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Description and Causes
Cornelia de Lange syndrome is a multiple congenital, anomaly mental-retardation syndrome with characteristic facial dysmorphism, primordial short stature, microcephaly, and variable reduction anomalies of the upper extremities. Also called Brachmann-de Lange Syndrome or simply Syndrome de Lange, the most striking feature of the syndrome is that all affected children resemble one another, as if they were related.
Most of the signs and symptoms of Cornelia de Lange Syndrome (CdLS) may be recognized at birth or even prenatally by ultrasound imaging. The etiology now known to be a mutation in the NIPBL gene on the short arm of chromosome 5 may be responsible. The mode of transmission is autosomal dominant, although typically appears as a sporadic de-novo random mutation. The types of mutations seen in CdLS rarely include large deletions and 50% have detectable point mutations (frame shift, splice site, nonsense, and missense).
A milder variant has been defined, referred to as “mild” CdLS, versus the more severe “classical” CdLS. Clinically, those with the mild CdLS show less significant psychomotor retardation, less marked pre and postnatal growth deficiency, and an uncommon association with major malformations, although mild limb anomalies may be present. In mild CdLS, the characteristic phenotype may be present at birth, but in some subjects the typical facial appearance may not be obvious for two or three years. In general, there is a tendency for patients with mild CdLS to have either undetectable mutations or missense mutations, whereas those with classical CdLS have mutations that would produce a truncated protein.
CdLS specialists increasingly recognize gastroesophageal reflux as the single most worrisome medical complication of the syndrome affecting a significant percentage of people with CdLS.
CdLS individuals demonstrate acquisition of new skills throughout life without regression. Developmental areas of strength include visual-spatial memory and perceptual organization. Almost all CdLS-affected children will learn to walk, though those with the classical form may not do so until they are five years old. Fine motor activities should be stressed in education; even with reduction anomalies of the limbs, affected individuals demonstrate fine motor abilities.
The most severely affected area of development is speech. Many children with the syndrome will never learn to speak, but with proper help and encouragement should acquire a number of words. Children with a mild form of the syndrome can learn to speak fluently, though they may be five or six years old before they do so. In almost all individuals, the ability to produce language was remarkably inferior to the ability to comprehend language.
Parental stress is very high, especially in parents of the older affected children.
Currently diagnosis is made on the basis of clinical observations. A thorough medical evaluation including a history and physical examination, family history, laboratory tests, X-rays and chromosome analysis is usually conducted before a diagnosis is made. DNA testing is helpful for confirmation of a clinical diagnosis, but the sensitivity is only 50% for mutations in NIPBL. There is the potential for CdLS to be caused by other genes which have yet to be identified.
MEDICAL MANAGEMENT CONSIDERATIONS
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Note: These considerations are in addition to the normal medical care provided to an individual without Cornelia de Lange syndrome. All recommendations can be addressed through clinical examination by the primary care provider, unless otherwise noted.
Infancy or Early Childhood (Birth to 5 years)
Late Childhood (5 to 13 years)
Adolescence and Adulthood (13 years and over)
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Peer-reviewed Journal Articles/Academies
Allanson, J. E., Hennekam, R. C., & Ireland, M. (1997). De Lange Syndrome: Subjective and Objective Comparison of the Classical and Mild Phenotypes. Journal of Medical Genetics, 34: 645-650.
Berney, T. P., Ireland, M., Burn, J. (1999). Behavioural Phenotype of Cornelia de Lange Syndrome. Archives of Disease in Childhood, 81(4), 333-336.
Braddock, S.R., et al. (1993). Radiological Features in Brachmann-de Lange Syndrome. American Journal of Medical Genetics, 47, 1006-1013.
Bull, M. J., et al. (1993). Gastrointestinal abnormalities: A Significant Cause of Feeding Difficulties and Failure to Thrive in Brachmann-de Lange Syndrome. American Journal of Medical Genetics, 47(7), 1029-1034.
Fitzpatrick, D.R. & Kline A.D. (2005). Cornelia de Lange Syndrome. In Cassidy S.B. & Allanson J.E. (Eds.), Management of Genetic Syndromes, New York: Wiley-Liss.
Gills L.A. et al. (2004). NIPBL Mutational Analysis in 120 Individuals with Cornelia de Lange Syndrome and Evaluation of Genotype-Phenotype Correlations. American Journal of Human Genetics, 75, 610-623.
Goodban, M.T. (1993). Survey of Speech and Language Skills with Prognostic Indicators in 116 Patients with Cornelia de Lange Syndrome. Journal of Medical Genetics, 47(7), 1059-1063.
Kline, A.D., et al. (1993). Developmental Data on Individuals with the Brachmann-de Lange Syndrome. American Journal of Medical Genetics, 47, 1053-1058.
Kousseff, B. G., et al. (1993). Physical growth in Brachmann-de Lange Syndrome. Journal of Medical Genetics, 47(7), 1050-1052.
Sarimski, K. (1997). Communication, Social-Emotional Development and Parenting Stress in Cornelia de Lange Syndrome. Journal of Intellectual Disability Research, 41 (1), 70-75.
Special Interest Groups/Other Publications
the publication of the Cornelia de Lange Syndrome-USA Foundation
302 West Main Street, Suite 100
Avon, CT 06001
(860) 676-8337 (fax)
National Organization for Rare Disorders
PO Box 8923
New Fairfield, CT 06812-8923
March of Dimes Birth Defects Foundation
1275 Mamaroneck Avenue
White Plains, NY 10605
RESOURCES FOR FAMILIES
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Theodore A. Kastner, M.D., M.S.
Felice Weber Parisi, M.D., M.P.H.
Mary Tierney, M.D.
Samuel P. Yang, M.D.
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This document does not provide advice regarding medical diagnosis or treatment for any individual case, and any opinions or statements contained in this document are not intended to serve as a standard of medical care. Physicians are encouraged to view the considerations presented in this document in light of evolving scientific information. This document is not intended for use by the layperson. Reproduction of this document may be done with proper credit given to California Department of Developmental Services.
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