Cornelia De Lange Syndrome 159
Cornelia De Lange Syndrome
M A Deardorff and I D Krantz, The Children’s
Hospital of Philadelphia, Philadelphia, PA, USA
ã 2009 Elsevier Ltd. All rights reserved.
Introduction
The first description of a patient with Cornelia de
Lange syndrome (CdLS) has been attributed to Vrolik
(1849) who described the case as an extreme example
of oligodactyly. In 1916 Brachman provided a
detailed account of another CdLS patient in a paper
whose 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, it
was not until the 1930s that the condition began to
be classified as a distinct entity. Cornelia de Lange, a
pediatrician in Amsterdam, described two unrelated
young girls with strikingly similar features and in
honor of the city in which she worked she termed
the condition ‘‘degeneration typus amstelodamensis.’’
In recognition of her major contribution, the disorder
has subsequently been widely described as CdLS,
although some publications refer to Brachmann-de
Lange syndrome. The prevalence of this syndrome has
been estimated to be approximately 1 in 10 000. Since
these early reports there have been over 100 papers
describing various aspects of this disorder and it was
not until recently that the underlying etiology was elu-
cidated as being caused by disruption of the normal
functioning of the cohesin complex. This implicated
the multiprotein cohesin complex, well characterized
for its role in chromosomal cohesion and segregation
during mitosis and meiosis, for the first time with a
human developmental disorder.
Clinical Features
Structural Features
The CdLS phenotype consists of neurocognitive and
somatic growth delays in addition to numerous struc-
tural differences. The typical structural anomalies
seen in CdLS include: characteristic facial features
(including synophrys, long eyelashes, ptosis, dep-
ressed nasal bridge with an uptilted tip of the nose
and anteverted nares, small widely spaced teeth,
small head, and low-set ears), hirsutism, various
ophthalmologic abnormalities, abnormalities of the
upper extremities (ranging from subtle changes in the
phalanges and metacarpal bones to oligodactyly
and severe reduction defects primarily affecting the
ulnar structures), and gastroesophageal abnormal-
ities (gastroesophageal reflux, malrotation, pyloric
stenosis) (Figure 1). Other frequently seen findings
include ptosis, myopia, cryptorchidism, hypospadias,
congenital diaphragmatic hernia, cardiac defects (most
commonly atrial septal defects), seizures, and hearing
loss (sensorineural, conductive and mixed have been
reported).
Neurodevelopmental Features
The mental retardation seen in CdLS is variable with
IQs ranging from less than 30 to 102 with an average
of 53. Many affected individuals also demonstrate
autistic behavior, including self-destructive tenden-
cies, and they may avoid or reject social interactions
and physical contact. Historically, most individuals
with classical CdLS have been reported to have severe
to profound mental retardation. More recently,
reports of CdLS children and adults with milder cog-
nitive retardation have suggested a broader range of
intellectual potentials. Achievement of all develop-
mental milestones are generally found to be signifi-
cantly delayed. On average, children with CdLS sit at
12 months, have their first words at 18 months, walk
alone at 24 months, speak (put words together) by
4.5 years, and are toilet trained by 3 years. In severely
affected individuals many or all of these milestones
are never met. There is no evidence to indicate that
individuals with CdLS experience regression (loss of
skills) and new skills are acquired even into adult-
hood. Areas of relative strength were noted to be
visual–spatial memory and perceptual organization,
while some of the weakest areas involved language
skills, especially expressive language. Less than 5% of
children with CdLS have language skills within nor-
mal to low-normal ranges. In general, those children
with essentially no speech and more severe cognitive
delays were found to also have more severe physical
manifestations of CdLS. CdLS individuals with a
greater 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 with
classical 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 milder
phenotype has been consistently described. With
increasing recognition of a milder CdLS phenotype,
both isolated and familial cases have been diagnosed
and reported. The mild phenotype, which has been
estimated to account for approximately 20–30% of
160 Cornelia De Lange Syndrome
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.
the CdLS population (although likely an underesti-
mate due to decreased ascertainment), is distinguished
by less significant psychomotor and growth retarda-
tion, a lower incidence of major malformations, and
milder limb anomalies.
Genetics
Although CdLS is one of the most distinctive dysmor-
phic syndromes known, having been formally described
over 70 years ago, identification of the molecular etiol-
ogy had remained elusive until recently. Due to a lack
of informative families and conserved chromosome
abnormalities, standard positional cloning approaches
had been difficult to undertake. The CdLS gene was
initially presumed to map to chromosome 3q26 based
on phenotypic similarities between individuals with
duplication of this region and individuals with CdLS.
Recently mutations in three genes, NIPBL and SMC1A
(also known as SMC1L1) and SMC3, have been found
to cause CdLS in approximately half of studied
probands.
NIPBL, located on chromosome 5p, is a regulator
of the cohesin complex and is the human homolog of
the Drosophila Nipped-B gene. While the role of
NIPBL in humans or mammals has not been eluci-
dated, much of what is known about its function
comes from work in Drosophila. Nipped-B was iden-
tified in Drosophila using a screen to map genes
involved in long-range enhancer promoter interac-
tions. Once isolated Nipped-B was found to be homol-
ogous to Saccharomyces cerevisiae sister chromatid
cohesion protein 2 (SCC-2) that played a critical role
in sister chromatid cohesion during mitosis and
meiosis. It was subsequently shown that through inter-
actions with the cohesin complex, Nipped-B has a
dual, but related, role in sister chromatid cohesion, as
well as in long-range enhancer–promoter interactions.
Preliminary studies evaluating genotype–phenotype
correlations in CdLS suggest that some of the pheno-
typic variability seen in CdLS (severity of cognitive and
growth retardation and severity of limb defects) is
dependant on the type of mutation identified (with
missense mutations for the most part resulting in a
milder phenotype when compared to protein truncat-
ing mutations).
SMC1A, located on the X chromosome, is a subunit
of the cohesin complex and has also recently been
demonstrated to cause CdLS when mutated. Even
though localized to the X chromosome, this gene is
not silenced by X inactivation and both males and
females have been reported to be equally affected by
mutations, although in familial cases males appear
to be more severely affected. SMC3 another subunit
that functions in concert with SMC1, was subsequently
found to be mutated in a single patient with CdLS.
Overall individuals with mutations in SMC1A and
SMC3 appear to be more mildly affected, both cogni-
tively and structurally, than individuals with CdLS
caused by mutations in NIPBL. None of the reported
individuals with SMC1A or SMC3 mutations had overt
limb abnormalities, several individuals had normal
head circumferences and a few appeared to have very
subtle features of CdLS and would appear for all intents
and purposes as having apparent isolated mental
retardation.
CdLS was the first developmental disorder shown
to be caused by disruption of cohesin function.

Subsequently, the Roberts/SC phocomelia syndrome
(an autosomal recessive condition of mental retarda-
tion, growth delay, craniofacial anomalies including
cleft lip and palate, upper and lower limb defects, and
chromosomal mitotic abnormalities including cohe-
sion defects) was found to be caused by mutations in
ESCO2, which is required for the establishment of
cohesion during S-phase. The implication of the cohe-
sin complex and its regulation in causing the highly
conserved phenotypes of specific human developmen-
tal disorders was somewhat surprising giving its fun-
damental role in chromosomal cohesion and is likely
due in part to disruption of its function as a mediator
of long-range enhancer–promoter interactions.
The Cohesin Complex
In eukaryotic cells, replicated DNA remains physi-
cally connected from its synthesis in S-phase until
separated during anaphase. This phenomenon called
sister chromatid cohesion is essential for the equal
separation 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 1
and 2 in humans), and SCC1 (RAD21 in humans).
Like other structural maintenance of chromosome
proteins, SMC1 and SMC3 fold back upon themselves
to form antiparallel coiled coils with their N- and
C-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 encircle
chromatids. The head domains of SMC3 and SMC1
interact with SCC1 that along with SCC3 serves to form
a clasp on the ring-like structure. NIPBL orthologs are
known to be a subunit of the adherin protein, which is
required for sister chromatid cohesion. It is believed
that adherins are required for the attachment of cohesin
to chromosomes.
Long-Range Enhancer–Promoter Interaction and
Control of Gene Expression
While chromosomal cohesion may be mildly per-
turbed in CdLS (there is some evidence for mild
precocious sister chromatid separation in CdLS pro-
bands), this mechanism is not felt to be the major
contributor resulting in the multiple clinical findings
seen in CdLS. Rather the critical means by which
disruption of NIPBL, SMC1A and SMC3 appears
to result in the CdLS phenotype is through the effects
on long-range enhancer–promoter interactions and
resultant disruption of transcriptional regulation.
For most genes the region immediately upstream of
the minimal promoter contains the requisite transcrip-
tion factor binding sites to regulate expression of the
gene; however, for many genes multiple cis-acting
distal elements (most commonly enhancers, but also
Cornelia De Lange Syndrome 161
Cohesin
SMC3 SMC1 (SMC1A, -B)
NIPBL (SCC2)
Ctf7 (Eco1)
Adherin
Pds5A , -B SCC4/Mau -2
RAD21 (SCC1)
SCC3 (Stromalin/STAG1, -2, -3)
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.
repressors and insulators) are required for correct
spatiotemporal expression. These elements may be
located upstream, downstream, or within introns
and can reside greater than 1 Mb from the target
gene. Disruption of these long-range regulatory inter-
actions can result in human disease phenotypes
through either global or partial tissue-specific loss or
gain of expression. The majority of genes responsible
for these disorders when disrupted are transcrip-
tion factors that in turn regulate the expression of
tissue-specific targets critical for normal morphogen-
esis of the organ systems involved. In the study that
first identified Nipped-b in Drosophila, alteration of
this gene and the resulting disruption of long-range
enhancer–promoter interaction was noted to affect
the regulation of the critical transcription factors
called homeobox genes. Homeobox genes are critical
in 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
and mild 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 Childhood
81: 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 clinical
genetics. 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 cdls
and 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 syndrome
and evaluation of genotype-phenotype correlations. American
Journal 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 the Drosophila 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. Nature
Genetics 38: 528–530.
Nasmyth K, Peters JM, and Uhlmann F (2000) Splitting the chro-
mosome: Cutting the ties that bind sister chromatids. Science
288: 1379–1385.
Opitz JM (1985) Editorial comment: The Brachmann-de Lange
syndrome. 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 in
activation 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 and
review of 25 previously reported familial recurrences. American
Journal 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 proteins
and 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 yeast
ECO1 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.