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Cornelia de Lange Syndrome (CdLS) is a very rare genetic disorder present from birth, but not always diagnosed at birth. It causes a range of physical, cognitive and medical challenges and affects both genders equally. Cornelia de Lange syndrome affects approximately one in ten thousand individuals. It is a heterogeneous disorder, a disease characterized and primarily diagnosed by specific dissimilar facial dysmorphia, upper-extremity malformations, and low intelligence. The syndrome is named after Dutch pediatrician Cornelia Catharina de Lange, who described it.

It is often termed Bushy Syndrome and is also known as Amsterdam dwarfism. It is a genetic disorder that can lead to severe developmental anomalies. It affects the physical and intellectual development of a child. Cornelia de Lange syndrome has been frequently described clinically as an inherited multisystem malformation, heterogeneous developmental syndrome with characterizations of deformities affecting multiple internal systems. Exact incidence is unknown, but it is estimated at 1 in 10,000 to 30,000.

Causes
This is a genetic disorder that can be caused by any one of a multiple number of alleles or non-allele (locus) mutations. The vast majority of cases are due to spontaneous genetic mutations.

Exploring the molecular genetic characteristics of Cornelia de Lange syndrome, the disease can be caused by various mutations in several specific genes. Among those genes affected that can result in Cornelia de Lange syndrome are HDAC8 gene, NIPBL gene, SMC1A gene, SMC3 gene, RAD21 gene, STAG2 gene, ESCO1 gene, ESCO2 gene, and the MAU2 gene. This disease can be associated with mutations affecting the cohesin complex in the genetic makeup.

There are three main genes associated with gene alterations leading to Cornelia de Lange Syndrome. NIPBL, SMC1L1, and HADC8 are the three genes associated. Previous studies have shown that mutations in either of these genes will lead directly to Cornelia de Lange Syndrome. Since multiple genes have been associated with the condition. In 2004, researchers at the Children's Hospital of Philadelphia (United States) and the University of Newcastle upon Tyne (England), identified a gene (NIPBL) on chromosome 5 that causes CdLS when it is mutated. Approximately60% of the individuals affected with Cornelia De Lange Syndrome has a mutation in the NIPBL gene on chromosome 5P13. Since then, additional genes have been found (SMC1A, SMC3 and HDAC8) that cause CdLS when changed. About 4% to 6% of patients have mutations is in the X-linked SMC1A gene.

There are likely other genes as well. Researchers hope to gain a better understanding of why CdLS varies so widely from one individual to another and what can be done to improve the quality of life for people with the syndrome. (For more information visit: http://www.cdlsusa.org/research/genetic-information.htm)

The latter two genes seem to correlate with a milder form of the syndrome.

In July 2012, the fourth “CdLS gene”—HDAC8—was announced. Many parents and professionals have questions about this latest finding and what it means. HDAC8 is an X-linked gene, meaning it is located on the X chromosome. This genes primary function is linked to cell cycle progression, transcription regulation, and developmental events. This specific protein catalyzes the deacetlyation, in the N-terminal tails, of of lysine residues, and blocks transcription in hefty multiprotein complexes with transcriptional co-repressors. This gene is most similar to HDAC1-3 classes. Individuals with CdLS who have the gene change in HDAC8 make up just a small portion of all people with CdLS. When this gene is mutated and, since HDAC8 sponsors the cohesion complex dynamic for CdLs, a loss in function consequences in a extensive transcriptional disregualtion, involving SMC3, SMC1, and RAD21 normal purpose, that is reflected in NIPBL cells that are modified in the CdLs cells.

Evidence of a linkage at chromosome 3q26.3 is mixed.

Possible Preventions
There are no possible preventions of CdLs. CdLs can occur randomly or in rare cases be inherited. However, CdLs can be caught at birth and treated with different measures. CdLs affects not only children but adults as well; it is more commonly diagnoised in children.

Features and characteristics
Pretentious individuals have dysmorphic facial features, cleft palate, distal limb defects, growth retardation, developmental delay recognized primarily on the basis of characteristic facial dysmorphism, including low anterior hairline, arched eyebrows, synophrys, anteverted nares, maxillary prognathism, long philtrum, thin lips, and 'carp' mouth, in association with prenatal and postnatal growth retardation, mental retardation, and in many cases, upper limb anomalies.



Following are the features and characteristics that help in spotting this disorder:
 * Low birth weight (usually under 5 pounds/2.5 kilograms)
 * Delayed growth and small stature
 * Developmental delay
 * Limb differences (missing limbs or portions of limbs)
 * Small head size (microcephaly)
 * Thick eyebrows, which typically meet at midline (synophrys)
 * Long eyelashes
 * Short upturned nose and thin downturned lips
 * Long philtrum
 * Excessive body hair
 * Small hands and feet
 * Small widely spaced teeth
 * Low-set ears
 * Hearing impairments
 * Vision abnormalities (e.g., ptosis, nystagmus, high myopia, hypertropia)
 * Partial joining of the second and third toes
 * Incurved 5th fingers (clinodactyly)
 * Gastroesophageal reflux
 * Seizures
 * Heart defects (e.g., pulmonary stenosis, VSD, ASD, coarctation of the aorta)
 * Cleft palate
 * Feeding problems
 * Hypoplastic genitalia

Symptoms
Children with this syndrome are often found to have long eyelashes, bushy eyebrows and synophrys (joined eyebrows). Body hair can be excessive and affected individuals are often shorter than their immediate family members.

CdLS can give rise to its own array of complexities. Children with CdLS often suffer from gastrointestinal tract difficulties, particularly gastroesophageal reflux. Vomiting, intermittent poor appetite, constipation, diarrhea or gaseous distention are known to be a regularity in cases where the GE tract problems are acute. Symptoms may range from mild to severe.

CdLS may include behavior problems, including self-stimulation, aggression, self-injury or strong preference to a structured routine. Many children with CdLS exhibit autistic-like behaviors.

Behavior problems in CdLS are not inevitable. Many behavior issues associated with CdLS are reactive (i.e., something happens within the person's body or environment to bring on the behavior) and cyclical (comes and goes). Often, an underlying medical issue causes a change in behavior. Once the medical issue is treated, the behavior diminishes.

Diagnosis
The diagnosis of CdLS is primarily a clinical one, based on medical signs that are evident in a medical history, physical examination, and laboratory tests. Since 2006, testing for NIPBL and SMC1A has been available through the University of Chicago. This is best accomplished through a referral to a genetics specialist or clinic.

CdLS is thought to be underdiagnosed and frequently misdiagnosed.

Mechanism
Exploring the molecular genetic characteristics of Cornelia de Lange syndrome, the disease can be caused by various mutations in several specific genes. Among those genes affected that can result in Cornelia de Lange syndrome are HDAC8 gene, NIPBL gene, SMC1A gene, SMC3 gene, RAD21 gene, STAG2 gene, ESCO1 gene, ESCO2 gene, and the MAU2 gene. There have been observations of majority heterozygous mutations in gene NIPBL, the human homolog of the Drosophila melanogaster Nipped-B gene. Almost every type of NIPBL mutation, nonsense, missense, frameshift, and splice-site mutations, has been observed to conclude in the Cornelia de Lange syndrome phenotype. Haploinsufficiency is observed prominently. Specific mutations of SMC1A include in-frame deletions and missense mutations, with only one report of SMC3 mutation as an in-frame deletion. The mutation-detection rate is approximately 50%. Genomic deletions and duplications of the NIPBL locus are rare. Approximately half of the individuals affected with Cornelia De Lange Syndrome has a mutation in the NIPBL gene. In nearly sixty percent of individuals with Cornelia de Lange syndrome, mutations in the cohesion loading protein NIPBL1,2 and mutations in SMC1A core cohesion component, and mutations in smaller fractions of probands in SMC3 are observed in individuals with CdLS3-5. In-frame Multi-Exon Deletion of SMC1A in a Severely Affected Female with Cornelia de Lange Syndrome About 60% of patients have mutations in the NIPBL gene on chromosome 5p13, and about 4% to 6% of patients have mutations in the X-linked SMC1A gene. X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations An established correlation between phenotype and genotype produced evidence that persons with an identifiable mutation in the NIPBL gene have a phenotype thats more severe than the phenotype of those without mutations. Even more,studies suggest that missense mutations in NIPBL are correlated with mild phenotypic features. Individuals with changes in SMC1A and SMC3 consistently have a milder phenotype, with no serious limb defects or other structural abnormalities. The phenotype in some patients is close to those with nonsyndromic mental retardation. Although HDAC8 is a key component in the metabolic pathway to the disruption of the NIPBL gene function, (seen in the pathway below) others such as SMC1L1 (also known as SMC1) and RAD21, have also proven as characteristics in the disruption of the pathway leading to CdLs characteristics. When either gene is disrupted and/or mutated phenotypic and genotypic characteristics of CdLs are observed.

Treatment
Often, an interdisciplinary approach to therapy and treatment of any medical issues that arise is recommended. A team for promoting the child's well-being often includes speech, occupational and physical therapists, teachers, physicians and the parent(s).

Individuals with CdLs case specific. Usually observation for CdLs includes behavior assessments, psychiatric evaluations, cardiac evaluations, dental exams, and developmental exams. Persons with CdLs, usually have lower than normal IQ scores, in the mental retardation range. Many times, observations of cardiac defects are observed. Specifically, congenial heart disease has be reported in up to 30% of children diagnosed with CdLs. Treatment for this begins with routine pediatric cardiac evaluations regularly in children diagnosed with CdLs.

Life expectancy has been observed for individuals with CdLs to live well into adulthood, especially when all expected conditions mentions above are monitored, and/or treated when necessary.

Longterm care includes monitoring the patient, and observation of CdLs with behavior assessments, psychiatric evaluations, cardiac evaluations, dental exams, and developmental exams.

Support
The Cornelia de Lange Syndrome (CdLS) Foundation is a nonprofit, family support organization based in Avon, Connecticut, that exists to ensure early and accurate diagnosis of CdLS, promote research into the causes and manifestations of the syndrome, and help people with a diagnosis of CdLS, and others with similar characteristics, make informed decisions throughout their lives.

History
Named after Cornelia Catherine de lange where in 1933 she immortalized her name with the report of two children with Similar CdLs features. In 1941 a third case of similar cdls characteristics were reported to the Amsterdam neurological society, and cornelia de lange syndrome gained its recognition.

The first US first case appeared in 1965 in Seattle, Wa.

The first ever documented case was in 1916 by Winfried Robert Clemens Brachmann followed up by Cornelia Catherina de Lange, a Dutch pediatrician, in 1933 after whom the disorder has been named.

Recent Research
In X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations, mutations in the SMC1L1 and NIPBL genes that correlates with Cornelia de Lange syndrome identification began with DNA samples from patients, with particular sections of the DNA amplified. In familiar patients, areas near the NIPBL gene that had single nucleotide polymorphisms near the gene, and CA repeats included inside the gene, were mapped and amplified with primers from the NCBI data bases. These primers were designed specifically for screening for SNPs inside the gene, and the CA repeats. In all patients the the entire NIPBL gene was sequenced and analyzed for SNPs. Those patients that did not have a mutation in the NIPBL gene were then genetically analyzed for mutations in the SMC1L1 genes. DNA was then amplified by PCR, using primers to amplify exons and intron boundaries as well as short flanking intronic sequences PCR products were then sequenced to determine DNA mutations related to Cornelia de Lange syndrome. X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations Identification of mutations in the SMC1 gene was done by performing a western blot using an actin antibody as a control and SMC1 antibody with the test DNA. X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations From this data, Musio et al., found a three nucleotide deletion mutation in family one, and a one nucleotide transversion of adenine to cytosine missense mutation in family two, resulting in the Cornelia de Lange Syndrome, using the NCBI blastp program relating ortholog sequences in GenBank.

Since HDAC8 is a gene that is responsible for making the histone deacetylase 8 enzyme, several mutations in this gene has been observed to correlate with Cornelia de Lange Syndrome (CdLs). HDAC8 is associated with the gene function, key component in a long metabolic pathway, of the NIPBL gene which is partially, 60%, the cause of all Cornelia de Lange Syndrome cases reported.