Cornelia De Lange Syndrome 

  • Author: Mustafa Tekin, MD; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Dec 20, 2011
 

Background

Cornelia de Lange syndrome (CdLS) is a syndrome of multiple congenital anomalies characterized by a distinctive facial appearance, prenatal and postnatal growth deficiency, feeding difficulties, psychomotor delay, behavioral problems, and associated malformations that mainly involve the upper extremities. Cornelia de Lange first described it as a distinct syndrome in 1933,[1] although Brachmann had described a child with similar features in 1916.[2] Diagnosing classic cases of Cornelia de Lange syndrome is usually straightforward; however, diagnosing mild cases may be challenging, even for an experienced clinician.

Facial appearance of a patient with Cornelia de LaFacial appearance of a patient with Cornelia de Lange syndrome. Courtesy of Ian Krantz, MD, Children's Hospital of Philadelphia. Facial profile of a patient with Cornelia de LangeFacial profile of a patient with Cornelia de Lange syndrome. Courtesy of Ian Krantz, MD, Children's Hospital of Philadelphia. Severe upper-extremity malformations in a patient Severe upper-extremity malformations in a patient with Cornelia de Lange syndrome. Courtesy of Ian Krantz, MD, Children's Hospital of Philadelphia.
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Pathophysiology

More than 99% of cases are sporadic. Cornelia de Lange syndrome is occasionally transmitted in an autosomal dominant pattern, according to several instances in which a usually mildly affected parent had one or more affected offspring. Twins with concordance and discordance have been reported. Although possible autosomal recessive inheritance has been reported in some families, these instances were likely to be due to germline mosaicism. The recurrence risk is 0.5-1.5% if parents are unaffected and 50% if a parent is affected.

Heterozygous mutations in a gene named NIPBL, the human homolog of the Drosophila melanogaster Nipped-B gene,[3] have been identified in approximately 50% of individuals with Cornelia de Lange syndrome.[4] Although the exact function of the protein product of NIPBL in humans (delangin) remains unknown, its homologs in other species are known to play roles in developmental regulation and in cohesion of sister chromatids. Mutations in genes, coding for two other proteins involved in cohesion of sister chromatids, SMC1A and SMC3, have been reported in 5% and 1% of patients with Cornelia de Lange syndrome, respectively.[5] Thus, Cornelia de Lange syndrome is considered to be a cohesinopathy, along with Roberts syndrome/SC phocomelia.

Inheritance is autosomal dominant in families with NIPBL and SMC3 mutations and is X-linked dominant in families with SMC1A mutations.

All types of NIPBL mutations, including missense, splice-site, nonsense, and frameshift mutations, have been reported to result in the Cornelia de Lange syndrome phenotype. The most likely effect of these mutations is haploinsufficiency. The mutation-detection rate is approximately 50%. Genomic deletions and duplications of the NIPBL locus are rare.[6] Reported mutations of SMC1A include missense mutations and in-frame deletions. One reported SMC3 mutation is an in-frame deletion.

The correlation between genotype and phenotype suggested that individuals with an identifiable mutation in NIPBL have a phenotype more severe than the phenotype of those without mutations. Moreover, missense mutations in NIPBL are associated with mild phenotypic features. Patients with mutations in SMC1A and SMC3 consistently have a milder phenotype, with absence of severe limb defects and other structural anomalies. The phenotype in some patients is close to those with nonsyndromic mental retardation.

A phenotype similar to that of Cornelia de Lange syndrome may be observed in patients with a duplication of band q26-27 on chromosome 3.[7] Molecular studies of genes mapped to this region of chromosome arm 3q have failed to reveal mutations in patients with Cornelia de Lange syndrome.

Some autopsy data have indicated cerebral dysgenesis, with a decreased number of neurons, neuronal heterotopias, and focal gyral folding abnormalities as causes of psychomotor delay.

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Epidemiology

Frequency

The incidence is 1 case per 10,000-50,000 live births. No differences based on sex or race have been described.

Mortality/Morbidity

Gastrointestinal disease complications are one of the most common causes of death in this syndrome. They include diaphragmatic hernia in infancy and aspiration pneumonia and volvulus at an older age.

A retrospective review of 295 propositi with Cornelia de Lange syndrome found that respiratory issues (eg, aspiration, reflux, pneumonia) were the most common causes of death (31%), followed by gastrointestinal disease, including obstruction/volvulus (19%), congenital anomalies (15%), neurological causes, (8%), accidents (8%), sepsis (4%), acquired cardiac disease (3%), cancer (2%), renal disease (1.7%), and other causes (9%).[8]

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Contributor Information and Disclosures
Author

Mustafa Tekin, MD  Associate Professor, Division of Pediatric Molecular Pathology and Genetics, Ankara University School of Medicine, Turkey

Mustafa Tekin, MD is a member of the following medical societies: American Society of Human Genetics

Disclosure: Nothing to disclose.

Coauthor(s)

Joann Bodurtha, MD, MPH  Professor, Department of Human Genetics, Virginia Commonwealth University

Disclosure: Nothing to disclose.

Specialty Editor Board

Michael Fasullo, PhD  Senior Scientist, Ordway Research Institute; Associate Professor, State University of New York at Albany; Adjunct Associate Professor, Center for Immunology and Microbial Disease, Albany Medical College

Michael Fasullo, PhD is a member of the following medical societies: American Society for Biochemistry and Molecular Biology, Environmental Mutagen Society, Genetics Society of America, and Radiation Research Society

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

David Flannery, MD, FAAP, FACMG  Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia

David Flannery, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics and American College of Medical Genetics

Disclosure: Nothing to disclose.

Paul D Petry, DO, FACOP, FAAP  Consulting Staff, Freeman Pediatric Care, Freeman Health System

Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association

Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

References

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  2. Brachmann W. Ein Fall von symmetrischer Monodaktylie durch Ulnadefekt, mit symmetrischer Flughautbildung in den Ellenbeugen, sowie anderen Abnormalitaten. Jahr Kinderheilkunde. 1916;84:225-35.

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Facial appearance of a patient with Cornelia de Lange syndrome. Courtesy of Ian Krantz, MD, Children's Hospital of Philadelphia.
Facial profile of a patient with Cornelia de Lange syndrome. Courtesy of Ian Krantz, MD, Children's Hospital of Philadelphia.
Severe upper-extremity malformations in a patient with Cornelia de Lange syndrome. Courtesy of Ian Krantz, MD, Children's Hospital of Philadelphia.
Table. Scoring System for Severity of Cornelia de Lange Syndrome[11]
Parameter 1 point 2 point 3 point
Birth weightAbove 2,500 g2,000–2,500 gBelow 2,000 g
Sitting alone< 9 mo9–20 mo>20 mo
Walking alone< 18 mo18–42 months>42 mo
Saying first word< 24 mo24–48 mo>48 mo
Upper limb malformationNo defectPartial defect (>2 digits)Severe defect (< 2 digits)
Number of other major malformations0-12-3>3
Hearing lossAbsent......
A score of less than 15 points indicates mild involvement, a score of 15-22 points indicates moderate involvement, and a score of more than 22 points indicates severe involvement.
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