Cornelia de Lange Syndrome

Etiology

CdLS is caused by pathogenic variants in genes belonging to the cohesin pathway (see Table 1). The cohesin protein complex is a multimeric system that regulates gene expression and genome organization. The cohesin complex plays a critical role in sister chromatid cohesion, DNA repair, transcriptional regulation, and genome stability.[3][4] The complex comprises 4 core subunits (SMC1A, SMC3, RAD21, and STAG), which are evolutionarily conserved.

These proteins form a ring-shaped structure that encircles chromatin. NIPBL and MAU2 chromatid cohesion factor homolog form a heterodimeric complex named kollerin that is required for cohesin loading onto DNA, and BRD4 interacts with NIPBL.[5] HDAC8 regulates the release of the cohesin complex from chromatin by deacetylating SMC3. ANKRD11 regulates gene expression through gene remodeling.[6] 

Table 1. Etiology of Cornelia de Lange Syndrome

CdLS, Cornelia de Lange syndrome; ANKRD11, ankyrin repeat domain 11 gene; BRD4, bromodomain containing 4 gene; HDAC8, histone deacetylase 8 gene; MAU2, MAU2 chromatid cohesion factor homolog gene; NIPBL, NIPBL cohesin loading factor gene; RAD21, RAD21 cohesin complex component gene; SMC1A, structural maintenance of chromosomes 1A gene; SMC3, structural maintenance of chromosomes 3 gene

Eight genes have been associated with CdLS: NIPBL (60% to 70% of cases), SMC1A (5% to 10%), SMC3, RAD21, HDAC8, MAU2, BRD4, and ANKRD11. Pathogenic variants in cohesin structural genes (SMC1A, SMC3, RAD21) and regulatory genes (NIPBL, HDAC8, MAU2, BRD4, ANKRD11) lead to dysregulated gene expression, increased oxidative stress, and genomic instability. Most mutations are de novo, although autosomal dominant and X-linked inheritance patterns have been observed. The cohesion of sister chromatids is unaffected in CdLS; rather, dysfunction of the cohesin complex dysregulates gene and protein expression.[7]

Variation in phenotypic expression is associated with both the gene and the type of mutation. Classic CdLS is more commonly associated with variants in proteins that regulate cohesin function (NIPBL, HDAC8, MAU2), whereas variants in proteins involved in the cohesin complex (SMC1A, SMC3, RAD21) or cohesin-associated proteins (BRD4, ANKRD11) are more often identified in nonclassic CdLS. Loss-of-function variants typically cause a more severe clinical picture, whereas missense variants are associated with a milder phenotype.

However, severity can vary even among patients with the same mutation, likely reflecting modifying factors such as X-linked inactivation, mosaicism, and other regulatory mechanisms.[6][8][9] Mosaicism is increasingly recognized in CdLS, most often involving the NIPBL gene. Approximately 10% of patients with CdLS have mosaicism, a higher prevalence compared with other neurodevelopmental disorders.[10] Recently, variants in NIPBL, SMC1A, and HDAC8 have been associated with premature aging in CdLS. These variants cause genomic instability, increased oxidative stress, and premature cellular aging, leading to early cellular senescence.[11] 

CdLS is a disorder with a complex genetic basis leading to an extremely variable phenotype, affecting multiple organ systems and resulting in a wide range of developmental and behavioral manifestations. Multiple genes with various types of mutations have been associated with CdLS, and their effects may be modified by factors such as gene dosage, mosaicism, and epigenetic changes. Recent developments in molecular analysis have expanded understanding of the pathogenetic mechanisms underlying clinical expression. However, a significant proportion of patients with features within the CdLS spectrum lack a molecular diagnosis.[6]

Epidemiology

The prevalence of CdLS is 1 in 10,000 to 1 in 30,000 live births. However, this number is likely to increase as more mild phenotypes are identified. Men and women are equally affected, although clinical expression may be influenced by X-linked mutations. No association with race or ethnicity has been identified. Although most cases are de novo and sporadic, autosomal dominant and X-linked inheritance have been observed.[2]

Prenatal diagnosis is possible, but approximately 70% of cases are not detected by routine ultrasonography.[12] Mortality is increased compared to the general population, with the greatest risk in infancy and early childhood. The leading causes of death are respiratory tract complications (aspiration, pneumonia), gastrointestinal tract complications (eg, volvulus), and congenital anomalies, especially cardiac anomalies. Patients who are more severely affected with congenital abnormalities and complications are at a higher risk of mortality.[13] With advances in diagnosis and management, more patients are living into adulthood with a near-normal lifespan.

History and Physical

Patients with classic CdLS are usually diagnosed at birth by unique distinguishing features, including facial gestalt, poor prenatal and postnatal growth, and extremity deformities.[2][6][8] Patients with CdLS can have a wide range of clinical abnormalities:

• Craniofacial: Thick arched eyebrows with synophrys (united in the middle), thick, long eyelashes, short upturned nose, long philtrum, thin lips with downturned corners, cleft or arched palate, hirsute forehead, microcephaly, retrognathia, short neck with low posterior hairline
• Growth:  Prenatal and postnatal growth retardation and short stature
• Extremity anomalies: Affect 80% of patients, with severe anomalies in 25% to 30%; reduction deformities of the upper extremities, small hands and feet, brachydactyly, clinodactyly, and single palmar crease
• Gastrointestinal tract: Gastroesophageal reflux disease (greater than 90%), congenital diaphragmatic hernia, intestinal malrotation, pyloric stenosis, and constipation
• Congenital heart disease: Affects 33% of patients; atrial septal defect, ventricular septal defect, pulmonary valve stenosis, tetralogy of Fallot, hypoplastic left heart syndrome, bicuspid aortic valve, and early cardiomyopathy
• Genitourinary: Cryptorchidism in boys (75%), bicornate uterus in girls (25%), genital hypoplasia (50%), and vesicoureteral reflux (10%)
• Sensory:  Hearing loss (65% to 80%), myopia (50%), nystagmus (40%), and ptosis
• Neurodevelopmental: Mild to severe cognitive impairment, developmental delay, behavioral disorders, autism spectrum disorder, self-injurious behaviors (up to 70%), anxiety, and sleep disturbances
  • Seizures are more common in patients with SMC1A variants (45%), including SMC1A-related neurocognitive disorder or developmental and epileptic encephalopathy 85 with or without midline brain defects, a severe disorder with epilepsy and neurocognitive impact that can mimic Rett syndrome.
• Premature aging: Early development of Barrett esophagus, osteoporosis in late adolescence, premature graying of hair, and aged facial appearance

An international consensus statement (2018) described a scoring system to facilitate CdLS diagnosis (see Table 2).[2] The authors proposed distinguishing cardinal features from suggestive characteristics. The cardinal features include synophrys or thick eyebrows, short nose, concave nasal ridge or upturned nasal tip, long or smooth philtrum, thin upper lip vermilion or downturned corners of the mouth, hand oligodactyly or adactyly, and congenital diaphragmatic hernia.

Suggestive features comprise global developmental delay or intellectual disability, prenatal growth retardation, postnatal growth retardation, microcephaly (prenatally or postnatally), small hands or feet, short fifth digit, and hirsutism. If present, each cardinal feature is scored with 2 points, whereas each suggestive feature is assigned 1 point. A total score of 11 points or greater (with at least 3 cardinal features) indicates classic CdLS; a score of 9 or 10 points (with at least 2 cardinal features) is suggestive of nonclassic CdLS. Moreover, a score of 4 to 8 points (with at least 1 cardinal feature) requires molecular testing, whereas a score of fewer than 4 points is insufficient to indicate further testing.

Table 2. Clinical Features of Cornelia de Lange Syndrome 

Clinical Score

• ≥11 points, of which at least 3 are cardinal: Classic CdLS
• 9 or 10 points, of which at least 2 are cardinal: Nonclassic CdLS
• 4–8 points, of which at least 1 is cardinal: Molecular testing for CdLS indicated
• <4 points: Insufficient to indicate molecular testing for CdLS

Evaluation

The diagnosis of CdLS can often be made clinically based on the criteria outlined in the 2018 international consensus statement.[2] Clinicians may also suspect CdLS prenatally.

Prenatal Evaluation

CdLS can be suspected prenatally using high-resolution ultrasonography and 3D volumetric imaging, which can identify characteristic facial features, extremity abnormalities, congenital diaphragmatic hernia, growth restriction, and cardiac malformations. In these individuals, as well as in those with a known family history of an affected relative or a genetic alteration, clinicians consider molecular testing using chorionic villus sampling, amniocentesis, or embryonic stem cells obtained from in vitro fertilization.[6]

Genetic Testing

Molecular genetic testing has several purposes. Identifying a pathogenic variant not only confirms the diagnosis but also guides further evaluation and treatment based on the known phenotype associated with that genotype. Testing can also identify inherited cases for genetic counseling. Additionally, because CdLS is a rare and highly heterogeneous disorder, testing can identify previously unknown pathogenic variants and further expand understanding of this disorder and the cohesin pathway.

First-line testing is next-generation sequencing (NGS) targeting the known pathogenic variants using the CdLS multigene panel, including NIPBL, SMC1A, HDAC8, SMC3, RAD21, and BRD4. Additional genes may include MAU2, ANKRD11, AFF4, CREBBP, and EP300. If the panel results are negative or the presentation is atypical, whole-exome or whole-genome sequencing is performed.

Evaluation for mosaicism using non–blood cells, such as buccal cells, skin fibroblasts, and bladder epithelial cells from urine, can identify mutations missed with blood-only testing. A DNA methylation epigenetic signature array can identify epigenetic patterns associated with milder or atypical forms of CdLS.[3][6][8] More recently, artificial intelligence–driven facial recognition technologies, such as Face2Gene (FDNA, Inc) or facial dysmorphology novel analysis (FDNA), have demonstrated the ability to identify patients with classic CdLS facial features and known pathogenic variants, suggesting that this technology may support diagnosis in settings with limited diagnostic resources.[14][15] 

Significant advances have occurred in the past 2 decades in the molecular diagnosis of CdLS. However, because of the complexity of this disorder, approximately 20% of patients with a clinical diagnosis of CdLS have negative test results for a pathogenic variant associated with CdLS.[7] When a diagnosis of CdLS is made, patients should be evaluated and treated by an interdisciplinary team, which may include:

• Gastroenterology, nutrition, otolaryngology, feeding team, and dental specialists: Gastroesophageal reflux disease and feeding problems are extremely common, and patients should undergo a modified barium swallow to evaluate aspiration risk and intestinal malrotation. Inadequate oral caloric intake may require placement of a nasogastric tube or a gastrostomy tube. Dental issues, micrognathia, and high-arched or cleft palate can affect feeding. Patient growth should be plotted on a CdLS-specific growth chart.
• Cardiology: An echocardiogram should be performed to screen for congenital heart defects.
• Genitourinary: Renal ultrasonography and baseline renal function testing are recommended. Testicular ultrasonography is indicated in boys with cryptorchidism.
• Audiology and speech: Otoacoustic emissions or brainstem auditory evoked potentials should be performed. Speech therapy should begin by 18 months of age or earlier for feeding-related issues and evaluations.
• Neurology: Patients with seizures should undergo electroencephalography and possibly MRI and should be treated with standard antiepileptic protocols.
• Orthopedics: Extremity abnormalities are common and may require surgical repair, rehabilitation, adaptive equipment, and safety equipment.
• Physical and occupational therapy: Patients with CdLS may have significant gross- and fine-motor delays and require early assessment and intervention.
• Ophthalmology: Ophthalmologic evaluation, including cycloplegic refraction and visual acuity testing, should be performed.
• Developmental pediatrician and behaviorist: Initial assessment, along with ongoing treatment and support, is recommended.
• Genetics: Genetic counseling should be provided regarding phenotypic expectations and the risk of recurrence in subsequent children.
• Caregiver support: This diagnosis presents significant physical, intellectual, and behavioral challenges requiring ongoing care. Caregivers often coordinate multiple specialists and therapies while caring for the patient. Families need ongoing support to navigate these demands. Support services may include social work, visiting nurse services, in-home applied behavior analysis, palliative or respite care, and parent and community support groups.

Treatment / Management

Early interdisciplinary intervention is essential for patients with CdLS. The goal is to maximize quality of life and developmental functioning. Treatment of patients with CdLS is generally supportive, involving an interdisciplinary team and targeting physical, developmental, and behavioral abnormalities.[2](B3)

Primary care

• Ongoing monitoring, surveillance, and coordination of specialty care
• Feeding, growth, nutritional status, gastroesophageal reflux disease, safety of oral intake, and aspiration risk
• Hearing and vision monitoring; assessment of mobility and self-help skills
• Monitoring of developmental milestones and educational needs; behavioral assessment for anxiety, attention, and aggressive or self-injurious behavior 

Gastroenterology, nutrition, and feeding team

• Aggressive treatment of gastroesophageal reflux disease (proton pump inhibitors, H2-blockers, positioning)
  • Severe gastroesophageal reflux disease may require fundoplication.
• Modified barium swallow to assess aspiration risk
• Endoscopy to monitor for Barrett esophagus
• Poor growth may require a nasogastric tube, gastrostomy, or thickened and high-calorie feeds
• Surgical correction of intestinal malrotation
• Volvulus is an emergency and should be considered with any presentation of acute abdominal pain
• Monitoring by the dental team for oral abnormalities and early cavities
• Monitoring by occupational therapy or speech therapy for feeding-related issues

Cardiology

• Baseline echocardiography and management of abnormalities per standard cardiac protocols

Audiology and otolaryngology

• Newborn hearing screening, including routine screening for conductive and sensorineural hearing loss
• Myringotomy tubes, hearing aids, and augmentative and assistive communication technology can significantly impact development and behavior in patients with hearing loss

Ophthalmology

• Annual vision screening
• Correction of refractive errors as soon as possible
• Strabismus and ptosis treatment

Behavioral management

• Most patients have significant intellectual disability and autism.
• Anxiety is common.
• Patients may engage in self-injurious behavior, especially when stressed or in pain.
• Behavior can worsen throughout childhood, adolescence, and adulthood, often requiring intensive behavioral management.
• Behavioral challenges are among the most significant difficulties for families.
• Early intervention is important for physical, occupational, and speech therapy needs.
• Behavioral interventions (psychotherapy, applied behavioral analysis) and or medications (selective serotonin reuptake inhibitors, atypical antipsychotics) for autistic behaviors, anxiety, and aggressive or self-injurious behaviors can be helpful.

Neurology

• Seizure assessment with electroencephalography and treatment with standard antiepileptic medications.
  • Sleep dysfunction is common and may require medication.

Orthopedics

• Surgical correction of anomalies
• Prosthetic assessment and treatment
• Dual-energy x-ray absorptiometry scans starting in adolescence to monitor for early-onset osteoporosis

 Urology and gynecology

• Routine monitoring and treatment of hydronephrosis and vesicoureteral reflux
• Surgical correction of cryptorchidism in infancy to decrease the risk of testicular cancer
• Girls with CdLS and significant intellectual and physical disabilities may benefit from suppression of menses

Endocrinology

• Consideration of recombinant human growth hormone for short stature in select patients
• Dual-energy x-ray absorptiometry scan to evaluate for early osteoporosis in adolescence
• Treatment of insulin resistance

Perioperative care

• Increased risk of perioperative stress, airway obstruction, and cardiovascular complications during anesthesia
• Clinicians should pay careful attention to the unique craniofacial anatomy

The Cornelia de Lange Foundation has age-specific guidelines for CdLS management and treatment.[CdLS Foundation. Management and Treatment Guidelines for Cornelia de Lange Syndrome]  

Future Perspectives

While CdLS currently has no cure, several studies are investigating potential treatment targets. L-leucine has been shown to partially rescue translation, protein synthesis, and developmental defects in zebrafish models of CdLS via the mammalian target of rapamycin pathway.[16] Results from another study using CdLS zebrafish models demonstrated that lithium chloride can rescue neural developmental defects. In the same study, lithium chloride also reduced cell death in fibroblasts from patients with CdLS.[17] 

Results from a subsequent study also demonstrated similar benefits of lithium chloride on in vitro and in vivo models. Lithium chloride restores Wnt pathway activity, which regulates embryonic development and cell proliferation and is impaired in CdLS.[18] CdLS cells show hallmarks of oxidative stress, including cell growth arrest, apoptosis, genome instability, and premature aging.

Antioxidants target oxidative stress and can extend the lifespan of CdLS cell cultures and decrease symptoms in zebrafish models.[19][20] Targeted therapies that modulate epigenetic dysregulation in chromatinopathies are another potential strategy.[6] The use of recombinant human growth hormone has been shown to increase height in some patients with CdLS.[21] Research into other disorders of the cohesin pathway may yield additional potential therapies in the future.(B2)

Differential Diagnosis

The clinical presentation of CdLS can vary widely, and its symptoms overlap with those of many other genetic disorders, particularly other chromatinopathies (see Table 3).[6][8][9][22] Chromatinopathies are a class of disorders caused by variants in proteins involved in chromatin remodeling and transcriptional regulation, leading to dysregulated gene expression. These disorders also have facial dysmorphism, growth problems, and intellectual disability. Genetic testing can help with identification, especially in nonclassical CdLS phenotypes. Phenotypic features of CdLS (including facial dysmorphism, growth restriction, and neurodevelopmental disability) can also overlap with nonchromatinopathic disorders.[23]

Table 3. Differential Diagnosis of Cornelia de Lange Syndrome

CdLS, Cornelia de Lange syndrome; CHOPS, cognitive impairment and coarse facies, heart defects, obesity, pulmonary involvement, short stature, and skeletal dysplasia; KBG, KBG syndrome

Prognosis

The prognosis of individuals with CdLS is dependent on phenotypic severity and medical complications. Patients with mild-to-moderate phenotypes may have a near-normal lifespan, whereas those with more severe disease and a complicated medical course are more likely to have a shortened lifespan. Mortality risk is greatest in infancy and early childhood and is often related to congenital abnormalities. Neurobehavioral challenges can worsen with age and significantly impact the quality of life and treatment of adult patients.[2]

Complications

CdLS affects multiple organ systems. Complications may arise throughout the lifespan, and patients should be closely monitored by an interdisciplinary team:

• Gastroenterology: Gastroesophageal reflux disease can cause aspiration pneumonia or aspiration pneumonitis from stomach acid, which is one of the leading causes of early mortality (31% of deaths). Gastroesophageal reflux disease may also predispose children to Barrett esophagus (10%). Bowel obstruction due to volvulus in cases of intestinal malrotation is associated with 19% of deaths. Repair of pyloric stenosis, malrotation, volvulus, or congenital diaphragmatic hernia may be necessary in early infancy.[Science Direct. Emergency and Urgent Surgery][Science Direct. Volvulus]
• Urology: Cryptorchidism or hypospadias is often seen in boys with CdLS during infancy. Orchidopexy to repair cryptorchidism is recommended because of the risk of testicular carcinoma. Genital hypoplasia is seen equally in boys and girls.
• Nephrology: Renal cysts and renal hypoplasia are common complications in children with CdLS. 

Complications from severe congenital anomalies, including congenital diaphragmatic hernia or heart defects, account for 15% of deaths. Other causes of early mortality include neurologic complications, accidental injury (8%), and sepsis (4%).[2][Science Direct. Neurologic Complications][Science Direct. Accidental Injury] In addition, signs of premature aging, including aged facial appearance, premature graying of hair, osteoporosis, and early development of Barrett esophagus, have been observed in young patients with CdLS.[11]