Cornelia de Lange syndrome

Background
Cornelia de Lange syndrome (CdLS) is a syndrome of multiple congenital anomalies characterized by a
distinctive facial appearance, prenatal and postnatal growth deficiency, feeding difficulties, psychomotor
delay, behavioral problems, and associated malformations that mainly involve the upper extremities.
Cornelia de Lange first described it as a distinct syndrome in 1933, [1] although Brachmann had described a
child with similar features in 1916.[2] Diagnosing classic cases of Cornelia de Lange syndrome is usually
straightforward; however, diagnosing mild cases may be challenging, even for an experienced clinician.
See the images below.

Facial appearance of a patient with Cornelia de Lange syndrome. Courtesy of Ian Krantz, MD, Children's Hospital of
Philadelphia.

Facial profile of a patient with Cornelia de Lange syndrome. Courtesy of Ian Krantz, MD, Children's Hospital of
Philadelphia.

Severe upper-extremity malformations in a patient with Cornelia de Lange syndrome. Courtesy of Ian Krantz, MD,
Children's Hospital of Philadelphia.

Pathophysiology
More than 99% of cases are sporadic. Cornelia de Lange syndrome is occasionally transmitted in an
autosomal dominant pattern, according to several instances in which a usually mildly affected parent had
one or more affected offspring. Twins with concordance and discordance have been reported. Although
possible autosomal recessive inheritance has been reported in some families, these instances were likely
to be due to germline mosaicism.[3] The recurrence risk is 0.5-1.5% if parents are unaffected and 50% if a
parent is affected.
Heterozygous mutations in a gene named NIPBL, the human homolog of theDrosophila
melanogaster Nipped-B gene,[4] have been identified in approximately 50% of individuals with Cornelia de
Lange syndrome.[5, 6, 7] Although the exact function of the protein product of NIPBL in humans (delangin)
remains unknown, its homologs in other species are known to play roles in developmental regulation and in
cohesion of sister chromatids. Mutations in genes, coding for two other proteins involved in cohesion of
sister chromatids, SMC1A and SMC3, have been reported in 5% and 1% of patients with Cornelia de
Lange syndrome, respectively.[8] Thus, Cornelia de Lange syndrome is considered to be a cohesinopathy,
along with Roberts syndrome/SC phocomelia.
Inheritance is autosomal dominant in families with NIPBL and SMC3 mutations and is X-linked dominant in
families with SMC1A mutations.
All types of NIPBL mutations, including missense, splice-site, nonsense, and frameshift mutations, have
been reported to result in the Cornelia de Lange syndrome phenotype. The most likely effect of these
mutations is haploinsufficiency. The mutation-detection rate is approximately 50%. Genomic deletions and
duplications of the NIPBL locus are rare.[9, 10] Reported mutations of SMC1Ainclude missense mutations and
in-frame deletions. One reported SMC3 mutation is an in-frame deletion.
The correlation between genotype and phenotype suggested that individuals with an identifiable mutation
in NIPBL have a phenotype more severe than the phenotype of those without mutations. Moreover,
missense mutations in NIPBL are associated with mild phenotypic features. Patients with mutations
in SMC1A andSMC3 consistently have a milder phenotype, with absence of severe limb defects and other
structural anomalies. The phenotype in some patients is close to those with nonsyndromic mental
retardation.
A study by Gil-Rodrguez et al of SMC3 -associated phenotypes in 16 patients found a tendency toward the
following[11] :

Less distinctive syndrome-related craniofacial features (although, as in other cases of Cornelia de

Lange syndrome, microcephaly is characteristic)

Fewer associated congenital heart defects

Normal limbs (as mentioned above)

Milder prenatal growth retardation (although it becomes more severe in childhood)

A phenotype similar to that of Cornelia de Lange syndrome may be observed in patients with a duplication
of band q26-27 on chromosome 3.[12] Molecular studies of genes mapped to this region of chromosome arm
3q have failed to reveal mutations in patients with Cornelia de Lange syndrome.
Some autopsy data have indicated cerebral dysgenesis, with a decreased number of neurons, neuronal
heterotopias, and focal gyral folding abnormalities as causes of psychomotor delay.

Epidemiology
Frequency
The incidence is 1 case per 10,000-50,000 live births. No differences based on sex or race have been
described.

Mortality/Morbidity
Gastrointestinal disease complications are one of the most common causes of death in this syndrome.
They include diaphragmatic hernia in infancy and aspirationpneumonia and volvulus at an older age.
A retrospective review of 295 propositi with Cornelia de Lange syndrome found that respiratory issues (eg,
aspiration, reflux, pneumonia) were the most common causes of death (31%), followed by gastrointestinal
disease, including obstruction/volvulus (19%), congenital anomalies (15%), neurological causes, (8%),
accidents (8%), sepsis (4%), acquired cardiac disease (3%), cancer (2%), renal disease (1.7%), and other
causes (9%).[13]

Special Concerns
A prenatal diagnosis is made after Cornelia de Lange syndrome (CdLS)-related abnormalities are carefully
evaluated using prenatal ultrasonography. These abnormalities include growth retardation, limb defects,
diaphragmatic hernia, hypoplastic forearms, underdeveloped hands, and typical facial defects.
The availability of molecular diagnosis should substantially improve prenatal diagnosis. Prenatal diagnosis
with molecular genetic techniques is currently available if a mutation is known in the family.
Failure to detect a mildly affected parent may result in incorrect risk estimation for future pregnancies.
Anatomic abnormalities of the face and neck may cause difficulties during intubation. GI obstruction or
feeding difficulties may occur. Early feeding management is important.
Severe speech delay and poor communication are concerns. The patient may have congenital heart
disease.

History
The history of patients with Cornelia de Lange syndrome (CdLS) may include the following:

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Intrauterine growth retardation (68%)

Average birth weight is 2221 g (4 lb 12 oz) for boys and 2145 g (4 lb 10 oz) for girls.
In most patients, growth occurs at rates lower than those on normal growth curves
throughout life.
Height velocity is equal to the reference range, but pubertal growth is slowed.
Weight velocity is lower than the reference range until late adolescence.
Average head circumferences remain less than the second percentile.

Prematurity (31%)

Low-pitched weak cry in infancy - Noted in classic cases and disappears as the child grows (74%)

Initial hypertonicity (100%)

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Respiratory and feeding difficulties in the newborn period and infancy (71%)
Respiratory and feeding difficulties usually result in failure to thrive.
Associated findings may include gastroesophageal reflux (90%), which affects many
children with irreversible esophageal scarring by the time intervention is attempted; pyloric stenosis
(3%); malrotation or duplication of the bowel with obstruction (10%); and congenital diaphragmatic
hernia.
Developmental delay and mental retardation
Most initial developmental skills are moderately delayed.
Severe speech delay is typical. Approximately one half of patients aged 4 years or older
combine 2 or more words into sentences, one third have no words or only 1-2 words, and only 4% have
normal or low-normal language skills. Children who have severe speech impairment are likely to have
intrauterine growth retardation, hearing impairment, upper-limb malformations, poor social interactions,
and severe motor delays.
Most affected individuals have mild-to-moderate mental retardation (intelligence quotient
[IQ] of 30-85, with an average of 53). Patients with IQs higher than this tend to have a relatively high
birth weight and head circumference.
Visual-spatial memory and perceptual organization skills are strengths. Perceptual
organization, which involves the use of fine motor skills and which incorporates visual-spatial memory,
is also on a higher level than that of other facets.
In patients with mild Cornelia de Lange syndrome, psychomotor retardation is less severe
and prenatal and postnatal growth deficiency is milder than in severe Cornelia de Lange syndrome. In
addition, major malformations are absent or surgically correctable. Children with mild disease may have
classic facial findings at birth but develop intellectual outcomes better than those expected in classic
Cornelia de Lange syndrome. As an alternative, their typical facial changes may develop during the first
2-4 years of life. Although individuals with mild Cornelia de Lange syndrome function at the low-normal

range and although they have certain characteristics of the syndrome, their disease is occasionally not
diagnosed until they have a child with classic findings.

Seizures (23%) with no specific EEG pattern

Behavioral manifestations
Hyperactivity (40%), self-injury (44%), daily aggression (49%), and sleep disturbance
(55%) occur.
Behavioral manifestations are correlated with the presence of an autisticlike syndrome
and with the degree of mental retardation.
Children with Cornelia de Lange syndrome prefer a structured routine and have difficulty
with changes in their daily routine. Activities that stimulate the vestibular system, such as swinging,
bouncing, swimming, and horseback riding, are pleasurable to patients with Cornelia de Lange
syndrome,
Forms of self-injurious behavior in some children with CdLS are associated with certain
environmental events. However, the characteristics of setting events are extremely variable among
individuals.
The main characteristics in severely affected children include a diminished ability to relate
socially, repetitive and stereotypic behavior, infrequent facial expression of emotion, and severe
language delays.
Even in mild cases, behavioral phenotype may be helpful for diagnosis.

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Physical
Physical findings in patients with Cornelia de Lange syndrome may include the following:

Short stature: In some patients, extreme short stature may be caused by growth hormone
deficiency. Specific growth curves in Cornelia de Lange syndrome are available. Average adult weight is
30.5 kg in females and 47.6 kg in males; average height is 131 cm in females and 156 cm in males.

Microcephaly (98%): Average adult head circumference is 49 cm in both sexes.

Facial features
These are perhaps the most diagnostic of all the physical signs and combine to create a
unique gestalt for the clinician. This combination of findings may be absent in postpubertal male
patients.

The following are classic features:

Confluent eyebrows (synophrys) (99%)
Long curly eyelashes (99%)
Low anterior and posterior hairline (92%)
Underdeveloped orbital arches (100%)
Neat, well-defined, and arched eyebrows (as though they had been penciled)
Long philtrum
Anteverted nares (88%)
Down-turned angles of the mouth (94%)
Thin lip (especially upper vermillion border)
Low-set and posteriorly rotated ears
Depressed nasal bridge (83%)
High arched palate (86%) and overt or submucous cleft palate (20%)
Late eruption of widely spaced teeth (86%)
Micrognathia (84%)
Short neck (66%)
Hirsutism (78%)

Cutis marmorata and perioral cyanosis (56%)

Hypoplastic nipples and umbilicus (50%)
Micromelia (93%)

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Severe abnormalities, such as oligodactyly (missing digits) or other deficiencies of the

arms, may be present (27%). They usually occur in severely affected patients.
Less-striking limb findings include single palmar flexion crease, clinodactyly of the fifth
fingers, proximally placed thumbs, partial syndactyly of the second and third toes, and limitation of
elbow extension.
Relative smallness of the hands or feet is almost universal.
Congenital heart disease (25%), typically ventricular septal defect or atrial septal defect: Any lesion
may be seen.
Hip abnormalities, including dislocation or dysplasia (10%), scoliosis, tight Achilles tendons and the
development of bunions
Hypoplastic external male genitalia (57%), small labia majora
Undescended testes (73%)
Hypospadias (33%)
Ophthalmologic manifestations (50%)
Myopia (58%), ptosis (44%), blepharitis (25%), epiphora (22%), microcornea (21%),
strabismus (16%), nystagmus (14%) occur. Peripapillary pigment ring was noted in most patients.
Glasses are often poorly tolerated.
Astigmatism, optic atrophy, coloboma of the optic nerve, aniridia, and congenital
glaucoma have been described.
Hearing loss: Although sensorineural hearing loss is a significant cause of auditory impairment in
Cornelia de Lange syndrome, studies suggest that conductive hearing loss is as well; a study by
Marchisio et al found conductive hearing loss in 26 of 44 (59%) pediatric patients with the syndrome [14, 15]

Causes
Heterozygous mutations in the NIPBL and SMC3 and heterozygous (in females) or hemizygous (in males)
mutations in SMC1A result in Cornelia de Lange syndrome. Most cases are sporadic due to de novo
mutations (see Pathophysiology).

Diagnostic Considerations
These include the following:

Dup(3q) syndrome
Coffin-Siris syndrome
Fryns syndrome

Differential Diagnoses

Fetal Alcohol Syndrome

Laboratory Studies
See the list below:

Genetic diagnosis: Molecular genetic diagnosis of Cornelia de Lange syndrome (CdLS) with
screening of mutations in the NIPBL and SMC1A genes is clinically available.
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Updated laboratory information can be obtained at Gene Tests.
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This testing can confirm the diagnosis, especially in mild or atypical cases, and the results
can help in identifying the family-specific mutation for prenatal testing in future pregnancies.
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Recently, a fetus with Cornelia de Lange syndrome was diagnosed after termination of
pregnancy at 21 weeks' gestation. The diagnosis was confirmed by a truncating mutation in
the NIPBL gene.[16]

CBC count: Thrombocytopenia has been reported.

Imaging Studies
See the list below:

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Radiography may reveal the following:

Retarded bone age (100%)
Spurs in the anterior angle of the mandible (42%) and a prominent symphysis (66%)
Digital abnormalities, which range from acheiria to oligodactyly
Long-bone abnormalities, including ulnar aplasia and/or hypoplasia, aplasia and/or
hypoplasia of the radial head, or fusion of the elbow: When a single forearm bone is present, fusion at
the elbow and oligodactyly often occur; this condition makes it difficult to determine if the radius or ulna
is absent.
Hypoplastic first metacarpal (79%), hypoplastic fifth middle phalanx (93%), and
clinodactyly (64%)
Short sternum with precocious fusion (54%)
Thirteen ribs (56%)
Thin rib cortices with undulating appearance (33%)
Hiatal hernia
Aspiration pneumonia (50%)
Gastroesophageal reflux (90%)
Intestinal obstruction, malrotation, volvulus (17%)
Pelvic abnormalities (33%)
Ultrasonography at diagnosis to assess for kidney and urinary tract abnormalities (40%) may
reveal the following:
Horseshoe kidney
Altered corticomedullary differentiation
Pelvic dilation
Small kidneys
Renal cysts
Renal ectopia

Voiding cystourethrography is indicated for evaluation of recurrent urinary tract infections or

hydronephrosis.
Echocardiography is indicated for evaluation of congenital heart disease.
Radiologic brain findings may include enlarged ventricles, including enlargement of basal cisterns;
thinning or atrophy of white matter, particularly frontal lobes, with relative sparing of parietal lobes;
brainstem hypoplasia; and cerebellar vermal hypoplasia or agenesis.

Other Tests
Hearing evaluation is recommended in Cornelia de Lange syndrome. High-resolution chromosomal studies
are indicated when the syndrome's diagnosis is uncertain.
A spectrum of endocrinopathies may be observed in this disorder in addition to growth-hormone deficiency.
These conditions include problems relating to gonadotropin and prolactin secretion and panhypopituitarism.

Staging

Diagnosis requires (1) positive mutation finding on Cornelia de Lange syndrome gene testing; (2) confirmed
facial findings and confirmed criteria from any 2 of the growth, developmental, or behavioral categories; or
(3) confirmed facial findings and confirmed criteria for 3 other categories, including one from growth,
developmental, or behavioral categories and 2 from the other categories. [17]

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Facial characteristics must include synophrys and at least 3 of the following:

Long eyelashes
Short nose, anteverted nares
Long, prominent philtrum
Broad or depressed nasal bridge
Small or square chin
Thin lips, down-turned corners
High palate
Widely spaced or absent teeth

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Growth characteristics must include at least 2 of the following:

Weight below the fifth percentile for age
Height or length below the fifth percentile for age
Occipitofrontal circumference below the second percentile for age

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Developmental characteristics must include at least 1 of the following:

Developmental delays or mental retardation
Learning disabilities

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Behavioral characteristics must include at least 2 of the following:

Attention deficit disorder, hyperactivity
Obsessivecompulsive characteristics
Anxiety
Constant roaming
Aggression
Self-injurious behavior
Extreme shyness or withdrawal
Autisticlike features

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Musculoskeletal characteristics include reduction defects with absent forearms alone, small hands
or feet (below the third percentile for age) or oligodactyly and at least two of the following, or none of
these features and at least three of the following:
Clinodactyly of the fifth finger
Abnormal palmar crease
Radial head dislocation, abnormal elbow extension
Short first metacarpal, proximally placed thumb
Bunion
Partial syndactyly toes
Scoliosis
Pectus excavatum
Hip dislocation or dysplasia

Neurosensory and skin characteristics must include at least 3 of the following:

Ptosis
Tear duct malformation or blepharitis
Myopia

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Major eye malformation or peripapillary pigmentation

Deafness or hearing loss
Seizures
Cutis marmorata
Hirsutism, generalized
Small nipples and/or umbilicus

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Other major system characteristics must include at least 3 of following:

GI malformation/malrotation
Diaphragmatic hernia
Gastroesophageal reflux disease
Cleft palate or submucous cleft palate
Congenital heart defect
Micropenis
Hypospadias
Cryptorchidism
Renal or urinary tract malformation

Table. Scoring System for Severity of Cornelia de Lange Syndrome [17]

Parameter

1 point

2 point

3 point

Birth weight

Above 2,500 g

2,0002,500 g

Below 2,000 g

Sitting alone

< 9 mo

920 mo

>20 mo

Walking alone < 18 mo

1842 months

>42 mo

Saying first
word

< 24 mo

2448 mo

>48 mo

Upper limb
malformation

No defect

Partial defect (>2 digits)

Severe defect (< 2 digits)

Number of
other major
malformation
s

0-1

2-3

>3

Hearing loss

Absent

...

...

A score of less than 15 points indicates mild involvement, a score of 15-22 points indicates
moderate involvement, and a score of more than 22 points indicates severe involvement.

Medical Care
See the list below:

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Early intervention in patients with Cornelia de Lange syndrome (CdLS) is necessary for feeding
problems, hearing and visual impairment, congenital heart disease, and urinary system abnormalities.
Early intervention for psychomotor delay is also indicated.
Computer programs that emphasize visual memory are more beneficial than standard
methods of verbal instruction.
Perceptual organizational tasks should be emphasized.
Tactile stimulation during indirection helps the children remember and perform maximally.
Fine motor activities, when physical impairments do not limit them, should be stressed in
education, especially activities related to activities of daily living.

Surgical Care
Surgery may be necessary for the following conditions:

Cleft palate
Nasal polyps
Gastroesophageal reflux disease
Pyloric stenosis
Intestinal malrotation/volvulus
Undescended testis
Lacrimal duct stenosis
Hip dislocations

Consultations
Consultation with the following specialists may be indicated:

Geneticist
Cardiologist
Gastroenterologist and nutritionist
Nephrologist (if recurrent urinary tract infections, impaired renal functions or congenital
abnormalities are present)
Ophthalmologist
Hearing specialist
Neurologist

Medication Summary

Drug therapy currently is not a component of the standard of care for this syndrome, except for clinically
indicated situations such as seizures, gastroesophageal reflux, and behavioral symptoms.