Cornelia de Lange syndrome

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10109

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Disease Profile

1-9 / 100 000

US Estimated

Europe Estimated

Age of onset

Neonatal

ICD-10

Q87.1

Inheritance

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]

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

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.

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.

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

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.

Not applicable

Other names (AKA)

Brachmann de Lange syndrome; CDLS; De Lange syndrome;

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

CdLS Foundation UK & Ireland
The Tower
Guardian Avenue
North Stifford
Grays, Essex
RM16 5US
United Kingdom
Telephone: 01375 376439
Fax: 01375 404478
E-mail: [email protected]
Website: https://www.cdls.org.uk/
CdLS World
Website: https://www.cdlsworld.org
Cornelia de Lange Syndrome Foundation, Inc.
302 West Main Street
#100
Avon, CT 06001
Telephone: 800-223-8355 (Toll-free Support Line); 860-676-816
Fax: 860-676-8337
E-mail: [email protected]
Website: https://www.cdlsusa.org

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

Cornelia de Lange syndrome. Genetics Home Reference (GHR). 2015; https://ghr.nlm.nih.gov/condition/cornelia-de-lange-syndrome.
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.
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.
Deardorff MA, Clark DM & Krantz ID. Cornelia de Lange Syndrome. GeneReviews. 2016; https://www.ncbi.nlm.nih.gov/books/NBK1104/#cdls.Diagnosis.
Mustafa Tekin, MD. Cornelia De Lange Syndrome. Medscape Reference. April 2015; https://emedicine.medscape.com/article/942792-overview.
CdLS Foundation. Genetic Information. https://www.cdlsusa.org/research/genetic-information.htm. Accessed 7/28/2015.
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.
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.
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.
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 Dermatology 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

Rare Dermatology News

Rare Dermatology News

Neonatal

Q87.1

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

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.

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.

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

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.

Not applicable

Other names (AKA)

Categories

Summary

Symptoms

Cause

Diagnosis

Testing Resources

Treatment

Organizations

Organizations Supporting this Disease

Learn more

Where to Start

In-Depth Information

References

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.

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