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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: 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 and 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 (https://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.

References

  • Boyle MI, Jespersgaard C, Brøndum-Nielsen K, Bisgaard AM, Tümer Z. Cornelia de Lange syndrome. Clin Genet. 2015 Jul;88(1):1-12. doi: 10.1111/cge.12499. Epub 2014 Oct 28. (http://www.ncbi.nlm.nih.gov/pubmed/25209348?dopt=Abstract)
  • Deardorff MA, Bando M, Nakato R, Watrin E, Itoh T, Minamino M, Saitoh K, Komata M, Katou Y, Clark D, Cole KE, De Baere E, Decroos C, Di Donato N, Ernst S, Francey LJ, Gyftodimou Y, Hirashima K, Hullings M, Ishikawa Y, Jaulin C, Kaur M, Kiyono T, Lombardi PM, Magnaghi-Jaulin L, Mortier GR, Nozaki N, Petersen MB, Seimiya H, Siu VM, Suzuki Y, Takagaki K, Wilde JJ, Willems PJ, Prigent C, Gillessen-Kaesbach G, Christianson DW, Kaiser FJ, Jackson LG, Hirota T, Krantz ID, Shirahige K. HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle. Nature. 2012 Sep 13;489(7415):313-7. doi: 10.1038/nature11316. (http://www.ncbi.nlm.nih.gov/pubmed/22885700?dopt=Abstract)
  • Deardorff MA, Wilde JJ, Albrecht M, Dickinson E, Tennstedt S, Braunholz D, Mönnich M, Yan Y, Xu W, Gil-Rodríguez MC, Clark D, Hakonarson H, Halbach S, Michelis LD, Rampuria A, Rossier E, Spranger S, Van Maldergem L, Lynch SA, Gillessen-Kaesbach G, Lüdecke HJ, Ramsay RG, McKay MJ, Krantz ID, Xu H, Horsfield JA, Kaiser FJ. RAD21 mutations cause a human cohesinopathy. Am J Hum Genet. 2012 Jun 8;90(6):1014-27. doi: 10.1016/j.ajhg.2012.04.019. Epub 2012 May 24. (http://www.ncbi.nlm.nih.gov/pubmed/22633399?dopt=Abstract)
  • Gene Review: Cornelia de Lange Syndrome (http://www.ncbi.nlm.nih.gov/books/NBK1104)
  • Kaiser FJ, Ansari M, Braunholz D, Concepción Gil-Rodríguez M, Decroos C, Wilde JJ, Fincher CT, Kaur M, Bando M, Amor DJ, Atwal PS, Bahlo M, Bowman CM, Bradley JJ, Brunner HG, Clark D, Del Campo M, Di Donato N, Diakumis P, Dubbs H, Dyment DA, Eckhold J, Ernst S, Ferreira JC, Francey LJ, Gehlken U, Guillén-Navarro E, Gyftodimou Y, Hall BD, Hennekam R, Hudgins L, Hullings M, Hunter JM, Yntema H, Innes AM, Kline AD, Krumina Z, Lee H, Leppig K, Lynch SA, Mallozzi MB, Mannini L, McKee S, Mehta SG, Micule I; Care4Rare Canada Consortium, Mohammed S, Moran E, Mortier GR, Moser JA, Noon SE, Nozaki N, Nunes L, Pappas JG, Penney LS, Pérez-Aytés A, Petersen MB, Puisac B, Revencu N, Roeder E, Saitta S, Scheuerle AE, Schindeler KL, Siu VM, Stark Z, Strom SP, Thiese H, Vater I, Willems P, Williamson K, Wilson LC; University of Washington Center for Mendelian Genomics, Hakonarson H, Quintero-Rivera F, Wierzba J, Musio A, Gillessen-Kaesbach G, Ramos FJ, Jackson LG, Shirahige K, Pié J, Christianson DW, Krantz ID, Fitzpatrick DR, Deardorff MA. Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance. Hum Mol Genet. 2014 Jun 1;23(11):2888-900. doi: 10.1093/hmg/ddu002. Epub 2014 Jan 8. (http://www.ncbi.nlm.nih.gov/pubmed/24403048?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)
  • Mannini L, Cucco F, Quarantotti V, Krantz ID, Musio A. Mutation spectrum and genotype-phenotype correlation in Cornelia de Lange syndrome. Hum Mutat. 2013 Dec;34(12):1589-96. doi: 10.1002/humu.22430. Epub 2013 Sep 16. Review. (http://www.ncbi.nlm.nih.gov/pubmed/24038889?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)
  • Yuan B, Pehlivan D, Karaca E, Patel N, Charng WL, Gambin T, Gonzaga-Jauregui C, Sutton VR, Yesil G, Bozdogan ST, Tos T, Koparir A, Koparir E, Beck CR, Gu S, Aslan H, Yuregir OO, Al Rubeaan K, Alnaqeb D, Alshammari MJ, Bayram Y, Atik MM, Aydin H, Geckinli BB, Seven M, Ulucan H, Fenercioglu E, Ozen M, Jhangiani S, Muzny DM, Boerwinkle E, Tuysuz B, Alkuraya FS, Gibbs RA, Lupski JR. Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes. J Clin Invest. 2015 Feb;125(2):636-51. doi: 10.1172/JCI77435. Epub 2015 Jan 9. (http://www.ncbi.nlm.nih.gov/pubmed/25574841?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: August 24, 2015