eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Cornelia De Lange Syndrome: Differential Diagnoses & Workup

Author: Mustafa Tekin, MD, Associate Professor, Division of Pediatric Molecular Pathology and Genetics, Ankara University School of Medicine, Turkey
Coauthor(s): Joann Bodurtha, MD, MPH, Professor, Department of Human Genetics, Virginia Commonwealth University
Contributor Information and Disclosures

Updated: Nov 13, 2009

Differential Diagnoses

Fetal Alcohol Syndrome

Other Problems to Be Considered

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

Workup

Laboratory Studies

  • Genetic diagnosis: Molecular genetic diagnosis of Cornelia de Lange syndrome (CdLS) with screening of mutations in the NIPBL and SMC1A genes is clinically available.
    • 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.
    • 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.47
  • CBC count: Thrombocytopenia has been reported.

Imaging Studies

  • 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

  • High-resolution chromosomal studies are indicated 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.8
  • A spectrum of endocrinopathies may be observed in addition to growth-hormone deficiency. These conditions include problems in 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.9

  • 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:
  • 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
Scoring System for Severity of Cornelia de Lange Syndrome9

Open table in new window

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Table
Parameter1 point2 point3 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

 ...

 ...

Parameter1 point2 point3 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.

More on Cornelia De Lange Syndrome

Overview: Cornelia De Lange Syndrome
Differential Diagnoses & Workup: Cornelia De Lange Syndrome
Treatment & Medication: Cornelia De Lange Syndrome
Follow-up: Cornelia De Lange Syndrome
Multimedia: Cornelia De Lange Syndrome
References
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References

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Further Reading

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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

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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.

Medical Editor

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: Radiation Research Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

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.

CME Editor

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, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics, 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.

 
 
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