What is Cornelia de Lange Syndrome?

Cornelia de Lange syndrome (CdLS) is a condition recognised since 1933, named after the Dutch pediatrician, Cornelia Catharina de Lange, who documented two unrelated girls with similar symptoms. Even earlier, in 1849 and 1916, similar cases were reported by an anatomist and a doctor, respectively. This syndrome has been known by several other names, including Amsterdam dwarfism, Bushy syndrome, or Brachmann syndrome.

CdLS is a complex disease affecting various body systems and can show different physical, cognitive, and behavioral traits. It’s a genetic disorder that impacts multiple organs, resulting in diverse clinical symptoms. This uncommon disease often features slow growth starting during pregnancy (second trimester), intellectual disability, unusual facial and limb structures, and excessive body hair. Other symptoms may include acid reflux, genitourinary malformations, and heart defects.

What Causes Cornelia de Lange Syndrome?

Many studies on people with CdLS, or Cornelia de Lange syndrome, have looked into various genes related to the function of the cohesin pathway. The cohesin pathway, made up of a protein complex and its regulators, plays a critical role in cell division. Beyond that, it is also involved in several crucial biological processes that help keep the genome stable, manage gene expression, and organize the structure of the chromatin and the genome.

Seven different genes that contribute to the development of the cohesin pathway complex have been linked to CdLS. Five of these genes cause about 70% of CdLS cases. Out of these five, one gene, called NIPBL found on chromosome 5, is responsible for approximately 60% of cases, with the other four genes causing about 10% of cases. The remaining 30% of CdLS patients are considered idiopathic, meaning the cause is unknown. You should also know that both male and female are equally affected by the syndrome.

Even though CdLS is a genetic disorder, the majority of cases develop sporadically, due to new mutations rather than inherited ones. Occasionally, the syndrome may be passed down in families either as a dominant trait from one parent or as an X-linked dominant trait, but this is less than 1% of the time.

The mutations that cause CdLS can affect several genes, including NIPBL, SMC1A, SMC3, BRD4, HDAC8, RAD21, and ANKRD11. Each gene mutation is linked to a different expression of CdLS, meaning the symptoms can be different depending on the gene. What’s more, some people with CdLS have what’s called mosaicism, where some cells have the gene mutation but others do not. This has been observed in up to 20% of individuals with typical CdLS features.

Let’s look more closely at the specific genes:

– NIPBL: Mutations in this gene typically result in the classic form of CdLS.
– SMC3: Mutations often result in an atypical form of CdLS, where intellectual disability is the main symptom.
– RAD21: Mutations in this gene can cause a non-classic type of CdLS and are rarely observed.
– BRD4 and ANKRD11: Mutations in these two genes are associated with non-classic types of CdLS.
– HDAC8: Mutations in this X-linked gene often cause a non-classic type of CdLS, but occasionally present classic features.
– SMC1A: Associated with a non-classic type of CdLS.

Risk Factors and Frequency for Cornelia de Lange Syndrome

Cornelia de Lange Syndrome (CdLS) is often less noticed in its mild form, which means the actual number of people affected might be more than anticipated. It is currently estimated that in the United States, between 1 in 10,000 and 1 in 50,000 newborns are affected. The condition doesn’t differentiate between boys and girls because it follows a dominant gene pattern. Cases that don’t show the typical characteristics of CdLS are occasionally reported individually.

Signs and Symptoms of Cornelia de Lange Syndrome

Cornelia de Lange Syndrome (CdLS) manifests in different ways as the patient grows, starting with restricted growth and low weight while in the womb. After birth, these children often continue to grow slowly and can have a weight lower than 2.2 kg. While it’s easier to recognize the classic form of this syndrome, less obvious forms can be difficult to diagnose. CdLS affects multiple organs and the nature of these effects can vary widely:

  • Craniofacial: Children with CdLS may have distinct features like thick eyebrows that meet in the middle, a short nose, thin lips, a cleft palate, or small jaws. They also often have long lashes, low set ears, and a short or smaller skull. They may have hair growth on their forehead and neck, and a short neck.
  • Neurodevelopmental: Children may experience significant developmental delays and intellectual disability. Issues like acid reflux are common in these patients, which can lead to other conditions like Barrett’s esophagus. They may also experience nausea, vomiting, indigestion, constipation, or a lack of appetite.
  • Genitourinary: These patients often have underdeveloped genitals and may have conditions like cryptorchidism, hypospadias, kidney cysts, or kidney hypoplasia. There are also cases of benign prostatic hypertrophy in males with CdLS.
  • Ophthalmologic: Eye problems such as dysfunctional tear ducts, drooping eyelids, strabismus, myopia, cataracts, glaucoma, detached retina, and inflammation of the eyelids are often observed. Around half of these patients experience visual impairments.
  • Cardiac: CdLS patients may have heart murmurs or conditions like coarctation of the aorta, pulmonary stenosis, tetralogy of Fallot, and atrial or ventricular septal defects.
  • Neurological: Up to 25% of these patients may have seizure disorders. Sleep issues, problems with the nervous system, and psychiatric problems like aggression, self-injury, self-stimulation, ADHD, depression, anxiety, and OCD are also common.
  • Dermatologic: Hirsutism or mottled skin discoloration can occur.
  • Musculoskeletal: Abnormalities in limb formation, scoliosis, partial toe fusion, curved fifth digit, radial hypoplasia, short sternum, and pectus excavatum were observed.
  • Respiratory: Rarely, patients may have laryngeal anomalies.
  • Immunodeficiency: CdLS patients can be prone to recurring infections due to antibody deficiency or impaired T-cell function.

Different scoring systems assess the severity of this syndrome based on physical characteristics. As per the international consensus, cardinal features include unique facial features, underdevelopment of hands, and diaphragmatic hernia. Suggestive features include developmental delay, slow growth, small head size, small hands, short fifth finger, and excessive hair growth. The presence of each cardinal feature gets a score of 2, while each suggestive feature scores 1. A total of 11 points, with at least 3 being cardinal points, indicates classic CdLS, while 9 or 10 points (with at least 2 cardinal) suggest a non-classic form of CdLS. A score of 4 to 8 should undergo molecular testing, and a score under 4 points might not require further exams.

Testing for Cornelia de Lange Syndrome

Cornelia de Lange Syndrome (CdLS) is diagnosed mainly through clinical observations. However, if the patient’s medical history and physical examination are not clear enough, genetic testing is recommended. This testing can also be used to confirm CdLS diagnoses in children with mild or unusual symptoms.

This genetic evaluation is done primarily through next-generation sequencing (NGS), which includes methods such as whole-exome sequencing (WES) and whole-genome sequencing (WGS). These techniques target specific genes. The first set of genes to be screened generally include NIPBL, SMC1A, SMC3, RAD21, BRD4, HDAC8, and ANKRD11, rather than simply focusing on the NIPBL gene. For those individuals who don’t exhibit the typical characteristics of CdLS, deciding on whether to undergo genetic testing is judged on a case-by-case basis.

If the genetic testing comes up with no definitive result, doctors usually check for mosaicism. Mosaicism is probed in tissues that are not blood, such as skin cells (fibroblasts), cheek swab cells, or certain types of cells taken from urine. If the mosaicism test also turns out negative, the NIPBL gene is further examined for possible deletions or duplication, using advanced methods like multiplex ligation-dependent probe amplification (MLPA) or chromosome microarray.

Besides the genetic evaluations, doctors also order several clinical, imaging, and lab tests. These typically include:

-Body Mass Index (BMI) and growth charts
-Complete blood count (CBC)
-Complete metabolic panel (CMP)
-Hearing and vision screening
-Eye examination (with cycloplegic refraction)
-Heart ultrasound (Echocardiogram)
-Electrocardiogram (ECG)
-Upper gastrointestinal series
-Endoscopy or pH probe
-Kidney ultrasound
-New technologies like Facial Dysmorphology Novel Analysis (FDNA) which works by spotting genetic disorders identified by facial anomalies. This system’s accuracy is comparable to a clinical expert’s.

In addition to these tests, CdLS can be suspected in unborn babies by using ultrasound which can expose slowed growth in the womb, facial aberrations, and limb abnormalities. While ultrasound is helpful, it does not provide 100% accurate results. So, it’s important to thoroughly explain these limits to the parents.

In cases where a gene mutation has been identified, prenatal molecular testing can be carried out on samples from chorionic villous sampling or amniocentesis, or testing embryonic cells in in-vitro fertilization. Finally, parents who seem to not carry the mutation can still be advised to have a genetic diagnosis to rule out the possibility of mosaicism, where they could potentially pass the disease onto their child.

Treatment Options for Cornelia de Lange Syndrome

To effectively manage a patient with CdLS, it’s crucial to have an multidisciplinary team who work together. The team can be composed of:

A wide range of medical professionals such as primary care doctors, ear, nose and throat specialists, gastroenterologists (for dealing with GERD, which is a type of persistent heartburn), eye doctors, heart doctors, urologists, kidney specialists, skin doctors, dentists, and orthodontists.

Neurologists can be part of the team as they are able to manage seizure disorders in CdLS using medications designed to control seizures.

Psychiatrists or psychologists also play an important role in managing self-harming or aggressive behaviors seen in CdLS. They can use medications along with other therapeutic methods like individual psychotherapy or ABA, a therapy often used in treating behavioral issues.

Surgeons come in handy for managing feeding difficulties, stomach issues (like severe reflux), vesicoureteral reflux (a condition where urine flows back into the kidneys), cryptorchidism (a condition where one or both testes fail to descend), or any bone abnormalities.

Apart from these, children with CdLS often need physical therapy, speech therapy, occupational therapy, and special education programs. These are required due to the delayed growth and intellectual disability commonly seen in these patients. Regular checks for hearing and vision are also highly recommended for all children with neurodevelopmental disorders. Talking to a nutritionist can be helpful in addressing feeding problems.

To manage people affected by CdLS, it’s recommended that they have an annual checkup for gastrointestinal issues, as well as regular monitoring of growth and psychomotor development. Regular eye and ear checks as well as monitoring of heart and kidney functions are also recommended.

People with Cornelia de Lange Syndrome (CdLS) can have a wide range of symptoms, making it sometimes hard to distinguish from other genetic disorders. That’s why it’s important to use genetic testing to accurately diagnose CdLS and eliminate the possibility of other genetic conditions. This is particularly important for cases of CdLS that don’t have the common signs and symptoms (also known as non-classical CdLS).

Conditions that may have similar symptoms to CdLS include:

  • Autism Spectrum Disorder
  • Rett syndrome
  • Roberts syndrome
  • Nicolaides-Baraitser syndrome
  • DiGeorge syndrome
  • Conditions related to deletions of genetic material from chromosome 2 (2q31)
  • Conditions related to extra (duplicated) genetic material from chromosome 3 (3q)
  • Fryns syndrome
  • CHOPS syndrome
  • Bohring-Opitz syndrome
  • Conditions related to TAF6 or TAF1 gene abnormalities

What to expect with Cornelia de Lange Syndrome

Cornelia de Lange syndrome has rarely been reported in adults. Usually, life expectancy remains largely unchanged. However, if a patient develops any complications related to the syndrome, their prognosis will largely depend on the intensity of these complications and how they’re managed.

Possible Complications When Diagnosed with Cornelia de Lange Syndrome

Cornelia de Lange Syndrome (CdLS) affects multiple body systems, leading to varied complications that need to be treated by different medical specialties. These complications include:

  • Gastroenterology: Early infancy might require correction of stomach, intestine, or diaphragm abnormalities. Conditions like Gastroesophageal Reflux Disease (GERD) can result in children developing Barrett’s esophagus (in 10% of cases) or aspiration pneumonia, a lung infection caused by inhaling food or drinks into the lungs.
  • Urology: In male infants with CdLS, conditions like undescended testicles (cryptorchidism) or a mislocated urethral opening (hypospadias) are common. In such cases, surgery to correct cryptorchidism is advisable due to the risk of testicular cancer. Genital underdevelopment is common in both boys and girls.
  • Nephrology: Kidney complications like kidney cysts and underdeveloped kidneys are common in children with CdLS.

Another noticeable symptom in young patients with CdLS is premature aging, including conditions like osteoporosis (brittle bones) or early greying of hair, possibly linked to the cohesin pathway genetic mutation hindering cell division.

Preventing Cornelia de Lange Syndrome

Taking care of patients with Cornelia de Lange Syndrome (CdLS) requires a team of experts from different medical fields. Any questions or concerns about treatment or management should be addressed to this specialized team. For more detailed information about the disorder, you can visit the Cornelia de Lange Syndrome Foundation (CdLS Foundation).

Frequently asked questions

Cornelia de Lange Syndrome (CdLS) is a genetic disorder that affects multiple organs and results in diverse clinical symptoms. It is a complex disease that can show different physical, cognitive, and behavioral traits. Some of the common symptoms include slow growth starting during pregnancy, intellectual disability, unusual facial and limb structures, and excessive body hair.

Between 1 in 10,000 and 1 in 50,000 newborns in the United States are affected by Cornelia de Lange Syndrome.

Signs and symptoms of Cornelia de Lange Syndrome (CdLS) include: - Craniofacial features: Thick eyebrows that meet in the middle, a short nose, thin lips, a cleft palate, small jaws, long lashes, low set ears, short or smaller skull, hair growth on forehead and neck, and a short neck. - Neurodevelopmental delays: Significant developmental delays, intellectual disability, acid reflux leading to conditions like Barrett's esophagus, nausea, vomiting, indigestion, constipation, and lack of appetite. - Genitourinary abnormalities: Underdeveloped genitals, conditions like cryptorchidism, hypospadias, kidney cysts, kidney hypoplasia, and benign prostatic hypertrophy in males. - Ophthalmologic issues: Dysfunctional tear ducts, drooping eyelids, strabismus, myopia, cataracts, glaucoma, detached retina, inflammation of the eyelids, and visual impairments in around half of the patients. - Cardiac problems: Heart murmurs, coarctation of the aorta, pulmonary stenosis, tetralogy of Fallot, atrial or ventricular septal defects. - Neurological complications: Seizure disorders in up to 25% of patients, sleep issues, problems with the nervous system, and psychiatric problems like aggression, self-injury, self-stimulation, ADHD, depression, anxiety, and OCD. - Dermatologic manifestations: Hirsutism (excessive hair growth) and mottled skin discoloration. - Musculoskeletal abnormalities: Abnormalities in limb formation, scoliosis, partial toe fusion, curved fifth digit, radial hypoplasia, short sternum, and pectus excavatum. - Respiratory issues: Rarely, patients may have laryngeal anomalies. - Immunodeficiency: CdLS patients can be prone to recurring infections due to antibody deficiency or impaired T-cell function. Different scoring systems are used to assess the severity of CdLS based on physical characteristics. Cardinal features include unique facial features, underdevelopment of hands, and diaphragmatic hernia. Suggestive features include developmental delay, slow growth, small head size, small hands, short fifth finger, and excessive hair growth. Scoring is done with 2 points for each cardinal feature and 1 point for each suggestive feature. A total score of 11 points with at least 3 being cardinal points indicates classic CdLS, while a score of 9 or 10 points with at least 2 cardinal points suggests a non-classic form. A score of 4 to 8 should undergo molecular testing, and a score under 4 points might not require further exams.

CdLS is primarily caused by new mutations rather than inherited ones. However, in rare cases, it can be passed down in families either as a dominant trait from one parent or as an X-linked dominant trait.

Autism Spectrum Disorder, Rett syndrome, Roberts syndrome, Nicolaides-Baraitser syndrome, DiGeorge syndrome, Conditions related to deletions of genetic material from chromosome 2 (2q31), Conditions related to extra (duplicated) genetic material from chromosome 3 (3q), Fryns syndrome, CHOPS syndrome, Bohring-Opitz syndrome, Conditions related to TAF6 or TAF1 gene abnormalities.

The types of tests needed for Cornelia de Lange Syndrome (CdLS) include: - Genetic testing, primarily through next-generation sequencing (NGS) such as whole-exome sequencing (WES) and whole-genome sequencing (WGS), targeting specific genes like NIPBL, SMC1A, SMC3, RAD21, BRD4, HDAC8, and ANKRD11. - Mosaicism testing in tissues other than blood, such as skin cells, cheek swab cells, or certain types of cells taken from urine. - Examination of the NIPBL gene for possible deletions or duplications using methods like multiplex ligation-dependent probe amplification (MLPA) or chromosome microarray. - Clinical, imaging, and lab tests including Body Mass Index (BMI) and growth charts, complete blood count (CBC), complete metabolic panel (CMP), hearing and vision screening, eye examination, heart ultrasound (Echocardiogram), electrocardiogram (ECG), upper gastrointestinal series, endoscopy or pH probe, kidney ultrasound, and new technologies like Facial Dysmorphology Novel Analysis (FDNA). - Ultrasound for prenatal diagnosis in unborn babies, which can reveal slowed growth, facial aberrations, and limb abnormalities. - Prenatal molecular testing on samples from chorionic villous sampling or amniocentesis, or testing embryonic cells in in-vitro fertilization, if a gene mutation has been identified. - Genetic diagnosis for parents to rule out the possibility of mosaicism, even if they do not carry the mutation themselves.

Cornelia de Lange Syndrome (CdLS) is treated through a multidisciplinary approach. A team of medical professionals, including primary care doctors, specialists such as ear, nose and throat specialists, gastroenterologists, eye doctors, heart doctors, urologists, kidney specialists, skin doctors, dentists, orthodontists, neurologists, psychiatrists or psychologists, and surgeons work together to manage the various aspects of the syndrome. Medications are used to control seizures and manage self-harming or aggressive behaviors. Therapeutic methods like individual psychotherapy or ABA therapy may also be employed. Physical therapy, speech therapy, occupational therapy, and special education programs are often necessary due to delayed growth and intellectual disability. Regular check-ups for gastrointestinal issues, growth, psychomotor development, hearing, vision, and heart and kidney functions are recommended.

The prognosis for Cornelia de Lange Syndrome largely depends on the intensity of any complications that may arise and how they are managed. Generally, life expectancy remains largely unchanged, but if a patient develops complications related to the syndrome, their prognosis will be influenced by the severity of these complications and their treatment.

A wide range of medical professionals, including primary care doctors, ear, nose and throat specialists, gastroenterologists, eye doctors, heart doctors, urologists, kidney specialists, skin doctors, dentists, orthodontists, neurologists, psychiatrists or psychologists, and surgeons, should be consulted for Cornelia de Lange Syndrome.

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