Cornelia De Lange Syndrome

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 the Drosophila 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 SMC1A include 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 and SMC3 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-Rodríguez 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.

Kaur et al showed that expression levels of NIPBL, as well as other genes, correlate with the phenotypic severity in Cornelia de Lange syndrome. Nonsense mutations in NIPBL led to about 35% reduced expression and gave rise to severe phenotypes. Missense and inframe deletions in NIPBL and other genes were associated with 20% reduced expression and produced milder phenotypes.[13]

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 aspiration pneumonia 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%).[14]

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.

Very few cases of adults with Cornelia de Lange syndrome have been reported in the literature. Two cohorts of adults, totaling 122 patients, have been studied. These individuals ranged in age from 15-50 years, with an average age of 17 and 24. Premature aging was seen among these patients. The most common medical issues included the following[15] :

• Gastroesophageal reflux diseases (GERD) - 71-82%
• Overweight/obesity - 16-31%
• Limb length discrepancy - 26-46%
• Epilepsy - 26%
• Hearing loss - 42-65%
• Vision problems - 38-50%
• Behavioral issues - 50%

All individuals reported having not required continuing assistance with nasogastric tubes and were able to feed orally in adulthood.

Epilepsy in Cornelia de Lange syndrome has proven to be amenable to medications, while cardiac issues typically do not require surgery in adulthood (18%). Intellectual disabilities are variable, as follows:

• Borderline - 11%
• Mild - 29%
• Moderate - 18%
• Severe - 16%
• Profound - 19%

A prognostic index created by Cereda et al for Cornelia de Lange syndrome uses a point system to help predict the severity of a child's intellectual disabilities early in development.[16]

Information can be obtained from the Cornelia de Lange Syndrome Foundation, Inc., at http://www.cdlsusa.org/.

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

• 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%)

• 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.

  • Cornelia de Lange syndrome is associated with a broad range of anxiety disorders, including generalized anxiety disorder and separation anxiety.[17]

A study by Srivastava et al of 50 children with Cornelia de Lange syndrome found that all of these individuals displayed at least one type of repetitive behavior, with 64% of the subjects engaging in such action for more than 1 hour per day. The investigators also reported that 44% of the children displayed self-injurious behavior. The study indicated that in youngsters with Cornelia de Lange syndrome, an association exists between lower adaptive functioning, as measured on the Vineland Adaptive Behavior Scales, and greater stereotypy and self-injurious behavior scores, as measured on the Aberrant Behavior Checklist.[18]  

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.[19] 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%)

  • Generalized hirsutism is observed most easily in dark-haired individuals.

  • Many infants lose their obvious excessive body hair later in life.

• Cutis marmorata and perioral cyanosis (56%)

• Hypoplastic nipples and umbilicus (50%)

• Micromelia (93%)

  • 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[20, 21]

Mutations in NIPBL, SMC3, RAD21, SMC1A, and HDAC8 have been shown to cause Cornelia de Lange syndrome. NIPBL, SMC3, and RAD21 are autosomal dominant. SMC1A and HDAC8 are X-linked dominant. There is emerging evidence that mutation in EP300 may also cause the syndrome. Most cases of Cornelia de Lange syndrome are sporadic, due to de novo mutations (see Pathophysiology).

A study by Aoi et al suggested that abnormalities in the genes ZMYND11, MED13L, and PHIP may also cause Cornelia de Lange syndrome or a similar condition.[22]

Molecular genetic diagnosis can be performed using sequencing and deletion/duplication analysis of NIPBL, SMC3, RAD21, SMC1A, and HDAC8.

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. Updated laboratory information can be obtained at Gene Tests.

CBC analysis has led to a finding of thrombocytopenia.

See the list below:

• Radiography may reveal the following:

  • Delayed 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 vermian hypoplasia or agenesis.

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.

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.[23]

• 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

• 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

• Developmental characteristics must include at least 1 of the following:

  • Developmental delays or mental retardation

  • Learning disabilities

• Behavioral characteristics must include at least 2 of the following:

  • Attention deficit disorder, hyperactivity

  • Obsessive–compulsive characteristics

  • Anxiety

  • Constant roaming

  • Aggression

  • Self-injurious behavior

  • Extreme shyness or withdrawal

  • Autisticlike features

• 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

  • Major eye malformation or peripapillary pigmentation

  • Deafness or hearing loss

  • Seizures

  • Cutis marmorata

  • Hirsutism, generalized

  • Small nipples and/or umbilicus

• 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 ^[23] (Open Table in a new window)

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. A retrospective study by Janek et al indicated that hearing loss in Cornelia de Lange syndrome can improve over time. More than half of the study’s 78 patients, seen in an adult Cornelia de Lange syndrome clinic, reported hearing improvement, including a subset of patients with sensorineural hearing loss.[24]

Psychomotor delay

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.

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

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

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. See Treatment.