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Cornelia de Lange syndrome

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Other Names:
Brachmann de Lange syndrome; CDLS; De Lange syndrome; Brachmann de Lange syndrome; CDLS; De Lange syndrome; Typus degenerativus amstelodamensis See More
Categories:
Cornelia de Lange syndrome (CdLS) is a developmental disorder that affects many parts of the body. The severity of the condition and the associated signs and symptoms can vary widely, but may include distinctive facial characteristics, growth delays, intellectual disability and limb defects. Approximately 60% of people affected by CdLS have a disease-causing variation (mutation) in the NIPBL gene, and about 10% of cases are caused by mutations in one of four known genes: SMC1A, SMC3, HDAC8 and RAD21. In the remaining 30% of cases, the underlying genetic cause of the condition is unknown. CdLS can be inherited in an autosomal dominant (NIPBL, SMC2, or RAD21) or X-linked (SMC1A or HDAC8) manner. However, most cases result from new (de novo) mutations and occur in people with no family history of the condition.[1][2][3] Treatment is based on the signs and symptoms present in each person.[4]
Last updated: 5/5/2018
The signs and symptoms of Cornelia de Lange syndrome (CdLS) vary widely among affected people and can range from relatively mild to severe. Affected people may experience:[4][5]
  • Slowed growth before and after birth
  • Intellectual disability
  • Developmental delay
  • Autistic and/or self-destructive behaviors
  • Skeletal abnormalities of the arms and hands
  • Gastrointestinal problems
  • Hirsutism (excess hair growth)
  • Hearing loss
  • Myopia
  • Congenital heart defects
  • Genital abnormalities (i.e. cryptorchidism)
  • Seizures
Affected people typically have distinctive craniofacial features, as well, which may include microcephaly; arched eyebrows that often grow together in the middle (synophrys); long eyelashes; low-set ears; small, widely spaced teeth; and a small, upturned nose.[4][5]
Last updated: 5/5/2018

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Showing of 137 |
Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Abnormally low-pitched voice 0010300
Anteverted nares
Nasal tip, upturned
Upturned nasal tip
Upturned nose
Upturned nostrils
[ more ] 		0000463
Atresia of the external auditory canal
Absent ear canal
0000413
Brachycephaly
Short and broad skull
0000248
Curly eyelashes 0007665
Delayed eruption of teeth
Delayed eruption
Delayed teeth eruption
Delayed tooth eruption
Eruption, delayed
Late eruption of teeth
Late tooth eruption
[ more ] 		0000684
Delayed skeletal maturation
Delayed bone maturation
Delayed skeletal development
[ more ] 		0002750
Depressed nasal bridge
Depressed bridge of nose
Flat bridge of nose
Flat nasal bridge
Flat, nasal bridge
Flattened nasal bridge
Low nasal bridge
Low nasal root
[ more ] 		0005280
Downturned corners of mouth
Downturned corners of the mouth
Downturned mouth
[ more ] 		0002714
Gastroesophageal reflux
Acid reflux
Acid reflux disease
Heartburn
[ more ] 		0002020
Generalized hirsutism
Excessive hairiness over body
0002230
High palate
Elevated palate
Increased palatal height
[ more ] 		0000218
Highly arched eyebrow
Arched eyebrows
Broad, arched eyebrows
High, rounded eyebrows
High-arched eyebrows
Thick, flared eyebrows
[ more ] 		0002553
Hypertonia 0001276
Intellectual disability, severe
Early and severe mental retardation
Mental retardation, severe
Severe mental retardation
[ more ] 		0010864
Long eyelashes
Increased length of eyelashes
Unusually long eyelashes
[ more ] 		0000527
Long philtrum 0000343
Low anterior hairline
Low frontal hairline
Low-set frontal hairline
[ more ] 		0000294
Low posterior hairline
Low hairline at back of neck
0002162
Microcephaly
Abnormally small skull
Decreased circumference of cranium
Decreased size of skull
Reduced head circumference
Small head circumference
[ more ] 		0000252
Micrognathia
Little lower jaw
Small jaw
Small lower jaw
[ more ] 		0000347
Micromelia
Smaller or shorter than typical limbs
0002983
Proximal placement of thumb
Attachment of thumb close to wrist
0009623
Short 1st metacarpal
Shortened 1st long bone of hand
0010034
Short foot
Short feet
Small feet
[ more ] 		0001773
Short neck
Decreased length of neck
0000470
Short nose
Decreased length of nose
Shortened nose
[ more ] 		0003196
Short stature
Decreased body height
Small stature
[ more ] 		0004322
Small hand
Disproportionately small hands
0200055
Synophrys
Monobrow
Unibrow
[ more ] 		0000664
Thick eyebrow
Bushy eyebrows
Dense eyebrow
Heavy eyebrows
Prominent eyebrows
Thick eyebrows
[ more ] 		0000574
Thin vermilion border
Decreased volume of lip
Thin lips
[ more ] 		0000233
Toe syndactyly
Fused toes
Webbed toes
[ more ] 		0001770
Widely spaced teeth
Wide-spaced teeth
Widely-spaced teeth
[ more ] 		0000687
30%-79% of people have these symptoms
Anxiety
Excessive, persistent worry and fear
0000739
Attention deficit hyperactivity disorder
Attention deficit
Attention deficit disorder
Attention deficit-hyperactivity disorder
Attention deficits
Childhood attention deficit/hyperactivity disorder
[ more ] 		0007018
Bilateral single transverse palmar creases 0007598
Blepharitis
Inflammation of eyelids
0000498
Clinodactyly of the 5th finger
Permanent curving of the pinkie finger
0004209
Conductive hearing impairment
Conductive deafness
Conductive hearing loss
[ more ] 		0000405
Cryptorchidism
Undescended testes
Undescended testis
[ more ] 		0000028
Cutis marmorata 0000965
Elbow dislocation
Dislocations of the elbows
Elbow dislocations
[ more ] 		0003042
Failure to thrive
Faltering weight
Weight faltering
[ more ] 		0001508
Feeding difficulties in infancy 0008872
Hypoplasia of penis
Underdeveloped penis
0008736
Hypoplastic labia majora
Small labia majora
Underdeveloped vaginal lips
[ more ] 		0000059
Hypoplastic nipples
Small nipples
0002557
Hypospadias 0000047
Intrauterine growth retardation
Prenatal growth deficiency
Prenatal growth retardation
[ more ] 		0001511
Joint stiffness
Stiff joint
Stiff joints
[ more ] 		0001387
Low-set, posteriorly rotated ears 0000368
Microcornea
Cornea of eye less than 10mm in diameter
0000482
Multicystic kidney dysplasia 0000003
Myopia
Close sighted
Near sighted
Near sightedness
Nearsightedness
[ more ] 		0000545
Neurological speech impairment
Speech disorder
Speech impairment
Speech impediment
[ more ] 		0002167
Obsessive-compulsive behavior
Obsessive compulsive behavior
0000722
Phthisis bulbi 0000667
Premature birth
Premature delivery of affected infants
Preterm delivery
[ more ] 		0001622
Ptosis
Drooping upper eyelid
0000508
Radioulnar synostosis
Fused forearm bones
0002974
Sensorineural hearing impairment 0000407
Severe postnatal growth retardation
Marked growth retardation
Severe growth delay in children
Severe postnatal growth failure
[ more ] 		0008850
Sleep disturbance
Difficulty sleeping
Trouble sleeping
[ more ] 		0002360
Vesicoureteral reflux 0000076
5%-29% of people have these symptoms
Abnormality of the uterus
Uterine abnormalities
Uterine malformations
[ more ] 		0000130
Aplasia/Hypoplasia of the cerebellum
Absent/small cerebellum
Absent/underdeveloped cerebellum
[ more ] 		0007360
Atrial septal defect
An opening in the wall separating the top two chambers of the heart
Hole in heart wall separating two upper heart chambers
[ more ] 		0001631
Autism 0000717
Cataract
Clouding of the lens of the eye
Cloudy lens
[ more ] 		0000518
Cerebral cortical atrophy
Decrease in size of the outer layer of the brain due to loss of brain cells
0002120
Choanal atresia
Blockage of the rear opening of the nasal cavity
Obstruction of the rear opening of the nasal cavity
[ more ] 		0000453
Cleft palate
Cleft roof of mouth
0000175
Congenital diaphragmatic hernia 0000776
Delayed puberty
Delayed pubertal development
Delayed pubertal growth
Pubertal delay
[ more ] 		0000823
Glaucoma 0000501
Hip dislocation
Dislocated hips
Dislocation of hip
[ more ] 		0002827
Hip dysplasia 0001385
Increased nuchal translucency 0010880
Intestinal malrotation 0002566
Macrotia
Large ears
0000400
Muscular hypotonia
Low or weak muscle tone
0001252
Nystagmus
Involuntary, rapid, rhythmic eye movements
0000639
Oligodactyly 0012165
Pectus excavatum
Funnel chest
0000767
Peripheral neuropathy 0009830
Prenatal movement abnormality 0001557
Primary amenorrhea 0000786
Proteinuria
High urine protein levels
Protein in urine
[ more ] 		0000093
Pyloric stenosis 0002021
Renal cyst
Kidney cyst
0000107
Renal hypoplasia
Small kidneys
Underdeveloped kidneys
[ more ] 		0000089
Renal insufficiency
Renal failure
Renal failure in adulthood
[ more ] 		0000083
Seizure 0001250
Strabismus
Cross-eyed
Squint
Squint eyes
[ more ] 		0000486
Talipes 0001883
Truncal obesity 0001956
Ventricular septal defect
Hole in heart wall separating two lower heart chambers
0001629
Ventriculomegaly 0002119
Volvulus 0002580
Percent of people who have these symptoms is not available through HPO
2-3 toe syndactyly
Webbed 2nd and 3rd toes
0004691
Abnormal incisura morphology 0031228
Abnormal umbilicus morphology
Abnormal belly button
Abnormal navel
[ more ] 		0001551
Astigmatism
Abnormal curving of the cornea or lens of the eye
0000483
Autosomal dominant inheritance 0000006
Behavioral abnormality
Behavioral changes
Behavioral disorders
Behavioral disturbances
Behavioral problems
Behavioral/psychiatric abnormalities
Behavioural/Psychiatric abnormality
Psychiatric disorders
Psychiatric disturbances
[ more ] 		0000708
Cleft upper lip
Harelip
0000204
Delayed speech and language development
Deficiency of speech development
Delayed language development
Delayed speech
Delayed speech acquisition
Delayed speech development
Impaired speech and language development
Impaired speech development
Language delay
Language delayed
Language development deficit
Late-onset speech development
Poor language development
Speech and language delay
Speech and language difficulties
Speech delay
[ more ] 		0000750
Duplication of internal organs 0005217
Ectopic kidney
Abnormal kidney location
Displaced kidney
[ more ] 		0000086
Elbow flexion contracture
Contractures of elbows
Elbow contracture
Elbow contractures
[ more ] 		0002987
Hand oligodactyly
Hand has less than 5 fingers
0001180
Hiatus hernia
Stomach hernia
0002036
High, narrow palate
Narrow, high-arched roof of mouth
Narrow, highly arched roof of mouth
[ more ] 		0002705
Hirsutism
Excessive hairiness
0001007
Hypoplasia of the radius
Underdeveloped outer large forearm bone
0002984
Hypoplastic male external genitalia
Small male external genitalia
Underdeveloped male genitalia
[ more ] 		0000050
Hypoplastic radial head 0003997
Inguinal hernia 0000023
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation
[ more ] 		0001249
Limited elbow extension
Decreased elbow extension
Elbow limited extension
Limitation of elbow extension
Limited extension at elbows
Limited forearm extension
Restricted elbow extension
[ more ] 		0001377
Low-set ears
Low set ears
Lowset ears
[ more ] 		0000369
Malrotation of colon 0004785
Optic atrophy 0000648
Optic nerve coloboma 0000588
Otitis media
Middle ear infection
0000388
Phocomelia 0009829
Pneumonia 0002090
Proptosis
Bulging eye
Eyeballs bulging out
Prominent eyes
Prominent globes
Protruding eyes
[ more ] 		0000520
Reduced renal corticomedullary differentiation 0005565
Self-injurious behavior
Self-injurious behaviour
0100716
Short sternum 0000879
Single transverse palmar crease 0000954
Sporadic
No previous family history
0003745
Supernumerary ribs
Extra ribs
0005815
Thrombocytopenia
Low platelet count
0001873
Weak cry 0001612
Showing of 137 |
Last updated: 7/1/2020
Most cases (approximately 60%) of Cornelia de Lange syndrome (CdLS) are caused by changes (mutations) in the NIPBL gene. About 10% of people affected by the condition have mutations in one of four known genes (SMC1A, SMC3, HDAC8 and RAD21). Many of the genes associated with CdLS encode proteins that play an important role in human development before birth. Mutations in these genes may result in an abnormal protein that is not able to carry out its normal function. This is thought to interfere with early development leading to the many signs and symptoms of CdLS.[1][6]

In the remaining 30% of people with CdLS, the underlying genetic cause of the condition is unknown.[6]
Last updated: 5/5/2018
Depending on the mutated gene, Cornelia de Lange syndrome (CdLS) can be inherited in an autosomal dominant manner, when it is caused by variations in the NIPBL, SMC2, or RAD21 genes, or it can have an X-linked inheritance when it is caused by variations in the SMC1A or HDAC8 genes. However, most cases (more than 99%) result from new (de novo) mutations, which means that are not inherited from the parents and occur in people with no family history of the condition.[4][5]
Last updated: 5/5/2018
The diagnosis is suspected when the following signs and symptoms are present:[4][5]
  • Head and face appearance (>95%): Very small and flat head (microbrachycephaly), unibrow (synophrys) and highly arched eyebrows (in 98% of the cases), long and thick eyelashes, low-set abnormally placed ears with a thick helix (curve of the outer ear), short nose with upturned tip with nares that are easily seeing from the front (anteverted nares), long space between the nose and the superior lip, thin downturned lips, high and arched palate with clefts (30% of the cases), very small jaw (micrognathia) in 80% of the cases, with spurs (42% of the cases), and short neck. 
  • Growth failure (>95%): Growth failure that starts while the baby is growing inside the womb, resulting in a very low height and weight throughout life, and failure to thrive secondary to gastroesophageal reflux and other issues with feeding.
  • Intellectual disability (>95%) Severe-to-profound developmental delay
  • Limb abnormalities (>95%). Small or absent forearms and missing fingers in about 30% of the cases. Some people do not have limb deficiencies but have micromelia (small hands), abnormal placed thumbs, and an abnormal curvature of the fifth finger (clinodactyly).  A fusion of the bones of the forearm (radioulnar synostosis) is common and may result in a defect of the elbows. Small feet and joined toes (syndactyly) in more than 80% of the cases.
  • Excess of hair in the face, back and arms (hirsutism) in more than 80% of the cases.
People with the milder syndrome usually have many of the characteristic facial features but with less severe cognitive and upper extremities defects, and mild intellectual disability (intelligence is normal in some cases). A milder syndrome is more common in people with variants in the  SMC3, RAD21, HDAC8 or SMC1A  genes.

The diagnosis of CdLS is established with the presence of the clinical features and/or by the genetic test showing a variation in any of the genes associated with the syndrome. However, about 30% of the people affected by the syndrome do not have any known cause.[4][5]


 
Last updated: 5/5/2018

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.
Because Cornelia de Lange syndrome (CdLS) affects many different systems of the body, medical management is often provided by a team of doctors and other healthcare professionals. Treatment for this condition varies based on the signs and symptoms present in each person. It may include:[4][5]
  • Supplemental formulas and/or gastrostomy tube placement to meet nutritional needs and improve the growth delay
  • Ongoing physical, occupational, and speech therapies 
  • Surgery to treat skeletal abnormalities, gastrointestinal problems, congenital heart defects and other health problems
  • Medications to prevent or control seizures.
The CdLS foundation's Web site offers more specific information about the treatment and management of CdLS. Please click on the link to access this resource.
Last updated: 5/5/2018
Life expectancy is relatively normal for people with Cornelia de Lange syndrome and most affected children live well into adulthood.[7][8] For example, one article mentioned a woman with Cornelia de Lange syndrome who lived to age 61 and an affected man who lived to age 54.[9] However, certain features of this condition, particularly severe malformations of the heart or throat, may decrease life expectancy in some affected people.[7][8][9][10]
Last updated: 7/29/2015

If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

Healthcare Resources

Research helps us better understand diseases and can lead to advances in diagnosis and treatment. This section provides resources to help you learn about medical research and ways to get involved.

Clinical Research Resources

  • ClinicalTrials.gov lists trials that are related to Cornelia de Lange syndrome. Click on the link to go to ClinicalTrials.gov to read descriptions of these studies.

    Please note: Studies listed on the ClinicalTrials.gov website are listed for informational purposes only; being listed does not reflect an endorsement by GARD or the NIH. We strongly recommend that you talk with a trusted healthcare provider before choosing to participate in any clinical study.

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

Living with a genetic or rare disease can impact the daily lives of patients and families. These resources can help families navigate various aspects of living with a rare disease.

Financial Resources

Education Resources

  • The Genetics Education Materials for School Success (GEMSS) aims to assure that all children with genetic health conditions succeed in school-life. Their Web site offers general and condition-specific education resources to help teachers and parents better understand the needs of students who have genetic conditions.

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

  • Genetics Home Reference (GHR) contains information on Cornelia de Lange syndrome. This website is maintained by the National Library of Medicine.
  • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

In-Depth Information

  • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
  • Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
  • PubMed is a searchable database of medical literature and lists journal articles that discuss Cornelia de Lange syndrome. Click on the link to view a sample search on this topic.

Questions sent to GARD may be posted here if the information could be helpful to others. We remove all identifying information when posting a question to protect your privacy. If you do not want your question posted, please let us know. Submit a new question

  • My niece was diagnosed with this syndrome. Could you put me in touch with other families who have experience with this syndrome? From the information we found online, I believe that those children are mentally disabled. Could you please confirm that this is true and that ALL the kids with this syndrome will be mentally disabled? See answer

  • What is the life expectancy of individuals with Cornelia de Lange syndrome? See answer


  1. Cornelia de Lange syndrome. Genetics Home Reference (GHR). 2015; http://ghr.nlm.nih.gov/condition/cornelia-de-lange-syndrome.
  2. Feng L, Zhou D, Zhang Z, Liu Y, Yang Y. Exome sequencing identifies a de novo mutation in HDAC8 associated with Cornelia de Lange syndrome. J Hum Genet. September 2014; 59(9):536-539.
  3. Minor A, Shinawi M, Hogue JS, Vineyard M, Hamlin DR, Tan C, Donato K, Wysinger L, Botes S, Das S, Del Gaudio D. Two novel RAD21 mutations in patients with mild Cornelia de Lange syndrome-like presentation and report of the first familial case. Gene. March 2014; 537(2):279-284.
  4. Deardorff MA, Clark DM & Krantz ID. Cornelia de Lange Syndrome. GeneReviews. 2016; http://www.ncbi.nlm.nih.gov/books/NBK1104/#cdls.Diagnosis.
  5. Mustafa Tekin, MD. Cornelia De Lange Syndrome. Medscape Reference. April 2015; http://emedicine.medscape.com/article/942792-overview.
  6. CdLS Foundation. Genetic Information. http://www.cdlsusa.org/research/genetic-information.htm. Accessed 7/28/2015.
  7. Deardorff MA, Clark DM, Krantz ID. Cornelia de Lange Syndrome. GeneReviews. October 2011; http://www.ncbi.nlm.nih.gov/books/NBK1104/. Accessed 1/15/2015.
  8. Frequently Asked Questions: Is life expectancy known?. CdLS Foundation. http://www.cdlsusa.org/what-is-cdls/frequently-asked-questions.htm#life-expectancy. Accessed 1/15/2015.
  9. Beck B, Fenger K. Mortality, pathological findings and causes of death in the de Lange syndrome. Acta Paediatrica Scandinavica. 1985; 74:765-769. http://www.ncbi.nlm.nih.gov/pubmed/4050424.
  10. Jackson L, Kline AD, Barr MA, Koch S. de Lange syndrome: a clinical review of 310 individuals. American Journal of Medical Genetics. 1993; 47:940-946. http://www.ncbi.nlm.nih.gov/pubmed/8291537.