Cornelia de Lange syndrome
Cornelia de Lange syndrome (CdLS) is a genetic disorder characterized by distinctive physical abnormalities and varying degrees of intellectual disabilities, typically noticeable at birth. It affects multiple body systems, including the arms, heart, and immune system, and is estimated to occur in 1 out of every 10,000 to 30,000 live births. The syndrome is primarily caused by mutations in several genes, most commonly the NIPBL gene, which disrupts the normal process of prenatal development. Symptoms include low birth weight, delayed growth and motor skills, deformed upper limbs, and characteristic facial features such as a small head and thin lips.
Patients may also experience heart defects, cleft palate, and impaired immune function, resulting in increased vulnerability to infections. Diagnosis is typically made through genetic testing or visual assessment of physical traits, and treatment may involve monitoring, medication, surgery, and various therapies to improve quality of life. While there is no cure for CdLS, medical interventions can enhance life expectancy and assist individuals in achieving greater autonomy. Some patients with milder forms of the syndrome can reach average adult heights and live to typical life spans. The syndrome was first documented in the early 20th century, and ongoing research continues to deepen the understanding of its genetic foundations and care strategies.
Cornelia de Lange syndrome
ALSO KNOWN AS: Amsterdam dwarfism, Brachmann-de Lange syndrome
ANATOMY OR SYSTEM AFFECTED: Arms, brain, ears, eyes, feet, hair, hands, head, heart, immune system, legs, mouth, nose, teeth
DEFINITION: A disorder with distinctive physical abnormalities and intellectual disabilities, usually apparent at birth.
CAUSES: Genetic
SYMPTOMS: Low size and weight, delayed growth and motor development, deformed upper limbs, webbed toes, small hands, small head, heavy body hair, heart abnormalities, cleft palate, reflux, convulsions, impaired immune system
DURATION: Lifelong
TREATMENTS: Incubation to monitor respiration and nutrition, antibiotics, surgical procedures for specific ailments, physical therapy, auditory devices, prosthetics
Causes and Symptoms
Cornelia de Lange syndrome is a genetic disorder that is estimated to occur in 1 out of every 10,000–30,000 live births. Sometimes siblings have this syndrome, reinforcing the hypothesis that it is hereditary, although it is most often caused by spontaneous genetic mutation. Researchers have identified mutations in several genes—including NIPBL, SMC1A, SMC3, HDAC8, and RAD21—that are associated with Cornelia de Lange syndrome. Mutations in the NIPBL are by far the most common cause, occurring in more than half of all patients.
The five primary genes that have been associated with Cornelia de Lange syndrome produce proteins that contribute to the cohesin complex, a group of proteins that contribute to prenatal development. Mutations in these genes cause this development process to be disrupted. As a result, patients with the syndrome are smaller in size and weight than average infants, and their growth and motor development are usually delayed. Upper limbs are often deformed, with missing tissues. Although legs attain average size and development appropriate to patients’ age, sometimes toes are webbed. Hands tend to be small. Patients share similar facial characteristics. Heads are abnormally small with upturned nostrils and thin lips and eyebrows. Heavy body hair often grows.
Intellectual development is impeded, particularly affecting vocalization. Hearing and vision sometimes are affected. Patients often suffer heart abnormalities, cleft palate, reflux, and convulsions. They are vulnerable to infections because of impaired immune systems.
Prenatal ultrasounds can reveal if fetuses have physical abnormalities that might be associated with Cornelia de Lange syndrome, such as cleft lip, diaphragmatic hernia, mild enlargement of cerebral ventricles, or abnormalities in the limbs (particularly upper limbs), heart, facial profile, or gastrointestinal tract. Once a child has been born, physicians identify the syndrome either by genetic testing or by observing the presence of characteristic facial features in conjunction with diagnostic criteria from two major categories (growth, development, behavior) or from one major category and two other categories, either major or minor (musculoskeletal, neurosensory/skin, other major systems).
Treatment and Therapy
Many newborns with Cornelia de Lange syndrome require incubation to monitor respiration and nutrition. Antibiotics and other medications, as well as surgical procedures, are administered to treat specific ailments affecting these individuals. Physical therapy, auditory devices, and prosthetics can aid children. Some patients have shortened life spans and are unable to live autonomously. Heart conditions cause most of the deaths associated with this syndrome.
Although no known cure or prevention exists, medical awareness and treatment of this syndrome can extend the life span and enhance the quality of life for many patients. Some patients with milder conditions survive to average life expectancies. Adults with this syndrome attain a height of between four and five feet and undergo puberty at normal ages. Various therapies can assist patients who exhibit aggressive and self-destructive behaviors and aid them in improving their communication and social skills.
Perspective and Prospects
In 1916, Winfried R. Brachmann became the first physician to document the characteristics of Cornelia de Lange syndrome in an infant. Dutch pediatrician Cornelia C. de Lange clinically described two patients in 1933 and discussed her work at neurological conferences. By the early twenty-first century, researchers had established a Cornelia de Lange syndrome database to coordinate information. Geneticists working jointly at the Children's Hospital of Philadelphia (Krantz et al.) and at Newcastle University (Tonkin et al.) were the first to identify a genetic cause of the syndrome, reporting on the associated NIPBL gene mutations in two letters published in a 2004 issue of Nature Genetics. Mutations in the other four mentioned genes, whose associations with Cornelia de Lange syndrome were discovered later, appear to cause milder forms of the syndrome.
Bibliography
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"Cornelia de Lange Syndrome." Medline Plus, 31 Dec. 2016, medlineplus.gov/croup.html. Accessed 1 Apr. 2024.
Fitzpatrick, David R., and Antonie D. Kline. "Cornelia de Lange Syndrome." Management of Genetic Syndromes, edited by Suzanne B. Cassidy and Judith E. Allanson, 3rd ed., Wiley-Blackwell, 2010, pp. 195–209.
Gardner, R. J. M. “Another Explanation for Familial Cornelia de Lange Syndrome.” American Journal of Medical Genetics, vol. 118A, no. 2, 2003, p. 198.
Gilbert, Patricia. "Cornelia de Lange Syndrome." A–Z of Syndromes and Inherited Disorders, 3rd ed., Nelson Thornes, 2000, pp. 70–72.
Krantz, Ian D., et al. "Cornelia de Lange Syndrome Is Caused by Mutations in NIPBL, the Human Homolog of Drosophila melanogaster Nipped-B." Nature Genetics, vol. 36, no. 6, 2004, pp. 631–35, doi:10.1038/ng1364. Accessed 1 Apr. 2024.
Poplawski, Elizabeth. "Cornelia de Lange Syndrome." Health Care for People with Intellectual and Developmental Disabilities across the Lifespan, edited by I. Leslie Rubin et al., 3rd ed., vol. 1, Springer, 2016, pp. 903–12.
Tonkin, Emma T., 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." Nature Genetics, vol. 36, no. 6, 2004, pp. 636–41, doi:10.1038/ng1363. Accessed 1 Apr. 2024..
"What Is CdLS?" Cornelia de Lange Syndrome (CdLS) Foundation, 2021, www.cdlsusa.org/what-is-cdls/index.htm. Accessed 1 Apr. 2024.