with absence of major structural anomalies (15, 18). Moeschler JB, Cunniff C, Graham JM Jr. Radiological features in Brach- However, another study reported that, in 53% of the mutations mann-de Lange syndrome.