Cornelia de Lange Syndrome

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Cornelia de Lange Syndrome

Definition

Cornelia de Lange syndrome is a congenital syndrome of unknown origin diagnosed on the basis of facial characteristics consisting of synophrys (eyebrows joined at the midline), long eyelashes, long philtrum (area between the upper nose and the lip), thin upper lip, and a downturned mouth. It is a multisystemic disease that most often affects the gastrointestinal tract and the heart. Patients also present with mental retardation as well as many skeletal system malformations. It is estimated that this syndrome affects one in 10,000 newborns.

Description

This syndrome was named after the physician who described the condition in Amsterdam in 1933. It is also known as Amsterdam Dwarf Syndrome of de Lange. In 1916, another physician named Brachmann first described a more severe form of this syndrome and therefore it is also known as Brachmann-de Lange syndrome. It is known that there are three distinct categories of this condition.

The most severe form of this condition is the Type I or "classic form." Patients with this form have a prenatal growth deficiency that is also noticeable after birth. In addition these patients are marked with a distinct face and moderate to profound mental retardation. These individuals often have major deformities in the gastrointestinal tract and heart which may lead to severe incapacity or death.

The mild form of this condition is known as the Type II form. This is characterized by similar facial features to that of Type I, however, they may not become apparent until later in life. Along with a less severe preand postnatal growth deficiency, major malformations are seen at a decreased rate or may be absent completely.

Type III Cornelia de Lange syndrome, also called phenocopy, includes patients who have phenotypic manifestations of the syndrome that are related to chromosomal aneuplodies or teratogenic factors.

Genetic profile

The syndrome is suspected to be genetic in origin but the mode of transmission is unknown. Most cases are sporadic and are thought to result from a new mutation (an abnormal sequence of the components that make a gene ). There is also evidence that this may be transmitted in an autosomal dominant fashion, thus if only one parent is affected there exists a 50% chance of transmitting the abnormal gene to each child. A gene of chromosome 3 may be responsible for the syndrome.

Demographics

Cornelia de Lange syndrome appears to affect males and females in equal numbers. It is more common to see affected females transmitting the trait, however, these women seem to transmit only the mild form to their offspring. It has also been noted that consanguineous relations, or relations within families, may result in an affected child. The recurrence risk has been estimated to be between two and six percent.

Signs and symptoms

Musculoskeletal abnormalities

Microcephaly. Microcephaly is the term used to describe individuals with an abnormally small head. People with microcephaly have an accompanying small brain, resulting in mild to profound mental retardation.
Micrognathia. This term is used when characterizing people with an abnormally small mandible or lower jaw bone.
Nasal. Individuals with Cornelia de Lange syndrome often have a small nose. Anteversion, or turning, of the nostrils is also seen. A long philtrum (area between the nose and the upper lip) is also characteristic of a patient with Cornelia de Lange syndrome.
Limb and digit malformations. Limb abnormalities sometimes include relatively short limbs. Limitations of elbow extension is often seen in mild forms. In addition, relative smallness of the hands and/or feet is almost always universal. Oligodactyly (presence of less than five digits on hand or feet), and clinodactyly or bending of the fifth finger and thumbs are also sometimes seen. Webbing of the toes (syndactyly) is also not rare in patients with Cornelia de Lange syndrome.
Characteristic facial features. Facial features are possibly the most diagnostic of the physical signs. Patients look similar to each other with the bushy eyebrows joined at the midline, which is known as synophrys. Patients also have long eyelashes, a thin upper lip, and a downturned mouth. In mild cases, this classical appearance may not be present at birth and may take two or three years before becoming obvious. These individuals also have hypertrichosis, which is excessive facial (as well as body) hair.
Other symptoms. Most patients are also of low birth weight, have a cleft palate, and a low-pitched growl or cry.

Gastrointestinal abnormalities

A number of gastrointestinal (GI) problems can manifest and are by far the most common system involved. Both the upper and lower GI tract can be involved.

Gastroesophageal reflux. This is caused when acid from the stomach refluxes back into the esophagus. This can lead to severe heartburn and, if left untreated, can cause damage to the esophagus (reflux esophagitis) due to repeated irritations. Gastroesophageal reflux can also cause symptoms of pulmonary congestion and irritation due to chemical pneumonitis (inflammation of the lung).
Barrett's esophagus. Barrett's esophagus is a change from the normal tissue type of the lower esophagus to a different type. This is normally a complication on gastroesophageal reflux and is significant because it may develop into an adenocarcinoma (carcinoma of glandular tissue).
Esophageal stenosis. A narrowing of the esophagus which may decrease esophageal motility and make feeding difficult.
Gastric ulcers. The majority of ulcers of the stomach are caused by bacteria. Ulcers of this nature may lead to abdominal discomfort.
Pyloric stenosis . A narrowing of the pyloric canal that leads from the stomach to the duodenum. This may result in vomiting and diarrhea complicated by electrolyte imbalances.
Intestinal malrotation. This is a failure during fetal development of normal rotation of the small intestine. This can cause a volvulus—a twisting of the intestine back on itself—cutting-off blood supply to the tissue or possibly an intestinal obstruction.
Meckel diverticulum. In this condition, there are tiny pouches that protrude in the small intestine. Sometimes ulceration develops and bleeding occurs.

Cardiac abnormalities

Heart problems are not uncommon in patients with Cornelia de Lange syndrome.

Ventricular septal defect. In this condition the septum of the ventricles (wall between the lower chambers of the heart) is not fully closed. This results in a murmur and can possibly lead to congestive heart failure. Other complications may include infective endocarditis, which is an infection of the endothelium, the tissue that lines the heart.
Atrial septal defect. This is a defect of the septum between the upper chambers of the heart. This is caused by the persistence of the foramen ovale which is a hole normally present in the fetus that closes at birth. Individuals with this condition may also have a heart murmur.
Symptoms are normally not present in patients with atrial septal defects but they are at an increased risk of infective endocarditis.
Patent ductus arteriosus . This is a failure of the ductus arteriosus, a blood vessel between the pulmonary artery and the aorta found only in the fetus, to close. Normally there are symptoms, but severe cases may require surgery to close.
Pulmonary valve stenosis. In this condition, the valve that allows blood to go from the right ventricle to the lungs becomes narrowed. This may result in right-sided heart enlargement and heart failure.
Tetralogy of Fallot. This is a condition consisting of pulmonary stenosis, ventricular septal defect, enlarged right ventricle, and a displaced aorta. This condition results in a decrease in oxygenated blood that is pumped to the body. It can normally be corrected by surgery.

Growth and developmental deficiency

Most people afflicted with Cornelia de Lange syndrome have both prenatal and postnatal growth deficiencies as well as a developmental delay. This may be due to endocrine system involvement concerning a growth hormone delivery problem. Most patients have a characteristically short stature, but often have a pubertal growth spurt at a comparable age to normal individuals.

Developmental delays are numerous and are found in most patients with Cornelia de Lange syndrome. Some of the delays include walking alone, speaking, toilet training, and dressing. In some instances these patients never reach these milestones. Other developmental delays include IQ, which is within the mild to moderate range for mental retardation and averages 53.

Disorders of ears and eyes

Many patients with Cornelia de Lange syndrome often have some form of hearing loss. Cases may range from mild to severe, and may affect either one or both ears. This loss can be attributed to a lack of prenatal development of some of the important bony structures associated with the inner ear. In addition, development failure of important neural elements play a role in this hearing loss.

A significant number of Cornelia de Lange syndrome patients have eye and/or vision problems including:

Myopia. Nearsightedness or shortsightedness is often seen in children diagnosed with Cornelia de Lange syndrome.
Nystagmus. This is the term used to describe the rhythmical oscillations of the eyes slowly to one side followed by a rapid reflex movement in the opposite direction. It is usually horizontal, although rotatory or vertical nystagmus may also occur.
Ptosis. Ptosis is the medical term used to characterize patients having a drooping eyelid(s). This may result from lesions either in the brainstem or in the nerves supplying the muscles that raise the eyelid.
Nasolacrimal duct fistula. The lacrimal gland secretes tears to keep the eyeball moist and protected. In a nasolacrimal duct fistula the tears do not get drained from the eyeball and therefore the patient may develop chronic tearing and discharge from the eyes.

Other symptoms

Other malformations include undescended testicles, which can cause fertility problems. Diaphragmatic hernia is another complication that may lead to GI difficulties. Patients may also have a cleft palate and a lowpitched growl or cry.

Diagnosis

Cornelia de Lange syndrome has no set criteria that can indicate with absolute certainty whether or not a child is afflicted. This is due in part to a lack of specific biochemical markers postnatally that would lead a clinician to a definitive diagnosis. However, diagnosis is made subjectively from the characteristic symptoms that are present in this condition including the ones listed above. Perhaps the most diagnostic tool is the distinguishing face that a patient has, combined with facial hypertrichosis.

Prenatal diagnosis is possible through the use of ultrasound. The association of intrauterine growth retardation, oligodactyly, an absent ulna, underdevelopment of hands, diaphragmatic hernia, and cardiac defects lead to the differential diagnosis. When uncertain, the presence of long eyelashes or unusually long hair on the back restrict the diagnosis to Cornelia de Lange syndrome.

Researchers have also found that maternal serum samples collected from women who gave birth to a child with Cornelia de Lange syndrome revealed low levels of a pregnancy associated plasma protein-A (PAPP-A) during the second trimester. In addition, it has been noted that an amniotic molecule (5-OH-indole-3-acetic acid), and a fetal serum protein (galactose-1-phosphate-uridyltrasferase) were increased in afflicted individuals.

Treatment and management

The treatment and management of patients with Cornelia de Lange syndrome is strictly symptomatic. This means that treatment is prescribed according to presenting symptoms.

Musculoskeletal concerns

For patients with limb and digit malformations a variety of prosthesis are advised if necessary. Physical and occupational therapy may also be needed. Surgery may be necessary to correct more severe deformities.

Gastrointestinal treatment

Gastroesophageal reflux disease (GERD) can be treated with special diets and a number of different drugs that either block acid secretion from the stomach or neutralize acid once it is produced. Drugs may include antacids, histamine receptor blockers, and proton pump inhibitors. If these treatments prove unsuccessful, surgery my be performed to eliminate the possibility of further complications such as Barrett's esophagus or esophageal stenosis.

Patients with Cornelia de Lange syndrome should have endoscopic evaluation with biopsies for Barrett's esophagus. If this occurs, treatment will include the aforementioned drugs to reduce stomach acid and removal of the precancerous tissue may be indicated. Surgery to shorten the esophagus may also be performed.

Esophageal stenosis treatment may include a procedure done in order to dilate the esophagus. Some patients may require surgery to implant a stent or to replace part of the esophagus.

Gastric ulcers are often treated by the same means used to treat GERD. In addition, antibiotics are used in order to eliminate any bacteria that may be the cause of the ulcer. Sucralfate may be used to form a barrier over the ulcer that protects it from stomach acid allowing it to heal.

Patients with pyloric stenosis normally require surgery in order to widen the canal leading from the stomach to the duodenum. In addition, those with intestinal malrotation may require surgery depending on the severity of the condition. Surgery may also be required for patients with Meckel diverticulum if bleeding is a problem.

Cardiovascular treatment

In mild cases of cardiovascular involvement, no treatment plan is initiated other than to monitor the dysfunctions. Some of the septal defects may be asymptomatic and heal on their own. Since most of these abnormalities can lead to infective endocarditis, patients should be given antibiotics before undergoing dental procedures or surgeries. Most often penicillin or amoxicillin are used.

For patients who develop congestive heart failure, a regiment of drugs known as beta blockers may be useful to slow down the heart. Other drugs that may be used are diuretics to prevent fluid retention or ACE inhibitors.

For more serious cardiac involvement surgery is recommended. Surgery for tetralogy of Fallot involves widening the pulmonary valve and repairing the ventricular septal defect. This surgery is normally performed on patients between the ages of eight months and three years. Ventricular septal defects can be repaired usually with a synthetic patch. Atrial septal defects are normally performed by catherization by placing a device between the atria in the septum. Patent ductus arteriosus correction is done by either ligating the vessel or cutting it off.

Hearing and visual concerns

Patients diagnosed with Cornelia de Lange syndrome should be examined for hearing loss as soon as possible due to the possibility of speech delay that may be experienced because of this loss. Patients should be fitted with hearing aids and may be considered for pharyngeal-esophageal tubes.

It is also important to identify vision problems early. Glasses may be necessary for nearsightedness. Children should be seen by an opthamologist in order to assess limitations and to develop a treatment plan.

Other issues

Since development of speech is often delayed, people affected with Cornelia de Lange syndrome should be seen by a speech pathologist at an early age. Alternative communication strategies, such as sign language, may be employed depending on the level of speech development.

Children and family members may also benefit from therapy available from a number of organizations. Patients may qualify for health related support services from a variety of national support services for retarded persons.

Prognosis

Patients with Cornelia de Lange syndrome can live well into adulthood, however, it is typical for most to have a shortened life span. In 1976, a nationwide survey in Denmark revealed the oldest patient was found to be 49 years old.

A patient's prognosis can be improved by early diagnosis and intervention. These two factors can influence not only the patients life expectancy, but also their quality of life and those lives of the family and caregivers.

Resources

BOOKS

Behrman, Richard, ed. "Intestinal Atresia, Stenosis, and Malrotation." In Nelson Textbook of Pediatrics. 16th ed. Philadelphia: W. B. Saunders Company, 2000.

Oski, Frank A., ed. "Cornelia de Lange's Syndrome." In Principles and Practice of Pediatrics. 2nd ed. Philadelphia: Lippincott, 1994.

Thoene, Jess G., ed. "Cornelia de Lange Syndrome." In Physicians' Guide to Rare Diseases. 2nd ed. Montvale, N.J.: Dowden Publishing Company, 1995.

PERIODICALS

Aitken, D.A., et al. "Second-trimester pregnancy associated plasma protein-A levels are reduced in Cornelia de Lange Syndrome pregnancies." Prenatal Diagnosis 19 (1999): 706–10.

Akhtar, M.I., et al. "Cornelia de Lange Syndrome and Barrett's Esophagus:123." Journal of Pediatric Gastro and Nutrition 25 (1997): 473.

Boog, G., et al. "Brachmann-de Lange syndrome: a cause of early symmetric fetal growth delay." European Journal of Obstetrics & Gynecology and Reproductive Biology 85 (1999): 173–77.

Jackson, L., et al. "de Lange Syndrome: a clinical review of 310 individuals." American Journal of Medical Genetics 47 (1993): 940–46.

Kimitaka, K., et al. "Auditory brainstem responses in children with Cornelia de Lange Syndrome." International Journal of Pediatric Otorhinolaryngology 31 (1995): 137–46.

Kline, A.D., et al. "Developmental data on individuals with the Brachmann-de Lange syndrome." American Journal of Medical Genetics 47 (1993): 1053–58.

Kousseff, B.G., et al. "Physical growth in Brachmann-de Lange Syndrome." American Journal of Medical Genetics 47 (1993): 1050–52.

Mehta, A.V., et al. "Occurrence of congenital heart disease in children with Brachmann-de Lange Syndrome." American Journal of Medical Genetics 71 (1997): 434–35.

Sasaki, T., et al. "Temporal bone and brain stem histopathological findings in Cornelia de Lange syndrome." International Journal of Pediatric Otorhinolaryngology 36 (1996): 195–204.

Scaillon, M., et al. "Oesophageal motility disorders in Cornelia de Lange Syndrome original feature or oesophagitis related abnormalities?" Journal of Pediatric Gastro and Nutrition. 25, supplement 1 (1997): 46.

ORGANIZATIONS

Alliance of Genetic Support Groups. 4301 Connecticut Ave. NW, Suite 404, Washington, DC 20008. (202) 966-5557. Fax: (202) 966-8553. <http://www.geneticalliance.org>.

Cornelia de Lange Syndrome Foundation, Inc. 302 West Main St., Suite 100, Avon, CT 06001. (860) 676-8166 (800) 223-8355. Fax: (860) 676-8337.

March of Dimes Birth Defects Foundation. 1275 Mamaroneck Ave., White Plains, NY 10605. (888) 663-4637. [email protected]. <http://www.modimes.org>.

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.