What's CdLS?

May 11, 2018

Tomorrow, May 12th, is Cornelia de Lange Syndrome Awareness Day!  A very rare condition, Cornelia de Lange Syndrome is a complex diagnosis about which much is still being discovered.  We thought we would detail some helpful information, to do our part to spread awareness of this developmental syndrome.

 

In 1933, a Dutch pediatrician named Cornelia Catharina de Lange took on a young patient who was struggling with pneumonia and feeding difficulties.  The little girl was small for her age and had very distinct, somewhat atypical facial characteristics.

 

Not long after, Dr. de Lange took on a second patient with similar health issues, and she noted a similarity in physical features to the first patient.  She combed through medical reports, works, and journals in search of an existing study featuring such characteristics in a patient, but she could find nothing similar.


So, she set about the task of researching, describing, and documenting what she had discovered.  She called the disorder “typus degenerativus Amstelodamensis,” but the syndrome she studied now bears her name: Cornelia de Lange Syndrome.

 

However, there was another physician who studied individuals affected by this syndrome.  His name was Dr. W. Brachmann, and his work dates to 1916.  CdLS is sometimes also called Brachmann-de Lange Syndrome, as his earlier work is now recognized to have pertained to individuals affected by the same syndrome that Dr. de Lange chronicled.

 

But Dr. Brachmann’s work focused primarily on cases of the syndrome which were severe enough to affect the development of the upper limbs, causing malformations of the fingers, hands, and arms.  His work did less to describe other characteristics of the syndrome, such as facial and neurological abnormalities, and developmental delays.  This is probably why de Lange did not correlate Brachmann’s work with her own.

 

What Dr. de Lange had definitively identified was a developmental disorder she suspected to be genetic in nature, and though she would not discover its exact cause during her lifetime, we now know the syndrome is in fact linked to mutations in an individual’s genes.

 

So What Is It?

 

A very rare genetic disorder, it is estimated that Cornelia de Lange Syndrome only affects about 1 in 10,000 individuals, at most.  It is difficult to determine the exact incidence of CdLS, because individuals who are only mildly affected may never be diagnosed with the syndrome.

 

Cornelia de Lange Syndrome is associated with a certain set of distinctive facial and cranial features, the prominence of which can vary greatly even among people with the same root type of mutation.  But alongside these and other aesthetic signifiers, CdLS also causes slow growth patterns and small stature even into adulthood, and can cause a condition called microcephaly, which is simply a term for when the head is proportionally smaller than average.

 

Depending on the severity of the condition in any one person, CdLS can also cause abnormalities in the formation and density of bones and joints, especially in the upper limbs.  These abnormalities are present at birth, and can range from symptoms as mild as a thumb that is just a bit too close to the wrist, to those as drastic as the complete absence of forearms.

Some cases of Cornelia de Lange Syndrome involve hearing loss and problems in the digestive tract.  In some cases, a cleft palate may be present at birth, and the condition has occasionally been associated with seizures, heart defects, and eye problems.

 

Cornelia de Lange Syndrome is also associated in the majority of cases with intellectual disability and developmental delays, which again vary widely from individual to individual.  In addition to this, many people with CdLS experience behavioral, social, and sensory issues similar to those of Autism Spectrum Disorder.

 

CdLS affects every individual differently.  Some people with CdLS may be so mildly affected that the syndrome goes unnoticed throughout their lives, while others with the disorder must struggle daily to overcome significant physical and developmental challenges.  This wide range of symptoms is one of the reasons CdLS was so difficult to classify when first studied by medical professionals, and remains somewhat tricky to diagnose even today.

 

What Causes It?

 

Cornelia de Lange Syndrome is caused by genetic mutations.  These mutations have been specifically identified in five genes to date, though research is being done into other genes which may be involved.  About 30% of known cases of CdLS are linked to genes beyond those already identified as confirmed causes of the disorder.

 

However, all the genes isolated in connection to Cornelia de Lange Syndrome have something in common.  Though their exact functions vary slightly, each of these genes contributes in some way to the structure or function of the cohesin complex.

 

The cohesin complex is a group of proteins that is heavily involved in the creation of a human being.  When a person is under construction, the blueprints for the finished design are contained inside each cell, in the form of their DNA.

 

As a tiny human grows, their cells duplicate themselves, going about their specialized crafts and tasks as they build their specific person.  But in each individual cell, the DNA blueprints must be perfectly copied for typical development.  Even the tiniest missing piece or genetic typo can disrupt the entire process.

 

The cohesin complex is involved in creating those perfect copies of each cell’s DNA blueprints.  The cohesin complex directs the grouping and composition of exactly-matched chromosomes, the transcription of the DNA blueprints, and double-checking and correcting any transcription errors in DNA.

 

All five of the currently recognized genes involved in CdLS have something to do with the proper creation and function of the cohesin complex.  When they are mutated, these genes impair the function of the cohesin complex, causing errors in DNA that go unchecked by the body’s cellular architect, creating the characteristics of the disorder we call Cornelia de Lange Syndrome.

 

Cornelia de Lange is heavily hereditary in the children of affected individuals, however, the vast majority of cases are due to what’s known as de novo mutations.  This simply means that the mutations in the genes causing CdLS in most individuals are first generation mutations, completely new, and appear in people who have no history of the condition in their family history.

 

So Is There a Cure?

 

There is currently no known cure for Cornelia de Lange Syndrome, nor are there any confirmed environmental factors that could aid in preventing its occurrence.  However, most people with Cornelia de Lange Syndrome are expected to live well into adulthood, if other serious conditions are not present.

 

Treatment options abound, and are targeted mainly at controlling the symptoms and health issues connected with CdLS.  Physical challenges can be addressed as needed by specialists in the field or by corrective surgeries in some cases.  Developmentally, early intervention with an individualized treatment plan is crucial.  Therapists, specialists, and physicians will work together with families to determine what is best for each child’s needs.

What Does Success Look Like?

 

Cornelia de Lange Syndrome causes such a wide range of symptoms and challenges, so successes will vary just as greatly.  Nevertheless, success can be as simple as learning a pincer grasp, or as complex as following multi-step instructions for the first time.

 

One of our little friends with CdLS celebrated a huge milestone the first time he took a strong step and propelled himself forward in a walker.  Another friend we know is working to overcome her hearing challenges through the use of adaptive hearing aids and speech therapy.

 

Every person with Cornelia de Lange Syndrome fights a unique battle, and they are all heroes in our eyes.  Celebrate with us as we spread awareness of Cornelia de Lange Syndrome and all the individuals affected by this complex condition!

 

SOURCES:

 

[1] Cornelia de Lange Syndrome Foundation, Inc. Treatment Protocols. 2017. Web. 11 May 2018. <http://www.cdlsusa.org/what-is-cdls/treatment-protocols.htm>.

 

—. What Is CdLS?: Frequently Asked Questions. 2017. Web. 11 May 2018. <http://www.cdlsusa.org/what-is-cdls/frequently-asked-questions.htm>.

 

[2] Matthew A Deardorff MD, PhD, Sarah E Noon MS and Ian D Krantz MD. Cornelia de Lange Syndrome. 28 January 2016. National Center for Biotechnology Information. Web. 22 May 2018. <https://www.ncbi.nlm.nih.gov/books/NBK1104/>.

 

[3] Schlesinger, Bernard, et al. "Typus Degenerativus Amstelodamensis." Archives of Disease in Childhood 38.200 (1963): 349-357. Web. 11 May 2018. <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2018927/?page=1>.

 

[4] U.S. National Library of Medicine: Genetics Home Reference. Cornelia de Lange syndrome. 8 May 2018. Web. 11 May 2018. <https://ghr.nlm.nih.gov/condition/cornelia-de-lange-syndrome>.

 

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