Cornelia de Lange syndrome (CdL syndrome) is a genetic dysmorphic syndrome. In association, there are severe to exceptionally mild cognitive disabilities. The expression and prognosis of this disorder are highly variable.
What is Cornelia de Lange syndrome?
When severe, Cornelia de Lange syndrome is very easy to diagnose based on the variety of physical dysmorphic features. Along with the physical changes, mental retardation always occurs. The mental disabilities are often severe to moderate. In exceptional cases, they may well be milder. Cornelia de Lange syndrome is a genetic disease, the exact cause of which is still not completely clear. The disease was described in 1933 by the Dutch pediatrician Cornelia de Lange in two children. The syndrome is also known as Brachmann-de Lange syndrome. Externally, the disease appears to be highly variable. The internal organs may also be affected. Patients particularly often suffer from reflux disease, which can be very painful. Cornelia de Lange syndrome occurs in one out of approximately 10,000 people. Life expectancy is limited, for example, because of complications from aspiration pneumonia after vomiting.
Causes
The cause of the syndrome is a genetic mutation. However, there is no single mutation. In about 50 percent of cases, mutations are found on the NIPBL gene, which is located in region p13 on chromosome 5. The gene produces the protein delangin (von de Lange), but its significance has not yet been recognized. The varying expression of the disease may be related to the fact that it is caused by different mutations of the NIPBL gene. In other cases, chromosomal alterations are conspicuous, but as in metabolic disorders, these are likely to be concomitant symptoms. Since variable manifestations of the disease also occur within a family, it is suspected that other genes are also involved in the pathogenesis of the disease. Studies have found that the siblings of an affected person may also suffer from this syndrome with a probability of 2 to 5 percent. In the case of autosomal recessive inheritance, the risk is 25 percent. In some cases, however, there are also indications of an autosomal dominant inheritance. In rare, more mild cases of CdL syndrome, recent findings suggest that it may be due to mutations in the SMC1A gene and the SMC3 gene.
Symptoms, complaints, and signs
The leading symptom of Cornelia de Lange syndrome is a general developmental delay that is observed long before birth during ultrasound examinations during pregnancy. The child is underweight and too small after birth. Right at the beginning, feeding problems occur due to gastroesophageal reflux. Reflux results from inadequate closure between the esophagus and stomach. The result is frequent vomiting with risk of aspiration. The frequently observed restlessness and autoaggressive behavior are probably due to the symptoms of reflux. Externally, fairly typical dysmorphic features occur, such as bushy meeting eyebrows, a large eye gap, long eyelashes, downward sloping eyelid axes, a large distance between the nose and mouth, a broad and flat nose with forward openings, low-set ears, a small lower jaw, and more. Abnormalities of the hands and feet can also be found. Sometimes congenital heart defects and epilepsies occur. The genitals are also poorly developed. Visual disturbances and hearing loss sometimes occur. Especially in the first years of life, the behavior is often autoaggressive with autistic features. Mental retardation is always present from severe to exceptionally mild forms.
Diagnosis
The diagnosis of Cornelia de Lange syndrome is based on the characteristic appearance. However, cytogenetic and molecular genetic findings are not yet available. Imaging techniques such as MRI can provide information about structural changes in the brain. Furthermore, developmental diagnostics with examination of sensory functions should be performed. X-ray examination is necessary if gastroesophageal reflux is suspected in order to treat it adequately.Differential diagnosis should delineate other syndromes such as Coffin-Siris syndrome, Peters-Plus syndrome, or oto-palato-digital syndrome.
Complications
Complications can occur at any time because of the complexity of Cornelia de Lange syndrome. The most obvious complication occurs when the lack of gastric closure makes it difficult to absorb food. If gastroesophageal reflux occurs due to this complication, the affected child may inhale portions of the food that has already been digested. Frequent vomiting can also lead to aspiration-related pneumonia or inhalation-related pneumonia. This complication may endanger the life of the affected person. Aspiration pneumonia always occurs when foreign substances such as gastric juice, seawater or other foreign substances are inhaled. The resulting pneumonia also causes local inflammatory reactions and respiratory disorders in Cornelia de Lange syndrome. This discomfort in turn favors a secondary or superinfection with other bacterial pathogens. The prognosis is particularly poor if gastric juice has been inhaled. It may take a long time for the symptoms of aspiration to manifest. Bronchospasm or increased secretions may be important signs of aspiration-related pneumonia. Breathing is difficult, and the patient may turn blue. Patients with Cornelia de Lange syndrome cannot be helped professionally without an immediate clinic visit. Sufferers must undergo bronchoscopy and antibiotic therapy immediately if radiography has confirmed the suspicion of aspiration-related pneumonia. Whether or not oxygen administration is necessary is decided on a case-by-case basis.
When should you go to the doctor?
If feeding problems occur after the sick child is born, this must be treated immediately. In most cases, Cornelia de Lange syndrome has already been diagnosed at this time. Parents should consult with the pediatrician on a regular basis and call 911 if complications arise. For example, signs of a heart defect or epilepsy should be clarified immediately so that countermeasures can be taken right away. In the event of an epileptic seizure or even a heart attack, the emergency services should be alerted immediately. With visual disturbances or hearing loss, it is best to consult the appropriate specialist. In the case of mental retardation, it is advisable to seek therapeutic support and to involve nursing staff at an early stage. Later in life, the affected child may also need psychological support, always depending on the severity of Cornelia de Lange syndrome and its symptoms. In principle, the affected person must receive medical and therapeutic care into adulthood and often beyond. The family doctor or pediatrician will assist the parents in finding the right contacts for the individual symptoms.
Treatment and therapy
Causal treatment of Cornelia de Lange syndrome is not possible. Early intervention as well as psychological and educational measures should begin as early as possible. Sometimes behavioral therapy is also necessary to attenuate the autoaggressive reactions. Targeted support results in continuous developmental progress. Treatment of gastroesophageal reflux is particularly important. It is responsible for the limited life expectancy of the affected person, as it can lead to aspiration pneumonia due to vomiting. In addition, it can often be responsible for the child’s autoaggressive behavior. If drug treatment is not sufficient, surgical intervention may be necessary. If facial abnormalities and limb malformations lead to functional limitations, surgical correction is also indicated. Furthermore, visual and hearing impairments should also be treated. From adolescence onwards, the hyperactive behavior slowly decreases on its own. The dwarfism as well as severe and moderate forms of mental retardation remain. Constant health monitoring of the patient is necessary to increase life expectancy.
Outlook and prognosis
A general prognosis cannot be given for Cornelia de Lange syndrome. This is very much dependent on the exact manifestation of the syndrome.However, there is no complete cure for this disease, as it is a hereditary disease that cannot be treated causally. For this reason, treatment is based only on the symptoms. Through special and targeted support, the symptoms can be alleviated and a normal development of the patient can be ensured. In most cases, medicinal treatment is sufficient for the further symptoms, and only in severe cases is surgical intervention necessary. If Cornelia de Lange syndrome is not treated, tumors may develop, reducing the patient’s life expectancy. Furthermore, the hearing difficulties and visual disturbances also have a very negative effect on the quality of life of the affected person and may continue to worsen without treatment. Although treatment cannot completely resolve these disorders, it can stop further deterioration. However, sufferers are still dependent on regular examinations in order to avoid further complications. In this regard, it cannot be generally predicted whether the syndrome will lead to a decreased life expectancy in the patient.
Prevention
Prevention of Cornelia de Lange syndrome is not possible. It is a genetic disorder that usually occurs sporadically. However, if it occurs sporadically, siblings of affected individuals already have a 2 to 5 percent chance of also being born with the syndrome. In the case of autosomal recessive inheritance, the probability is as high as 25 percent. Therefore, genetic counseling should be sought in affected families.
Follow-up
The problem with Cornelia de Lange syndrome is that although it is inherited in childhood, it is usually not diagnosed until much later. Symptomatic treatment therefore often takes a long time. Drug treatment is difficult. Because of the rarity of Cornelia de Lange syndrome, only a few drugs are currently available with a suitability for the complex symptomatology. Early medical intervention and surgical treatments for the severe defects associated with Cornelia de Lange syndrome are the first line of treatment. After diagnosis, socio-medical aftercare often becomes the most important issue. The goal of aftercare is to make life as tolerable as possible for the affected children and adolescents and their severely burdened families. The integration of interdisciplinary treatment strategies is useful in Cornelia de Lange syndrome. Aftercare also includes offering patients aids to combat cognitive deficits through computer-assisted memory training or learning training sessions. For the aftercare of Cornelia de Lange syndrome, financial assistance can be applied for from various institutions – if necessary, also through associations that provide support for the socio-medical aftercare or for any necessary preventive care. In most cases, the affected children are awarded a higher care level.
What you can do yourself
Cornelia de Lange syndrome is associated with a variety of congenital anomalies. The causes of the disease have not been conclusively determined to date. There are neither conventional medical nor alternative procedures aimed at treating the disease causally. However, those affected and their relatives can help to alleviate the symptoms and make everyday life more bearable. The disease is already noticeable in infants. In children, there is often a slowed development that particularly affects intellectual abilities. All those affected suffer from mental retardation, but the severity of this can vary. For the affected children, it is important that they receive optimal support as early as possible. The mental development can be positively influenced by adequate psychological and educational measures. Furthermore, behavioral therapy is often necessary to moderate the autoaggressive reactions of the patients. Since caring for and living with a mentally and physically handicapped child can also be very stressful for the parents and other family members, this group of people should not be afraid to seek psychological help or join a self-help group.
