Cornelia de Lange syndrome (CdLS) is an extremely rare clinically heterogeneous developmental disorder of unknown etiology. Although the described clinical symptomatology is very broad, the majority of cases include growth impairment, learning disability and dysmorphic facies.

Epidemiology

The estimated incidence is at ~1:10,000-30,000 births ¹⁵. There is no recognized racial or gender predilection ⁸.

Clinical presentation

The syndrome carries a wide spectrum of clinical features which include:

• facial dysmorphism

  • low set hairline in the front and back

  • long eyelashes

  • bushy eyebrows

  • synophrys (unibrow) ¹⁵

  • upturned nose with anteverted nostrils

  • thin lips with long philtrum

  • micrognathia

  • microbrachycephaly, microcephaly or brachycephaly

• upper limb malformations 

  • short 1^st metacarpal

  • oligodactyly

  • acheiria

  • micromelia

• growth restriction including intrauterine growth restriction

• intellectual disability

• hirsutism

• hearing impairment ²

• intestinal malrotation ³

• congenital diaphragmatic herniation 

• congenital cardiac anomalies

• genitourinary anomalies

  • hypospadias

  • cryptorchidism

• hip dysplasia

Pathology

Genetics

Most cases are thought to be sporadic resulting in a new autosomal dominant mutation ⁸. Occasional autosomal dominant and autosomal recessive forms are known. Some have abnormalities in chromosome 3q26.3. Heterozygous mutations in the cohesin regulator, NIPBL, or the cohesin structural components SMC1A and SMC3, have been identified in approximately 65% of individuals with Cornelia de Lange syndrome ⁶. Other implicated genes are RAD21 and HDAC8 ¹⁵.

Markers

• low PAPP-a

• abnormally low maternal serum alpha-fetoprotein (MSAFP) levels have been described in some cases ¹²

Radiographic features

Ultrasound

May demonstrate many of the above clinical features. An early - first trimester - ultrasound scan may show an increased nuchal translucency as a non-specific but early sign ^4,13.

History and etymology

The condition was initially described by the German physician Winfried Brachmann (1888-1969) in 1916 ⁵ but was described in its full clinical presentation by Cornelia de Lange (1871-1950), a Dutch pediatrician for whom it is named, in 1933 ¹⁶.