Cornelia De Lange Syndrome 159

Cornelia De Lange Syndrome

M A Deardorff and I D Krantz, The Children’sHospital of Philadelphia, Philadelphia, PA, USA

ã 2009 Elsevier Ltd. All rights reserved.

Introduction

The first description of a patient with Cornelia deLange syndrome (CdLS) has been attributed to Vrolik(1849) who described the case as an extreme exampleof oligodactyly. In 1916 Brachman provided adetailed account of another CdLS patient in a paperwhose title translates as ‘‘a case of symmetrical mono-dactyly representing ulnar deficiency, with symmet-rical antecubital webbing and other abnormalities(dwarfism, cervical ribs, hirsutism).’’ However, itwas not until the 1930s that the condition began tobe classified as a distinct entity. Cornelia de Lange, apediatrician in Amsterdam, described two unrelatedyoung girls with strikingly similar features and inhonor of the city in which she worked she termedthe condition ‘‘degeneration typus amstelodamensis.’’In recognition of her major contribution, the disorderhas subsequently been widely described as CdLS,although some publications refer to Brachmann-deLange syndrome. The prevalence of this syndrome hasbeen estimated to be approximately 1 in 10000. Sincethese early reports there have been over 100 papersdescribing various aspects of this disorder and it wasnot until recently that the underlying etiology was elu-cidated as being caused by disruption of the normalfunctioning of the cohesin complex. This implicatedthe multiprotein cohesin complex, well characterizedfor its role in chromosomal cohesion and segregationduring mitosis and meiosis, for the first time with ahuman developmental disorder.

Clinical Features

Structural Features

The CdLS phenotype consists of neurocognitive andsomatic growth delays in addition to numerous struc-tural differences. The typical structural anomaliesseen in CdLS include: characteristic facial features(including synophrys, long eyelashes, ptosis, dep-ressed nasal bridge with an uptilted tip of the noseand anteverted nares, small widely spaced teeth,small head, and low-set ears), hirsutism, variousophthalmologic abnormalities, abnormalities of theupper extremities (ranging from subtle changes in thephalanges and metacarpal bones to oligodactylyand severe reduction defects primarily affecting the

ulnar structures), and gastroesophageal abnormal-ities (gastroesophageal reflux, malrotation, pyloricstenosis) (Figure 1). Other frequently seen findingsinclude ptosis, myopia, cryptorchidism, hypospadias,congenital diaphragmatic hernia, cardiac defects (mostcommonly atrial septal defects), seizures, and hearingloss (sensorineural, conductive and mixed have beenreported).

Neurodevelopmental Features

The mental retardation seen in CdLS is variable withIQs ranging from less than 30 to 102 with an averageof 53. Many affected individuals also demonstrateautistic behavior, including self-destructive tenden-cies, and they may avoid or reject social interactionsand physical contact. Historically, most individualswith classical CdLS have been reported to have severeto profound mental retardation. More recently,reports of CdLS children and adults with milder cog-nitive retardation have suggested a broader range ofintellectual potentials. Achievement of all develop-mental milestones are generally found to be signifi-cantly delayed. On average, children with CdLS sit at12months, have their first words at 18months, walkalone at 24months, speak (put words together) by4.5 years, and are toilet trained by 3 years. In severelyaffected individuals many or all of these milestonesare never met. There is no evidence to indicate thatindividuals with CdLS experience regression (loss ofskills) and new skills are acquired even into adult-hood. Areas of relative strength were noted to bevisual–spatial memory and perceptual organization,while some of the weakest areas involved languageskills, especially expressive language. Less than 5% ofchildren with CdLS have language skills within nor-mal to low-normal ranges. In general, those childrenwith essentially no speech and more severe cognitivedelays were found to also have more severe physicalmanifestations of CdLS. CdLS individuals with agreater degree of mental retardation had more pro-nounced autistic features, hyperactivity, self-injury,aggression, and sleep disturbances.

Clinical Variability

While the facial features seen in individuals withclassical CdLS are striking and easily recognizable(Figure 1), and may be one of the most useful diag-nostic signs, there is marked variability and a milderphenotype has been consistently described. Withincreasing recognition of a milder CdLS phenotype,both isolated and familial cases have been diagnosedand reported. The mild phenotype, which has beenestimated to account for approximately 20–30% of

Figure 1 Phenotypic features of CdLS. Top row: characteristic facial features including arched eyebrows connected in the midline

(synophrys), ptosis, long eyelashes, short upturned nose, long philtrum with thin upper lip, and small chin (micrognathia) with low set and

posteriorly rotated ears. Bottom row: phenotypic variability in the involvement of the forearms ranging from severe olygodactyly on the left,

through variable types of reduction defects to small hands as seen on the lower right.

160 Cornelia De Lange Syndrome

the CdLS population (although likely an underesti-mate due to decreased ascertainment), is distinguishedby less significant psychomotor and growth retarda-tion, a lower incidence of major malformations, andmilder limb anomalies.

Genetics

Although CdLS is one of the most distinctive dysmor-phic syndromes known, having been formally describedover 70 years ago, identification of the molecular etiol-ogy had remained elusive until recently. Due to a lackof informative families and conserved chromosomeabnormalities, standard positional cloning approacheshad been difficult to undertake. The CdLS gene wasinitially presumed to map to chromosome 3q26 basedon phenotypic similarities between individuals withduplication of this region and individuals with CdLS.Recently mutations in three genes,NIPBL and SMC1A(also known as SMC1L1) and SMC3, have been foundto cause CdLS in approximately half of studiedprobands.NIPBL, located on chromosome 5p, is a regulator

of the cohesin complex and is the human homolog ofthe Drosophila Nipped-B gene. While the role ofNIPBL in humans or mammals has not been eluci-dated, much of what is known about its functioncomes from work in Drosophila. Nipped-B was iden-tified in Drosophila using a screen to map genesinvolved in long-range enhancer promoter interac-tions. Once isolated Nipped-B was found to be homol-ogous to Saccharomyces cerevisiae sister chromatidcohesion protein 2 (SCC-2) that played a critical rolein sister chromatid cohesion during mitosis and

meiosis. It was subsequently shown that through inter-actions with the cohesin complex, Nipped-B has adual, but related, role in sister chromatid cohesion, aswell as in long-range enhancer–promoter interactions.Preliminary studies evaluating genotype–phenotypecorrelations in CdLS suggest that some of the pheno-typic variability seen in CdLS (severity of cognitive andgrowth retardation and severity of limb defects) isdependant on the type of mutation identified (withmissense mutations for the most part resulting in amilder phenotype when compared to protein truncat-ing mutations).

SMC1A, located on the X chromosome, is a subunitof the cohesin complex and has also recently beendemonstrated to cause CdLS when mutated. Eventhough localized to the X chromosome, this gene isnot silenced by X inactivation and both males andfemales have been reported to be equally affected bymutations, although in familial cases males appearto be more severely affected. SMC3 another subunitthat functions in concertwith SMC1,was subsequentlyfound to be mutated in a single patient with CdLS.Overall individuals with mutations in SMC1A andSMC3 appear to be more mildly affected, both cogni-tively and structurally, than individuals with CdLScaused by mutations in NIPBL. None of the reportedindividualswith SMC1A or SMC3mutations hadovertlimb abnormalities, several individuals had normalhead circumferences and a few appeared to have verysubtle features ofCdLS andwould appear for all intentsand purposes as having apparent isolated mentalretardation.

CdLS was the first developmental disorder shownto be caused by disruption of cohesin function.

Cohesin

SMC1 (SMC1A, -B)

NIPBL (SCC2)

Adherin

SCC4/Mau-2

RAD21 (SCC1)

Pds5A, -B

Ctf7 (Eco1)

SCC3 (Stromalin/STAG1, -2, -3)

SMC3

Figure 2 The cohesin complex and its key regulators. The four

main proteins composing the cohesin complex (SMC1, SMC3,

SCC1, and SCC3) are indicated. The adherin complex of which

NIPBL is a component is in the lower left and is involved in loading

the complex on and off of the chromosomes.

Cornelia De Lange Syndrome 161

Subsequently, the Roberts/SC phocomelia syndrome(an autosomal recessive condition of mental retarda-tion, growth delay, craniofacial anomalies includingcleft lip and palate, upper and lower limb defects, andchromosomal mitotic abnormalities including cohe-sion defects) was found to be caused by mutations inESCO2, which is required for the establishment ofcohesion during S-phase. The implication of the cohe-sin complex and its regulation in causing the highlyconserved phenotypes of specific human developmen-tal disorders was somewhat surprising giving its fun-damental role in chromosomal cohesion and is likelydue in part to disruption of its function as a mediatorof long-range enhancer–promoter interactions.

The Cohesin Complex

In eukaryotic cells, replicated DNA remains physi-cally connected from its synthesis in S-phase untilseparated during anaphase. This phenomenon calledsister chromatid cohesion is essential for the equalseparation of the duplicated genome. The cohesin com-plex is a multimer that consists of at least four proteins:SMC1 (SMC1A in humans), SMC3, SCC3 (STAG 1and 2 in humans), and SCC1 (RAD21 in humans).Like other structural maintenance of chromosomeproteins, SMC1 and SMC3 fold back upon themselvesto form antiparallel coiled coils with their N- andC-termini forming ATPase head domains (Figure 2).Their hinge regions interact to form the SMC hetero-dimer, which acts as a ring-like structure to encirclechromatids. The head domains of SMC3 and SMC1interactwith SCC1 that alongwith SCC3 serves to forma clasp on the ring-like structure. NIPBL orthologs areknown to be a subunit of the adherin protein, which isrequired for sister chromatid cohesion. It is believedthat adherins are required for the attachment of cohesinto chromosomes.

Long-Range Enhancer–Promoter Interaction andControl of Gene Expression

While chromosomal cohesion may be mildly per-turbed in CdLS (there is some evidence for mildprecocious sister chromatid separation in CdLS pro-bands), this mechanism is not felt to be the majorcontributor resulting in the multiple clinical findingsseen in CdLS. Rather the critical means by whichdisruption of NIPBL, SMC1A and SMC3 appearsto result in the CdLS phenotype is through the effectson long-range enhancer–promoter interactions andresultant disruption of transcriptional regulation.For most genes the region immediately upstream oftheminimal promoter contains the requisite transcrip-tion factor binding sites to regulate expression of thegene; however, for many genes multiple cis-actingdistal elements (most commonly enhancers, but also

repressors and insulators) are required for correctspatiotemporal expression. These elements may belocated upstream, downstream, or within intronsand can reside greater than 1Mb from the targetgene. Disruption of these long-range regulatory inter-actions can result in human disease phenotypesthrough either global or partial tissue-specific loss orgain of expression. The majority of genes responsiblefor these disorders when disrupted are transcrip-tion factors that in turn regulate the expression oftissue-specific targets critical for normal morphogen-esis of the organ systems involved. In the study thatfirst identified Nipped-b in Drosophila, alteration ofthis gene and the resulting disruption of long-rangeenhancer–promoter interaction was noted to affectthe regulation of the critical transcription factorscalled homeobox genes. Homeobox genes are criticalin normal body plan formation and in the develop-ment of the brain and other organ systems.

See also: Autism; Developmental Disability and Fragile X

Syndrome: Clinical Overview.

Further Reading

Allanson JE, Hennekam RCM, and Ireland M (1997) De Lange

syndrome: Subjective and objective comparison of the classical

andmild phenotypes. Journal of Medical Genetics 34: 645–650.Berney TP, Ireland M, and Burn J (1999) Behavioural phenotype of

Cornelia de Lange syndrome. Archives of Disease in Childhood81: 333–336.

162 Cornelia De Lange Syndrome

Deardorff MA, Kaur M, Yaeger D, et al. (2007) Mutations in

cohesin complex members SMC3 and SMC1A cause a mild

variant of Cornelia de Lange syndrome with predominant men-

tal retardation. American Journal of Human Genetics 80(3):485–494.

de Knecht-van Eekelen A and Hennekam RCM (1994) Historical

study: Cornelia C. de Lange (1871–1950) – a pioneer in clinicalgenetics. American Journal of Medical Genetics 52: 257–266.

DeScipio CA, Kaur M, Yaeger D, et al. (2005) Chromosome rear-

rangements in cornelia de lange syndrome (cdls): report of a der

(3)t(3;12) (p25.3;p13.3) in two half sibs with features of cdlsand review of reported CdLS cases with chromosome rearrange-

ments. American Journal of Medical Genetics A 137: 276–282.

Gillis LA, McCallum J, Kaur M, et al. (2004) NIPBL Mutational

analysis in 120 individuals with Cornelia de Lange syndromeand evaluation of genotype-phenotype correlations. AmericanJournal of Human Genetics 75: 610–623.

Jackson L, Kline AD, Barr MA, and Koch S (1993) de Lange

syndrome: A clinical review of 310 individuals. American Jour-nal of Medical Genetics 47: 940–946.

Kleinjan DJ and van Heyningen V (2005) Long-range control of

gene expression: Emerging mechanisms and disruption in dis-ease. American Journal of Human Genetics 76: 8–32.

Krantz ID, McCallum J, DeScipio C, et al. (2004) Cornelia de

Lange syndrome is caused by mutations in NIPBL, the human

homolog of theDrosophila Nipped-B gene.Nature Genetics 36:631–635.

Musio A, Selicorni A, Focarelli ML, et al. (2006) X-linked Cornelia

de Langesyndrome owing to SMC1L1 mutations. NatureGenetics 38: 528–530.

Nasmyth K, Peters JM, and Uhlmann F (2000) Splitting the chro-

mosome: Cutting the ties that bind sister chromatids. Science288: 1379–1385.

Opitz JM (1985) Editorial comment: The Brachmann-de Langesyndrome. American Journal of Medical Genetics 22: 89–102.

Rollins RA, Morcillo P, and Dorsett D (1999) Nipped-B, a Dro-

sophila homologue of chromosomal adherins, participates inactivation by remote enhancers in the cut and Ultrabithorax

genes. Genetics 152: 577–593.Russell KL, Ming JE, Patel K, et al. (2001) Dominant paternal

transmission of Cornelia de Lange syndrome: A new case andreview of 25 previously reported familial recurrences. AmericanJournal of Medical Genetics 104: 267–276.

Tonkin ET, Wang TJ, Lisgo S, et al. (2004) NIPBL, encoding a

homolog of fungal Scc2 type sister chromatid cohesion proteinsand fly Nipped-B, is mutated in Cornelia de Lange syndrome.

Nature Genetics 36: 636–641.Vega H, Waisfisz Q, Gordillo M, et al. (2005) Roberts syndrome is

caused by mutations in ESCO2, a human homolog of yeastECO1 that is essential for the establishment of sister chromatid

cohesion. Nature Genetics 37: 468–470.

Relevant Websites

http://www.cdlsusa.org – Cornelia de Lange Syndrome Founda-

tion, Inc.

http://www.cdlsworld.org – CdLS-World is an international ‘hub’for worldwide organizations and communities united by Cor-

nelia de Lange Syndrome.