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Cornelia de Lange Syndrome

Synonyms: BDLS, Brachmann-de Lange Syndrome, CdLS, de Lange Syndrome

, MD, PhD, , MS, and , MD.

Author Information

Initial Posting: ; Last Update: January 28, 2016.

Estimated reading time: 34 minutes


Clinical characteristics.

Classic Cornelia de Lange syndrome (CdLS) is characterized by distinctive facial features, growth retardation (prenatal onset; <5th centile throughout life), hirsutism, and upper-limb reduction defects that range from subtle phalangeal abnormalities to oligodactyly (missing digits). Craniofacial features include synophrys, highly arched eyebrows, long eyelashes, short nose with anteverted nares, small widely spaced teeth, and microcephaly. IQ ranges from below 30 to 102 (mean: 53). Many individuals demonstrate autistic and self-destructive tendencies. Frequent findings include cardiac septal defects, gastrointestinal dysfunction, hearing loss, myopia, and cryptorchidism or hypoplastic genitalia. Individuals with a milder phenotype have less severe growth, cognitive, and limb involvement, but often have facial features consistent with CdLS.


Diagnosis is based on clinical findings and/or the identification of a heterozygous pathogenic variant in NIPBL, RAD21, or SMC3 or a hemizygous pathogenic variant in HDAC8 or SMC1A.


Treatment of manifestations: Aggressive management of gastroesophageal reflux with assessment of potential gastrointestinal malrotation in all affected individuals; consideration of fundoplication if reflux is severe. Supplementary formulas and/or gastrostomy tube placement to meet nutritional needs as necessary. Physical, occupational, and speech therapy to optimize psychomotor development and communication skills. Standard treatment for hearing loss, cardiac defects, seizures, vesicoureteral reflux, and cryptorchidism.

Prevention of secondary complications: Preoperative evaluation for thrombocytopenia and cardiac disease with careful monitoring of the airway during anesthesia; malignant hyperthermia precautions.

Surveillance: Annual GI evaluation, monitoring of growth and psychomotor development; routine eye and hearing evaluations, and monitoring of heart and kidney abnormalities.

Genetic counseling.

NIPBL-related CdLS, RAD21-related CdLS, and SMC3-related CdLS are inherited in an autosomal dominant manner; HDAC8-related CdLS and SMC1A-related CdLS are inherited in an X-linked manner. The majority of affected individuals have a de novo heterozygous pathogenic variant in NIPBL; fewer than 1% of individuals with NIPBL-related CdLS have an affected parent. When the parents are clinically unaffected, the risk to the sibs of a proband with NIPBL-related CdLS is estimated to be 1.5% because of the possibility of germline mosaicism. The risk to sibs of a proband with HDAC8-related CdLS or SMC1A-related CdLS depends on the status of the proband's mother. Prenatal testing for pregnancies at increased risk is possible for families in which the pathogenic variant has been identified.


The diagnosis of Cornelia de Lange syndrome (CdLS) syndrome is suspected based on clinical findings although no consensus clinical diagnostic criteria have been established.

Suggestive Findings

Cornelia de Lange syndrome (CdLS) should be suspected in individuals with the following clinical features [Kline et al 2007a]:

Craniofacial appearance (>95%)

Figure 1.

Figure 1.

Classic CdLS craniofacial features

Figure 2.

Figure 2.

Affected individual with a pathogenic variant in SMC1A

Growth failure (>95%). Growth failure occurs prenatally (although it may not be noted until the third trimester). Height and weight remain below the fifth centile throughout life [Bruner & Hsia 1990, Kliewer et al 1993, Kline et al 1993a, Kousseff et al 1993, Boog et al 1999]. CdLS-specific growth charts have been developed. See (girls; boys).

In addition, failure to thrive may be superimposed on the constitutional growth retardation secondary to gastroesophageal reflux and other issues with feeding.

Intellectual disability (>95%)

  • Classic CdLS. Severe-to-profound pervasive developmental delay is characteristic.
  • Mild CdLS. Less affected individuals with higher functioning and higher IQs (some in the normal range) have been identified. The overall IQ in CdLS ranges from below 30 to 102, with an average IQ of 53 [Kline et al 1993b, Saal et al 1993].

Limb abnormalities (>95%). Upper extremities are primarily involved, with relative sparing of the lower extremities. Limb abnormalities may be symmetric or asymmetric.

  • Classic CdLS. Upper-extremity deficiencies ranging from severe reduction defects with complete absence of the forearms to various forms of oligodactyly (missing digits) occur in approximately 30%. In the absence of limb deficiency, micromelia (small hands), proximally placed thumbs, and fifth-finger clinodactyly occur in nearly all individuals (see Figure 3).
    Radioulnar synostosis is common and may result in flexion contractures of the elbows.
    The lower extremities are less involved than the upper extremities. The feet are often small and syndactyly of the second and middle toes occurs in more than 80% of affected individuals [Jackson et al 1993].
  • Mild CdLS. The radiographic finding of a short first metacarpal resulting in a proximally placed thumb can be useful in diagnosis.
Figure 3.

Figure 3.

Range of limb anomalies in CdLS

Hirsutism (>80%). Thick scalp hair extends onto the temporal regions and at times involves the face, ears, back, and arms.

Establishing the Diagnosis

The diagnosis of CdLS is established in a proband with the above clinical features and/or by the identification of a heterozygous pathogenic variant in NIPBL, RAD21, or SMC3 or a hemizyous pathogenic variant in HDAC8 or SMC1A by molecular genetic testing (see Table 1).

Molecular testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

Serial single-gene testing. Sequential molecular genetic testing of NIPBL, SMC1A, HDAC8, SMC3, and RAD21 may be considered:


NIPBL sequence analysis should be performed first. If no pathogenic variant is identified, gene-targeted deletion/duplication analysis of NIPBL should be considered next.


If no NIPBL pathogenic variant is identified and the affected individual has milder physical features of CdLS, consider SMC1A sequence and gene-targeted deletion/duplication analysis.


If no NIPBL or SMC1A pathogenic variant is identified and CdLS is highly suspected especially in an individual with milder features, consider SMC3, RAD21, and HDAC8 sequence analysis and gene-targeted deletion/duplication analysis.

Somatic mosaicism for NIPBL has been reported in a small percentage of individuals. Obtaining a buccal sample at the time of collecting a peripheral blood sample can be considered [Huisman et al 2013]. Screening for NIPBL mosaicism can be pursued if CdLS is strongly suspected and molecular genetic testing above is normal.

Note: When the diagnosis of CdLS is not clear or molecular genetic testing does not identify a pathogenic variant, consider cytogenetic testing or chromosomal microarray (CMA) because a few individuals with deletions of 5p13 that include NIPBL have been reported [Taylor & Josifek 1981, Hulinsky et al 2005, Hayashi et al 2007]. The features of several other chromosome abnormalities overlap with those of CdLS [DeScipio et al 2005, Rohatgi et al 2010].

A multigene panel that includes NIPBL, SMC1A, HDAC8, SMC3, RAD21 and other genes of interest (see Differential Diagnosis) may also be considered. Note: The genes included and sensitivity of multigene panels vary by laboratory and are likely to change over time.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

More comprehensive genomic testing (when available) including exome sequencing, genome sequencing, and mitochondrial sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes NIPBL, SMC1A, HDAC8, SMC3, and RAD21) fails to confirm a diagnosis in an individual with features of CdLS.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Cornelia de Lange Syndrome

Gene 1Proportion of CdLS Attributed to Pathogenic Variants in This GeneTest Method
NIPBL~60% 2, 3Sequence analysis 4
Gene-targeted deletion/duplication analysis 5
SMC1A~5% 6Sequence analysis 4
Gene-targeted deletion/duplication analysis 5
HDAC8~4%Sequence analysis 4
Gene-targeted deletion/duplication analysis 5
SMC31%-2% 7Sequence analysis 4
Gene-targeted deletion/duplication analysis 5
RAD21<1%Sequence analysis 4
Gene-targeted deletion/duplication analysis 5
Unknown 8NANA

NA = not applicable


See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.


Gene-targeted deletion/duplication analysis of NIPBL detects ~3% of NIPBL-related CdLS [Russo et al 2012].


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.


Lack of identified NIPBL pathogenic variants in 50% of individuals with CdLS suggest possible locus heterogeneity [Borck et al 2004].

Clinical Characteristics

Clinical Description

Although CdLS was formally characterized more than 70 years ago and well delineated clinically [Ptacek et al 1963, Motl & Opitz 1971, Jackson et al 1993], the natural history of CdLS has only recently been studied [Kline et al 2007a].

Life expectancy appears to be normal in affected individuals who do not have the complications described below. See Classic Cornelia de Lange Syndrome, Cause of death.

The majority of familial cases suggest that expressivity is relatively consistent within a family.

The medical issues faced by individuals with the mild and classic forms of CdLS are similar; however, the greater cognitive impairment in individuals with classic CdLS may make identification of medical complications more difficult.

Classic Cornelia de Lange Syndrome

Growth. Prenatal-onset growth failure occurs in most newborns with CdLS. Symmetric slow growth resulting in proportionate short stature becomes more significant by age six months. Mean height and weight are below the fifth centile throughout life [Bruner & Hsia 1990, Kliewer et al 1993, Kline et al 1993b, Kousseff et al 1993, Boog et al 1999].

Intellectual disability. Most individuals with classic CdLS have been reported to have severe-to-profound intellectual disability with IQs ranging from 30 to 86 (mean: 53). However, reports of children with CdLS and adults with milder intellectual disability have suggested a broader range of intellectual abilities [Barr et al 1971, Kline et al 1993b, Moeschler & Graham 1993]. Individuals with both pathogenic missense variants and in-frame deletions in NIPBL and one individual with a pathogenic missense variant in SMC1A were found to have milder intellectual disability [Ajmone et al 2014].

Neuropsychiatric. Many individuals demonstrate autistic behavior, including self-destructive tendencies, and they may avoid or reject social interactions and physical contact.

Behavior problems are often directly related to frustration from inability to communicate.

Approximately 25% of children have had seizures.

Some parents have described temperature intolerance and decreased pain sensation.

Limb involvement. Severe abnormalities of the upper extremities are seen in 25% of individuals with CdLS.

Gastrointestinal. Gastroesophageal reflux (GER) is almost universally a problem [Bull et al 1993, Sommer 1993, Kline et al 2007b]. Other complications of GER including esophagitis, aspiration, chemical pneumonitis, and irritability can be avoided by diagnosis and treatment of GER in the neonatal period (see Management).

Pyloric stenosis is the most frequent cause of persistent vomiting in the newborn period and was identified in 4%.

Other gastrointestinal abnormalities include intestinal malrotation (2%) and congenital diaphragmatic hernia (CDH) (1%). CDH has been diagnosed both pre- and postnatally [Fryns 1987, Cunniff et al 1993, Jelsema et al 1993, Pankau & Jänig 1993, Marino et al 2002], but may be underascertained, especially in infants who die in the perinatal period.

Otolaryngologic. Sensorineural hearing loss is noted in 80% of children with CdLS, with 40% being profoundly affected [Sataloff et al 1990]. (See Hereditary Hearing Loss and Deafness Overview.)

Ophthalmologic. As many as 50% of affected individuals demonstrate some degree of ptosis as well as other ocular problems including myopia (60%) and nystagmus (37%) [Levin et al 1990]. Other ophthalmologic abnormalities include glaucoma, nasolacrimal duct stenosis, microcornea, astigmatism, optic atrophy, coloboma of the optic nerve, strabismus, and proptosis [Nicholson & Goldberg 1966, Milot & Demay 1972, Folk et al 1981, Levin et al 1990].

Genitourinary. Cryptorchidism occurs in 73% of males with CdLS and hypoplastic (small) genitalia occur in 57%. Renal abnormalities, primarily vesicoureteral reflux, have been reported in 12% [Jackson et al 1993].

Cardiovascular. Approximately 25% of individuals with CdLS have congenital heart disease [Jackson et al 1993, Mehta & Ambalavanan 1997, Tsukahara et al 1998]. The most common abnormalities include (in descending order): ventricular septal defects, atrial septal defects, pulmonic stenosis, tetralogy of Fallot, hypoplastic left heart syndrome, and bicuspid aortic valve.

Immunologic. Antibody deficiency has been described in several individuals with CdLS indicating a need for immunologic screening and management of immunodeficiency in those affected individuals with severe or recurrent infections [Jyonouchi et al 2013]. The most common reported recurrent infections include chronic ear infections, chronic viral respiratory infections, and pneumonia. Impaired T-cell function may be associated with antibody deficiencies observed in persons with CdLS.

Other features

  • A characteristic low-pitched cry that tends to disappear in late infancy has been described in 75% of children with CdLS and is associated with more severe cases [Jackson et al 1993].
  • Thrombocytopenia has been reported in a few children [Froster & Gortner 1993, Fryns & Vinken 1994], two of whom subsequently developed pancytopenia.
  • Cutis marmorata is seen in 60%.
  • Hypoplastic nipples and umbilicus are seen in 50%.
  • Single palmar creases and abnormal dermatoglyphic patterns have been reported [Smith 1966, Opitz 1985].

Bicornuate uterus, which can cause abdominal pain, has been observed in five (25%) of 20 affected females [Oliver et al 2010, Kline et al 2015].

Cause of death. Beck & Fenger [1985] looked at mortality in 48 individuals with CdLS born between 1917 and 1982 and found a modest increase in mortality over the general population when comparing cumulative survival rates; the increase is more significant among the younger age groups. They also reported two individuals who died at ages 54 and 61 years.

Beck & Fenger [1985] and Jackson et al [1993] reported a total of 24 deaths from aspiration pneumonia (9), recurrent apnea (3), congenital heart disease (3), volvulus and intestinal obstruction (2), post-surgical complications (thrombocytopenia and intracranial bleeding) (1), and cerebral edema and herniation after spine surgery (1). Severe bronchopulmonary dysplasia, mediastinitis, uremia, bronchial asthma, coronary artery occlusion, and pulmonary embolus were other causes of death.

Schrier et al [2011] reported 295 affected individuals in whom a cause of death was known. Respiratory causes, including aspiration/reflux and pneumonias, were the most common primary causes (31%), followed by gastrointestinal disease, including obstruction/volvulus (19%). Congenital anomalies accounted for 15% of deaths and included congenital diaphragmatic hernia and congenital heart defects. Acquired cardiac disease accounted for 3% of deaths. Neurologic causes and accidents each accounted for 8%, sepsis for 4%, cancer for 2%, renal disease for 1.7%, and other causes 9% of deaths.

Genotype-Phenotype Correlations

Whereas individuals with classic findings of CdLS, including characteristic facial features and limb anomalies, are likely to have a pathogenic variant in NIPBL, NIPBL pathogenic variants have been found in individuals with both mild and severe phenotypes. NIPBL pathogenic variants are evenly distributed throughout the coding sequence. Individuals with pathogenic NIBPL missense variants typically have milder disease.

Individuals with SMC1A or SMC3 pathogenic variants typically have fewer structural anomalies and less severe growth restriction than those with NIPBL pathogenic variants; however, they have significant intellectual disability that can range from moderate to severe [Deardorff et al 2007]. Facial features in individuals with SMC1A or SMC3 pathogenic variants include slightly flatter and broader eyebrows and a broader and longer nasal bridge than are seen in individuals with an NIPBL pathogenic variant [Rohatgi et al 2010]. Those with pathogenic variants in SMC3 specifically often have subtle or absent synophrys, wider bulbous nose, and a long but well-formed philtrum. Cardiac malformations are also observed (~56%) in individuals with SMC3 pathogenic variants – and less frequently seen in individuals with SMC1A pathogenic variants [Gil-Rodríguez et al 2015].

Those with a heterozygous pathogenic variant in RAD21 typically do not have major structural differences. Individuals with a heterozygous RAD21 pathogenic variant have milder cognitive impairment compared to those with classic CdLS. These individuals typically display growth retardation, minor skeletal anomalies, and facial features that overlap with CdLS [Deardorff et al 2012b].

Those males with a hemizygous pathogenic variant in HDAC8 have facial features that overlap with CdLS but typically display delayed closure of the anterior fontanelle, hooded eyelids, widely spaced eyes, a wide nose, mosaic skin pigmentation, dental anomalies, and happy or friendly personalities. Growth also tends to be less severely affected with lower frequency of postnatal growth retardation and microcephaly reported. In females, the severity of clinical presentation caused by a heterozygous pathogenic variant in HDAC8 is greatly influenced by the pattern of X inactivation [Kaiser et al 2014].


No unaffected individuals with a somatic heterozygous pathogenic variant in NIPBL have been reported; thus, penetrance appears to be 100%.

Similarly, in individuals identified with a heterozygous pathogenic variant in RAD21 or in males with a hemizygous pathogenic variant in SMC1A, penetrance appears to be very high. Some variability in severity in females heterozygous for an SMC1A or RAD21 pathogenic variant has been noted [Musio et al 2006, Deardorff et al 2007, Minor et al 2014].

Clinical phenotypes caused by a heterozygous pathogenic variant in HDAC8 in females are heavily influenced by the pattern of X-inactivation [Kaiser et al 2014]. It is suggested that females with an unfavorable X-inactivation pattern in the brain would display a more severe phenotype.

Despite relatively few individuals identified with pathogenic variants in SMC3, the penetrance appears to be high, though there is variability between phenotypes associated with identical pathogenic variants.


Cornelia de Lange syndrome (CdLS) was first described in 1849 by Vrolik, who reported a case as an extreme example of oligodactyly [Oostra et al 1994]. Brachmann [1916] provided a detailed account of a case of symmetric monodactyly, antecubital webbing, dwarfism, cervical ribs, and hirsutism.

In the 1930s, Cornelia de Lange, a Dutch pediatrician, described two unrelated girls with similar features and named the condition after the city in which she worked: typus degenerativus amstelodamensis [de Lange 1933, de Knecht-van Eekelen & Hennekam 1994]. Some examples in the literature refer to the disorder as Brachmann-de Lange syndrome; however, it is more widely referred to as Cornelia de Lange syndrome in honor of Dr. de Lange's contributions to the understanding of the disorder.


The prevalence of CdLS is difficult to estimate as individuals with milder features are likely under-recognized. Published estimates for the prevalence range from 1:100,000 [Pearce & Pitt 1967] to as high as 1:10,000 [Opitz 1985]. Recent data from the EUROCAT dataset have estimated the prevalence at 1:50,000 for the classic form of CdLS [Barisic et al 2008]; this figure is less likely to include the milder, more common phenotype.

Differential Diagnosis

Several conditions demonstrate overlap of clinical features with CdLS:

  • Partial duplication of 3q. Features in common with CdLS include developmental delay, failure to thrive, low anterior hairline, prominent eyelashes, depressed nasal bridge, anteverted nares, long and prominent philtrum (retaining the central canal), micrognathia, rhizomelic shortening of the limbs, and genital hypoplasia. However, individuals with partial duplication of 3q usually have normal birth weight, bushy eyebrows, widely spaced eyes, upward-slanted palpebral fissures, epicanthus, broad nose, and normal vermilion of the lips [Fineman et al 1978, Fear & Briggs 1979, Annerén & Gustavson 1984, Tranebjaerg et al 1987].
  • Deletions of chromosome 2q31. Deletions in this region that encompass the HOXD cluster produce limb reduction defects similar to those seen in CdLS as well as genitourinary and developmental abnormalities [Del Campo et al 1999]. Individuals with deletion of 2q31 do not have the characteristic facies of CdLS.
  • Fryns syndrome is characterized by diaphragmatic defects (diaphragmatic hernia, eventration, hypoplasia or agenesis); characteristic facial appearance (coarse facies, widely spaced eyes, broad and depressed nasal bridge, broad nasal tip, long philtrum, low-set and poorly formed ears, tented vermilion of the upper lip, macrostomia, micrognathia); distal digital hypoplasia (nails, terminal phalanges); pulmonary hypoplasia; and associated anomalies (polyhydramnios, cloudy corneas and/or microphthalmia, orofacial clefting, renal dysplasia / renal cortical cysts, and/or malformation involving brain, cardiovascular system, gastrointestinal system, genitalia). Survival beyond the neonatal period has been rare. Data on postnatal growth and psychomotor development are limited; however, severe developmental delay and intellectual disability are common. Inheritance of Fryns syndrome is autosomal recessive. See also Congenital Diaphragmatic Hernia Overview.
  • Fetal alcohol syndrome (FAS). Features common to both FAS and CdLS include intrauterine growth retardation, failure to thrive, developmental abnormalities, microcephaly, facial hirsutism in the newborn, short palpebral fissures, short nose with anteverted nares, long and smooth philtrum, thin vermilion of the upper lip, and cardiac defects. However, the hands and feet in FAS are not small and speech is less affected than in CdLS. A history of alcohol use during pregnancy is useful in discriminating FAS from CdLS.
  • CHOPS syndrome is characterized by cognitive impairment and coarse facies, heart defects, obesity, pulmonary involvement, short stature, and skeletal dysplasia. It is caused by heterozygous pathogenic gain-of-function variants in AFF4. While CHOPS syndrome and CdLS have phenotypic overlap, individuals with CHOPS syndrome have coarse facial features, are overweight, and have significant pulmonary involvement, which is not typically observed in CdLS [Izumi et al 2015].
  • TAF6 variants have been associated with an autosomal recessive CdLS-like presentation. Biallelic pathogenic variants in TAF6 have been reported in two unrelated families with an autosomal recessive disorder characterized by features reminiscent of CdLS: intellectual disability and characteristic dysmorphic facial features (including thick bushy eyebrows with synophrys). Homozygous pathogenic missense variants were identified in one proband from a Turkish family and in three affected individuals from a single Saudi Arabian family [Yuan et al 2015].
  • TAF1 variants have been associated with an X-linked intellectual disability syndrome characterized by global developmental delay, generalized hypotonia, variable neurologic manifestations, and dysmorphic features including long face, prominent supraorbital ridges, long philtrum, anteverted nares, pointed chin, and protruding ears [O'Rawe et al 2015]. Additional features commonly shared by the affected individuals reported by O'Rawe et al [2015] include microcephaly and hearing loss.
  • Bohring-Opitz syndrome is characterized by microcephaly, trigonocephaly, severe developmental delay, failure to thrive, feeding difficulties, palate abnormalities, and characteristic facial features that include depressed nasal bridge, upslanting palpebral fissures, anteverted nares, low-set posteriorly rotated ears, and low hairline with hirsutism. Individuals with Bohring-Opitz syndrome (BOS) can have a specific limb posture termed "BOS posture," described as an external rotation or adduction of the shoulders with flexion of the wrists and fingers at the metacarpophalangeal joint. Additional features that can be associated with BOS include cardiac anomalies, gastrointestinal manifestations (e.g., inguinal hernia, malrotation), structural brain abnormalities, and ophthalmologic findings. Seizures may be present in some affected individuals. BOS is caused by a heterozygous pathogenic variant in ASXL1 [Dangiolo et al 2015].


Evaluations Following Initial Diagnosis

The following recommendations for evaluation of individuals diagnosed with Cornelia de Lange syndrome (CdLS) are based on recent guidelines [Kline et al 2007b] (full text) and the authors' experience:

  • Gastrointestinal evaluation (including upper GI series, endoscopy, milk scan, and/or pH probe) to evaluate for malrotation and gastrointestinal reflux, which, if undiagnosed or undertreated, can lead to feeding intolerance, life-threatening recurrent aspiration, and volvulus
  • Plotting growth parameters on CdLS-specific growth charts. See (girls; boys).
  • Evaluation by a nutritionist if CdLS growth curves reveal failure to thrive
  • Radiographs of the upper extremities to evaluate for radioulnar synostosis. Physical therapy must be performed with caution to avoid causing fractures if radioulnar synostosis is present.
  • Multidisciplinary developmental evaluation to formulate education/therapeutic interventions with an emphasis on communication skills
  • Audiology evaluation with auditory brain stem response testing and otoacoustic emission testing to assess for hearing loss
  • Ophthalmologic evaluation, including assessment of visual acuity, dilated fundus examination, measurement of intraocular pressure, and evaluation of tear ducts for patency and function
  • Echocardiogram to screen for cardiac defects. ASDs are common and may not be picked up by auscultation.
  • Neurologic evaluation and EEG in all affected individuals
  • Renal ultrasonography to evaluate for structural kidney anomalies; if indicated, a vesicoureterogram (VCUG) to evaluate for vesicoureteral reflux
  • Urologic evaluation in males with hypospadias and/or cryptorchidism
  • Pelvic ultrasound to evaluate for bicornuate uterus in females; pelvic ultrasound can be performed at the same time as the renal ultrasound
  • Complete blood count if signs of anemia, bruising, bleeding are present
  • Complete blood count, immune profile (consisting of immunoglobulins; antibodies to tetanus, diptheria, and pneumococcus; B-cell panel; and T-cell panel), and consideration of immunologic evaluation if recurrent infections are present
  • Consultation with a clinical geneticist

Treatment of Manifestations

The following are appropriate:

  • Aggressive management of gastroesophageal reflux with consideration of fundoplication if GER is severe
  • Surgical correction of intestinal malrotation if present
  • Supplementary formulas and/or gastrostomy tube placement to meet nutritional needs if there is failure to thrive
  • Surgical intervention of arms/hands if limb defects hinder utilization or mobility
  • Ongoing physical, occupational, and speech therapies to optimize developmental outcomes; alternative communicative methods (e.g., sign language, picture exchange communication system [PECS]) to facilitate communication if verbal skills are inadequate to express wants and needs
  • Standard treatment for hearing loss
  • Aggressive treatment for nasolacrimal duct obstruction as massage therapy is often unsuccessful because of malformed ducts; standard treatment for refractive errors, strabismus, glaucoma, and ptosis
  • Standard interventions for cardiac defects
  • Appropriate treatment for seizures
  • Antibiotic prophylaxis and follow up for vesicoureteral reflux
  • Orchiopexy if cryptorchidism is present
  • Standard intervention for bicornuate uterus, if present

Prevention of Secondary Complications

To prevent secondary complications:

  • Preoperative evaluation for thrombocytopenia and cardiac disease
  • Care during sedation and/or operative procedures in an institution with pediatric anesthesiologists experienced in the management of the small airways of children with CdLS
  • During anesthesia, attention to the risk of malignant hyperthermia (see Malignant Hyperthermia Susceptibility), which has been reported in a few children with CdLS [Papadimos & Marco 2003]


The following are appropriate:

  • Annual gastrointestinal evaluation including monitoring of growth
  • Annual evaluation by a developmental pediatrician to assess developmental progress and to target therapeutic interventions and educational modalities
  • Regular follow up of ophthalmologic and/or audiologic abnormalities
  • Routine monitoring of existing cardiac or renal anomalies

Agents/Circumstances to Avoid

No known agents exacerbate the severity of CdLS; however, caution should be exercised to avoid exacerbation of existing comorbidities including gastroesophageal reflux, self-injurious behavior, pica, and less commonly, thrombocytopenia and immunologic features.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to evaluation of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search in the US and in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

NIPBL-related Cornelia de Lange syndrome (CdLS), RAD21-related CdLS, and SMC3-related CdLS are inherited in an autosomal dominant manner. Mutation of one of these genes is most often de novo; approximately 1% of parents have germline mosaicism.

HDAC8- and SMC1A-related CdLS are inherited in an X-linked manner. Mutation of one of these genes is most often de novo.

Risk to Family Members – Autosomal Dominant Inheritance

Parents of a proband

  • Fewer than 1% of individuals diagnosed with Cornelia de Lange syndrome have an affected parent.
  • Approximately 99% of individuals with CdLS have the disorder as the result of a de novo pathogenic variant.
  • Recurrent risks for CdLS have been estimated to be as high as 1.5% [Jackson et al 1993]. In a cohort of 351 families, approximately 3.4%-5.4% of parents were found to have germline mosaicism for the causative pathogenic variant [Slavin et al 2012]. However, this study by Slavin et al represents a highly biased sample, as familial cases were specifically ascertained to give power to linkage studies to aid in identifying the gene(s) in which mutation causes CdLS. Therefore, these data may be skewed.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include clinical examination for features of CdLS, complete with plotting of growth parameters, and molecular genetic testing if the pathogenic variant has been identified in the proband.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the cause may be either germline mosaicism in a parent or a de novo pathogenic variant in the proband. Prior to the identification of NIPBL pathogenic variants as an etiology of CdLS, germline mosaicism had been hypothesized based on reports of unaffected parents with more than one affected child [Gillis et al 2004, Krantz et al 2004]. With the identification of heterozygous NIPBL pathogenic variants as the cause of CdLS, germline mosaicism has been confirmed in several cases (see Parents of a proband).

Offspring of a proband

  • Each child of an individual with CdLS has a 50% chance of inheriting the pathogenic variant.
  • While most familial recurrences of CdLS are the result of germline mosaicism in a phenotypically normal parent, rare cases of a mildly affected individual with CdLS having children with CdLS have been reported.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents: if a parent is affected, his or her family members are at risk.

Risk to Family Members – X-Linked Inheritance

Parents of a proband

Note: Unlike a typical X-linked gene, SMC1A is not inactivated in the process of X-chromosome inactivation; thus, carrier mothers are likely to display some features of CdLS that are milder than those of their affected sons. However, to date, too few families with SMC1A-related CdLS have been identified to fully evaluate this model.

Sibs of a proband

  • The risk to sibs depends on the carrier status of the mother.
  • If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the pathogenic variant will be affected; female sibs who inherit the pathogenic variant will be carriers and will usually not be affected.
  • If the pathogenic variant cannot be detected in the leukocyte DNA of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband

  • Although many individuals with classic CdLS do not reproduce, mildly affected individuals may have offspring.
  • Males with X-linked CdLS transmit the pathogenic variant to all of their daughters and none of their sons.

Other family members of a proband. The proband's maternal aunts may be at risk of being carriers, and the aunt's offspring, depending on their gender, may be at risk of being carriers or of being affected.

Carrier Detection

Carrier testing for at-risk females requires prior identification of the SMC1A or HDAC8 pathogenic variant in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the pathogenic variant has been identified in an affected family member, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic diagnosis for CdLS are possible.

Ultrasound examination. High-resolution ultrasound examination to follow growth and to evaluate the limbs, heart, diaphragm, palate, and other organs or structures affected in CdLS may be offered to families in which a pathogenic variant has not been identified. Reported prenatal ultrasound findings:

Maternal serum screening. Maternal serum PAPP-A (pregnancy-associated plasma protein A) level may be low in the first and second trimester if the fetus has CdLS [Westergaard et al 1983, Aitken et al 1999, Arbuzova et al 2003, Clark et al 2012].


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • CdLS World
    CdLS World is an international "hub" for worldwide organizations and communities united by Cornelia de Lange Syndrome. Country-specific contact information is available on the CdLS website.
  • Cornelia de Lange Syndrome Foundation, Inc.
    302 West Main Street
    Avon CT 06001
    Phone: 800-223-8355 (Toll-free Support Line); 860-676-8166
    Fax: 860-676-8337
  • My46 Trait Profile

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Cornelia de Lange Syndrome: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Cornelia de Lange Syndrome (View All in OMIM)



Gene structure. The NIPBL transcript spans approximately 9.5 kb and is composed of 47 exons (NM_133433.3). The gene was identified in 2004 by two independent groups [Krantz et al 2004, Tonkin et al 2004]. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. More than 80 pathogenic variants have been reported; they include missense (~20%), frameshift (~40%), nonsense (~20%), and splice-site variants (~15%) [Borck et al 2004, Gillis et al 2004, Krantz et al 2004, Tonkin et al 2004, Bhuiyan et al 2006, Yan et al 2006, Selicorni et al 2007]. The majority of identified pathogenic variants have been private; however, the same pathogenic variants have been seen in several unrelated probands [Gillis et al 2004].

It has been suggested that milder forms of CdLS are more likely to be caused by missense variants and more severe forms by truncating variants [Gillis et al 2004]. (For more information, see Table A.)

Normal gene product. The NIPBL (delangin or nipped-B-like) protein is composed of 2,804 amino acids and is a novel protein displaying homology to the Drosophila nipped-b and yeast sister chromatid cohesion protein 2 (scc2) [Krantz et al 2004, Tonkin et al 2004]. The normal functioning NIPBL protein appears to play a role in sister chromatid cohesion and in regulating long-range enhancer-promoter interactions, possibly through interactions with the cohesin complex reviewed in Dorsett [2004]. The reference sequence is NP_597677.2.

Abnormal gene product. Pathogenic variants in NIPBL either lead to haploinsufficiency (frameshift, nonsense, and possibly splice site variants) or to altered proteins (missense variants) whose function and viability is unknown at this time. Haploinsufficiency of the NIPBL protein results in CdLS as demonstrated by two reports of CdLS in infants with deletions of the entire gene [Taylor & Josifek 1981, Hulinsky et al 2005]. Alteration of NIPBL can have some effect on sister chromatid cohesion [Kaur et al 2005]; however, the manifestations of CdLS are more likely caused by disruption of long-range enhancer-promoter interactions with resultant dysregulation of multiple downstream genes.


Gene structure. The SMC1A transcript spans approximately 9.7 kb and comprises 25 exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. At least 29 pathogenic variants in SMC1A have been reported (NM_006306.2) [Liu et al 2009]. All of these pathogenic variants have resulted in the retention of an open reading frame and consisted of missense and in-frame deletions [Musio et al 2006, Borck et al 2007, Deardorff et al 2007, Liu et al 2009, Mannini et al 2010]. The phenotypes of the affected individuals reported in these studies indicate that pathogenic variants in SMC1A result in a milder form of CdLS, with no predominant structural anomalies of the limbs or viscera, but notable cognitive involvement in many of the patients.

Normal gene product. The SMC1A protein is composed of 1,233 amino acids and is the human homolog of the yeast Smc1 gene, a core component of the cohesin complex forming a heterodimer with Smc3. The cohesin complex plays a critical role in sister chromatid cohesion as well as a role in regulating gene expression by long-range enhancer-promoter interactions [Dorsett 2004]. SMC1A, although residing on chromosome Xp11.22, has been reported to escape X-chromosome inactivation [Brown et al 1995], which has important implications for phenotypic penetrance and genetic counseling.

Abnormal gene product. The reported pathogenic variants result in an altered but presumably intact protein [Deardorff et al 2007, Liu et al 2009, Revenkova et al 2009]. Since SMC1A is reported to escape X-chromosome inactivation [Brown et al 1995], it is presumed that the normal allele in females is somewhat protective. No pathogenic variants that completely disrupt the protein (e.g., nonsense, frameshift) have been reported, although complete lack of the SMC1A protein in males may be an embryonic lethal. However, data are insufficient to extrapolate any conclusions at this time. The phenotypic manifestations caused by pathogenic variants in SMC1A are likely the result of mechanisms similar to those seen with NIPBL: namely, alterations of gene expression [Dorsett et al 2005].


Gene structure. The SMC3 transcript spans approximately 4.1 kb and comprises 29 exons (NM_005445.3). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. To date, one pathogenic variant (a 3-bp deletion) has been reported in an individual with a mild variant form of CdLS. Findings included arched eyebrows, synophrys, and long eyelashes, thin lips, small hands and feet, proximally set thumbs, fifth-finger clinodactyly, restriction of elbow movements, and hirsutism, in addition to high nasal bridge and high palate. He lacked brachycephaly, low anterior hairline, anteverted nostrils, long philtrum, downturned corners of the mouth, micrognathia, and hearing loss. He was employed in a supervised position. The authors noted that individuals with either a SMC3 or SMC1A pathogenic variant exhibit very mild facial dysmorphism, no absence or reduction of limbs or digits, and no other major structural anomalies [Deardorff et al 2007].

Normal gene product. The SMC3 protein comprises 1,217 amino acids (NP_005436.1) and is the human homolog of the yeast Smc3 gene, a core component of the cohesin complex forming a heterodimer with Smc1.

Abnormal gene product. The single report of a de novo 3-bp deletion in SMC3 in an affected individual was predicted to result in an altered, but presumably intact, protein that behaved similarly to the missense variants noted in SMC1A [Deardorff et al 2007].


Gene structure. The longest HDAC8 transcript variant NM_018486.2 has 11 exons and spans 243 kb. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. HDAC8 pathogenic variants have been identified in approximately 4% of individuals with typical CdLS or an overlapping phenotype [Deardorff et al 2012a, Kaiser et al 2014]. Chromosome deletions and duplications as well as pathogenic nonsense, missense, and splice site variants that disrupt HDAC8 have been reported. Kaiser et al [2014] reports a cohort of 25 probands, three affected family members, and three unaffected mothers with pathogenic variants in HDAC8. Of the identified pathogenic variants reported, 23 occurred de novo in the affected individual, six were maternally inherited (in 4 families), and for seven individuals the inheritance could not be determined.

Individuals with pathogenic variants in HDAC8 have clinical overlap with CdLS but do not present with typical CdLS. Typically, individuals do not present with major structural differences and they tend to present with delayed closure of the anterior fontanelle, widely spaced eyes, and a broad nasal tip. Kaiser et al [2014] reported that 20/23 females heterozygous for a pathogenic HDAC8 variant had skewed X-chromosome inactivation (>95:5), one showed no X-chromosome inactivation skewing and two were uninformative due to homozygous polymorphisms present at the testing locus.

Normal gene product. The histone deacetylase 8 protein NP_060956.1 comprises 377 amino acids and is the vertebrate SMC3 deacetylase which plays a role in recycling cohesin in the cell cycle process.

Abnormal gene product. Loss of histone deacetylase 8 activity results in increased SMC3 acetylation and decreased occupancy of cohesin localization sites resulting in altered transcription [Deardorff et al 2012a].


Gene structure. RAD21 consists of 14 exons (NM_006265.2) and 3,604 bps. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Several individuals with pathogenic variants (missense, frameshift, in-frame deletion) and whole-gene deletions of RAD21 have been identified [Deardorff et al 2012b, Minor et al 2014]. These individuals displayed features consistent with CdLS including arched thick eyebrows, synophrys, and short stature, though they minor cognitive delays. Two probands with atypical CdLS features were each found to have a novel heterozygous de novo missense pathogenic variant. Both individuals also had mild neurodevelopmental involvement. Minor et al [2014] described two additional probands with RAD21 pathogenic variants, a frameshift and a maternally inherited in-frame deletion of exon 13, who presented with an atypical CdLS phenotype that is also consistent with more mild developmental delay.

Table 2.

RAD21 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.

Normal gene product. RAD21 comprises 631 amino acids and is a subunit of the cohesion complex. RAD21 links the SMC1/SMC3 heterodimer and STAG1 subunit which allows for proper regulation of cohesion and chromatin association and disassociation [Deardorff et al 2012b].

Abnormal gene product. Functional studies suggested that a RAD21 deletion would result in haploinsufficiency while missense variants contributed to an altered protein structure or loss of function [Deardorff et al 2012b]. The p.Pro376Arg missense variant previously identified by Deardorff et al [2012b] resulted in altered RAD21-STAG activity interfering with cohesin activity by increasing binding of STAG1 and STAG2 to RAD21. This altered activity may lead to altered sister chromatid cohesion, particularly more closely bound sister chromatids, which suggests a delay in the cell cycle progression from G2/M to G1 phase. The second pathogenic missense variant identified by Deardorff et al [2012b], p.Cys585Arg, is predicted to alter Rad21-SMC1A interactions; functional studies suggest loss of function. The frameshift duplication in exon 6 described by Minor et al [2014] results in a premature stop codon that may be targeted for nonsense-mediated decay.


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Chapter Notes


We would like to acknowledge the continued support of the families we follow with CdLS as well as the CdLS-USA Foundation.

Author History

Dinah M Clark, MS; The Children's Hospital of Philadelphia (2005-2016)
Matthew A Deardorff, MD, PhD (2005-present)
Ian D Krantz, MD (2005-present)
Sarah E Noon, MS (2016-present)

Revision History

  • 28 January 2016 (me) Comprehensive update posted live
  • 27 October 2011 (me) Comprehensive update posted live
  • 14 August 2006 (cd) Revision: SMC1L1 mutation scanning clinically available
  • 31 July 2006 (cd) Revision: sequence analysis of entire NIPBL coding region clinically available
  • 18 May 2006 (cd) Revision: mutations in SMC1L1 identified in some individuals with CdLS
  • 24 March 2006 (cd) Revision: prenatal testing clinically available
  • 16 September 2005 (me) Review posted live
  • 12 January 2005 (ik) Original submission
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