Introduction: Cornelia de Lange syndrome is an uncommon developmental disorder. Due to the low incidence of these cases and therefore the limited knowledge about them, it was necessary to carry out this review in order to help raise the level of knowledge on the subject, allow the detection of some clinical features of patients with this syndrome and thus improve their care. Objective: describe the main cognitive-behavioral characteristics of Cornelia de Lange syndrome, taking into account its definition, etiology, symptoms and signs, diagnosis, treatment and life expectancy of patients suffering from it. Method: a bibliographical review of the editions of the classic books of Genetics, Embryology and Obstetrics was carried out, in addition to online databases such as: Medline, Scielo, Scopus, Ebesco, Google academico; a total of 45 bibliographies were reviewed, of which 26 were selected for the preparation of the article. Development: the causes of this syndrome are genetically heterogeneous. Prenatal diagnosis is limited to the detection of major abnormalities, therefore it is difficult to identify the phenotypic features of this pathology. Treatment varies depending on the signs and symptoms in each person. To improve their quality of life, the child may undergo language therapy. Conclusions: at the cognitive level this syndrome is associated with intellectual disability and psychomotor retardation. Among the behavioral alterations are: hyperactivity, heteroaggressiveness, self-aggressiveness and obsessive-compulsive behaviors.
Cognitive development, Behavioral development, Psychomotor development, Genetic diseases, Genetic mutations, Cornelia de Lange syndrome.
Genetic diseases constitute a large group among those that affect the pediatric population, constantly increasing infant mortality in developed and developing countries, in addition to being also responsible for a large part of admissions to pediatric hospitals [1] .
Among genetic diseases, there is a very characteristic and little-known syndrome: Cornelia de Lange syndrome ( CdLS ), named after Dr. Cornelia de Lange, a Dutch pediatrician born in 1871 who was a pioneer in medicine and became a classical scholar and a decisive authority in pediatrics in the first half of the twentieth century. In 1933, she described and published two cases with a remarkable clinical appearance and surprising similarity. [23] .
Cornelia de Lange syndrome is a rare, genetically heterogeneous disorder that affects the physical and intellectual development of the patient. It is a multisystem disorder marked by growth retardation. It is caused by hypoplasia of the embryonic mesenchyme due to a chromosomal abnormality that generates alterations in the nervous, musculoskeletal and gastrointestinal systems along with craniofacial and limb malformations, characterized by intrauterine and postnatal growth retardation, microcephaly, distinctive facial features, synophris , hirsutism , mental retardation and micromelia, among others (3-6).
In 2004, researchers at Children's Hospital of Philadelphia discovered the first mutated gene, the NIPBL gene located in the 5p13.2 region, responsible for more than half of the cases with this syndrome. Two years later, Italian scientists found a second mutated gene related to this syndrome, the SMC1A gene, in the Xp11.22 region [6] .
In 2007, the same Philadelphia research team that discovered the first gene causing the syndrome, found a third mutated gene, the SMC3 gene located in the 10q25 region, which seems to correlate with a milder form of the syndrome , together with the SMC1A gene. In 2012, these Philadelphia researchers located two other mutated genes that are related to this genetic disorder, the RAD21 gene, in the 8q24.11 region and the HDAC8 gene on the X chromosome; it intervenes, like the first three genes found, in the so-called cohesin complex [6] .
CdLS does not discriminate by race or ethnic origin and affects both sexes equally, with a slight female predominance. Although cases of this syndrome are sporadic, it has been described in several families and in twins, due to consanguinity between parents and with chromosomal abnormalities, and some epidemiological aspects have been reported in certain series. Worldwide research on the subject is related to promoting psychomotor development through physiotherapy intervention strategies (7-9).
worldwide prevalence is currently estimated to be between 1:10,000 and 1:30,000 births and is genetically related to alterations in chromosomal cohesion. In Europe, the birth prevalence of this syndrome has been estimated at 1:80,000. In Cuba, there is little research on this syndrome, due to the few diagnosed cases or because of the few cases. At the Julio Díaz Rehabilitation Center, two cases received physical therapy, and progress was achieved in their motor development. In the province of Granma (Manzanillo municipality), there is one diagnosed case that was evaluated at four months of age, published in the Correo Científico Médico journal of Holguín, which constitutes a reference for the present study (6-9).
Currently, there are support groups and organizations that are very useful for those diagnosed with this disease to connect with other patients and families. Many of them provide patient-centered information and promote research to develop better treatments and find possible cures [6], [8] .
These organizations are very helpful in conducting research studies and utilizing relevant resources and services, as many of them have expert medical advisors or can provide lists of physicians and/or clinics . In Cuba, there is still no organized multidisciplinary team for the management of these patients, so early diagnosis is essential to allocate resources for the multifaceted management of these patients [8], [9] .
Despite being a rare genetic disease, the fact that the only case historically diagnosed in Manzanillo [9] belongs to the same health area as the authors, was the motivation to carry out a review of the causes of this disorder, as well as the treatment and life expectancy, among other aspects, to contribute in a certain way to raise the level of knowledge on the subject, collaborate so that people can detect some clinical features of patients with this syndrome and help improve their care, since the difficulty in early diagnosis of patients with Cornelia de Lange syndrome continues to be a practical problem [8] .
Therefore, the objective of this study is to describe the main cognitive-behavioral characteristics of Cornelia de Lange syndrome, taking into account its definition, etiology, symptoms and signs, diagnosis, treatment, and life expectancy of patients who suffer from it.
An electronic and manual bibliographic review was carried out of the editions of the classic books on Genetics, Embryology, Obstetrics that were found in force in the library of the Faculty of Medical Sciences of Manzanillo, belonging to the University of Medical Sciences of Granma and of online databases such as: PubMed, SciELO, Scopus , EBSCO and Google Scholar, of articles on Cornelia de Lange syndrome published mainly in the period from 2018 to 2023; a total of 45 were reviewed, of which 26 were selected for the preparation of the article. The keywords used were: Cornelia de Lange syndrome, Psychomotor development, Genetic mutations, Genetic diseases.
Cornelia de Lange syndrome is a group of developmental abnormalities affecting multiple parts of the body. The exact percentage of the population affected by this disorder is unknown, but it is estimated that the condition affects 1 in every 10,000 to 30,000 newborns (7-10).
The causes of Cornelia de Lange syndrome are genetically heterogeneous. To date, a total of 7 genes related to this disorder have been discovered, which differ in the clinical findings they present: NIPBL, SMC1A, SMC3, RAD21, HDAC8, ANKRD11 and BRD4. When there is an alteration in one of these genes, the so-called ' cohesin complex ' is affected, which means that this protein complex does not function properly in the body's cells, thus altering normal human development [6], [8], [11], [12] .
The main genetic alteration that causes Cornelia de Lange syndrome is a mutation (or pathogenic variant) in the NIPBL gene. However, there are other cases caused by mutations in the SMC1A, SMC3, HDAC8, and RAD21 genes, although mutations in the latter are found in smaller numbers . [8], [11], [12] . The NIPBL gene is given great importance in human development, since it is responsible for encode the protein delangin , which controls the activity of chromosomes during cell division and intervenes in the tasks of other genes responsible for the normal development of the fetus [12], [13] .
However, Ballesta in his chapter on genetic diseases in the book Medical Genetics, states that the cause of this syndrome is unknown, but the diversity of anomalies it presents suggests that the intervention of the pathogenic agent takes place in a very early phase of embryonic development [2] .
This syndrome involves various congenital defects that can affect the upper limbs and the digestive, cardiovascular, genitourinary, auditory and ophthalmological systems. The pathogenetic basis of the syndrome is not clear, but appears to be related to problems in the regulation of gene expression and chromosomal cohesion [14] .
SCdL can be easily recognized by a clinical geneticist or pediatrician from birth, because these patients usually present some characteristic facial features, growth disorders and limb malformations that configure the classic SCdL phenotype , although this does not mean that a person diagnosed with SCdL will show all the characteristics described within the syndrome, since there may be different degrees of affectation in the face or limbs [8] .
Cornelia de Lange syndrome is commonly characterized by:
Poor growth before or after birth (>95%): Growth difficulty that begins when the baby grows inside the womb, resulting in very low height and weight throughout life and difficulty gaining weight due to gastroesophageal reflux and other feeding problems.
Short stature .
Intellectual developmental delay (>95%) that can be mild or severe, although it is usually severe .
Small, flat head ( microbrachycephaly ) .
Thick, highly arched eyebrows that meet at the forehead ( synophris ) (in 98% of cases) .
Long and thick eyelashes .
Visual disorders that include a variety of levels of vision loss.
Ears in a low position with a thick rim (helix) .
Hearing loss .
Small nose with an upturned tip and nostrils that can be easily seen ( anteverted nares ) .
Long space between the nose and the upper lips .
Thin, downturned lips .
Small, widely spaced teeth .
High arched palate with clefts (30% of cases) .
Very small jaw (micrognathia) in 80% of cases and with spurs (42% of cases) .
Short neck .
Heart defects .
Digestive system disorders .
Limb abnormalities (>95%). Small or absent forearms and missing fingers are present in approximately 30% of cases. Some individuals have micromelia (small arms and hands), abnormally positioned thumbs, and clinodactyly (permanent deviation of one or more fingers or toes laterally or medially from their midaxis) . Fusion of the forearm bones ( radioulnar synostosis ) is common and can result in elbow defects. Small feet with some of the fingers joined together (syndactyly) are present in more than 80% of cases.
Hirsutism on the face, back and arms in more than 80% of cases.
Seizures .
Behavioral problems similar to those of children with autism (12-17).
Clinically, three phenotypes are distinguished: mild, moderate, and severe, each determined by three parameters: level of development and cognitive abilities, growth percentile, and degree of limb reduction. In the mild phenotype, there is no limb reduction, there is motor delay <2 years, they have speech and communication capacity and in terms of growth, >75 percentiles. In the moderate phenotype, there are partial alterations, oligodactyly (>2 fingers on each hand), motor delay >2 years with limited speech and communication, with a percentile between 25-75. Regarding the severe phenotype, there is the presence of severe limb alterations, profound motor delay, significant loss of communication, with a percentile <25 [10] . Most cases are sporadic, although some present autosomal dominant inheritance. Although there is variability in the clinical expression and intensity of the features, this syndrome is recognizable by the phenotype, and a certain physical resemblance is observed between affected patients. The diagnosis of Cornelia de Lange syndrome is based on the recognition of physical findings and is confirmed by chromosomal study [12] .
Mutations in the NIPBL gene are responsible for the presence of congenital malformations in the central nervous system of some patients diagnosed with this syndrome. These structural abnormalities can affect the cerebrum, cerebellum, and brainstem [8], [18] .
Regarding cognitive level, this syndrome is linked to intellectual disability and psychomotor delay. Depending on the degree of intellectual impairment, the intelligence level can be lower than 30, in cases with severe disability, to scores similar to the population average, linked to learning deficits. Greater importance has been attributed to language, which is directly related to the degree of intellectual disability and varies from a lack of understanding of language to a greater ability to understand it than to express it, in addition to its limited use once learned (18,19 ).
This lack of communication, together with the discomfort caused by some of the medical conditions described above, as well as gastroesophageal reflux, encourage the sudden mood and behavioural changes that people with this syndrome may experience. Thus, the behavioural alterations of SCdL are quite common and occur more frequently in cases of greater intellectual disability, among which the following stand out: hyperactivity, heteroaggression and autoaggression , rigidity in the face of change, obsessive-compulsive behaviour and depression [19] .
Likewise, an association has been found between autistic traits and CdLS , which are also more pronounced at a lower intellectual level. Some of these are: stereotypies, avoidance of social interaction and physical contact, and rocking. The breadth of the alterations described requires early multidisciplinary attention that encompasses actions aimed at improving and monitoring medical conditions, the development and/or maintenance of individual cognitive abilities that affect the possibility of communication and language, and the modification of future behavioral manifestations [19] .
With age, the behavioral, cognitive, and emotional characteristics of CdLS may vary; some studies suggest a relationship between a greater number of behavioral limitations in patients with this syndrome and age. [8] . These changes have been reported to affect verbal working memory, autism spectrum disorder (ASD) symptoms, anxiety, low mood, self-injurious behavior, and impulsivity. Aggression, hyperactivity, and sleep difficulties in CdLS do not necessarily become more common with age [18] .
Prenatal diagnosis of this syndrome is limited to the detection of major abnormalities, since its phenotypic features are not easily detectable, although it may be suspected by ultrasound during the second and third trimesters of pregnancy. It usually presents with increased nuchal translucency, cystic hygroma, and low PAPP-A values in the first trimester of pregnancy; intrauterine growth retardation, retromicrognathia , anomalies of varying severity in the upper extremities, and other cardiovascular, gastrointestinal, or genitourinary abnormalities that affect the fetal prognosis. The diagnosis is suspected when the aforementioned characteristics are present (20-22).
In underdeveloped countries, where molecular studies are not available to establish the diagnosis of patients with SCdL , it is essential to define the morphological characteristics of the fetus to provide families with multiple reproductive options, an adequate prognosis , anticipate the needs of the newborn and promptly implement available treatments [8] .
People with the mildest manifestations of the syndrome mostly have many of the same facial characteristics, but cognitive and lower limb limitations are less severe, and intellectual deficit is mild (intelligence is normal in some cases) [22], [23] .
The diagnosis of Cornelia de Lange syndrome is established by the presence of clinical features and/or by genetic testing that reveals a variant in any of the genes described above. However, approximately 30% of individuals affected by the syndrome do not have any of the known variants [24] .
Until a few years ago, many of these children died from very severe medical problems and the cause was unknown, now this is no longer the case, since they can live a long time in the family environment if they are provided with good therapies and good medical care, there have been great achievements in treatment during the last years [25] . Treatment varies according to the signs and symptoms present in each person. It may include [4] :
Medications to control seizures and prevent them.
In some cases, surgery is required to correct skeletal abnormalities, gastrointestinal problems, or other health problems.
Speech, occupational and physical therapies.
Sometimes the placement of gastrostomy tubes is necessary to correct nutritional problems and prevent growth retardation.
Orthopedic intervention may be necessary for contractures, bunions, scoliosis, etc.
Dental care.
Health personnel recommend that children suffering from SCdL should stay in places with a calm, low-excitability environment to avoid hyperactivity and other behaviors characteristic of these patients, in which they can harm themselves [4] .
Newborns with CdLS can experience full and happy growth, as the syndrome itself does not threaten their life expectancy. Timely medical care, rehabilitation, and family counseling are key to improving the quality of life of these patients. Each person with this syndrome is unique, and their treatment and therapeutic management will be guided by their personal characteristics and development [8], [9], [26] .
Likewise, to improve the quality of life, the child can undergo language therapies and thus stimulate speech and communication, a delay that occurs in most cases [9] .
Cornelia de Lange syndrome is a rare genetic disorder that occurs equally in men and women, with a slight female predominance. The behavioral, emotional, and cognitive characteristics of CdLS may change with age. At the cognitive level, this syndrome is associated with intellectual disability and psychomotor delay. Behavioral disorders include hyperactivity, heteroaggression , autoaggression , and obsessive-compulsive behaviors. Multisectoral care based on an early diagnosis of the disease will allow for the child's full development and reduce the risk of future complications.
KCGB: conceptualization, research, data curation, formal analysis, writing of the initial draft, review and editing, approval of the final version.
NMMLl: Conceptualization, investigation, data curation, formal analysis, writing of initial draft, review and editing, approval of final version. YMP
The authors declare that there are no conflicts of interest.
The authors did not receive funding for the development of this article.
Copyright 2024 Katherine de la Caridad Garrido-Benítez 1 et al.
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