Cornelia De Lange Syndrome Clinical Presentation

  • Author: Mustafa Tekin, MD; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Dec 20, 2011
 

History

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.
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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%)
    • 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.
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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).

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Contributor Information and Disclosures
Author

Mustafa Tekin, MD  Associate Professor, Division of Pediatric Molecular Pathology and Genetics, Ankara University School of Medicine, Turkey

Mustafa Tekin, MD is a member of the following medical societies: American Society of Human Genetics

Disclosure: Nothing to disclose.

Coauthor(s)

Joann Bodurtha, MD, MPH  Professor, Department of Human Genetics, Virginia Commonwealth University

Disclosure: Nothing to disclose.

Specialty Editor Board

Michael Fasullo, PhD  Senior Scientist, Ordway Research Institute; Associate Professor, State University of New York at Albany; Adjunct Associate Professor, Center for Immunology and Microbial Disease, Albany Medical College

Michael Fasullo, PhD is a member of the following medical societies: American Society for Biochemistry and Molecular Biology, Environmental Mutagen Society, Genetics Society of America, and Radiation Research Society

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

David Flannery, MD, FAAP, FACMG  Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia

David Flannery, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics and American College of Medical Genetics

Disclosure: Nothing to disclose.

Paul D Petry, DO, FACOP, FAAP  Consulting Staff, Freeman Pediatric Care, Freeman Health System

Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association

Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

References

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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.
Table. Scoring System for Severity of Cornelia de Lange Syndrome[11]
Parameter 1 point 2 point 3 point
Birth weightAbove 2,500 g2,000–2,500 gBelow 2,000 g
Sitting alone< 9 mo9–20 mo>20 mo
Walking alone< 18 mo18–42 months>42 mo
Saying first word< 24 mo24–48 mo>48 mo
Upper limb malformationNo defectPartial defect (>2 digits)Severe defect (< 2 digits)
Number of other major malformations0-12-3>3
Hearing lossAbsent......
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.
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