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What is Cornelia de Lange syndrome and explain in detail?
Cornelia de Lange syndrome (CdLS) is a genetic disorder. People with this syndrome experience a range of physical, cognitive, and medical challenges ranging from mild to severe. The syndrome has a widely varied phenotype, meaning people with the syndrome have varied features and challenges. The typical features of CdLS include thick or long eyebrows, a small nose, small stature, developmental delay, long or smooth philtrum, thin upper lip and downturned mouth.The syndrome is named after Dutch pediatrician Cornelia Catharina de Lange, who described it in 1933.
It is often termed Brachmann de Lange syndrome or Bushy syndrome and is also known as Amsterdam dwarfism. Its exact incidence is unknown, but it is estimated at 1 in 10,000 to 30,000.

Signs and symptoms
The phenotype of CdLS is highly varied and is described as a spectrum; from Classic CdLS (with a greater number of key features) to mild variations with only a few features. Some people will have a small number of features but dont have CdLS.Key features:

Long and/or thick eyebrows
Short nose
Concave nasal ridge  and/or upturned nasal tip
Long and/or smooth philtrum
Thin upper lip vermilion and/or downturned corners of mouth
Missing fingers or toes
Congenital diaphragmatic herniaOther suggestive features:

Developmental delay and/or intellectual disability
Small prenatal and birth size / weight
Small stature
Microcephaly (prenatally and/or postnatally)
Small hands and/or feet
Short fifth finger
HirsutismThe following health conditions are more common in people with CdLS than in the general population.

Respiratory illness
Heart defects (e.g., pulmonary stenosis, VSD, ASD, coarctation of the aorta)
Hearing impairment
Vision abnormalities (e.g., ptosis, nystagmus, high myopia, hypertropia)
Partial joining of the second and third toes
Incurved 5th fingers (clinodactyly)
Gastroesophageal reflux
Gastrointestinal abnormalities
Musculoskeletal problems
Scoliosis
Social anxiety
Seizures
Cleft palate
Feeding problemsChildren 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. They present a characteristic facial phenotype.Children with CdLS often have 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 GI tract problems are acute. Symptoms may range from mild to severe.
People with CdLS may exhibit behaviours that have been described as "autistic-like," including self-stimulation, aggression, self-injury or strong preference to a structured routine. Behavior problems in CdLS are not inevitable. Many behaviour issues associated with CdLS are reactive (i.e., something happens within the persons body or environment to bring on the behavior) and cyclical (comes and goes). Often, an underlying medical issue, pain, social anxiety, environmental or caregiver stress can be associated with a change behaviour. If pain or a medical issue is the cause, once treated, the behaviour diminishes.
There is evidence for some features of premature aging including the early development of Barrett’s esophagus, osteoporosis present in the teenage years, premature greying of hair and some changes to the skin of the face causing a more aged appearance compared to chronological age.

Causes
The vast majority of cases are thought to be due to spontaneous genetic mutations. It can be associated with mutations affecting the cohesin complex.As of 2018, it was confirmed that 500 genetic mutations have been associated with the condition; occurring on 7 different genes.  In around 30% of cases of CdLS the genetic cause remains undiscovered. The wide variation in phenotype is attributed to a high degree of somatic mosaicism in CdLS as well as the different genes and type of mutations. For this reason people with CdLS can have very different appearance,  abilities,  and associated health issues.
The latter two genes seem to correlate with a milder form of the syndrome.In 2004, researchers at the Childrens 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. Since then, additional genes have been found (SMC1A, SMC3 and HDAC8, RAD21) that cause CdLS when changed. In July 2012, the fourth "CdLS gene"—HDAC8—was announced.  HDAC8 is an X-linked gene, meaning it is located on the X chromosome. Individuals with CdLS who have the gene change in HDAC8 make up just a small portion of all people with CdLS. Evidence of a linkage at chromosome 3q26.3 is mixed.Genetic alterations associated with CdLS have been identified in genes NIPBL, SMC1A and SMC3 as well as the more recently identified genes RAD21 and HDAC8.  All of these genetic alterations occurring in CdLS patients affect proteins that function in the cohesin pathway.  SMC1A, SMC3 and RAD21 proteins are structural components of the cohesin ring complex. NIPBL is involved in the loading of the cohesin ring onto chromosomes, and HDAC8 deacylates SMC3 to facilitate its function.  The cohesin pathway is involved in cohesion of sister chromatids during mitosis, DNA repair, chromosome segregation and the regulation of developmental gene expression