Rare Pediatrics News

Disease Profile

Cornelia de Lange syndrome

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
1-9 / 100 000

3,310 - 29,790

US Estimated

1-9 / 100 000

5,135 - 46,215

Europe Estimated

Age of onset

Neonatal

ICD-10

Q87.1

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Brachmann de Lange syndrome; CDLS; De Lange syndrome;

Categories

Congenital and Genetic Diseases; Digestive Diseases; Ear, Nose, and Throat Diseases;

Summary

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]

Symptoms

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]

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.

Cause

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]

Diagnosis

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]

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.

    Treatment

    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.

    Organizations

    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

      Learn more

      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

      • MedlinePlus Genetics 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.

          References

          1. Cornelia de Lange syndrome. Genetics Home Reference (GHR). 2015; https://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; https://www.ncbi.nlm.nih.gov/books/NBK1104/#cdls.Diagnosis.
          5. Mustafa Tekin, MD. Cornelia De Lange Syndrome. Medscape Reference. April 2015; https://emedicine.medscape.com/article/942792-overview.
          6. CdLS Foundation. Genetic Information. https://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; https://www.ncbi.nlm.nih.gov/books/NBK1104/. Accessed 1/15/2015.
          8. Frequently Asked Questions: Is life expectancy known?. CdLS Foundation. https://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. https://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. https://www.ncbi.nlm.nih.gov/pubmed/8291537.

          Rare Pediatrics News

          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