Cornelia de Lange Syndrome

NORD gratefully acknowledges Antonie Kline, MD, Medical Director, Cornelia de Lange Syndrome (CdLS) Foundation, Inc., Director of Pediatric Genetics, Harvey Institute of Human Genetics, Greater Baltimore Medical Center, for assistance in the preparation of this report.

Synonyms of Cornelia de Lange Syndrome

BDLS
Brachmann-de Lange syndrome
CdLS
de Lange syndrome

General Discussion

Cornelia de Lange syndrome (CdLS) is a rare genetic disorder that is apparent at birth (congenital). Associated symptoms and findings typically include delays in physical development before and after birth (prenatal and postnatal growth retardation); characteristic abnormalities of the head and facial (craniofacial) area, resulting in a distinctive facial appearance; malformations of the hands and arms (upper limbs); and mild to severe intellectual disability. Many infants and children with the disorder have an unusually small, short head (microbrachycephaly); a prominent vertical groove between the upper lip and nose (philtrum); a depressed nasal bridge; upturned nostrils (anteverted nares); and a protruding upper jaw (maxillary prognathism) with small chin (micrognathia). Additional characteristic facial abnormalities may include thin, downturned lips; low-set ears; arched, well-defined eyebrows that grow together across the base of the nose (synophrys); an unusually low hairline on the forehead and the back of the neck; and curly, unusually long eyelashes. Affected individuals may also have distinctive malformations of the limbs, such as unusually small hands and feet, inward deviation (clinodactyly) of the fifth fingers, and webbing (syndactyly) of certain toes. Less commonly, there may be absence of the forearms, hands, and fingers. Infants with CdLS may also have feeding and breathing difficulties; an increased susceptibility to respiratory infections; a low-pitched "growling" cry and low voice; heart defects; delayed skeletal maturation; hearing loss; or other physical abnormalities. The range and severity of associated symptoms and findings may be extremely variable from person to person.

CdLS can be inherited as an autosomal dominant condition or an X-linked condition. Five genes have been found to be associated with CdLS including the NIPBL gene on chromosome 5, the SMC1A gene on the X chromosome, the SMC3 gene on chromosome 10, the Rad21 gene on chromosome 8 and the HDAC8 gene on the X chromosome. Most affected individuals have an abnormal gene as a result of a new gene mutation and do not have an affected parent. Other genes may be found to be associated with CdLS in the future.

Signs & Symptoms

CdLS is a very rare disorder characterized by growth delays; distinctive facial features; malformations of the hands, feet, arms, and/or legs (limb anomalies); other physical abnormalities; intellectual disability; and/or developmental delays. The range and severity of symptoms and physical characteristics may vary greatly from person to person.

Individuals with CdLS exhibit abnormal growth delays that affect both weight and linear growth before and after birth (prenatal and postnatal growth retardation). Most affected infants may have a low birth weight and may fail to gain weight or grow at the expected rate (failure to thrive). CdLS growth charts are available to compare growth to other affected individuals. Individuals may experience feeding, chewing, and swallowing difficulties during the first several months/years of life.

Many affected infants may frequently “spit up” food that has already been swallowed (regurgitation) and may experience episodes of severe, forceful vomiting (projectile vomiting). Infants with CdLS may also demonstrate abnormally increased muscle tone (hypertonicity) and have an unusual, low-pitched, growling cry.

Individuals with CdLS also have distinctive features of the head and facial (craniofacial) area including an abnormally small head (microcephaly) that may also be unusually short (brachycephaly); a short, thick neck; a low hairline; a small, broad, upturned nose with nostrils that tip upwards (anteverted nares); neat, arched eyebrows that grow together (synophrys); long, curly eyelashes; and/or excessive hair growth on various areas of the body (hypertrichosis). Additional features may include thin, downturned lips; an abnormally long vertical gap between the upper lip (philtrum) and the nose; an abnormally small, underdeveloped jaw (micrognathia); late-erupting, widely-spaced, unusually small teeth; and low-set ears. In some cases, affected infants may also exhibit incomplete closure of the roof of the mouth (cleft palate), a hidden incomplete closure (submucous cleft palate) and/or a highly arched palate.

In most infants with CdLS, the hands and feet are small for their size. In addition, affected individuals may have short fingers that become smaller and thinner toward the ends (tapered fingers), fifth fingers that are permanently curved toward the ring finger (clinodactyly), and/or, in some people, absence of one or more fingers (oligodactyly). The thumbs may be abnormally positioned (i.e., proximally placed) and the arms may be permanently bent or flexed at the elbows due to bone fusions. In addition, in many cases, affected individuals may demonstrate underdevelopment (hypoplasia) of some of the bones of the fingers and toes, and the second and third toes are often abnormally fused or webbed (syndactyly). Some affected infants may also have, in rare cases, fingers, hands, and forearms which are missing. In individuals with CdLS, upper limb abnormalities may involve one side (unilateral) or both sides (bilateral) of the body. If bilateral limb malformations are present, the abnormalities on one side of the body may be completely different from those on the other side (asymmetrical). Although the feet are small, only in extremely rare cases are there absent bones in the feet or lower legs.

Individuals with CdLS also demonstrate delayed bone age (retarded osseous maturation). In addition, affected individuals may remain low in weight and exhibit abnormally short stature (prenatal and postnatal growth retardation), failure to thrive during infancy, delayed bone age, and/or other abnormalities. Many individuals with CdLS also exhibit additional skeletal abnormalities. These may include a deformity of the hip (coxa valga), a short breastbone (sternum), and/or abnormally thin ribs.

Many infants and children with CdLS may exhibit delays in the acquisition of skills requiring the coordination of mental and muscular activity (psychomotor retardation), have mild to severe intellectual disability, and/or demonstrate behavioral problems (e.g., episodes of biting, screaming, hitting themselves, etc.). In addition, although affected children have decreased facial expression based on emotion, they appear to respond positively to certain stimuli (e.g., fast movements). A CdLS developmental chart is available to compare milestones.

Many children with CdLS also have hearing impairment as well as abnormal speech development. Middle ear infections (otitis media), which sometimes occur chronically with an accumulation of sticky fluid (otitis media with effusion or glue ear), are common. Younger children may have difficulty speaking (dysphonia), while older children may have abnormally hoarse speech.

Many individuals with CdLS also exhibit additional physical abnormalities. In many cases, the skin may appear “marbled” (cutis marmorata), and the skin above the eyes, mouth, and nose may have an unusual bluish tone. In addition, many affected individuals demonstrate irregularities in the skin ridge patterns on the palms of the hands (dermatoglyphics). As mentioned earlier, most affected individuals may exhibit excessive hair growth (hypertrichosis) on various areas of the body including the ears. Hair may also tend to appear on the lower back, limbs, and/or other areas of the body.

Many individuals with CdLS also have various abnormalities of the gastrointestinal system including gastroesophageal reflux, a condition in which the acidic contents of the stomach flow upward into the lower esophagus; inflammation of the lining of the esophagus (esophagitis); and/or narrowing of the esophagus (esophageal stenosis). In addition, affected individuals may have abnormal twisting (malrotation) of the intestines, potentially causing intestinal obstruction (volvulus). In some children, the bands of muscle fibers (pyloric sphincter) at the junction between the stomach and small intestine (pyloric stenosis) may become abnormally narrowed (stenosis) in infancy, resulting in obstruction of the normal flow of stomach contents into the small intestine. In addition, some individuals with CdLS may also have protrusion of portions of the large intestine through an abnormal opening in musculature lining the abdominal cavity in the area of the groin (inguinal hernia) and/or part of the stomach through an abnormal opening where the esophagus passes through the diaphragm (hiatal hernia). In some individuals with CdLS, certain gastrointestinal abnormalities may lead to intestinal obstruction, potentially causing serious or life-threatening complications if left untreated.

Some individuals with CdLS may also have malformations of the genitourinary tract. In affected males, such abnormalities may include underdevelopment (hypoplasia) of the genitals, failure of one or both of the testes to descend into the scrotum (cryptorchidism), and/or abnormal placement of the urinary opening (urinary meatus) on the underside of the penis (hypospadias). Affected females may have abnormal development of the uterus (e.g., bicornate or septate uterus), and menstruation may be irregular.

Many children with CdLS have additional physical abnormalities including various heart (cardiac) abnormalities. Some affected individuals may also have an increased susceptibility to repeated respiratory infections, eye abnormalities such as nearsightedness (myopia), rapid, involuntary eye movements (nystagmus), and/or abnormal drooping of the upper eyelid(s) (ptosis). Some infants and children with CdLS may also experience episodes of uncontrolled electrical disturbances in the brain (seizures).

Causes

CdLS can be inherited as an autosomal dominant condition or an X-linked condition. Most affected individuals have an abnormal gene as a result of a new gene mutation. Five genes have been found to be associated with CdLS including the NIPBL gene on chromosome 5, the SMC1A gene on the X chromosome, the SMC3 gene on chromosome 10, the Rad21 gene on chromosome 8 and the HDAC8 gene on the X chromosome. Approximately 60% of those affected have a NIPBL gene mutation and a small percentage (about 10%) have mutations in the other genes. Other genes may be found to be associated with CdLS in the future.

Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.

X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and occur mostly in males. Females that have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and one is inactivated so that the genes on that chromosome are nonfunctioning. It is often the X chromosome with the abnormal gene that is inactivated. However, in CdLS, because the gene change is likely dominant over the corresponding gene on the X chromosomes, females also often show similar findings as males.

Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a disease gene he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. Males with X-linked disorders pass the disease gene to all of their daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.

Affected Populations

CdLS is a very rare disorder that is apparent at birth (congenital). Males and females appear to be affected in equal numbers. It has been estimated that CdLS occurs in approximately one in every 10,000 live births in the United States. More than 400 cases have been reported in the medical literature, including affected individuals within several families (kindreds). Multiple affected siblings have been reported in some families. It is estimated that there is a 1-2 % rate of recurrence within affected families.

Related Disorders

Symptoms of the following disorders can be similar to those of Cornelia de Lange syndrome. Comparisons may be useful for a differential diagnosis:

Coffin-Siris syndrome is an extremely rare genetic disorder that is present at birth (congenital). Infants with this disorder typically have underdeveloped (hypoplastic) or missing fifth fingers on both hands. The toenails may be underdeveloped or absent. Affected individuals may also exhibit characteristic abnormalities of the head and facial (craniofacial) area including an abnormally small head (microcephaly), a broad nose, a wide mouth with thick lips, a low nasal bridge, widely-spaced eyes (ocular hypertelorism), droopy upper eyelids (ptosis), thick eyelashes, dental abnormalities, and/or sparse scalp hair. During infancy, many affected individuals may experience feeding difficulties, vomiting, slow growth, and/or frequent respiratory infections. During the first two years of life, developmental delays, unusually short stature, and varying degrees of intellectual disability may become apparent. Some children with Coffin-Siris syndrome may also exhibit additional physical abnormalities including abnormally loose joints (laxity) that may result in frequent dislocations, particularly of the elbows; mild to severe muscle weakness (hypotonia); motor delays; sideways curvature of the spine (scoliosis); and/or other skeletal, gastrointestinal, genitourinary, and/or cardiac malformations. In some cases, Coffin-Siris syndrome may occur randomly, for no apparent reason (sporadically); in other cases, the disorder may be inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “Coffin Siris” as your search term in the Rare Disease Database.)

Rubinstein-Taybi syndrome is a rare genetic disorder associated with multiple abnormalities that include characteristic facial features, such as a prominent end to the nose, narrows eyes and short fingers with abnormally wide thumbs and great toes. They are usually shorter than average and can have excessive hair on the body (hypertrichosis). Vision and hearing problems along with intellectual disability may also occur. (For more information on this disorder, choose “Rubinstein-Taybi” as your search term in the Rare Disease Database.)

Fetal alcohol spectrum disorder (FASD) is a syndrome of altered fetal growth resulting in certain birth defects due to maternal consumption of alcohol during pregnancy. When a pregnant woman drinks alcoholic beverages, a pattern of defects in the fetus may occur at different stages of pregnancy. In many cases, affected infants are unusually small at birth, have an abnormally small head (microcephaly), and may fail to gain weight and grow at the expected rate (failure to thrive). Affected infants and children may exhibit delays in intellectual development as well as in the acquisition of fine and gross motor skills. In addition, affected individuals may have characteristic craniofacial abnormalities including a protruding forehead, an abnormally short opening between the upper and lower eyelids (palpebral fissures), the presence of vertical skin folds on the inner corners of the eyes (epicanthal folds), a long flat area between nose and mouth (philtrum), an incompletely developed, abnormally small upper jaw (maxillary hypoplasia), and/or incomplete closure of the roof of the mouth (cleft palate). Affected infants may also have other physical abnormalities including joint abnormalities, heart (cardiac) defects, and/or genital malformations. Infants with FASD often experience alcohol addiction withdrawal symptoms within 24 hours after birth. These may include tremors and/or convulsions, irritability, increased muscle tone, muscle and/or whole body spasms, increased respiratory rate, abdominal swelling (distention), and/or vomiting. (For more information on this disorder, choose “Fetal Alcohol” as your search term in the Rare Disease Database.)

Ruvalcaba syndrome is a very rare disorder thought to be inherited as an autosomal dominant genetic trait. The symptoms vary greatly among individuals with the disorder. Characteristic facial features are among the most distinguishable symptoms of this disorder. Affected individuals may have an abnormally small head (microcephaly) with an oval face; downslanting eyelid folds; abnormalities of the nose; a small, downturned mouth; a narrow, pointed jaw; and/or low-set ears. Additional features may include short stature; a narrow chest; protruding breastbone (pectus carinatum); abnormal sideways and/or front-to-back curvature of the spine (scoliosis and/or kyphosis); short fingers, toes, arms, and/or legs; abnormally small hands and feet; and/or abnormal bending of the fingers (clinodactyly). Affected individuals may also have certain skin abnormalities, underdevelopment (hypoplasia) of the reproductive organs, delayed puberty, and/or other physical abnormalities. Many individuals with Ruvalcaba syndrome may also have varying degrees of intellectual disability. (For more information on this disorder, choose “Ruvalcaba” as your search term in the Rare Disease Database.)

Scott craniodigital syndrome with intellectual disability is an extremely rare disorder that is thought to be inherited as an X-linked recessive genetic trait. This disorder is characterized by intellectual disability and various physical abnormalities affecting the head and facial (craniofacial) area and the fingers and/or toes (digits). Characteristic craniofacial features may include a short, wide head (brachycephaly); a small, narrow nose; widely-spaced eyes (ocular hypertelorism); and/or an abnormally small lower jaw (mandible). In addition, some children may have a “startled” expression to their faces. Other characteristic features may include webbing of some of the fingers and toes (syndactyly); uncommon skin ridge patterns (dermatoglyphic patterns) on the palms of the hands; and/or abnormal inward turning of the heel of the foot (talipes varus). In addition, individuals with this disorder may have scalp hair that is very thick with hair growing down onto the temples and in front of the ears; long, dark eyelashes; abnormally thick eyebrows; and/or excessive hair growth (hirsutism) on other areas of the body. (For more information on this disorder, choose “Scott Craniodigital” as your search term in the Rare Disease Database.)

Duplication on the long arm of chromosome 3, or partial trisomy 3q2, is an extremely rare chromosomal disorder in which the end (distal) portion of the long arm (q) of chromosome 3 (3q) is present three times (trisomy) rather than twice in cells of the body. This disorder is characterized by abnormalities of the head and facial (craniofacial) area, other physical malformations, moderate to severe developmental delays, and/or intellectual disability. Many of the craniofacial abnormalities and/or other physical malformations associated with partial trisomy 3q2 are very similar to those often associated with CdLS. For example, many infants and children with partial trisomy 3q2 may have an abnormally small head (microcephaly) that also appears unusually short and wide (brachycephaly); a low hairline; a small, broad nose; thick, well-defined, bushy eyebrows that grow together (synophyrys); long eyelashes; and/or thin, downturned lips. Affected infants and children may also have excessive hair growth (hypertrichosis) on various areas of the body; abnormalities of the hands, feet, arms, and/or legs; hearing loss and speech impairment; and/or eye (ocular) abnormalities including crossing of the eyes (strabismus), rapid, involuntary eye movements (nystagmus), clouding of the lenses of the eyes (cataracts), and/or other ocular abnormalities. Individuals with partial trisomy 3q2 may also have seizure episodes and/or genital, heart (cardiac), gastrointestinal, and/or kidney (renal) malformations. In most children, partial trisomy 3q2 is due to a balanced translocation in one of the parents. (For more information on this disorder, choose “Trisomy 3q2” as your search term in the Rare Disease Database.)

There may be other chromosomal disorders that are characterized by symptoms similar to those of CdLS. The only way to determine which chromosomal disorder an individual has is through chromosomal testing. Most individuals with CdLS have normal chromosomes. (For more information on such disorders, choose the exact disease name in question or “Chromosome” as your search term in the Rare Disease Database.)

Diagnosis

Most children with CdLS are diagnosed clinically after birth or in childhood based upon a thorough clinical evaluation and identification of characteristic physical findings. A diagnosis of CdLS should be considered in children who exhibit certain distinctive facial features in association with limb anomalies, prenatal and postnatal growth retardation, and intellectual disability. Diagnosis may be more difficult if symptoms and physical characteristics associated with the disorder are very mild. Molecular genetic testing for mutations in the five genes associated with CdLS is available to confirm the diagnosis and may be particularly helpful when the physical features are mild or unusual. Prenatal diagnosis is available if a specific NIPBL, SMC1A, SMC3, Rad21 or HDAC8 gene mutation has been identified.

Sometimes a diagnosis of CdLS may be suspected before birth (prenatally) through the use of ultrasound imaging. During such testing, reflected sound waves create an image of the fetus that may reveal certain abnormalities characteristic of CdLS such as retarded growth, limb abnormalities, facial anomalies and/or organ malformations.

Standard Therapies

Treatment

The treatment of CdLS is directed toward the specific symptoms that are apparent in each individual. Treatment may require the efforts of a team of specialists working together to systematically and comprehensively plan an affected child’s treatment. Such specialists may include pediatricians; geneticists; surgeons; specialists who diagnose and treat skeletal disorders (orthopedists); plastic surgeons; orthopedic surgeons; specialists who diagnose and treat abnormalities of the digestive system (gastroenterologists), disorders of the urinary tract (urologists), and abnormalities of the ears, nose, and throat (otolaryngologists); pediatric heart specialists (cardiologists); dental specialists; speech pathologists; specialists who assess and treat hearing problems (audiologists); eye specialists; physical and occupational therapists; and/or other health care professionals.

Affected infants and children may be closely monitored for certain abnormalities potentially associated with CdLS (e.g., potential intestinal obstruction due to gastrointestinal abnormalities, cardiac defects, gastroesophageal reflux, glue ear, and/or susceptibility to respiratory infections) to ensure early detection and prompt treatment.

Specific therapies for the treatment of CdLS are symptomatic and supportive. In some children, surgery may be performed to help correct cleft palate, cardiac defects and/or diaphragmatic hernias. Plastic surgery may be helpful in reducing excessive hair. Some gastrointestinal, genitourinary, and/or cardiac malformations may be treated with certain medications, surgical intervention, and/or other techniques. The surgical procedures performed will depend upon the location and severity of the anatomical abnormalities and their associated symptoms. Respiratory infections may be treated with antibiotic drug therapy and/or other medications that may help fight infection.

Various orthopedic techniques may be used to help treat limb deformities. Hearing aids may be beneficial in some children. Treatment with anticonvulsant medications may help prevent, reduce, or control seizures in some affected children.

Early intervention is important in ensuring that children with CdLS reach their highest potential. Services that may be beneficial include special remedial education, vocational training, speech therapy, and/or other medical and/or social services.

Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov . All studies receiving U.S. government funding, and some supported by private industry, are posted on this web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

NORD Member Organizations

Children’s Craniofacial Association
- 13140 Coit Road
- Suite 517
- Dallas, TX 75240 USA
- Phone: (214) 570-9099
- Toll-free: (800) 535-3643
- Email: contactCCA@ccakids.com
- Website: http://www.ccakids.com
Cornelia de Lange Syndrome Foundation, Inc.
- 302 West Main Street, #100
- Avon, CT 6001
- Phone: (860) 676-8166
- Toll-free: (800) 753-2357
- Email: info@cdlsusa.org
- Website: http://www.cdlsusa.org

Other Organizations

American Academy of Audiology
- 11480 Commerce Park Drive
- Suite 220
- Reston, VA 20191
- Phone: (703) 790-8466
- Toll-free: (800) 222-2336
- Email: infoaud@audiology.org
- Website: http://www.audiology.org
FACES: The National Craniofacial Association
- PO Box 11082
- Chattanooga, TN 37401
- Phone: (423) 266-1632
- Toll-free: (800) 332-2373
- Email: faces@faces-cranio.org
- Website: http://www.faces-cranio.org
Genetic and Rare Diseases (GARD) Information Center
- PO Box 8126
- Gaithersburg, MD 20898-8126
- Phone: (301) 251-4925
- Toll-free: (888) 205-2311
- Website: http://rarediseases.info.nih.gov/GARD/
Let Them Hear Foundation
- 1900 University Avenue, Suite 101
- East Palo Alto, CA 94303
- Phone: (650) 462-3174
- Email: info@letthemhear.org
- Website: http://www.letthemhear.org
Medical Home Portal
- Dept. of Pediatrics
- University of Utah
- Salt Lake City, UT 84158
- Phone: (801) 587-9978
- Email: mindy.tueller@utah.edu
- Website: http://www.medicalhomeportal.org
National Center on Deaf-Blindness
- The Teaching Research Institute
- 345 N. Monmouth Avenue
- Monmouth, OR 97361
- Phone: (503) 838-8754
- Email: info@nationaldb.org
- Website: https://nationaldb.org/
NIH/National Institute on Deafness and Other Communication Disorders
- 31 Center Drive, MSC 2320
- Communication Avenue
- Bethesda, MD 20892-3456
- Phone: (301) 402-0900
- Toll-free: (800) 241-1044
- Email: nidcdinfo@nidcd.nih.gov
- Website: http://www.nidcd.nih.gov
Perkins School for the Blind
- 175 North Beacon Street
- Watertown, MA 2472
- Phone: (617) 924-3434
- Email: Info@Perkins.org
- Website: http://www.Perkins.org
The Arc
- 1825 K Street NW, Suite 1200
- Washington, DC 20006
- Phone: (202) 534-3700
- Toll-free: (800) 433-5255
- Email: info@thearc.org
- Website: http://www.thearc.org

References

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JOURNAL ARTICLES
Kline AD, Calof AL, Lander AD, Gerton JL, Krantz ID, Dorsett D, Deardorff MA, Blagowidow N, Yokomori K, Shirahige K, Santos R, Woodman J, Megee PC, O’Connor JT, Egense A, Noon S, Belote M, Goodban MT, Hansen BD, Timmons JG, Musio A, Ishman SL, Bryan Y, Wu Y, Bettini LR, Mehta D, Zakari M, Mills JA, Srivastava S, Haaland E. 2015. Clinical, development and molecular update on Cornelia de Lange syndrome and the cohesin complex: abstracts from the 2014 Scientific and Educational Symposium. Am J Med Genet A. 2015 Jun;167(6):1179-92.

Srivastava S, Landy-Schmitt C, Clark B, Kline AD, Specht M, Grados MA. Autism traits in children and adolescents with Cornelia de Lange syndrome. 2014 Jun;164A(6):1400-10.

Deardorff MA, Wilde JJ, Albrecht M, Dickinson E, Tennstedt S, Braunholz D, Monnich M, Yan Y, Xu W, Gil-Rodriguez Mc, Clark D, Hakonarson H, . RAD21 mutations cause a human cohesinopathy. Am J Hum Genet. 2012;Jun 8;90(6):1014-27.

Deardorff MA, Bando M, Nakato R, Watrin E, Itoh T, Minamino M, Saitoh K, Komata M, Katou Y, Clark D, Cole KE, De Baere E. HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle. Nature 2012;Sep 13;489(7415):313-7.

Moss J, Howlin P, Magiati I, Oliver C. Characteristics of autism spectrum disorder in Cornelia de Lange syndrome. J Child Psychol Psychiatry 2012;53:883-91

Nakanishi M, Deardorff MA, Clark D, Levy SE, Krantz I, Pipan M. Investigation of autistic features among individuals with mild to moderate Cornelia de Lange Syndrome. Am J Med Genet. 2012;158:1841-1847.

Stavinoha RC, Kline AD, Levy HP, Kimball A, Mettel TL, Ishman SL. Characterization of sleep disturbance in Cornelia de Lange Syndrome. Internat J Ped Otorhinolaryngol. 2011;75:215-8.

Oliver C, Arron K, Sloneem J, Hall S. Behavioral phenotype of Cornelia de Lange syndrome: a case-control study. Br J Psychiatry 2008;193:466-70.

Basile E, Villa L, Selicorni A, Molteni M. The behavioral phenotype of Cornelia de Lange syndrome: A study of 56 individuals. J Intellect Disabil Res. 2007;51:671-81.

Deardorff M, Kaur M, Yaeger D, Rampuria A, Korolev S, Pie J, Gil-Roriguez C, Arnedo M, Loeys B, Kline AD, Wilson M, Lillquist K, Siu V, Ramos R, Musio A, Jackson LG, Dorsett D, Krantz ID. Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of Cornelia de Lange syndrome with predominant mental retardation. Am J Hum Genet. 2007;80:485-94.

Kline AD, Grados M, Sponseller P, Levy HP, Blagowidow N, Schoedel C, Rampolla J, Clemens DK, Krantz ID, Kimball A, Pichard C, Tuchman D. Natural history of aging in Cornelia de Lange syndrome. Am J Med Genet C Semin Med Genet. 2007;Aug 15;145C(3):248-60.

Kline AD, Krantz ID, Sommer A, Kliewer M, Jackson LG, FitzPatrick DR, Levin AV, Selicorni A. Cornelia de Lange syndrome: clinical review, diagnostic and scoring systems, and anticipatory guidance. Am J Med Genet. 2007;143A:1287-1296.

Musio A, Selicorni A, Focarelli ML, et al. X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations Nat Genet. 2006:38:528-30.

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. 2004;36:636-41.

INTERNET
McCusick VA, ed. Online Mendelian Inheritance in Man, (OMIM). Cornelia deLange Syndrome. The John Hopkins University. Entry Number 122470; Available at: http://omim.org/entry/122470. Last edit 11/11/2015. Accessed August 18, 2016.

Cornelia de Lange syndrome. Genetics Home Reference. Reviewed Sept. 2015.Available at: https://ghr.nlm.nih.gov/condition/cornelia-de-lange-syndrome Accessed August 18, 2016.

Tekin, M. Cornelia De Lange Syndrome. Updated: Apr 03, 2015. Available at: http://emedicine.medscape.com/article/942792-overview. Accessed August 18, 2016.
Deardorff MA, Noon SE, Krantz ID. Cornelia de Lange Syndrome. 2005 Sep 16 [Updated 2016 Jan 28]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1104/ Accessed August 18, 2016.

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