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.
Cornelia de Lange syndrome (CdLS) is a rare genetic disorder that is generally 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 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. Seven 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, the HDAC8 gene on the X chromosome, the ANKRD11 on chromosome 16 and the BRD4 gene on chromosome 19. 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. It is now referred to as Cornelia de Lange syndrome spectrum because of the broad nature of the presentations.
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 may 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 and/or apraxia), 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 are at risk for 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). Some babies with CdLS can be born with diaphragmatic hernia, in which some of the contents of the abdomen have not been separated from the lungs as a fetus; this needs to be repaired for survival. 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).
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. Seven 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, the HDAC8 gene on the X chromosome, the ANKRD11 on chromosome 16 and the BRD4 gene on chromosome 19. 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.
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.
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, HDAC8, ANKRD11 or BRD4 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.
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), feeding specialists, 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.
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