Clinical Diagnosis

Diagnosis of Cornelia de Lange syndrome (CdLS) is made on a clinical basis. The most important clinical signs of CdLS are the following [Kline et al 2007a]:

Craniofacial appearance (>95%)

• Classic CdLS. The craniofacial features are easily recognized and are some of the most useful in diagnosis: (Figure 1)
  • Microbrachycephaly (mean occipital frontal circumference [OFC] <2nd centile)
  • Synophrys, arched eyebrows in 98% [Jackson et al 1993]
  • Long, thick eyelashes
  • Low-set posteriorly rotated and/or hirsute ears with thickened helices
  • Depressed or broad nasal bridge, upturned nasal tip with anteverted nares, and prominence of the lateral aspects
  • Long smooth philtrum, thin vermillion border of the upper lip with a midline "drip" appearance (lowering of the apical part of the upper lip at the base of the philtrum below the arc of the upper lip), downturned corners of the mouth
  • High and arched palate with clefts in 30% [Sataloff et al 1990]
  • Small widely-spaced teeth
  • Micrognathia in 80% [Jackson et al 1993]; mandibular spurs in 42% [Braddock et al 1993]
  • Short neck
• Mild CdLS. A milder phenotype that retains many of the characteristic facial features but with less severe cognitive and limb involvement has been consistently described and is more typical of individuals with mutations in SMC1A and SMC3 [Deardorff et al 2007, Selicorni et al 2007, Rohatgi et al 2010]. Diagnostic criteria for milder cases have been proposed [Ireland et al 1993, Jackson et al 1993, Selicorni et al 1993, Van Allen et al 1993, Allanson et al 1997]. (Figure 2)
  
  Note: This milder phenotype, which is less striking clinically than the classic or severe form of CdLS, may represent the majority of individuals with CdLS [Greenberg & Robinson 1989, Jackson et al 1993, Moeschler & Graham 1993, Selicorni et al 1993, Van Allen et al 1993, Allanson et al 1997, Deardorff et al 2007, Rohatgi et al 2010].

Figure

Figure 1. Classic CdLS Craniofacial features

Figure

Figure 2. Patient with SMC1A mutation

Growth failure (>95%). Growth failure occurs prenatally (although it may not be noted until the third trimester). Height and weight remain below the 5th centile throughout life [Bruner & Hsia 1990, Kliewer et al 1993, Kline et al 1993a, Kousseff et al 1993, Boog et al 1999]. CdLS-specific growth charts have been developed (www.cdlsusa.org).

In addition, failure to thrive may be superimposed on the constitutional growth retardation secondary to gastroesophageal reflux and other issues with feeding.

Intellectual disability (>95%)

• Classic CdLS. Severe-to-profound pervasive developmental delay
• Mild CdLS. Less affected individuals with higher functioning and higher IQs (some in the normal range) have been identified. The overall IQ in CdLS ranges from below 30 to 102, with an average IQ of 53 [Kline et al 1993b, Saal et al 1993].

Limb abnormalities (>95%). Upper extremities are primarily involved, with relative sparing of the lower extremities. Limb abnormalities may be symmetric or asymmetric.

• Classic CdLS. Upper extremity deficiencies ranging from severe reduction defects with complete absence of the forearms to various forms of oligodactyly (missing digits) occur in approximately 30%. In the absence of limb deficiency, micromelia (small hands), proximally placed thumbs, and fifth finger clinodactyly occur in nearly all individuals. (Figure 3)
  
  Radioulnar synostosis is common and may result in flexion contractures of the elbows.
  
  The lower extremities are less involved than the upper extremities. The feet are often small and two-three syndactyly of the toes occurs in more than 80% of affected individuals [Jackson et al 1993].
• Mild CdLS. The radiographic finding of a short first metacarpal resulting in a proximally placed thumb can be useful in diagnosis.

Figure

Figure 3. Range of limb anomalies in CdLS

Hirsutism (>80%). Thick scalp hair extends onto the temporal regions and at times involves the face, ears, back, and arms.

Molecular Genetic Testing

Gene. NIPBL, SMC1A, and SMC3 are the only genes in which mutations are currently reported to be associated with CdLS [Krantz et al 2004, Tonkin et al 2004, Musio et al 2006, Deardorff et al 2007].

Evidence for further locus heterogeneity. Lack of identified NIPBL mutations in 50% of individuals with CdLS suggested possible genetic heterogeneity [Borck et al 2004].

Note: Although earlier work based on chromosomal breakpoint analysis in individuals with CdLS-like disorders suggested 3q26 as a possible locus [Falek et al 1966, Ireland et al 1991, Ireland et al 1995], evidence in support of linkage to this region was not seen consistently in a study of ten familial cases of CdLS [Krantz et al 2001]. Further assessment of individuals with 3q26 duplications suggests that they have features that differ from typical CdLS.

Interpretation of test results

Given the current 60% mutation detection rate of NIPBL mutations, failure to identify a mutation would not preclude the diagnosis of CdLS, particularly in a mild case, where mutation detection rates are closer to 30%.

Testing Strategy

To confirm the diagnosis of CdLS in classic cases and to establish the diagnosis in an atypical case, molecular genetic testing of NIPBL:

• Perform sequence analysis or mutation scanning first. If no mutation is identified, perform deletion/duplication analysis.
• If no NIPBL mutation is identified and the patient has milder physical features of CdLS, consider SMC1A sequence analysis or mutation scanning.
• If no NIPBL or SMC1A mutation is identified and CdLS is highly suspected especially in a patient with milder features, consider SMC3 sequence analysis.

When the diagnosis of CdLS is not clear or molecular genetic testing does not identify a mutation, consider cytogenetic testing or array-based testing (i.e., chromosome microarray analysis or array genomic hybridization) because a few individuals with deletions of 5p13 that include the NIPBL locus have been reported [Taylor & Josifek 1981, Hulinsky et al 2005, Hayashi et al 2007]. In addition, this testing may be helpful in evaluating for other possible etiologies, as the clinical findings in several chromosomal abnormalities overlap with those of CdLS [DeScipio et al 2005, Rohatgi et al 2010].

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in NIPBL, SMC1A, or SMC3.

Natural History

Although CdLS was formally characterized over 70 years ago and well delineated clinically [Ptacek et al 1963, Motl & Opitz 1971, Jackson et al 1993], the natural history of CdLS has only been studied recently [Kline et al 2007a].

Life expectancy appears to be normal in affected individuals who do not have the complications described below. See Cause of death.

The majority of familial cases suggest that expressivity is relatively consistent within a family.

The medical issues faced by individuals with the mild and classic forms of CdLS are similar; however, the greater cognitive impairment in individuals with classic CdLS may make identification of medical complications more difficult.

Genotype-Phenotype Correlations

Whereas individuals with classic findings of CdLS, including characteristic facial features and limb anomalies, are likely to have a mutation in NIPBL, NIPBL mutations have been found in individuals with both mild and severe phenotypes. NIPBL mutations are evenly distributed throughout the coding sequence. Individuals with missense NIBPL mutations typically have milder disease.

Individuals with a SMC1A or SMC3 mutation typically have fewer structural anomalies than those with NIPBL mutations; however, they have significant intellectual disability that can range from moderate to severe [Deardorff et al 2007]. Facial features include slightly flatter and broader eyebrows and a broader and longer nasal bridge than are seen in individuals with an NIPBL mutation [Rohatgi et al 2010].

Penetrance

No unaffected individuals with somatic NIPBL mutations have been reported; thus, penetrance appears to be 100%.

Similarly, despite relatively few individuals identified with an SMC1A mutation, penetrance appears to be very high, although some variability in severity in mothers heterozygous for an SMC1A mutation has been noted [Musio et al 2006, Deardorff et al 2007].

Nomenclature

Cornelia de Lange syndrome (CdLS) was first described by Vrolik in 1849, who reported a case as an extreme example of oligodactyly [Oostra et al 1994]. Brachmann [1916] provided a detailed account of a case of symmetric monodactyly, antecubital webbing, dwarfism, cervical ribs, and hirsutism.

In the 1930s, Cornelia de Lange, a Dutch pediatrician, described two unrelated girls with similar features and named the condition after the city in which she worked: typus degenerativus amstelodamensis [de Lange 1933, de Knecht-van Eekelen & Hennekam 1994]. Some examples in the literature refer to the disorder as Brachmann-de Lange syndrome; however, it is more widely referred to as Cornelia de Lange syndrome in honor of Dr. de Lange’s contributions to the understanding of the disorder.

Prevalence

The prevalence of CdLS is difficult to estimate since individuals with milder features are likely underrecognized. Published estimates for the prevalence range from 1:100,000 [Pearce & Pitt 1967] to as high as 1:10,000 [Opitz 1985]. Recent data from the EUROCAT dataset have estimated the prevalence at 1:50,000 for the classic form of CdLS [Barisic et al 2008], which is less likely to include the milder, more common phenotype.

Evaluations Following Initial Diagnosis

The following recommendations for evaluation of individuals diagnosed with Cornelia de Lange syndrome (CdLS) are based on recent guidelines [Kline et al 2007b (click for full text)] and the authors' experience:

• Gastrointestinal evaluation (including upper GI series, endoscopy, milk scan and/or pH probe) to evaluate for malrotation and gastrointestinal reflux which, if undiagnosed or undertreated, can lead to feeding intolerance, life-threatening recurrent aspiration, and volvulus
• Plotting growth parameters on CdLS-specific growth charts. See www.cdlsusa.org (girls; boys).
• Evaluation by a nutritionist if CdLS growth curves reveal failure to thrive
• Radiographs of the upper extremities to evaluate for radioulnar synostosis. Physical therapy must be performed with caution to avoid causing fractures if radioulnar synostosis is present.
• Multidisciplinary developmental evaluation to formulate education/therapeutic interventions with an emphasis on communication skills
• Audiology evaluation with auditory brain stem response testing and otoacoustic emission testing to assess for hearing loss
• Ophthalmologic evaluation, including assessment of visual acuity, dilated fundus examination, measurement of intraocular pressure, and evaluation of tear ducts for patency and function
• Echocardiogram to screen for cardiac defects. ASDs are common and may not be picked up by auscultation.
• Neurologic evaluation and EEG in all affected individuals
• Renal ultrasonography to evaluate for structural kidney anomalies; if indicated, a vesicoureterogram (VCUG) to evaluate for vesicoureteral reflux
• Urologic evaluation in males with hypospadias and/or cryptorchidism
• Complete blood count if signs of anemia, bruising, bleeding are present
• Complete blood count and consideration of immunologic evaluation if recurrent infections are present

Treatment of Manifestations

The following is appropriate:

• Aggressive management of gastroesophageal reflux with consideration of fundoplication if GER is severe
• Surgical correction of intestinal malrotation if present
• Supplementary formulas and/or gastrostomy tube placement to meet nutritional needs if there is failure to thrive
• Surgical intervention of arms/hands if limb defects hinder utilization or mobility
• Ongoing physical, occupational, and speech therapies to optimize developmental outcomes; alternative communicative methods (e.g., sign language, picture exchange communication system [PECS]) to facilitate communication if verbal skills are inadequate to express wants and needs
• Standard treatment for hearing loss
• Aggressive treatment for nasolacrimal duct obstruction as massage therapy is often unsuccessful because of malformed ducts; standard treatment for refractive errors, strabismus, glaucoma, and ptosis
• Standard interventions for cardiac defects
• Appropriate treatment for seizures
• Antibiotic prophylaxis and follow-up for vesicoureteral reflux
• Orchiopexy if cryptorchidism is present
• Complete blood count if signs of anemia, bruising, bleeding are present
• Complete blood count and consideration of immunologic evaluation if recurrent infections are present

Prevention of Secondary Complications

To prevent secondary complications:

• Care during sedation and/or operative procedures in an institution with pediatric anesthesiologists experienced in the management of the small airways of children with CdLS
• During anesthesia, attention to the risk of malignant hyperthermia (see Malignant Hyperthermia Susceptibility), which has been reported in a few children with CdLS [Papadimos & Marco 2003]

Surveillance

The following are appropriate:

• Annual gastrointestinal evaluation including monitoring of growth
• Yearly evaluations by a developmental pediatrician to assess developmental progress and to target therapeutic interventions and educational modalities
• Regular follow-up of ophthalmologic and/or audiologic abnormalities
• Routine monitoring of existing cardiac or renal anomalies

Agents/Circumstances to Avoid

No known agents exacerbate the severity of CdLS; however, caution should be exercised to avoid exacerbation of existing comorbidities including gastroesophageal reflux, self-injurious behavior, pica, and less commonly, thrombocytopenia and immunologic features.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to evaluation of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

NIPBL-related Cornelia de Lange syndrome (CdLS) and SMC3-related CdLS are inherited in an autosomal dominant manner; SMC1A-related CdLS is inherited in an X-linked manner.

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

• Fewer than 1% of individuals diagnosed with Cornelia de Lange syndrome have an affected parent.
• Individuals with CdLS usually have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is approximately 99%.
• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include clinical examination for features of CdLS, complete with plotting of growth parameters and molecular genetic testing if the NIPBL mutation has been identified in the proband.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• If a parent of the proband is affected, the risk to the sibs is 50%.
• When the parents are clinically unaffected, the risk to the sibs of a proband has been estimated at 1.5% because of the possibility of germline mosaicism [Jackson et al 1993].
• If a NIPBL disease-causing mutation cannot be detected in the DNA of either parent, the cause may be either germline mosaicism in a parent or a de novo mutation in the proband. Prior to the identification of NIPBL mutations as the etiology of CdLS, germline mosaicism had been hypothesized based on reports of unaffected parents with more than one affected child [Gillis et al 2004, Krantz et al 2004]. With the identification of NIPBL mutations as the cause of CdLS, germline mosaicism has been confirmed in several cases.

Offspring of a proband

• Each child of an individual with CdLS has a 50% chance of inheriting the mutation.
• While most familial recurrences of CdLS are the result of germline mosaicism in a phenotypically normal parent, rare cases of a mildly affected individual with CdLS having children with CdLS have been reported.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members are at risk.

Risk to Family Members — X-Linked Inheritance

Parents of a proband

• The father of an affected male will not develop CdLS nor is he a carrier of the mutation.
• In a family with more than one affected individual, the mother is either a carrier or has germline mosaicism.
• In a family with (an) affected daughter(s), either the mother or father can have a SMC1A mutation or germline mosaicism.
• In the case of a single affected child, the mutation could have occurred de novo in that individual.
• When an affected male is the only affected individual in the family, several possibilities regarding his mother's carrier status need to be considered:
  • He has a de novo disease-causing mutation in SMC1A and his mother is not a carrier.
  • His mother has a de novo disease-causing mutation in SMC1A, either (a) as a "germline mutation" (i.e., present at the time of her conception and therefore in every cell of her body); or (b) as "germline mosaicism" (i.e., present in some of her germ cells only).
  • His mother has a disease-causing mutation that she inherited from an ancestor.

Note: Unlike a typical X-linked gene, SMC1A is not inactivated in the process of X-chromosome inactivation; thus, carrier mothers are likely to display some features of CdLS that are milder than those of their affected sons. However, to date, too few families with SMC1A-related CdLS have been identified to fully evaluate this model.

Sibs of a proband

• The risk to sibs depends on the carrier status of the mother.
• If the mother of the proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and will usually not be affected.
• If the disease-causing mutation cannot be detected in the DNA of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because the possibility of germline mosaicism exists.

Offspring of a proband

• Although many individuals with classic CdLS do not reproduce, mildly affected individuals may have offspring.
• Males with X-linked CdLS transmit the disease-causing mutation to all of their daughters and none of their sons.

Other family members of a proband. The proband's maternal aunts may be at risk of being carriers and the aunt's offspring, depending on their gender, may be at risk of being carriers or of being affected.

Carrier Detection

Carrier testing of at-risk female relatives is possible if the mutation has been identified in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Ultrasound examination. High-resolution ultrasound examination to follow growth and to evaluate the limbs, heart, diaphragm, palate, and other organs or structures affected in CdLS may be offered to families in which a disease-causing mutation has not been identified. Reported prenatal ultrasound findings:

• Increased nuchal translucency in the first trimester [Sekimoto et al 2000, Huang & Porto 2002]
• Growth failure, which typically presents in the second trimester
• The typical in utero facial profile of a fetus with CdLS consisting of micrognathia, a prominent upper lip, and a depressed nasal bridge with somewhat anteverted nares [Ranzini et al 1997, Boog et al 1999, Urban & Hartung 2001]

Maternal serum screening. Maternal serum PAPP-A (pregnancy-associated plasma protein A) level may be low in the first and second trimester if the fetus has CdLS [Westergaard et al 1983, Aitken et al 1999, Arbuzova et al 2003].

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

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Suggested Reading

1. Fitzpatrick DR, Kline AD. Cornelia de Lange syndrome. In: Cassidy SB, Allanson JE, eds. Management of Genetic Syndromes. 3 ed. New York, NY: Wiley-Liss; 2010:195-210. (A recent chapter by Drs. Fitzpatrick and Kline, Directors of the Cornelia de Lange Foundation of the UK and the United States, respectively).

Acknowledgments

We would like to acknowledge the continued support of the families we follow with CdLS as well as the CdLS-USA Foundation.

Revision History

• 27 October 2011 (me) Comprehensive update posted live
• 14 August 2006 (cd) Revision: SMC1L1 mutation scanning clinically available
• 31 July 2006 (cd) Revision: sequence analysis of entire NIPBL coding region clinically available
• 18 May 2006 (cd) Revision: mutations in SMC1L1 identified in some individuals with CdLS
• 24 March 2006 (cd) Revision: prenatal testing clinically available
• 16 September 2005 (me) Review posted to live Web site
• 12 January 2005 (ik) Original submission