Cornelia De Lange Syndrome

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Synonyms: Cornelia de Lange syndrome (CdLS) is also known as de Lange syndrome because Cornelia was her first name. Other names include Brachmann syndrome, Brachmann-de Lange syndrome. It is also known as Amstelodamensis typus degenerativus, as Cornelia de Lange named it, or Amsterdam dwarf syndrome (in recognition of de Lange's paediatric practice in Amsterdam).

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. While causative mutations in three genes have been identified, the aetiology of a significant number of cases remains unknown.[3] The mutation at gene point is at 5p13.1.[4] It is thought to be inherited as an autosomal dominant condition but it is so lethal that it is rarely transmitted from parent to child.[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.[6]

There is an X-linked variation of this disorder linked to gene locus Xp11.22-p11.21.[7]

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Data from the database of 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.

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, 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 2.5 SD below the mean at birth but falls to 3.5 SD 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:[9]

  • 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.[10]
  • Hyperactivity (40%).
  • Compulsive behaviours.
  • Social anxiety.[11]

Skeletal abnormalities

  • Major upper limb abnormalities are the most common associated defects (73.1% in one series).[8] 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 (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.[12]

Cutaneous abnormalities

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.

Gastrointestinal problems

Abnormalities of the alimentary canal are common.They contribute to feeding difficulties and failure to thrive.[13] Pyloric stenosis is the most frequent cause of persistent vomiting in the newborn period. Diaphragmatic herniae are common.[3]

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 46%.[8] Most common are ventricular septal defect, atrial septal defect, pulmonary stenosis and Fallot's tetralogy. 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 60-100% 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

  • Central nervous system disorders (40%).[8] Seizures have been reported in nearly 25%.
  • Heat intolerance is sometimes observed.
  • There may be an absence of pain sensation.
  • Cleft palate is present in approximately 22%.[8]

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. CT scanning of the temporal bone can be used to identify typical abnormalities of the external auditory meatus, middle and inner ear.[14]

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.

Most early deaths are in severely affected babies and occur in the first two years of life. Survivors tend to have a slightly shortened life span.[16]

Obstetric ultrasound may show IUGR. In one series, 68% of cases with major abnormalities were not detected by this method[8] but 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.[17] Second trimester maternal serum pregnancy-associated plasma protein-A (PAPP-A) measurements may have predictive value as an addition.[18]

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.[19]

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.

Further reading & references

  1. Van Allen MI, Filippi G, Siegel-Bartelt J, et al; Clinical variability within Brachmann-de Lange syndrome: a proposed classification system.; Am J Med Genet. 1993 Nov 15;47(7):947-58.
  2. Allanson JE, Hennekam RC, Ireland M; De Lange syndrome: subjective and objective comparison of the classical and mild phenotypes.; J Med Genet. 1997 Aug;34(8):645-50.
  3. Baynam G, Goldblatt J, Walpole I; Deletion of 8p23.1 with features of Cornelia de Lange syndrome and congenital Am J Med Genet A. 2008 Jun 15;146A(12):1565-70.
  4. Cornelia de Lange Syndrome 1; CDLS1, Online Mendelian Inheritance in Man (OMIM)
  5. Feingold M, Lin AE; Familial Brachmann-de Lange syndrome: further evidence for autosomal dominant inheritance and review of the literature.; Am J Med Genet. 1993 Nov 15;47(7):1064-7.
  6. Liu J, Krantz ID; Cornelia de Lange syndrome, cohesin, and beyond. Clin Genet. 2009 Oct;76(4):303-14.
  7. Cornelia de Lange Syndrome, X-linked, Online Mendelian Inheritance in Man (OMIM)
  8. Barisic I, Tokic V, Loane M, et al; Descriptive epidemiology of Cornelia de Lange syndrome in Europe. Am J Med Genet A. 2008 Jan 1;146A(1):51-9.
  9. Berney TP, Ireland M, Burn J; Behavioural phenotype of Cornelia de Lange syndrome.; Arch Dis Child. 1999 Oct;81(4):333-6.
  10. Sloneem J, Arron K, Hall SS, et al; Self-injurious behaviour in Cornelia de Lange syndrome: 2. Association with J Intellect Disabil Res. 2009 Jul;53(7):590-603.
  11. Richards C, Moss J, O'Farrell L, et al; Social anxiety in Cornelia de Lange syndrome. J Autism Dev Disord. 2009 Aug;39(8):1155-62. Epub 2009 Mar 28.
  12. Braddock SR, Lachman RS, Stoppenhagen CC, et al; Radiological features in Brachmann-de Lange syndrome.; Am J Med Genet. 1993 Nov 15;47(7):1006-13.
  13. Bull MJ, Fitzgerald JF, Heifetz SA, et al; Gastrointestinal abnormalities: a significant cause of feeding difficulties and failure to thrive in Brachmann-de Lange syndrome.; Am J Med Genet. 1993 Nov 15;47(7):1029-34.
  14. Kim J, Kim EY, Lee JS, et al; Temporal bone CT findings in Cornelia de Lange syndrome. AJNR Am J Neuroradiol. 2008 Mar;29(3):569-73. Epub 2007 Dec 7.
  15. Theile AR, Gowans G; Cornelia de Lange Syndrome: a case report with clinical review and recommended J Ky Med Assoc. 2009 Sep;107(9):351-4.
  16. Beck B, Fenger K; Mortality, pathological findings and causes of death in the de Lange syndrome.; Acta Paediatr Scand. 1985 Sep;74(5):765-9.
  17. Wilmink FA, Papatsonis DN, Grijseels EW, et al; Cornelia de lange syndrome: a recognizable fetal phenotype. Fetal Diagn Ther. 2009;26(1):50-3. Epub 2009 Oct 10.
  18. Aitken DA, Ireland M, Berry E, et al; Second-trimester pregnancy associated plasma protein-A levels are reduced in Cornelia de Lange syndrome pregnancies.; Prenat Diagn. 1999 Aug;19(8):706-10.
  19. Jeanty P; Cornelia de Lange syndrome TheFetus.net 2004.

Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. EMIS has used all reasonable care in compiling the information but make no warranty as to its accuracy. Consult a doctor or other health care professional for diagnosis and treatment of medical conditions. For details see our conditions.

Original Author:
Dr Laurence Knott
Current Version:
Last Checked:
20/04/2011
Document ID:
1257 (v23)
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