de Lange Syndrome 

  • Author: Krystyna H Chrzanowska, MD, PhD; Chief Editor: Dirk M Elston, MD   more...
 
Updated: Jan 25, 2012
 

Background

Cornelia de Lange syndrome is a rare but well-known multiple congenital anomaly/mental retardation (MCA/MR) disorder. Cornelia de Lange syndrome is entry 122470 in the Online Mendelian Inheritance in Man (OMIM) database for Cornelia de Lange syndrome 1 (CDLS1), autosomal dominant, and 300590 for Cornelia de Lange syndrome 2 (CDLS2), X-linked.

The essential features of this multisystem developmental disorder include prenatal and postnatal growth retardation, distinctive facial appearance, various structural upper limb abnormalities, neurodevelopmental delay, and behavioral problems. In 1916, Brachmann reported the first case in the literature, describing a child at autopsy with severe growth retardation, hirsutism, and an additional finding of upper limb deficiencies. In 1933, Cornelia de Lange described 2 unrelated infant girls with mental retardation and similar dysmorphic features under the designation typus degenerativus amstelodamensis. de Lange suggested that these manifestations comprised a new malformation syndrome.

Because of their contributions, both Brachmann's and de Lange's names have been attached to the syndrome, Brachmann-de Lange syndrome (BDLS). Several hundred cases have been reported. Consensus among clinical geneticists on the phenotypic dichotomy with classic and mild cases was reached at the 12th Annual D.W. Smith Workshop on Malformations and Morphogenesis in 1991.

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Pathophysiology

Mutations in 3 genes, SCC2/NIPBL, SMC1A or SMC3, coding protein components of the cohesion pathway, cause approximately 55-60% of Cornelia de Lange syndrome (CDLS) cases. Genetic studies have revealed that genes of this pathway, whose fundamental role is in chromosomal cohesion and coordinated segregation of sister chromatids, are also involved in gene regulation during development. As a result of these findings, CDLS has been classified into a novel category of human genetic disorders called cohesinopathies.[1, 2]

The first CDLS gene, NIPBL (Nipped-B-Like), mapped to band 5p13.1 and cloned in 2004, codes for protein delangin.[3, 4] A loss or altered function of a single NIPBL gene allele, which is consistent with a dominant pattern of inheritance, has been subsequently identified in 20-55% of individuals in different studies, both with the severe and mild Brachmann-de Lange syndrome (BDLS) phenotypes.[3, 4, 5, 6, 7, 8, 9, 10, 11, 12] A trend toward a milder phenotype is observed in persons with missense mutations compared with those with truncating mutations.[4, 9, 10, 11]

In a series of 50 NIPBL mutation-negative patients, Bhuiyan et al found one with a deletion encompassing 2 exons, 41 and 42, by multiplex ligation-dependent probe amplification (MLPA) analysis, which means that large NIPBL rearrangements are probably infrequent events.[13]

Mutations in another member of the cohesion complex, SMC1A (structural maintenance of chromosomes 1A) gene, were found to be responsible for the CDLS phenotype in 3 affected male siblings and in 1 sporadic case, suggesting that X-linked CDLS might represent a clinical subset.[14] Two novel de novo mutations in this gene were identified by Borck et al in 2 boys.[15] In contrast to previous reports, Deardoff et al found 10 females among 14 total SMC1A mutation-positive patients.[16] Based on similar manifestations in affected males and females, they suggested an X-linked dominant mode of inheritance.

A single mutation in the SMC3 (structural maintenance of chromosomes 3) gene, localized on band 10q25, was found in one patient with a mild phenotype.[16]

Mutations in SMC1A and SMC3 genes contribute to approximately 5% of patients ascertained as having CDLS of the mild variant phenotype with predominant mental retardation, but the frequency remains uncertain.[16, 17]

The etiology of a significant proportion of CDLS cases remains undetermined.

A deletion of 8p23.1 was found in a boy with CDLS characteristics and diaphragmatic hernia, and a novel candidate gene for CDLS, TANKYRASE1, mapping within a deleted segment, was proposed due to his function in regulating of a sister telomere cohesion.[18]

A number of patients with CDLS were found to have one or another type of chromosomal aberration.[19, 20, 21, 22] A phenotypic overlap between CDLS and partial trisomy on band 3q26-27 was found, and it was proposed that the gene for CDLS may be located at band 3q26.3.[23] However, mutation screening for the gene in a series of CDLS individuals failed to detect patient-specific mutations.[3]

Most cases are sporadic, but a familial occurrence and parental consanguinity have been recorded. Autosomal dominant transmission, both maternal and paternal, has been documented in more than 25 families.[15, 24, 25] Recurrence when parents were clinically unaffected was also noted, and this has been explained by the possibility of germline mosaicism.[7, 26, 27] Paternal germline mosaicism of the NIPBL mutation was documented in analyzed sperm.[28]

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Epidemiology

Frequency

International

Estimation of the overall prevalence of Cornelia de Lange syndrome (CDLS) is difficult because of the unknown proportion of milder cases. Birth prevalence was calculated from 1 in 100,000 live births[29] to as high as 1 in 10,000 live births, when patients with either the severe or mild form were considered.[30] A population-based epidemiological study of the classic form of CDLS using the European Surveillance of Congenital Anomalies (EUROCAT) database established a prevalence for the classic form CDLS to be 1.24 cases per 100,000 births and the overall CDLS prevalence to be 1.6-2.2 cases per 100,000 births.[31]

Mortality/Morbidity

  • Patients with Brachmann-de Lange syndrome (BDLS) have a slightly elevated mortality rate. The most frequent direct causes of death are pneumonia, cardiac malformations, and GI malformations. Most recorded deaths (approximately two thirds) occur during the first year of life or in the following 2 years, and most deaths occur in patients with severe disease.[26, 29, 32]

Race

  • No racial predilection is reported for Brachmann-de Lange syndrome (BDLS). One of the largest clinical surveys in the United States, by Jackson et al in 1993, included 310 Cornelia de Lange syndrome (CDLS) patients, of which black, white, Hispanic, Asian groups were represented.[26]

Sex

  • No sex predilection is observed for Cornelia de Lange syndrome (CDLS).

Age

  • Approximately one third of children with Brachmann-de Lange syndrome (BDLS) are delivered prematurely.
  • The characteristic facial gestalt of classic BDLS is present at birth and changes little throughout life.[33, 34, 35]
  • In mild BDLS, the typical facial appearance may become obvious only after 2-3 years. In addition, the patient's face loses the characteristic appearance by adulthood, with normalization of the dimensions.[34, 36]
  • During the neonatal period, respiratory and feeding difficulties (failure to thrive) predominate.
  • The low-pitched cry frequently noted in the newborn period or in early infancy may disappear in late infancy.[26]
  • Self-injury is common in patients older than 12 years.
  • Pubertal development and fertility are normal in BDLS individuals. Control of fertility in young adult women should be considered.
  • Some patients with BDLS survive to adulthood; 61 years and 54 years of survival in a woman and a man, respectively, have been recorded.[29]
  • A detailed natural history of aging in Cornelia de Lange syndrome (CDLS) based on longitudinal follow-up observations of 49 patients has been recently presented by Kline et al.[35]
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Contributor Information and Disclosures
Author

Krystyna H Chrzanowska, MD, PhD  Head of Genetic Counseling Unit, Associate Professor, Department of Medical Genetics, Children's Memorial Health Institute, Warsaw, Poland

Disclosure: Nothing to disclose.

Coauthor(s)

Camila K Janniger, MD  Clinical Professor of Dermatology, Clinical Associate Professor of Pediatrics, Chief of Pediatric Dermatology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Camila K Janniger, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Specialty Editor Board

Albert C Yan, MD  Section Chief, Associate Professor, Department of Pediatrics, Section of Dermatology, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine

Albert C Yan, MD is a member of the following medical societies: American Academy of Dermatology, American Academy of Pediatrics, Society for Investigative Dermatology, and Society for Pediatric Dermatology

Disclosure: Nothing to disclose.

David F Butler, MD  Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic

David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH  Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi

Disclosure: Nothing to disclose.

Catherine M Quirk, MD  Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania

Catherine M Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD  Director, Ackerman Academy of Dermatopathology, New York

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

The authors and editors of eMedicine gratefully acknowledge the contributions of previous Chief Editor, William D. James, MD, to the development and writing of this article.

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  96. Tonkin ET, Wang TJ, Lisgo S, et al. 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. Jun 2004;36(6):636-41. [Medline].

 
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Case study 1 of classic de Lange phenotype is shown (same patient as in Images 2-6). Facial characteristics of a 10-month-old girl are pictured. Note well-defined eyebrows with synophrys, depressed nasal bridge, and long smooth philtrum.
Case study 1 (same patient as in Images 1 and 3-6). Lateral facial profile is pictured. The eyebrows are neat, arched, and well defined. The nasal bridge is depressed, and the nares are upturned.
Case study 1 (same patient as in Images 1-2 and 4-6). The patient, aged 5 years, is shown; note microbrachycephaly, well-defined eyebrows, anteverted nares, long and thin upper lip, down-turned angles of mouth, and widely spaced teeth.
Case study 1 (same patient as in Images 1-3 and 5-6). Upper limb reduction anomalies are pictured with only 2 fingers present.
Case study 1 (same patient as in Images 1-4 and 6). Note short hypoplastic fifth finger.
Case study 1 (same patient as in Images 1-5). Small feet with short hypoplastic toes and syndactyly of the second and third toes is pictured.
Case study 2 of mild de Lange syndrome is shown (same patient as in Images 8-10). The face of a 1.5-year-old girl is pictured. Note neat eyebrows with delicate synophrys, long eyelashes, depressed nasal bridge, upturned nares, long philtrum, thin upper lip, and small chin.
Case study 2 (same patient as in Images 7 and 9-10). Lateral facial profile shows depressed nasal bridge, thin upper lip, and small mandible.
Case study 2 (same patient as in Images 7-8 and 10). The patient, aged 8 years, is shown; note delicate synophrys of the eyebrows, upturned nares, long philtrum, and thin upper lip.
Case study 2 (same patient as in Images 7-9). Lateral facial profile of the patient, aged 8 years, is shown.
 
 
 
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