Laboratory Studies

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.

Imaging Studies

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.

Other Tests

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.

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.^[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)

Parameter	1 point	2 point	3 point
Birth weight	Above 2,500 g	2,000–2,500 g	Below 2,000 g
Sitting alone	< 9 mo	9–20 mo	>20 mo
Walking alone	< 18 mo	18–42 months	>42 mo
Saying first word	< 24 mo	24–48 mo	>48 mo
Upper limb malformation	No defect	Partial defect (>2 digits)	Severe defect (< 2 digits)
Number of other major malformations	0-1	2-3	>3
Hearing loss	Absent	...	...
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.

Treatment & Management

de Lange C. Sur un type nouveau de degeneration (typus amstelodamensis). Arch Med Enfants. 1933. 36:713-9.
Brachmann W. Ein Fall von symmetrischer Monodaktylie durch Ulnadefekt, mit symmetrischer Flughautbildung in den Ellenbeugen, sowie anderen Abnormalitaten. Jahr Kinderheilkunde. 1916. 84:225-35.
Huisman SA, Redeker EJ, Maas SM, Mannens MM, Hennekam RC. High rate of mosaicism in individuals with Cornelia de Lange syndrome. J Med Genet. 2013 May. 50(5):339-44. [QxMD MEDLINE Link].
Krantz ID, McCallum J, DeScipio C, et al. Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B. Nature Genet. 2004. 36:631-635. [QxMD MEDLINE Link].
Gillis LA, McCallum J, Kaur M, et al. NIPBL mutational analysis in 120 individuals with Cornelia de Lange syndrome and evaluation of genotype-phenotype correlations. Am J Hum Genet. 2004. 75:610-23. [QxMD MEDLINE Link]. [Full Text].
Gervasini C, Parenti I, Picinelli C, Azzollini J, Masciadri M, Cereda A, et al. Molecular characterization of a mosaic NIPBL deletion in a Cornelia de Lange patient with severe phenotype. Eur J Med Genet. 2013 Mar. 56(3):138-43. [QxMD MEDLINE Link].
Mende RH, Drake DP, Olomi RM, Hamel BC. Cornelia de Lange Syndrome: A Newborn with Imperforate Anus and a NIPBL Mutation. Case Rep Genet. 2012. 2012:247683. [QxMD MEDLINE Link]. [Full Text].
Deardorff MA, Kaur M, Yaeger D, et al. Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of cornelia de Lange syndrome with predominant mental retardation. Am J Hum Genet. 2007 Mar. 80(3):485-94. [QxMD MEDLINE Link].
Bhuiyan ZA, Stewart H, Redeker EJ, Mannens MM, Hennekam RC. Large genomic rearrangements in NIPBL are infrequent in Cornelia de Lange syndrome. Eur J Hum Genet. 2007 Apr. 15(4):505-8. [QxMD MEDLINE Link].
Gervasini C, Picinelli C, Azzollini J, Rusconi D, Masciadri M, Cereda A, et al. Genomic imbalances in patients with a clinical presentation in the spectrum of Cornelia de Lange syndrome. BMC Med Genet. 2013 Apr 3. 14:41. [QxMD MEDLINE Link]. [Full Text].
Gil-Rodriguez MC, Deardorff MA, Ansari M, et al. De Novo Heterozygous Mutations in SMC3 Cause a Range of Cornelia de Lange Syndrome-Overlapping Phenotypes. Hum Mutat. 2015 Apr. 36(4):454-62. [QxMD MEDLINE Link].
Krantz ID, Tonkin E, Smith M, et al. Exclusion of linkage to the CDL1 gene region on chromosome 3q26.3 in some familial cases of Cornelia de Lange syndrome. Am J Med Genet. 2001 Jun 15. 101(2):120-9. [QxMD MEDLINE Link].
Kaur M, Mehta D, Noon SE, Deardorff MA, Zhang Z, Krantz ID. NIPBL expression levels in CdLS probands as a predictor of mutation type and phenotypic severity. Am J Med Genet C Semin Med Genet. 2016 Jun. 172 (2):163-70. [QxMD MEDLINE Link].
Schrier SA, Sherer I, Deardorff MA, Clark D, Audette L, Gillis L, et al. Causes of death and autopsy findings in a large study cohort of individuals with Cornelia de Lange syndrome and review of the literature. Am J Med Genet A. 2011 Dec. 155A(12):3007-24. [QxMD MEDLINE Link]. [Full Text].
Kline AD, Grados M, Sponseller P, Levy HP, Blagowidow N, Schoedel C, et al. Natural history of aging in Cornelia de Lange syndrome. Am J Med Genet C Semin Med Genet. 2007 Aug 15. 145C(3):248-60. [QxMD MEDLINE Link].
Cereda A, Mariani M, Rebora P, et al. A new prognostic index of severity of intellectual disabilities in Cornelia de Lange syndrome. Am J Med Genet C Semin Med Genet. 2016 Jun. 172 (2):179-89. [QxMD MEDLINE Link].
Crawford H, Waite J, Oliver C. Diverse Profiles of Anxiety Related Disorders in Fragile X, Cornelia de Lange and Rubinstein-Taybi Syndromes. J Autism Dev Disord. 2017 Dec. 47 (12):3728-40. [QxMD MEDLINE Link]. [Full Text].
Srivastava S, Clark B, Landy-Schmitt C, et al. Repetitive and Self-injurious Behaviors in Children with Cornelia de Lange Syndrome. J Autism Dev Disord. 2020 Aug 18. [QxMD MEDLINE Link].
Dowsett L, Porras AR, Kruszka P, et al. Cornelia de Lange syndrome in diverse populations. Am J Med Genet A. 2019 Feb. 179 (2):150-8. [QxMD MEDLINE Link].
Marchisio P, Selicorni A, Bianchini S, et al. Audiological findings, genotype and clinical severity score in Cornelia de Lange syndrome. Int J Pediatr Otorhinolaryngol. 2014 Jul. 78(7):1045-8. [QxMD MEDLINE Link].
Marchisio P, Selicorni A, Pignataro L, et al. Otitis media with effusion and hearing loss in children with Cornelia de Lange syndrome. Am J Med Genet A. 2008 Feb 15. 146A(4):426-32. [QxMD MEDLINE Link].
Aoi H, Mizuguchi T, Ceroni JR, et al. Comprehensive genetic analysis of 57 families with clinically suspected Cornelia de Lange syndrome. J Hum Genet. 2019 Oct. 64 (10):967-78. [QxMD MEDLINE Link].
[Guideline] Kline AD, Krantz ID, Sommer A, et al. Cornelia de Lange syndrome: Clinical review, diagnostic and scoring systems, and anticipatory guidance Am J Med Genet Part A 143A:1287-1296. Am J Med Genet A. 2008 Sep 24. 146A(20):2713. [QxMD MEDLINE Link].
Janek KC, Smith DF, Kline AD, et al. Improvement in hearing loss over time in Cornelia de Lange syndrome. Int J Pediatr Otorhinolaryngol. 2016 Aug. 87:203-7. [QxMD MEDLINE Link].

Media Gallery

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.

of 3

Author

Dayna Morel Swols, MSc General Genetic Counselor, University of Miami

Dayna Morel Swols, MSc is a member of the following medical societies: National Society of Genetic Counselors

Disclosure: Nothing to disclose.

Coauthor(s)

Mustafa Tekin, MD Professor and Chief, Division of Clinical and Translational Genetics, Dr John T Macdonald Foundation, Department of Human Genetics, John P Hussman Institute for Human Genomics, University of Miami, Leonard M Miller School of Medicine

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

Disclosure: Nothing to disclose.

Specialty Editor Board

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.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

Additional Contributors

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, American Society for Biochemistry and Molecular Biology, Genetics Society of America, Environmental Mutagenesis and Genomics Society

Disclosure: Nothing to disclose.

Joann Bodurtha, MD, MPH Associate Chairman, Associate Professor, Department of Human Genetics, Medical College of Virginia

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, American College of Medical Genetics and Genomics

Disclosure: Nothing to disclose.

Sections Cornelia De Lange Syndrome
Overview
Presentation
- History
- Physical
- Causes
- Show All
DDx
Workup
Treatment
Medication
Media Gallery
Tables
References

Cornelia De Lange Syndrome Workup

Laboratory Studies

Imaging Studies

Other Tests

Staging

References

Tables

Contributor Information and Disclosures

What would you like to print?