מידע

מה זה תסמונת  קורנליה דה לנגה ?


 תיסמונת זה קורנליה דה לנגה (CdLS) is a rare developmental disorder that is present from birth. The syndrome was named after the Dutch children’s doctor Cornelia de Lange, who first described the disorder in 1933 (1). It is estimated that between 1 in 10,000 and 1 in 30,000 people in the population have CdLS (2).

CdLS can affect many parts of the body and individuals with CdLS may display physical, cognitive and behavioural characteristics (1). Cognitive characteristics are brain-based processes like memory and thinking. Behavioural characteristics refer to certain behaviours that individuals with CdLS are more likely to have. These characteristics can vary widely among affected individuals and range from small differences compared to other people to very noticeable differences.

Classic (or typical) CdLS can be easily recognised from birth by an experienced children’s doctor (paediatrician) or clinical geneticist (a doctor who diagnoses and supports families with genetic disorders). This is because individuals with CdLS often have distinctive facial features, growth patterns, and limb differences (see Figure 1 ). These characteristics form the classic CdLS phenotype, which the physical, cognitive and behavioural characteristics associated with the syndrome.

It is important to note that if a person has a diagnosis of CdLS it does not mean they will display all the characteristics associated with the syndrome. There may be different degrees of difference in the face and limbs for example. It is also very important to remember that everyone with CdLS is an individual and will also have characteristics passed down from their family.

CdLS is a genetic disorder. This means that it is caused by a change in genetic material; this change is called a mutation. The genetic causes of CdLS are complicated and research to fully understand all the genetic causes is still ongoing. CdLS is usually caused by a change in one of seven genes (individual genetic instructions in DNA that make us who we are). The seven genes associated with CdLS are named: NIPBL, SMC1A, SMC3, RAD21, BRD4, HDAC8 and ANKRD11. A change in one of these genes affects the ‘cohesin complex’. This means that the cohesin protein complex does not function as it should in the cells of the body, causing altered human development. See the section ‘What causes Cornelia de Lange Syndrome’ for more information.

a
b
c
d
e
f
g
h

Fig. 1 | Facial phenotype of individuals with Cornelia de Lange Syndrome.
a | Classic Cornelia de Lange Syndrome (CdLS) phenotype resulting from an NIPBL variant. b | Non-classic CdLS phenotype in an individual with an NIPBL variant. c | Adult with NIPBL variant and classic phenotype. d | Non-classic phenotype in individual with an SMC1A variant. e | Classic phenotype in an individual with an SMC3 variant. f | Non-classic phenotype in an individual with a RAD21 variant. g | Non-classic phenotype in an individual with an HDAC8 variant. h | Non-classic phenotype in an individual with an ANKRD11 variant.

Over the last 10 years, genetic tests have been developed for the diagnosis of individuals with developmental disorders. These genetic tests are performed by molecular geneticists and can identify changes in any of the seven genes that are associated with CdLS. Genetic tests have shown that there is an overlap in the causal genes and characteristics of individuals with CdLS and other developmental disorders.

For example, some changes in the SMC1A gene have been identified in individuals with characteristics that resemble Rett syndrome (another neurodevelopmental disorder associated with intellectual disability) and few characteristics that resemble CdLS. This is despite SMC1A being confirmed as a causal gene for CdLS (3). Another example is that some individuals have changes in genes (such as ANKRD11 and NAA10) that are associated with developmental disorders other than CdLS but they show characteristics associated with the CdLS phenotype (4,5).

As a result, the overall CdLS phenotype has been characterised as a spectrum, implying a range of clinical findings and characteristics (see Figure 2). The CdLS spectrum includes the classic (typical) CdLS phenotype, alongside other syndromes with similar but non-classic (atypical) characteristics of CdLS, which are caused by changes in genes associated with CdLS.

Note: Syndromes caused by changes in genes associated with CdLS, but without many CdLS characteristics are not included in the spectrum.

Other phenotypes sharing limited signs of CdLS Non-classic CdLS phenotype Classic CdLS phenotype Variant in a gene involved in dysregulated cohesin functioning CdLS spectrum ? Variant in other gene

Fig. 2 | The phenotypes classified as Cornelia de Lange Syndrome (CdLS) can be defined as a spectrum.
All seven identified genes that are associated with CdLS affect the cohesin complex. The CdLS spectrum includes individuals with the classic CdLS phenotype in whom the affected gene has or has not been identified (if a genetic test is unable to identify a CdLS diagnosis, this can be determined through assessment of clinical features). The spectrum also includes individuals with a non-classic CdLS phenotype who have a gene variant affecting the cohesin complex. There are also individuals who carry a gene variant involved in cohesin functioning but present little or no resemblance to the classic CdLS phenotype. These individuals do not fall within the CdLS spectrum. Note that both classic and non-classic CdLS may affect individuals mildly or severely. The question mark in the figure indicates that there may be genes causing CdLS spectrum that do not have a cohesin function; such genes are unknown at present, but they may exist and must not be excluded.

Grouping individuals affected into the CdLS spectrum helps knowledge exchange and contact between affected individuals and their families. This means individuals and families can support each other; and leads to increased attention from researchers. However, identification of differences between individuals within the CdLS spectrum is also important to tailor care to each individual.

The International CdLS Consensus Group

Due to the great variability of the CdLS spectrum, as well as in the care and management of individuals, a group of international experts have formed the “International CdLS Consensus Group” to make a series of recommendations. Experts in this group are part of the Scientific Advisory Council of the World Federation of CdLS Support Groups. These recommendations are outlined and explained throughout this document and the full list of recommendations is also available at the end.

What are the Physical Characteristics of Cornelia de Lange Syndrome?

There are a combination of signs and symptoms that define the CdLS spectrum phenotype. Experts from the International CdLS Consensus Group (see Table 1 for voting process) have classified these into cardinal features (considered to be most common in CdLS) and suggestive features (which are less specific to CdLS) (Recommendation 1 = R1). When assessing characteristics, cardinal features are assigned 2 points each if present, and suggestive features are given 1 point each if present (R2; See Box 1).

Table 1: Details of the Delphi consensus voting process (structured communication process between a panel of experts used to gain consensus on the CdLS recommendations).

Level of evidenceDefinitionVotes (%)
+++Evidence or general agreement indicate full agreement with the recommendation≥70
++Evidence or general agreement favour the recommendation50–69
+Evidence or general agreement are weak for the recommendation26–49
Insufficient evidence or general agreement for the recommendation<26

37 international experts voted on the recommendations digitally. For all recommendations, over 90% of experts were in full agreement with the recommendations. Patient group representatives did not vote.

Box 1: Clinical features of Cornelia de Lange Syndrome

 Feature Cardinal Features1 Suggestive features2
Meeting of the medial eyebrows in the midline and/or thick eyebrowsX
Short noseX
concave nasal ridge (nasal ridge curving posteriorly to an imaginary line that connects the nasal root and tip)X
nose with an upturned tipX
Long, indistinct philtrum (vertical indentation in the middle area of the upper lip)X
Thin upper lipX
downturned corners of mouthX
Presence of fewer than the normal number of fingers and/or absence of fingers or toes from birthX
Congenital diaphragmatic hernia (abnormal opening in the diaphragm present from birth)X
Global developmental delay and/or intellectual disability/learning disabilityX
Prenatal growth retardation (restricted growth prior to birth)X
Postnatal growth retardation (restricted growth after birth)X
Microcephaly (decreased size of head, can occur prior to or after birth)X
Small hands and/or feetX
Short fifth fingerX
Abnormally increased hair growthX
  1. ^ considered to be the most common; 2 points each if present
  2. ^ less specific to CdLS; 1 point each if present

Clinical score

  • 11 points and above, of which at least 3 are cardinal: classic CdLS
  • 9 or 10 points, of which at least 2 are cardinal: non-classic CdLS
  • 4-8 points, of which at least 1 is cardinal: individual should be genetically tested for CdLS
  • Less than 4 points: insufficient to indicate genetic testing for CdLS should conducted

It is important to remember that an individual with CdLS may not have all of these characteristics. An individual with CdLS may have many of these characteristics or only a few.

CdLS Spectrum Clinical Criteria (scoring)

The International CdLS Consensus Group has agreed on criteria for the CdLS spectrum which is based on the cardinal and suggestive features (as shown in Box 1). These criteria are based on points.

  • A score of 11 or more indicates classic CdLS if at least 3 cardinal features are present.
    If a score of 11 or more is reached the diagnosis of CdLS is confirmed, regardless of whether there is a change in one of the 7 known genes for CdLS.

  • A score of 9 or 10 indicates non-classic CdLS, if at least 2 cardinal features are present.
  • A score of 4 or more is sufficient to warrant genetic testing for CdLS if there is at least 1 cardinal feature present.
  • A score of 4 or less is insufficient to warrant genetic testing.

The following figure shows some of the cardinal features of CdLS:

Fig. 3: Cardinal facial features of Cornelia de Lange syndrome. Facial features that are the most characteristic for Cornelia de Lange Syndrome (CdLS) include the meeting of the medial eyebrows in the midline, thick eyebrows, a short nose, concave nasal ridge and upturned nasal tip, a long and smooth philtrum, a thin upper lip and downturned corners of the mouth. Non-facial features (not shown) that are considered to be cardinal features of CdLS include the absence of one or more fingers, the absence of all fingers and/or toes and hernias in the diaphragm.

Severity Scores

Severity scoring procedures have been described to indicate the severity of CdLS (2,10,11,12). It should be noted that none of these procedures consider the severity of CdLS as experienced by families. Scoring procedures also do not estimate the severity of all organ systems that may be affected in CdLS.

The International CdLS Consensus Group suggests current severity scoring schemes should be used cautiously. The group acknowledges the need for the development of a severity score that represents severity as experienced by families (R3).

summary section

Physical characteristic recommendations:

R1: The CdLS spectrum encompasses a range of phenotypes consisting of classic (or typical) CdLS and non-classic CdLS, which are characterised by a combination of features (see Box 1).


R2: The International CdLS Consensus Group propose consensus criteria based on the presence of a combination of signs and features (see Box 1). A diagnosis of classic CdLS can be confirmed if a score of 11 is reached, irrespective of the presence of a variant in a gene known to result in CdLS.


R3: Presently available severity scoring schemes should be used cautiously as these do not adequately reflect the severity as experienced by the individuals with CdLS and their families.

מצא דפים אחרים שחולקים את אותו נושא כמו דף זה Introduction2 Introduction7 Introduction2
Antonie D. Kline, Joanna F. Moss, […]Raoul C. Hennekam
Antonie D. Kline, Joanna F. Moss, […]Raoul C. Hennekam

Adapted from: Kline, A. D., Moss, J. F., Selicorni, A., Bisgaard, A., Deardorff, M. A., Gillett, P. M., Ishman, S. L., Kerr, L. M., Levin, A. V., Mulder, P. A., Ramos, F. J., Wierzba, J., Ajmone, P.F., Axtell, D., Blagowidow, N., Cereda, A., Costantino, A., Cormier-Daire, V., FitzPatrick, D., Grados, M., Groves, L., Guthrie, W., Huisman, S., Kaiser, F. J., Koekkoek, G., Levis, M., Mariani, M., McCleery, J. P., Menke, L. A., Metrena, A., O’Connor, J., Oliver, C., Pie, J., Piening, S., Potter, C. J., Quaglio, A. L., Redeker, E., Richman, D., Rigamonti, C., Shi, A., Tümer, Z., Van Balkom, I. D. C. and Hennekam, R. C. (2018).

היסטוריית הדף
Last modified by Paola הודיה Mannucci הראל on 2020/12/18 19:50
Created by Gerritjan Koekkoek on 2019/03/27 15:09
Translated into iw by Paola הודיה Mannucci הראל on 2020/12/18 19:41

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