Clinical characteristics.

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

Diagnosis/testing.

The diagnosis of CdLS is established in a proband with suggestive clinical features and/or by identification of a heterozygous pathogenic variant in NIPBL, RAD21, SMC3, or BRD4, or a hemizyous pathogenic variant in HDAC8 or SMC1A by molecular genetic testing.

Management.

Treatment of manifestations: Aggressive management of gastroesophageal reflux with assessment of potential gastrointestinal malrotation; 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 epilepsy, vision issues, nasolacrimal duct obstruction, hearing loss, cleft palate, anomalies of tooth formation and/or position, cardiac defects, cryptorchidism/hypospadias, bicornuate uterus, vesicoureteral reflux, anemia and/or thrombocytopenia, and immunodeficiency. If surgery is being considered, malignant hyperthermia precautions and preoperative evaluation for thrombocytopenia and cardiac disease with careful monitoring of the airway during anesthesia are recommended.

Surveillance: At each visit: measurement of growth parameters and evaluation of nutritional status and safety of oral intake; monitor for signs and symptoms of GERD and for evidence of aspiration with respiratory insufficiency; assessment for new manifestations such as seizures or signs of autonomic dysfunction; monitor developmental progress and educational needs; behavioral assessment for anxiety, attention, and aggressive or self-injurious behavior; assessment of mobility and self-help skills. At least annually: ophthalmology evaluation; dental evaluation with cleaning; audiology evaluation in childhood and adolescence.

Genetic counseling.

NIPBL-CdLS, RAD21-CdLS, SMC3-CdLS and BRD4-CdLS are inherited in an autosomal dominant manner; HDAC8-CdLS and SMC1A-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 autosomal dominant CdLS have an affected parent. When the parents are clinically unaffected, the risk to the sibs of a proband with CdLS is estimated to be 1.5% because of the possibility of germline mosaicism. The risk to sibs of a male proband with X-linked CdLS depends on the status of the proband's mother; the risk to sibs of a female proband with X-linked CdLS depends on the status of the proband's mother and father. Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible for families in which the pathogenic variant has been identified.

Suggestive Findings

Cornelia de Lange syndrome (CdLS) should be suspected in individuals with the following clinical and radiographic features.

Clinical findings

• Distinctive craniofacial appearance (often recognizable; see Figure 1) including:
  • Microcephaly (mean occipital frontal circumference <2nd centile)
  • Synophrys with highly arched and/or thick eyebrows
  • Long, thick eyelashes
  • Short nasal bridge, upturned nasal tip with anteverted nares
  • Long and/or smooth philtrum, thin vermilion of the upper lip, downturned corners of the mouth
  • Highly arched palate with or without cleft palate
  • Small widely spaced teeth
  • Micrognathia with or without mandibular spurs
• Growth failure, which may be detected prenatally and persists postnatally
• Developmental delay / intellectual disability, varying from mild to profound
• Limb abnormalities (either symmetric or asymmetric) ranging from severe reduction defects with complete absence of the forearms, to various forms of oligodactyly (missing digits) involving primarily the upper extremities, to small hands (micromelia) and phalangeal abnormalities (5th digit clinodactyly and short first metacarpal resulting in a proximally placed thumb) at the mild end
• Hypertrichosis. Thick scalp hair that often extends onto the temporal regions and at times involves the face, ears, back, and arms

Figure 1.

Classic CdLS craniofacial features

Radiographic findings. In those without limb deficiencies, the presence of a short first metacarpal on plain x-ray resulting in a proximally placed thumb can be useful in diagnosis.

Establishing the Diagnosis

The diagnosis of CdLS is established in a proband with the above clinical features and/or by the identification on molecular genetic testing of a heterozygous pathogenic (or likely pathogenic) variant in NIPBL, RAD21, SMC3, or BRD4 or a hemizyous pathogenic (or likely pathogenic) variant in HDAC8 or SMC1A (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (serial single-gene testing or multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Cornelia de Lange syndrome can be broad, individuals with distinctive features described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of Cornelia de Lange syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

While classic Cornelia de Lange syndrome (CdLS) was formally characterized more than 70 years ago and well delineated clinically [Ptacek et al 1963, Jackson et al 1993], the identification of the molecular genetic basis of CdLS has led to the recognition of affected individuals who have milder or atypical features. Therefore, this condition encompasses a spectrum of findings from mild to severe (see Phenotype Correlations by Gene). Those with a milder phenotype, which is less striking clinically than the classic form of CdLS, may represent the majority of individuals with CdLS [Deardorff et al 2007, Rohatgi et al 2010].

Growth. Prenatal-onset growth failure is present in a majority of individuals 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 [Boog et al 1999] in individuals with classic CdLS. Growth may be less severely affected in those with overall milder clinical features and/or mosaic pathogenic variants. In addition, failure to thrive may be superimposed on the constitutional growth restriction secondary to gastroesophageal reflux disease and other issues with feeding (see Gastrointestinal below).

CdLS-specific growth charts have been developed. See www.cdlsusa.org (girls; boys).

Intellectual disability. Most individuals with CdLS have developmental delay. The overall range of IQ levels is broad, from below 30 to 102, with an average IQ of 53 [Kline et al 1993, Saal et al 1993]. Those affected individuals with classic features are more likely to have severe-to-profound intellectual disability (see Genotype-Phenotype Correlations).

• Expressive language is often more compromised than receptive language, and receptive language more compromised than cognition [Ajmone et al 2014].
• Effective verbal and nonverbal communication skills can facilitate quality of life enormously [Kline et al 2018]. Early augmentative and alternative communication interventions are highly effective [Ajmone et al 2014].
• Half of children walk by 24 months and 95% by age ten. Half of children are able to feed themselves by age three years and 95% by age ten [Kline et al 1993].

Behavior. A range of behavioral issues have been reported [Kline et al 2018].

• Behavior problems are often directly related to frustration from an inability to communicate (see Intellectual disability above).
• Difficulties in sensory processing can lead to hyposensitivity, hypersensitivity, disorientation, and fixation.
• Autistic behavior may lead to avoidance or rejection of social interaction and physical contact.
• Repetitive behaviors, which can be exacerbated by anxiety, are common and are associated with more marked intellectual disability and autistic features.
• Clinically significant self-injurious behavior occurs in 56% of individuals, with hand-directed self-injurious behavior the most common.

Neurologic. Overall, approximately 25% of individuals with CdLS have seizures. Partial epilepsy is the most common type with age of onset typically before age two years. Most affected individuals respond well to standard medical therapy and are able to be weaned off medical therapy after a few years [Verrotti et al 2013] (see Management, Treatment of Manifestations).

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

• Upper-extremity deficiencies ranging from severe reduction defects with complete absence of the forearms to various forms of oligodactyly (missing digits) are present in about one third of those with classic features.
• 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 third toes occurs in more than 80% of affected individuals [Jackson et al 1993].

Figure 3.

Range of limb anomalies in CdLS

Gastrointestinal. Gastroesophageal reflux disease (GERD) is present in a majority of affected indivdiuals. Other complications of GERD including esophagitis, aspiration, chemical pneumonitis, and irritability can be avoided by diagnosis and treatment of GERD in the neonatal period (see Management). Approximately one third have evidence of aspiration and 15% require a feeding tube [Luzzani et al 2003]. Other gastrointestinal abnormalities include:

• Pyloric stenosis (4%), the most frequent cause of persistent vomiting in the newborn period
• Intestinal malrotation (2%)
• Congenital diaphragmatic hernia (CDH) (1%)
  CDH has been diagnosed both pre- and postnatally, but may be underascertained, especially in infants who die in the perinatal period.

Ophthalmologic. As many as 60% 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:

• Nasolacrimal duct stenosis
• Glaucoma
• Microcornea
• Astigmatism
• Optic atrophy
• Coloboma of the optic nerve
• Strabismus
• Proptosis

Otolaryngologic. Sensorineural hearing impairment is noted in 40% of children with CdLS, and conductive hearing impairment in 60% [Marchisio et al 2014]. Notably, for a significant proportion hearing loss (both sensorineural and conductive) improves over time [Janek et al 2016]

Genitourinary. Renal abnormalities, primarily vesicoureteral reflux, have been reported in 12%.

• Cryptorchidism occurs in 73% of males with CdLS
• Hypoplastic (small) genitalia occur in 57% and hypospadias in 9% of males [Jackson et al 1993]
• 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].

Cardiovascular. Approximately 30% of individuals with CdLS have congenital heart disease [Chatfield et al 2012]. The most common abnormalities include (in descending order):

• Pulmonic or peripheral pulmonic stenosis
• Ventricular septal defects
• Atrial septal defects
• Coarctation or hypoplastic aortic arch
• Aortic valve anomaly
• Tetralogy of Fallot
• Double-outlet right ventricle
• Atrioventricular canal defect

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.

Hematologic. Thrombocytopenia often resolves after infancy, but can rarely transition to persistent idiopathic thrombocytopenia purpura [Lambert et al 2011]. In most cases, anemia is transient.

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].
• Hypoplastic nipples and umbilicus are seen in 50%.

Prognosis. The majority of familial cases suggest that expressivity is relatively consistent within a family. In the absence of severe congenital anomalies of internal organs, life expectancy is not significantly reduced.

• Beck & Fenger [1985] studied 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.
• 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.

Phenotype Correlations by Gene

Other Genes

Milder phenotypes that retain some of the characteristic facial features but with variable cognitive and limb or structural involvement compared to individuals with a pathogenic variant in NIPBL have been consistently described and can be seen in individuals with a heterozygous pathogenic variant in BRD4, SMC3 or RAD21 or a hemizygous pathogenic variant in HDAC8 or SMC1A [Deardorff et al 2007, Selicorni et al 2007, Rohatgi et al 2010, Kaiser et al 2014, Minor et al 2014, Gil-Rodríguez et al 2015, Olley et al 2018] (see Figure 2).

Figure 2.

Affected individual with a pathogenic variant in SMC1A

SMC1A and SMC3

• 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, Gil-Rodríguez et al 2015, Huisman et al 2017].
• Compared to individuals with a heterozygous NIPBL pathogenic variant, the facial features in those with SMC1A or SMC3 pathogenic variants include slightly flatter and broader eyebrows and a broader and longer nasal bridge [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, although typically mild, are also observed (~56%) in individuals with SMC3 pathogenic variants, and less frequently in individuals with SMC1A pathogenic variants [Gil-Rodríguez et al 2015].

RAD21. Individuals with a heterozygous RAD21 pathogenic variant:

• Typically do not have major structural differences.
• Have milder cognitive impairment compared to those with classic CdLS.
  Specifically, 10% have normal cognition, 45% have mild cognitive impairment and none have severe or profound cognitive disability [Krab et al 2020].
• Often display growth restriction, minor skeletal anomalies, and facial features that overlap with CdLS [Deardorff et al 2012, Krab et al 2020].

HDAC8

• 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 restriction and microcephaly reported.
• Females. The clinical presentation for a female with a heterozygous pathogenic variant in HDAC8 overlaps that of males, but the severity is greatly influenced by the pattern of X inactivation [Kaiser et al 2014].

Genotype-Phenotype Correlations

NIPBL. Individuals with pathogenic missense variants and in-frame deletions in NIPBL have been found to have less severe growth deficiency, milder intellectual disability, and fewer structural anomalies [Gillis et al 2004, Ajmone et al 2014, Ansari et al 2014] compared to those with pathogenic loss-of-function NIPBL variants.

SMC1A. Pathogenic variants that cause a CdLS phenotype are typically missense and can result in a range of severity. Of note, loss of function pathogenic variants in SMC1A cause an early-infantile epileptic encephalopathy (OMIM 301044; see Genetically Related Disorders).

Nomenclature

Cornelia de Lange syndrome (CdLS) was first described by Vrolik in 1849, 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.

Prevalence

The prevalence of CdLS is difficult to estimate as individuals with milder or variable 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]. 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.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Cornelia de Lange syndrome, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

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 ClinicalTrials.gov in the US and EU Clinical Trials Register 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.

Mode of Inheritance

NIPBL Cornelia de Lange syndrome (CdLS), RAD21-CdLS, SMC3-CdLS, and BRD4-CdLS are autosomal dominant disorders typically caused by a de novo pathogenic variant.

HDAC8-CdLS and SMC1A-CdLS are X-linked disorders usually caused by a de novo pathogenic variant.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Approximately 99% of individuals with autosomal dominant CdLS have the disorder as the result of a de novo pathogenic variant.
• Fewer than 1% of individuals diagnosed with CdLS have an affected parent.
• Recommendations for the evaluation of parents of a proband who appears to represent a simplex case (i.e., a single occurrence in a family) include clinical examination for features of CdLS, complete with plotting of growth parameters, and molecular genetic testing if the causative pathogenic variant has been identified in the proband.
• If a pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. The frequency of parental germline mosaicism is approximately 1.5%; a frequency of 3.4%-5.4% was reported in a cohort highly enriched for rare familial cases [Slavin et al 2012; Author, unpublished data].

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the recurrence risk to the sibs is 50%.
• If the proband has a known CdLS-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent and/or the parents are clinically unaffected, the risk to the sibs of a proband has been estimated at 1.5% because of the possibility of germline mosaicism [Jackson et al 1993].

Offspring of a proband

• Each child of an individual with autosomal dominant 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 mildly affected individuals with CdLS having children with CdLS have been reported.

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

X-Linked Inheritance – Risk to Family Members

Parents of a male proband

• The predominance of individuals with X-linked CdLS have the disorder as the result of a de novo SMC1A or HDAC8 pathogenic variant.
• The father of an affected male will not have CdLS nor will he be hemizygous for the pathogenic variant.
• In a family with more than one affected individual, the mother of an affected male is typically heterozygous for the causative variant; alternatively, if she has no other affected relatives and the causative variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• Note: Unlike a typical X-linked gene, SMC1A is not fully inactivated in the process of X-chromosome inactivation. In this setting, a heterozygous mother is likely to display some features of CdLS that are milder than those of her affected son. However, to date, too few families with SMC1A-CdLS have been identified to fully evaluate this model.

Parents of a female proband

• A female proband may have inherited the causative variant from either her mother or her father, or the pathogenic variant may be de novo.
• Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a de novo pathogenic variant from those with an inherited pathogenic variant. Molecular genetic testing of the parents can determine if the pathogenic variant was inherited. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• Germline mosaicism for an SMC1A pathogenic variant was reported in the father of multiple affected daughters [Deardorff et al 2007].

Sibs of a male proband. The risk to sibs of a male proband depends on the genetic status of the mother:

• If the mother of the proband has an SMC1A or HDAC8 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 heterozygous. Females who are heterozygous for an SMC1A pathogenic variant are likely to have some features of CdLS; females who are heterozygous for an HDAC8 pathogenic variant may or may not have clear clinical findings of CdLS depending on the pattern of X-linked inactivation.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is approximately 1% because of the possibility of maternal germline mosaicism.

Sibs of a female proband. The risk to sibs depends on the genetic status of the parents:

• If the mother of the proband has an SMC1A or HDAC8 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes (see Sibs of a male proband).
• If the father of the proband has a pathogenic variant, he will transmit it to all his daughters and none of his sons.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of either parent, the risk to sibs is approximately 1% because of the possibility of parental germline mosaicism.

Offspring of a proband

• Although individuals with severe CdLS do not typically reproduce, mildly affected individuals may have children.
• Males with X-linked CdLS would transmit the pathogenic variant to all of their daughters and none of their sons.
• Females with X-linked CdLS would have a 50% chance of transmitting the pathogenic variant to each child.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has a pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the CdLS-causative pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing 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:

• Increased nuchal translucency in the first trimester [Sekimoto et al 2000, Huang & Porto 2002, Clark et al 2012]
• Growth failure, which typically presents in the second trimester
• The typical in utero facial profile of a fetus with CdLS consisting of micrognathia, a prominent upper lip, and a depressed nasal bridge with somewhat anteverted nares [Ranzini et al 1997, Boog et al 1999, Urban & Hartung 2001, Clark et al 2012]

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].

Molecular Pathogenesis

Pathogenic variants that result in Cornelia de Lange syndrome disrupt genes that regulate chromatin, most commonly the cohesin complex. Cohesin is a bracelet-like structure that regulates many elements of chromatin biology, including chromosome segregation, genomic stability, genome organization, and transcriptional regulation. The core proteins of the cohesin complex include SMC1A, SMC3, and RAD21. The regulatory proteins NIPBL and MAU2 play key roles in loading cohesin onto chromatin, while HDAC8 is important in enabling the loading and stabilization of cohesin on chromatin. Quite interestingly, some of the key roles of cohesin that enable looping of chromatin to facilitate enhancer regulation of promoters and promote RNA polymerase activity, are also regulated by ANKRD11, EP300, BRD4, and AFF4, suggesting functional overlap in how pathogenic variants in these genes can result in CdLS-like presentations. For these reasons, CdLS has been termed a "cohesinopathy" and a "transcriptomopathy."

Gene-specific laboratory technical considerations. RAD21 exon 14 is within a segmental duplication.

Notable variants by gene. Given that most variants are de novo, they are typically present as private pathogenic variants. However, rare SMC1A recurrent pathogenic variants exist; see Table 9.

Acknowledgments

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

• 15 October 2020 (ma) Comprehensive update posted live
• 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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