Cornelia de Lange Syndrome - Initial Diagnosis

Page Contents

• Overview
• Presentations
• Diagnostic Criteria
• Pearls And Alerts
• Practice Guidelines
• Differential Diagnosis
• History And Examination
• Resources

Overview

Around the time diagnosis, children with Cornelia de Lange syndrome (CdLS) should have several one-time evaluations to rule out potential malformations, including:

• chromosome analysis
• echocardiogram
• renal ultrasound
• upper GI barium study to rule out malrotation and to look for GERD
• audiology assessment
• ophthalmologic examination

Presentations

As more is learned about individuals with Cornelia de Lange Syndrome (CdLS), it has become evident that both milder and more severe phenotypic forms of the syndrome exist. [Kline: 2007] [Allanson: 1997] More severe phenotypes are more likely to have low birth weights.

Diagnostic Criteria

Diagnostic Criteria for CdLS, from Diagnosis of CdLS (Cornelia de Lange Syndrome Foundation)

1. Positive mutation on CdLS gene testing, OR
2. Facial findings AND criteria met for two major categories (growth, development or behavior), OR
3. Facial findings AND criteria met for at least one major category and two additional categories (major or minor)

Facial Features:

• Synophrys (eyebrows that meet at the midline) plus 3 or more of the following:
  • Long eyelashes
  • Short nose, anteverted nares
  • Long, prominent philtrum (area between upper lip and nose)
  • Broad or depressed nasal bridge
  • Small or square chin
  • Thin lips, down-turned corners
  • High palate
  • Widely spaced or absent teeth

Major Criteria:

• Growth: 2 or more of the following:
  • Weight below 5th percentile for age
  • Height/length below 5th percentile for age
  • Head circumference below 5th percentile for age
• Development: 1 or more of the following:
  • Developmental delay or mental retardation
  • Learning disabilities
• Behavior: 2 or more of the following:
  • Attention deficit disorder with hyperactivity
  • Obsessive-compulsive characteristics
  • Anxiety
  • Constant roaming
  • Aggression
  • Self-injurious behavior
  • Extreme shyness or withdrawal
  • Autistic features

Minor Criteria:

• Musculoskeletal: 1 or more of the following:
  • Reduction defects, with absent forearms
  • Small hands and feet and/or oligodactyly (missing digits) with 2 or more of the following:
    • 5th finger clinodactyly (curved 5th finger)
    • Abnormal palmar crease
    • Radial head dislocation/abnormal elbow extension
    • Short 1st metacarpal/ proximally placed thumb
    • Bunion
    • Partial 2,3 syndactyly (webbing between 2nd and 3rd toes)
    • Scoliosis (curvature of the spine)
    • Pectus excavatum (chest or sternum deformity)
    • Hip dislocation or dysplasia
  • Three or more of the following:
    • 5th finger clinodactyly (inwardly curved fifth finger)
    • Abnormal palmar crease
    • Radial head dislocation/abnormal elbow extension
    • Short 1st metacarpal/proximally-placed thumb
    • Bunion
    • Partial 2,3 syndactyly (webbing between 2nd and 3rd toes)
    • Scoliosis (curvature of the spine)
    • Pectus excavatum (chest/sternum deformity)
    • Hip dislocation or dysplasia

• Neurosensory/Skin: 3 or more of the following:
  • Ptosis (droopy eyelid)
  • Tear duct malformation or blepharitis (inflammation of eyelid)
  • Myopia (-6.00 D or more)
  • Major eye malformation or peripapillary anomaly
  • Deafness or hearing loss
  • Seizures
  • Cutis marmorata (mottled appearance to skin)
  • Hirsutism, generalized (excessive body hair)
  • Small nipples and/or umbilicus
• Other major systems: 3 or more of the following:
  • Gastrointestinal malformation/malrotation (approximately 2% of children with CdLS syndrome Cornelia de Lange syndrome (GeneReviews) )
  • Diaphragmatic hernia (approximately 1% of children with CdLS syndrome Cornelia de Lange syndrome (GeneReviews))
  • Gastroesophageal reflux disease or GERD (majority of children with CdLS syndrome Cornelia de Lange syndrome (GeneReviews))
  • Cleft palate or submucous cleft palate
  • Micropenis
  • Hypospadias (abnormally placed opening of urethra on penis)
  • Cryptorchidism (undescended testes)
  • Renal or urinary tract malformation (approximately 12% of children with CdLS syndrome Cornelia de Lange syndrome (GeneReviews))

Pearls And Alerts

Gastroesophageal reflux is extremely common in children with CdLS. Consider an evaluation if there are frequent episodes of distress, irritability, and/or arching. Other signs of GERD include vomiting, weight loss or failure to gain expected weight, food refusal, dysphagia (difficulty swallowing) and/or hematemesis (vomiting of blood).

Practice Guidelines

Differential Diagnosis

The facial features of children with CdLS are striking and these, in addition to growth retardation, delayed development, and associated malformations, will usually lead to a correct diagnosis. Individual elements of the physical exam in children with CdLS may be observed in children with many different syndromes, as illustrated in the following examples:

• Upper limb deformities are present in children with Roberts syndrome;
• Hirsutism and small stature are seen in individuals with Rubinstein-Taybi syndrome;
• Developmental, behavioral, and growth abnormalities are observed in children with fetal alcohol syndrome;
• Developmental delay, behavioral disturbance, and sleep dysfunction are typically present in children with Smith-Magenis syndrome;
• Microcephaly and autism-like features are observed in girls with Rett syndrome; and
• Growth retardation is observed in many syndromes.

History And Examination

Resources

Authors

Page Bibliography

Allanson JE, Hennekam RC, Ireland M.
De Lange syndrome: subjective and objective comparison of the classical and mild phenotypes.
J Med Genet. 1997;34(8):645-50. PubMed abstract / Full Text

Barisic I, Tokic V, Loane M, Bianchi F, Calzolari E, Garne E, Wellesley D, Dolk H.
Descriptive epidemiology of Cornelia de Lange syndrome in Europe.
Am J Med Genet A. 2008;146A(1):51-9. PubMed abstract

Kline AD, Krantz ID, Sommer A, Kliewer M, Jackson LG, FitzPatrick DR, Levin AV, Selicorni A.
Cornelia de Lange syndrome: clinical review, diagnostic and scoring systems, and anticipatory guidance.
Am J Med Genet A. 2007;143A(12):1287-96. PubMed abstract