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Cornelia de Lange syndrome

Reviewed July 2012

What is Cornelia de Lange syndrome?

Cornelia de Lange syndrome is a developmental disorder that affects many parts of the body. The features of this disorder vary widely among affected individuals and range from relatively mild to severe.

Cornelia de Lange syndrome is characterized by slow growth before and after birth, intellectual disability that is usually severe to profound, skeletal abnormalities involving the arms and hands, and distinctive facial features. The facial differences include arched eyebrows that often grow together in the middle (synophrys); long eyelashes; low-set ears; small, widely spaced teeth; and a small, upturned nose. Many affected individuals also have behavior problems similar to autism, a developmental condition that affects communication and social interaction.

Additional signs and symptoms of Cornelia de Lange syndrome can include excessive body hair (hypertrichosis), an unusually small head (microcephaly), hearing loss, short stature, and problems with the digestive tract. Some people with this condition are born with an opening in the roof of the mouth called a cleft palate. Seizures, heart defects, eye problems, and skeletal abnormalities also have been reported in people with this condition.

How common is Cornelia de Lange syndrome?

Although the exact incidence is unknown, Cornelia de Lange syndrome likely affects 1 in 10,000 to 30,000 newborns.

What genes are related to Cornelia de Lange syndrome?

Mutations in the NIPBL, SMC1A, and SMC3 genes can cause Cornelia de Lange syndrome. NIPBL gene mutations have been identified in more than half of all people with this condition; mutations in the other two genes are much less common. The proteins produced from all three genes play important roles in directing development before birth. Within cells, these proteins help regulate the structure and organization of chromosomes and are involved in the repair of damaged DNA. They also regulate the activity of certain genes in the developing limbs, face, and other parts of the body.

Mutations in the NIPBL, SMC1A, and SMC3 genes can cause Cornelia de Lange syndrome by disrupting gene regulation during critical stages of early development. Studies suggest that SMC1A and SMC3 gene mutations tend to cause somewhat milder signs and symptoms than those seen with mutations in the NIPBL gene.

In about 35 percent of cases, the cause of Cornelia de Lange syndrome is unknown. Researchers are looking for additional changes in the NIPBL, SMC1A, and SMC3 genes, as well as mutations in other genes, that may be responsible for this condition.

Related Gene(s)

Changes in these genes are associated with Cornelia de Lange syndrome.

  • NIPBL
  • SMC1A
  • SMC3

How do people inherit Cornelia de Lange syndrome?

When Cornelia de Lange syndrome is caused by mutations in the NIPBL or SMC3 gene, this condition is considered to have an autosomal dominant pattern of inheritance. Autosomal dominant inheritance means one copy of the altered gene in each cell is sufficient to cause the disorder. Almost all cases result from new gene mutations and occur in people with no history of the condition in their family.

Cases of Cornelia de Lange syndrome caused by SMC1A gene mutations have an X-linked pattern of inheritance. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes. Studies of X-linked Cornelia de Lange syndrome indicate that one copy of the altered gene in each cell may be sufficient to cause the condition. Unlike most X-linked conditions, in which males are more frequently affected or experience more severe symptoms than females, X-linked Cornelia de Lange syndrome appears to affect males and females similarly. Most cases result from new mutations in the SMC1A gene and occur in people with no history of the condition in their family.

Where can I find information about diagnosis or management of Cornelia de Lange syndrome?

These resources address the diagnosis or management of Cornelia de Lange syndrome and may include treatment providers.

  • Gene Review: Cornelia de Lange Syndrome (http://www.ncbi.nlm.nih.gov/books/NBK1104)
  • Genetic Testing Registry: Congenital muscular hypertrophy-cerebral syndrome (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1802395)
  • Genetic Testing Registry: Cornelia de Lange syndrome 1 (http://www.ncbi.nlm.nih.gov/gtr/conditions/CN029798)
  • Genetic Testing Registry: De Lange syndrome (http://www.ncbi.nlm.nih.gov/gtr/conditions/C0270972)
  • MedlinePlus Encyclopedia: Autism (http://www.nlm.nih.gov/medlineplus/ency/article/001526.htm)
  • MedlinePlus Encyclopedia: Microcephaly (http://www.nlm.nih.gov/medlineplus/ency/article/003272.htm)

You might also find information on the diagnosis or management of Cornelia de Lange syndrome in Educational resources (http://www.ghr.nlm.nih.gov/condition/cornelia-de-lange-syndrome/show/Educational+resources) and Patient support (http://www.ghr.nlm.nih.gov/condition/cornelia-de-lange-syndrome/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about Cornelia de Lange syndrome?

You may find the following resources about Cornelia de Lange syndrome helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for Cornelia de Lange syndrome?

  • BDLS
  • Brachmann-De Lange Syndrome
  • CDLS
  • De Lange Syndrome

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about Cornelia de Lange syndrome?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding Cornelia de Lange syndrome?

autism ; autosomal ; autosomal dominant ; cell ; chromosome ; cleft palate ; cohesion ; digestive ; disability ; DNA ; gene ; gene regulation ; hypertrichosis ; incidence ; inheritance ; microcephaly ; palate ; pattern of inheritance ; sex chromosomes ; short stature ; stature ; syndrome

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • Borck G, Redon R, Sanlaville D, Rio M, Prieur M, Lyonnet S, Vekemans M, Carter NP, Munnich A, Colleaux L, Cormier-Daire V. NIPBL mutations and genetic heterogeneity in Cornelia de Lange syndrome. J Med Genet. 2004 Dec;41(12):e128. (http://www.ncbi.nlm.nih.gov/pubmed/15591270?dopt=Abstract)
  • Borck G, Zarhrate M, Bonnefont JP, Munnich A, Cormier-Daire V, Colleaux L. Incidence and clinical features of X-linked Cornelia de Lange syndrome due to SMC1L1 mutations. Hum Mutat. 2007 Feb;28(2):205-6. (http://www.ncbi.nlm.nih.gov/pubmed/17221863?dopt=Abstract)
  • Deardorff MA, Kaur M, Yaeger D, Rampuria A, Korolev S, Pie J, Gil-Rodríguez C, Arnedo M, Loeys B, Kline AD, Wilson M, Lillquist K, Siu V, Ramos FJ, Musio A, Jackson LS, Dorsett D, Krantz ID. Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of cornelia de Lange syndrome with predominant mental retardation. Am J Hum Genet. 2007 Mar;80(3):485-94. Epub 2007 Jan 17. (http://www.ncbi.nlm.nih.gov/pubmed/17273969?dopt=Abstract)
  • Dorsett D, Krantz ID. On the molecular etiology of Cornelia de Lange syndrome. Ann N Y Acad Sci. 2009 Jan;1151:22-37. doi: 10.1111/j.1749-6632.2008.03450.x. Review. (http://www.ncbi.nlm.nih.gov/pubmed/19154515?dopt=Abstract)
  • Gene Review: Cornelia de Lange Syndrome (http://www.ncbi.nlm.nih.gov/books/NBK1104)
  • Gillis LA, McCallum J, Kaur M, DeScipio C, Yaeger D, Mariani A, Kline AD, Li HH, Devoto M, Jackson LG, Krantz ID. NIPBL mutational analysis in 120 individuals with Cornelia de Lange syndrome and evaluation of genotype-phenotype correlations. Am J Hum Genet. 2004 Oct;75(4):610-23. Epub 2004 Aug 18. (http://www.ncbi.nlm.nih.gov/pubmed/15318302?dopt=Abstract)
  • Jackson L, Kline AD, Barr MA, Koch S. de Lange syndrome: a clinical review of 310 individuals. Am J Med Genet. 1993 Nov 15;47(7):940-6. (http://www.ncbi.nlm.nih.gov/pubmed/8291537?dopt=Abstract)
  • Krantz ID, McCallum J, DeScipio C, Kaur M, Gillis LA, Yaeger D, Jukofsky L, Wasserman N, Bottani A, Morris CA, Nowaczyk MJ, Toriello H, Bamshad MJ, Carey JC, Rappaport E, Kawauchi S, Lander AD, Calof AL, Li HH, Devoto M, Jackson LG. Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B. Nat Genet. 2004 Jun;36(6):631-5. Epub 2004 May 16. (http://www.ncbi.nlm.nih.gov/pubmed/15146186?dopt=Abstract)
  • Liu J, Krantz ID. Cornelia de Lange syndrome, cohesin, and beyond. Clin Genet. 2009 Oct;76(4):303-14. doi: 10.1111/j.1399-0004.2009.01271.x. Review. (http://www.ncbi.nlm.nih.gov/pubmed/19793304?dopt=Abstract)
  • Musio A, Selicorni A, Focarelli ML, Gervasini C, Milani D, Russo S, Vezzoni P, Larizza L. X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations. Nat Genet. 2006 May;38(5):528-30. Epub 2006 Apr 9. (http://www.ncbi.nlm.nih.gov/pubmed/16604071?dopt=Abstract)
  • Tonkin ET, Wang TJ, Lisgo S, Bamshad MJ, Strachan T. NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome. Nat Genet. 2004 Jun;36(6):636-41. Epub 2004 May 16. (http://www.ncbi.nlm.nih.gov/pubmed/15146185?dopt=Abstract)
  • Yan J, Saifi GM, Wierzba TH, Withers M, Bien-Willner GA, Limon J, Stankiewicz P, Lupski JR, Wierzba J. Mutational and genotype-phenotype correlation analyses in 28 Polish patients with Cornelia de Lange syndrome. Am J Med Genet A. 2006 Jul 15;140(14):1531-41. (http://www.ncbi.nlm.nih.gov/pubmed/16770807?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: July 2012
Published: November 24, 2014