Cornelia de Lange syndrome (CDLS) 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; 300590 for Cornelia de Lange syndrome 2 (CDLS2), X-linked; 610759 for Cornelia de Lange syndrome 3 (CDLS3), autosomal dominant; 614701 for Cornelia de Lange syndrome 4 (CDLS4), autosomal dominant; and 300882 for Cornelia de Lange syndrome 5 (CDLS5), X-linked.
The essential features of this multisystem developmental disorder include prenatal and postnatal growth retardation, distinctive facial appearance, hirsutism, various structural limb abnormalities (mostly upper), neurodevelopmental delay, and behavioral problems. In 1849 Vrolic and in 1916 Brachmann reported the first cases 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.
Mutations in 5 genes, SCC2/NIPBL, SMC1A or SMC3, RAD21, and HDAC8, coding protein components of the cohesion pathway, cause approximately 65% 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. [3, 4]
The first CDLS gene, NIPBL (Nipped-B-Like), mapped to band 5p13.1 and cloned in 2004, codes for protein delangin. [5, 6] 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 approximately 60% of individuals (75% of patients with classical phenotype). [5, 6, 7, 8, 9, 10, 11, 12, 13, 14] A trend toward a milder phenotype is observed in persons with missense mutations compared with those with truncating mutations. [6, 11, 12, 13]
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.  Ratajska et al found 2 patients with a classic CDLS phenotype and large genomic deletions encompassing NIPBL and some others contiguous genes.  Of the 162 patients with CDLS, previously negative by sequencing, deletions containing NIPBL exons were observed in 7 subjects (< 5%), which means that large NIPBL rearrangements are probably infrequent events. 
Other cohesin complex genes have also been implicated, particularly in atypical and mild CDLS cases.
Mutations in SMC1A (structural maintenance of chromosomes 1A) the gene, localized on Xp11.2, were found to be responsible for the CDLS phenotype in 3 affected male siblings and in 1 sporadic case.  Two novel de novo mutations in this gene were identified by Borck et al in 2 boys.  In contrast to previous reports, Deardoff et al found 10 females among 14 total SMC1A mutation–positive patients.  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. 
A genome array–based copy number analysis of 290 NIPBL -, SMC1A -, and SMC3 -negative probands led to identification of the boy with 8q21,4 microdeletion, which included the RAD21 gene. To date, only some RAD21 mutations have been identified. [21, 22]
The mutations in the X-linked gene HDAC8 ( Xq13.1) were identified as the cause of some CDLS cases. More HDAC8 -positive cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. Hemizygous males are more severely affected then heterozygous females. [23, 24]
Mutations in SMC1A, SMC3, RAD21, and HDAC8 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. [20, 21, 23, 24, 25]
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 because of his function in regulating of a sister telomere cohesion. 
Parenti et al found heterozygous loss-of-function mutations in the ANKRD1 gene (16q24,3) in two patients with the clinical diagnosis of CDLS. 
A number of patients with CDLS were found to have one or another type of chromosomal aberration. [28, 29, 30, 31] 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.  However, mutation screening for the gene in a series of CDLS individuals failed to detect patient-specific mutations. 
A deletion of 11q12.3-11q13.1, including the CDCA5 gene, which is a part of the cohesin pathway, was described by Boyle at al in a patient with intellectual disability and childhood facial features resembling CDLS. 
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. [19, 34, 35] Recurrence when parents were clinically unaffected was also noted, and this has been explained by the possibility of germline mosaicism. [9, 36, 37] Paternal germline mosaicism of the NIPBL mutation was documented in analyzed sperm. 
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  to as high as 1 in 10,000 live births, when patients with either the severe or mild form were considered.  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. 
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. 
No sex predilection is observed for Cornelia de Lange syndrome (CDLS).
Approximately one third of children with Brachmann-de Lange syndrome (BDLS) are delivered prematurely.
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. The faster changes in facial features than expected for age are typical in nearly all adolescents and adults. [43, 45]
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. 
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. 
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. 
The prognosis for patients with the mild form of Cornelia de Lange syndrome (CDLS) is much better than that for patients with the classic form. Life expectancy is generally normal; patient survival to adult age is recorded. Most recorded deaths occur in infancy, and they mostly happen in severely affected individuals. Aspiratory pneumonia or apnea, cardiac defects, and/or GI anomalies are reported as the most frequent direct causes of death.
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. The sudden deaths are strongly connected with GI complications, namely ileus. [36, 39, 46]
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