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Cornelia de Lange syndrome

Background
Medical Management Considerations
References
Resources for Families
Advisory Committee
Publication Information

Learning Points

  • Recognize that 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.
  • Restate the estimated incidence of Cornelia de Lange syndrome (between 1 in 10,000 and 1 in 30,000 live births).
  • Differentiate between “mild” Cornelia de Lange syndrome and the more severe “classical” Cornelia de Lange syndrome.
  • Identify the most striking feature of the Cornelia de Lange syndrome (that all affected children resemble one another, as if they were related).
  • Restate that gastroesophageal reflux affects a significant percentage of people with Cornelia de Lange syndrome and is the single most worrisome medical complication of the syndrome.
  • Realize that diagnosis is made on the basis of clinical observations.
  • Refer families to appropriate resources on Cornelia de Lange syndrome.

BACKGROUND
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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.

Diagnosis

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.

Occurrence

  • Although the exact incidence is unclear, it is thought to be between 1:10,000 and 1:30,000 live births.
  • The mutant gene is almost never passed on to the next generation because affected individuals seldom have children of their own.
  • Statistics suggest a one to two percent recurrence within families.
  • Males and females are affected in equal numbers.

Characteristic Features

  • Low birth weight, usually (but not always) under five pounds
  • Developmental delay
  • Small stature
  • Microcephaly
  • Thin arched eyebrows which meet at midline
  • Mental retardation, from mild to profound
  • Long, curled eyelashes
  • Short, upturned nose
  • Thin, downturned lips
  • Bone spur of midline mandible during infancy
  • Small widely-spaced teeth
  • Hirsutism
  • Upper Limb abnormalities, including phocomelia and ulnar oligodactyly
  • Small hands and feet
  • Proximally placed thumbs
  • Syndactyly of 2nd and 3rd toes
  • Incurved fifth fingers
  • Low-pitched, growling cry

Common Associations

  • Feeding problems
  • Gastroesophageal reflux disease (>80%)
  • Intestinal malrotation
  • Pyloric stenosis
  • Diaphragmatic hernia
  • Hearing impairment (80%)
  • Nearsightedness (60%)
  • Cleft palate (30%)
  • Dental problems
  • Speech and language problems
  • Sleep disturbance
  • Predisposition to respiratory tract infections
  • Heart abnormalities (25%)
  • Seizures (25%)
  • Undescended testicles
  • Hypospadius
  • Hyperactivity
  • Self-injurious behaviors (a result of pain and frustration)
  • Daily aggression
  • Irritability
  • Mental retardation with average IQ of 50-55 (>95%)

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.

Ongoing

  • Monitor dental health
  • Monitor physical and occupational therapy
  • Monitor special education
  • Monitor visual and auditory capacity
  • Monitor growth on CdLS specific charts
  • Refer for family therapy as necessary throughout infancy, adolescence and adulthood
  • Refer as a candidate for Supplemental Security Income (SSI)
  • There is some recurrence within families. Refer for genetic counseling or for high-risk pregnancy.

Infancy or Early Childhood (Birth to 5 years)

  • Refer to a genetics specialist for an evaluation if CdLS is suspected
  • Refer to a pediatric gastroenterologist to rule-out reflux
  • Refer to pediatric ophthalmologist for assessment and intervention
  • Refer to an audiologist or otolaryngologist for assessment and intervention
  • Refer for dental evaluation, treatment and prevention planning
  • Refer as necessary for prosthetic limbs
  • Refer as necessary to a pediatric neurologist, child psychiatrist or developmental pediatrician.
  • Order echocardiogram and renal ultrasound to rule-out associated anomalies
  • Consider feeding or nutritional therapy when cleft palate is present or percentiles are decreasing on CdLS growth charts
  • Refer for closure of cleft palate by 18 months, along with orthodontic care when necessary

Late Childhood (5 to 13 years)

  • Recheck for nearsightedness or hearing impairment
  • Reassess for other associated problems, such as a vesicoureteral reflux or recurrent “silent” aspiration
  • Consult with parents regarding educational possibilities

Adolescence and Adulthood (13 years and over)

  • Consult with parents regarding puberty and fertility issues

REFERENCES
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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

Reaching Out,
the publication of the Cornelia de Lange Syndrome-USA Foundation

302 West Main Street, Suite 100
Avon, CT 06001
(800) 223-8355
(860) 676-8166,
(860) 676-8337 (fax)

National Organization for Rare Disorders
PO Box 8923
New Fairfield, CT 06812-8923
(203) 746-6518
e-mail: orphan@rarediseases.org

March of Dimes Birth Defects Foundation
1275 Mamaroneck Avenue
White Plains, NY 10605
(888) 663-4637
(914) 428-7100
e-mail: resourcecenter@modimes.org

RESOURCES FOR FAMILIES
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The Cornelia de Lange Syndrome Foundation, Inc.
302 West Main Street, Suite 100
Avon, CT 06001
(800) 223-8355
(800) 753-CDLS
(860) 676-8166
(860) 676-8337 (fax)
http://www.cdlsworld.org

ADVISORY COMMITTEE
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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.

PUBLICATION INFORMATION
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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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