Synonyms: de Lange syndrome, Brachmann syndrome, Brachmann-de Lange syndrome, Amstelodamensis typus degenerativus, Amsterdam dwarf syndrome
Cornelia de Lange syndrome (CdLS) is a rare and clinically variable disorder that affects multiple organs. It is characterised by intellectual disability (mild to severe), distinctive facial features, prenatal and postnatal growth restriction and hirsutism. Congenital anomalies include malformations of upper limbs, gastrointestinal malformations, diaphragmatic hernia, heart defects and genitourinary malformations.Besides the classical presentation, milder variants exist and clinical variability is well recognised. A classification dividing the disease into type 1 which is classical presentation and type 2 which is mild has been suggested.
Most often there is no family history of the condition and they are thought to be sporadic spontaneous genetic mutations. To date, five genes (NIPBL, SMC1A, SMC3, RAD21 and HDAC8) have been associated with CdLS and mutations in these genes comprise the underlying defect in 70% of these patients. However, the aetiology of a significant number of cases (about 30%) remains unknown.It is thought to be inherited largely as an autosomal dominant condition, although the mutations in HDAC8 or SMC1A gene are transmitted in an X-linked dominant manner. The empirical recurrence risk in a sibling of an affected child is estimated to be between 2-5%.
There are some descriptions of families with several affected children, although it is not thought to be a recessive disorder in those families. The basic problem appears to be the effect of the genetic mutation on cohesin, a protein which controls faithful chromosome segregation during mitotic and meiotic cell cycles.
Data from the database of the European Surveillance of Congenital Anomalies (EUROCAT), a European network of birth defect registries, showed a prevalence of the classical form of CdLS to be 1.24/100,000 births, or 1:81,000 births, and estimated the overall CdLS prevalence at 1.6-2.2/100,000. Severe limb anomalies were significantly more often present in males.
The exact incidence is unknown but CdLS possibly affects 1 in 10,000 to 30,000 newborns. It is probably underdiagnosed, as individuals with mild features may never be diagnosed.
In classical disease there is a highly distinctive and easily recognisable facial appearance at birth and it changes little throughout life. In children with mild disease this may be less obvious at birth but become more noticeable over the first two or three years of life; however, the characteristic face is lost by adulthood.
- There is premature delivery in a third of cases with evidence of intrauterine growth restriction (IUGR) in many.
- There is a highly distinctive facial appearance. There are well-defined and arched (pencilled) eyebrows, anteverted nostrils, a long philtrum, thin lips and a crescent-shaped mouth. The facial appearances are so distinctive that facial analysis systems may be used by the non-expert health provider in making the diagnosis.
- Both growth and intellectual development are impaired, frequently with behavioural problems.
- There are skeletal abnormalities.
- Other frequent problems involve the gastrointestinal system, the cardiovascular system, the eye and the ear.
Growth and development
In most newborns with CdLS there is prenatal onset growth failure with low weight and length at birth. There is symmetrical slow growth resulting in proportionate short stature which becomes significant by 6 months of age. This is much less marked in mild disease and this is a good, early criterion to distinguish the two. Mean height and weight are below the fifth centile throughout life.
Severe intellectual disability occurs in most individuals with CdLS with IQs ranging from 30 to 86 (mean 53). However, individuals with milder intellectual disability have also been reported.
Most individuals demonstrate autistic behaviour, including excessive repetitive behaviour and expressive language deficit. The profile of autistic behaviour in individuals with CdLS is different from idiopathic autistic spectrum disorder, with a significantly higher prevalence of self-destructive tendencies.
- Major upper limb abnormalities are the most common associated defects (73.1% in one series). They include hypoplastic or absent ulna.
- Oligodactyly can be bilateral but is not necessarily symmetrical. Both these findings are confined to classical disease.
- Severe malformations of the lower limbs are less common. Relatively small hands and feet are usually noted.
- Minor and variable anomalies include clinodactyly (deviation or deflection of the fingers), single palmar crease, proximal placement of the thumb or thumbs and syndactyly (union of two or more digits) of toes 2 and 3. All these may be features of other conditions. Radiological survey may help with uncertain diagnosis in mild cases.
Hypertrichosis may include long eyelashes, hirsutism on the back, and hypoplastic nipples and umbilicus. They are more common in the classical type than the mild phenotype.
Gastro-oesophageal reflux occurs in almost all children with CdLS and can lead to reflux oesophagitis and aspiration pneumonia unless recognised and treated.
Abnormalities of the gastrointestinal tract are common and contribute to feeding difficulties and failure to thrive. Pyloric stenosis is the most frequent cause of persistent vomiting in the newborn period and identified in 4%. Other abnormalities include intestinal malrotation (2%) and congenital diaphragmatic hernia (1%).
Congenital malformations of the heart occur in about 46%. Most common are ventricular septal defect, atrial septal defect, pulmonary stenosis and Fallot's tetralogy. The significance varies from minor to fatal.
These may be upper respiratory tract infections or pneumonia and affect up to 25%. Many respiratory problems are probably associated with gastro-oesophageal reflux. Severe complications due to bronchopulmonary dysplasia have also been described.
Sensorineural hearing loss is reported in 80% of children with CdLS with 40% being profoundly affected.
These are common. One study found myopia in 60%, ptosis in 45% and nystagmus in 37% of the 22 patients who were studied. Spectacles are poorly tolerated. Other problems described include glaucoma, nasolacrimal duct stenosis, microcornea, optic atrophy and coloboma of optic nerve.
They are common and include hydronephrosis, vesicoureteric reflux, subcortical renal cysts, renal dysplasia and hypoplasia. Renal function may be impaired. Hypogonadism and cryptorchidism affect more than half the boys.
- Central nervous system disorders occur in 40%, with seizures reported in nearly 25%.
- Heat intolerance is sometimes observed.
- There may be an absence of pain sensation.
- A characteristic low-pitched cry that tends to disappear in late infancy has been described in 75% of children with CdLS and is associated with more severe cases.
This is mainly between various other rare genetic disorders (partial duplication of 3q, deletions of chromosome 2q31, Fryns' syndrome) and fetal alcohol syndrome.
The diagnosis is based on a characteristic phenotype. The increased understanding of the genetic basis of CdLS has led to diagnostic improvement and expansion of phenotype. More than 300 CdLS-causing mutations are known and genetic confirmation can be achieved in nearly 70% of cases.
Investigations may be in order for the various abnormalities which are listed. Hearing screening should be undertaken. Echocardiography and ultrasound screening of the renal tract may be indicated. CT scanning of the temporal bone can be used to identify typical abnormalities of the external auditory meatus, middle ear and inner ear.
Although the management is mainly specialist-based, the GP's role is in ensuring overall health supervision, making sure hospital reviews take place and referring for genetic counselling. For spontaneous mutations the risk of recurrence is low.
Guidelines detailing recommendations for evaluation and management of individuals diagnosed with CdLS have been published.
Most early deaths are in severely affected babies and occur in the first two years of life. Survivors tend to have a slightly shortened lifespan. Respiratory causes, including aspiration and pneumonia, are the most common primary causes (31%) followed by gastrointestinal disease, including obstruction/volvulus (19%). Congenital anomalies, including congenital diaphragmatic hernia and congenital heart defects, account for 15% of the deaths.
Obstetric ultrasound may show IUGR. In one series, 68% of cases with major abnormalities were not detected by this method.However, careful observation for typical features such as diaphragmatic hernia, cystic hygroma or a right hand with only three rays can increase the detection rate in the second trimester.
The typical in utero facial profile of a fetus with CdLS has been described and consists of micrognathia, a prominent upper lip and a depressed nasal bridge with somewhat anteverted nares.
If the pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk can be done using molecular genetic testing.
The condition was first referred to by Brachmann in 1916 when he described an isolated case with autopsy findings. Cornelia de Lange published in 1933 and described two unrelated girls and proposed a new syndrome.
Little is known about Winfried Robert Clemens Brachmann. He was probably born in 1888 and killed in the First World War in 1916. His portrait and CV were destroyed in the Second World War.
Cornelia de Lange (1871-1950) was a Dutch paediatrician. She entered general practice but took an interest in paediatrics and, in 1907, was appointed physician to the Emma Kinderziekenhuis, where a new infants' ward was established on her initiative. She was appointed professor of paediatrics in 1927.
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