Cornelia de Lange Syndrome

The signs and symptoms of CdLS include distinctive facial features such as a prominent philtrum with thin, downturned lips; narrow palpebral fissures; low-set ears; depressed, flat nasal bridge; anteverted nostrils; well-defined, arched eyebrows with synophrys; long eyelashes; cleft palate; microcephaly (e.g., small head); and micrognathia. 

Psychomotor delay and intellectual disability are defining symptoms of CdLS, with learning disabilities ranging from mild to severe. Children may experience delays in reaching developmental milestones, such as rolling over, sitting up, and crawling. Many also experience delays in speech and language development. Up to 30% of children with CdLS have been reported to have absent speech. Behavioral challenges can be more prevalent in this population, including anxiety, attention-deficit hyperactivity disorder, self-injurious behavior, defiance, extreme shyness, perseveration, obsessive–compulsive disorders, depression, and sleep disturbances. 

In addition to distinguishing facial features and developmental delays, individuals with CdLS can present with other systemic symptoms, including gastrointestinal abnormalities; hearing and speech difficulties; vision problems; and skin, musculoskeletal, cardiac, neurological, and genitourinary disorders. 

Gastrointestinal complications may include a low birth weight and failure to thrive. As a result, those with CdLS have intrauterine growth restriction with resultant small stature that may persist throughout life. Infants may experience feeding difficulties within the first months to years of life, such as regurgitation of food and projectile vomiting. Gastroesophageal reflux is present in almost all individuals with CdLS. Other gastrointestinal system disorders that have been reported include esophageal stenosis, esophagitis, intestinal malrotation and volvulus, pyloric stenosis, and hernias (e.g., inguinal, hiatal, and diaphragmatic hernias). 

Many children with CdLS also have a hearing impairment, which may be associated with a narrowed ear canal, leading to chronic infections such as otitis media and sinusitis. Younger children may have dysphonia or apraxia, while older children may have abnormally hoarse speech accompanied by a low-pitched, growling cry. 

Skin manifestations of CdLS include generalized hirsutism (i.e., excessive and coarse hair growth), mainly of the face, back, and extremities. Up to 60% of children have cutis marmorata, a skin disorder resulting in a blue-red marbling pattern when exposed to cold temperatures. Several may exhibit premature aging, skin sagging, and gray hair. 

The incidence of congenital heart defects in children with CdLS is around 25 to 30%. The most common abnormalities include ventricular septal defects, atrial septal defects, pulmonic stenosis, tetralogy of Fallot, and hypoplastic left heart syndrome. 

The most common ophthalmological findings are myopia (i.e., near-sightedness), ptosis (i,e., lid-droop or lag), and blepharitis (i.e., red or swollen eyelid). Neurological abnormalities may be seen, including epilepsy, most specifically partial epilepsy, in up to 20% of those diagnosed with CdLS. Additionally, individuals have unusually high pain tolerance, which may be due to peripheral neuropathy. 

Lastly, up to 40% of individuals with CdLS have structural kidney or urinary tract anomalies such as vesicoureteral reflux, pelvic dilation, and renal dysplasia. Genital hypoplasia, cryptorchidism, hypospadias, bicornuate or septate uterus, and irregular menses have likewise been reported.

Cornelia de Lange syndrome is suspected clinically after birth or in childhood based upon a thorough clinical evaluation by a healthcare professional. They may evaluate the child for certain distinctive facial features indicative of CdLS, limb anomalies, growth restriction, and intellectual disability. As the child ages, several facial features associated with Cornelia de Lange may start to look atypical. At this point, a photograph from early childhood may be helpful for diagnosis.

CdLS may have overlapping features with other syndromes, such as fetal alcohol syndrome, Rubinstein-Taybi, and KBG syndrome. Therefore, a diagnosis made on examination alone may be difficult. Molecular genetic testing, specifically a technique known as Sanger sequencing, may be used as an adjunct. Mutations in any of the genes associated with CdLS can confirm the diagnosis. In some cases, a diagnosis of CdLS may be suspected prenatally through ultrasound if there is intrauterine growth restriction, asymmetric limb abnormalities, microcephaly, and diaphragmatic hernia. Chorionic villus sampling (CVS) can also extract DNA from fetal cells obtained by amniocentesis while the baby is in utero. 

There is no cure for CdLS; however, early diagnosis and management of Cornelia de Lange syndrome can significantly improve the quality of life for those with this condition. Genetic counseling can be recommended for affected individuals and their families, especially in cases where the causative gene is known, and there is a recurrence risk. 

Management of CdLS is mainly symptomatic and supportive. All children with CdLS have some intellectual disability; early developmental assessment can help improve prognosis. A child may undergo motor, adaptive, cognitive, and speech/ language evaluation. A motor evaluation can assess gross and fine motor skills and look for limb abnormalities and scoliosis. Physical therapy or occupational therapy can be utilized to improve gross motor and fine motor skills, respectively. If speech delay is present, speech therapy may be recommended to optimize communication skills, preferably before 18 months of life. The developmental assessment may refer to an early intervention or special education program. It is important to connect families early on with appropriate social work involvement to ensure they have the necessary resources and support.

Since many children with CdLS have trouble with gastrointestinal symptoms and feeding, nutritional counseling may be warranted. A gastroenterologist may consider an upper gastrointestinal study for malrotation or an endoscopy to assess for GERD. There is a lower threshold for managing GERD with proton pump inhibitors in individuals with CdLS. A fundoplication procedure may be indicated to treat the GERD if symptoms are severe. A nutritionist can evaluate the child’s nutritional status and consider gastric tube placement in those with failure to thrive or who have poor weight gain. 

Other specialists who can help care for children with CdLS include ophthalmologists who can assess visual acuity, cardiologists who perform echocardiograms to evaluate for congenital defects, and urologists who test for urogenital abnormalities. Other tests may include audiologic evaluations for hearing loss and neuropsychiatric evaluations for underlying behavior problems.

Those with CdLS will often need supervised living and working situations as adults. The life expectancy is estimated to be 10 to 20 years shorter compared to the general population, mainly depending on the number and severity of the complications that one has. The most common complications leading to death include respiratory disease leading to aspiration; gastrointestinal obstruction; diaphragmatic hernias; and seizures.