Cornelia de Lange Syndrome

Overview

Cornelia de Lange Syndrome (CdLS) is a rare genetic disorder that affects multiple parts of the body and is characterized by distinctive facial features, growth delays, intellectual disability, limb abnormalities, and behavioral challenges. First described by Dutch pediatrician Cornelia de Lange in 1933, the condition varies widely in severity, ranging from mild to severe. While some individuals with CdLS can live independently, others may have significant physical and cognitive impairments requiring lifelong care and support.

Causes

Cornelia de Lange Syndrome is caused by mutations in genes involved in the development and regulation of chromosomes and gene expression. The most commonly affected genes include:

• NIPBL: Accounts for 60–80% of cases and is associated with the classic, more severe form of CdLS

• SMC1A and SMC3: Typically associated with milder forms and X-linked inheritance patterns

• RAD21 and HDAC8: Also linked to CdLS, often with variable clinical presentations

Most cases of CdLS result from new (de novo) mutations and are not inherited from parents. However, in rare cases, familial transmission can occur, particularly with X-linked forms.

Symptoms

The signs and symptoms of CdLS can vary significantly but often include:

• Facial features: Arched eyebrows that often meet in the middle (synophrys), long eyelashes, short upturned nose, thin downturned lips, and low-set ears

• Growth delays: Prenatal and postnatal growth deficiency resulting in short stature and low weight

• Intellectual disability: Ranges from mild to severe

• Limb differences: Especially upper limbs, including missing fingers or forearms (in severe cases)

• Behavioral issues: Including autistic-like behaviors, self-injury, anxiety, and hyperactivity

• Feeding difficulties: Especially in infancy, due to poor muscle tone and reflux

• Gastrointestinal problems: Including gastroesophageal reflux and constipation

• Hearing loss: Common due to recurrent ear infections or structural abnormalities

• Eye problems: Including ptosis (droopy eyelids), nearsightedness, or strabismus

• Cardiac and genitourinary anomalies: May be present in some individuals

Diagnosis

Diagnosis of Cornelia de Lange Syndrome is based on clinical features and confirmed through genetic testing. Diagnostic steps include:

• Physical examination: Recognition of characteristic facial and limb features

• Growth measurements: To identify prenatal and postnatal growth deficiency

• Developmental assessments: To evaluate cognitive and motor delays

• Genetic testing: Targeted sequencing of the NIPBL, SMC1A, SMC3, RAD21, and HDAC8 genes

• Differential diagnosis: Important to rule out other syndromes with overlapping features, such as Rubinstein-Taybi syndrome

Treatment

There is no cure for CdLS, but early and comprehensive management can significantly improve outcomes. A multidisciplinary team approach is typically needed. Treatment includes:

• Early intervention: Including physical, occupational, and speech therapy to support development

• Educational support: Individualized education plans (IEPs) tailored to cognitive and behavioral needs

• Behavioral therapy: To manage self-injury, anxiety, and autism-like behaviors

• Medical management:

  • Treatment for GERD and feeding issues

  • Hearing aids or surgery for hearing loss

  • Ophthalmologic care for vision problems

  • Cardiac and urogenital evaluations if anomalies are present

• Surgical intervention: For limb abnormalities, ptosis, or gastrointestinal complications when needed

• Genetic counseling: For families with a confirmed diagnosis or history of the condition

Prognosis

The prognosis for individuals with Cornelia de Lange Syndrome varies depending on the severity of physical and intellectual impairments. While some individuals can achieve relative independence with support, others may require lifelong care. Life expectancy can be normal in milder cases but may be reduced in those with severe congenital anomalies or medical complications. With appropriate interventions, many individuals with CdLS can make significant developmental progress and enjoy a good quality of life.