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Pediatrics: Genetics and Metabolic Disease > Genetics
Cornelia De Lange Syndrome
Article Last Updated: Jan 3, 2006
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Mustafa Tekin, MD, Associate Professor, Division of Pediatric Molecular Pathology and Genetics, Ankara University School of Medicine, Turkey
Mustafa Tekin is a member of the following medical societies: American Society of Human Genetics
Coauthor(s):
Joann Bodurtha, MD, MPH, Professor, Department of Human Genetics, Virginia Commonwealth University
Editors: Michael Fasullo, PhD, Associate Professor, Center for Immunology and Microbial Disease, Albany Medical College; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; David Flannery, MD, FAAP, FACMG, Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; Bruce Buehler, MD, Professor, Department of Pathology and Microbiology, Director, Hattie B Munroe Center for Human Genetics, Chairman, Department of Pediatrics, University of Nebraska Medical Center
Author and Editor Disclosure
Synonyms and related keywords:
Cornelia de Lange syndrome, CdLS, Brachmann-de Lange syndrome, de Lange syndrome, Amsterdam syndrome, typus degenerativus amstelodamensis, growth deficiency, feeding difficulties, psychomotor delay, behavioral problems, upper extremity malformation, characteristic facies, NIPBL
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, though Brachmann had described a child with similar features in 1916. Diagnosing classic cases of CdLS is usually straightforward, but diagnosing mild cases may be challenging, even for an experienced clinician.
Pathophysiology
Heterozygous mutations in a gene named NIPBL, the human homolog of the Drosophila melanogaster Nipped-B gene, have recently been identified in a group of individuals with CdLS. 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.
More than 99% of cases are sporadic. CdLS is occasionally transmitted in an autosomal dominant pattern, according to several instances in which a usually mildly affected parent had 1 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. The recurrence risk is 0.5-1.5% if parents are unaffected and 50% if a parent is affected.
All types of NIPBL mutations, including missense, splice-site, nonsense, and frameshift mutations, have been reported to result in the CdLS phenotype. The most likely effect of these mutations is haploinsufficiency. The mutation-detection rate is approximately 50% with current molecular screening techniques; this observation may suggest genetic heterogeneity. Undetectable mutations in the NIPBL gene cannot be excluded at this time.
The correlation between genotype and phenotype is not clear cut. Data from initial studies 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 might be associated with mild phenotypic features.
A phenotype similar to that of CdLS may be observed in patients with a duplication of band q26-27 of chromosome 3. Molecular studies of genes mapped to this region of chromosome arm 3q have failed to reveal mutations in patients with CdLS.
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.
Frequency
International
The incidence is 1 case per 10,000-50,000 live births.
Race
No differences based on race have been described.
Sex
No sex-based predilection is reported.
History
- 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 (30-60%), 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; 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 (CdLS), psychomotor retardation is less severe and prenatal and postnatal growth deficiency is milder than in severe CdLS. 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 CdLS. As an alternative, their typical facial changes may develop during the first 2-4 years of life. Although individuals with mild CdLS function at the low-normal range and though they have certain characteristics of the syndrome, their disease is occasionally not diagnosed until they have a child with classic findings.
- Behavioral manifestations
- Hyperactivity (40%), self-injury (44%), daily aggression (49%), and sleep disturbance (55%) occur.
- Behavioral manifestations are correlated with the presence of an autistic-like syndrome and with the degree of mental retardation.
- Children with CdLS 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 CdLS,
- 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 are 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.
Physical
- Short stature: In some patients, extreme short stature may be caused by growth hormone deficiency.
- Microcephaly (98%)
- 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 ears
- Depressed nasal bridge (83%)
- High arched palate (86%) and reports of cleft palate
- 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.
- 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 83% of patients in 1 study.
- Glasses are often poorly tolerated.
- Astigmatism, optic atrophy, coloboma of the optic nerve, aniridia and congenital glaucoma have been described.
Causes
Heterozygous mutations in the NIPBL gene result in CdLS. Most cases are sporadic due to de novo mutations (see Pathophysiology).
Fetal Alcohol Syndrome
Other Problems to be Considered
Dup(3q) syndrome
Coffin-Siris syndrome
Fryns syndrome
Lab Studies
- Molecular diagnosis with screening of the NIPBL gene is clinically available in a small number of laboratories.
- Updated laboratory information can be obtained at Gene Tests.
- 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.
- Complete blood count: Thrombocytopenia has been reported.
Imaging Studies
- Radiography may show 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 (58%)
- Intestinal obstruction (17%)
- Pelvic abnormalities (33%)
- Ultrasonography at diagnosis to assess for kidney and urinary tract abnormalities (40%) may show the following:
- Horseshoe kidney
- Altered corticomedullary differentiation
- Pelvic dilation
- Vesicoureteral reflux
- Small kidneys
- Renal cysts
- Renal ectopia
- Echocardiography may be indicated if congenital heart disease is suspected.
Other Tests
- High-resolution chromosomal studies when the diagnosis is uncertain
- Hearing evaluation is recommended. More than 90% of individuals with Cornelia de Lange syndrome have sensorineural hearing loss when properly evaluated.
- A spectrum of endocrinopathies may be observed in addition to growth-hormone deficiency. These conditions include problems in gonadotropin and prolactin secretion and panhypopituitarism.
Medical Care
- Early intervention for feeding problems, hearing and visual impairment, congenital heart disease, and urinary system abnormalities
- Early intervention for psychomotor delay
- 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.
Consultations
- Geneticist
- Cardiologist
- Gastroenterologist and nutritionist
- Nephrologist (if recurrent urinary tract infections, impaired renal functions or congenital abnormalities are present)
- Ophthalmologist
- Hearing specialist
Drug therapy currently is not a component of the standard of care for this syndrome. See Treatment.
Prognosis
- Life expectancy is normal if no major malformations occur.
- Causes of death include apnea after respiratory aspiration, cardiac malformations, and complications related to gastrointestinal problems.
Patient Education
- Teaching methods of conveying pleasure and affection that do not require facial expression can improve acceptance by relatives.
- Resources for parent education may be found at the CDLS Foundation Web site.
Medical/Legal Pitfalls
- Anatomic abnormalities of the face and neck may cause difficulties during intubation.
- Failure to detect a mildly affected parent may result in incorrect risk estimation for future pregnancies.
Special Concerns
- Severe speech delay and poor communication are concerns.
- The patient may have congenital heart disease.
- Gastrointestinal obstruction or feeding difficulties may occur. Early feeding management is important.
- A prenatal diagnosis is made after Cornelia de Lange Syndrome-related abnormalities are carefully evaluated on prenatal sonograms. 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.
| Media file 1:
Facial appearance of a patient with Cornelia de Lange syndrome. Courtesy of Ian Krantz, MD, Children's Hospital of Philadelphia. |
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| Media file 2:
Facial profile of a patient with Cornelia de Lange syndrome. Courtesy of Ian Krantz, MD, Children's Hospital of Philadelphia. |
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| Media file 3:
Severe upper-extremity malformations in a patient with Cornelia de Lange syndrome. Courtesy of Ian Krantz, MD, Children's Hospital of Philadelphia. |
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Cornelia De Lange Syndrome excerpt Article Last Updated: Jan 3, 2006
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