Cornelia De Lange Syndrome

Cornelia de Lange syndrome is also known as de Lange syndrome because Cornelia was her Christian name. Other names include Brachmann syndrome and Brachmann-de Lange syndrome. It is also known as Amstelodamensis typus degenerativus, as Cornelia de Lange named it and Amsterdam dwarf.

This is a syndrome of multiple congenital abnormalities with mental retardation. Not all features are invariably present and the severity can vary considerably. The disease is divided into type 1 that is classical presentation and type 2 that is mild.¹ The classical and mild phenotypes seem almost as different entities.²

Most often there is no family history of the condition and they are thought to be sporadic spontaneous genetic mutations. OMIM lists it as #122470 with mutation at gene point 5p13.1. It is thought to be inherited as a autosomal dominant but it is so lethal that it is rarely transmitted from parent to child.³ There are some descriptions of families with several affected children although it is not thought to be a recessive disorder in those families.

OMIM also gives as #300590, an X-linked variation of this disorder linked to gene locus Xp11.22-p11.21.

The incidence is variously given as 1 in 40,000 to 1 in 50,000⁴ with the occasional estimate as high as 1 in 10,000.

If a previous sibling is affected, the risk to another is between 0.5 and 1.5%. If a parent is affected the risk is 50%.

In classical disease there is a highly distinctive and easily recognizable 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 2 or 3 years of life but the characteristic face is lost by adulthood.

• There is premature delivery in a third of cases with evidence of intrauterine growth retardation in many.
• There is a highly distinctive facial appearance. There are well-defined and arched (pencilled) eyebrows, anteverted nostrils, long philtrum, thin lips, and crescent-shaped mouth.
• Both growth and mental development are retarded, 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 classical disease, the weight is often 2.5SD below the mean at birth but falls to 3.5SD soon after. This is much less marked in mild disease and this is a good, early criterion to distinguish the two. Height, weight and head circumference all remain low right through until adult life.

Mental development and behaviour

Severe mental retardation occurs with the classical phenotype but in mild disease it is mild to borderline.

Behavioural problems include:⁵

• Sleep disturbance (55%)
• Daily aggression (49%)
• Self-injury (44%) This is more common over the age of 12. A diminished responsiveness to pain has been associated both with mental retardation and with autism, and it might contribute to self-injury.
• Hyperactivity (40%)
• Compulsive behaviours

Skeletal abnormalities

• Major upper limb abnormalities 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 (usually suggests Down's syndrome), 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.⁶

Cutaneous abnormalities

Hypertrichosis may include long eyelashes and hirsutism on the back, and hypoplastic nipples and umbilicus. They are more common in the classical type than the mild phenotype.

Gastro-intestinal problems

Abnormalities of the alimentary canal are common. They contribute to feeding difficulties and failure to thrive.⁷ Pyloric stenosis is the most frequent cause of persistent vomiting in the newborn period.

Approximately two thirds of children are first seen with clinical signs that might originate from this area.

Gastro-oesophageal reflux is also very common and may cause hyperactivity.

Cardiovascular disease

Congenital malformations of the heart occur in about 15%. Most common are ventricular septal defect, atrial septal defect, pulmonary stenosis, and tetralogy of Fallot. The significance varies from minor to fatal.

Respiratory problems

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.

Hearing deficits

This is reported in 60 to 100% of all affected children. A study found stenosis of the external auditory canals in 80% and hearing loss ranging from mild to severe.

Ophthalmic abnormalities

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.

Genitourinary anomalies

They are common and include hydronephrosis, urethral reflux, subcortical renal cysts, renal dysplasia, and hypoplasia. Renal function may be impaired. Hypogonadism and cryptorchidism affect more than half the boys.

Other problems

• Seizures have been reported in nearly a quarter.
• Heat intolerance is sometimes observed.
• There may be an absence of pain sensation.

This is mainly between various other rare genetic disorders and fetal alcohol syndrome.

The diagnosis is based on a characteristic phenotype. In some cases, molecular analysis of the NIPBL gene allows confirmation of a mutation and provides the basis for prenatal diagnosis in families with transmission from a parent.

Investigations may be in order for the various abnormalities that are listed. Hearing screening should be undertaken. Echocardiography and ultrasound screening of the renal tract may be indicated.

Medical and surgical interventions may be required for the various associated problems.
Genetic counselling should be offered. For spontaneous mutations the risk of recurrence is low.

Most early deaths are in severely affected babies and occur in the first 2 years of life. Survivors tend to have a slightly shortened life span.⁴

Obstetric ultrasound may show IUGR and second trimester maternal serum pregnancy-associated plasma protein-A (PAPP-A) measurements may have predictive value as an addition.⁸

The condition was first described by Brachmann in 1916 when he described an isolated case with autopsy findings.⁹ Cornelia de Lange published in 1933¹⁰ 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 was a Dutch paediatrician, born in 1871 and died in 1950. She entered general practice but took an interest in paediatrics and in 1907 she 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.