CDL

Cornelia de Lange Syndrome

Clinical Characteristics

Ocular Features:

Many patients have few ocular findings beyond the usual synophyrs, a highly arched brow with hypertrichosis, and long eyelashes. Synophrys is often prominent. However, some also have significant ptosis, nystagmus, and high refractive errors. Optic pallor and a poor macular reflex have also been reported.

Systemic Features:

The facial features may be distinctive with low anterior hairline, anteverted nares, maxillary prognathism, long philtrum, crescent-shaped mouth and, of course, the bushy eyebrows and long lashes (in 98%). Mental and growth retardation are common while many patients have features of the autism spectrum and tend to avoid social interactions. The lips appear thin, the mouth is crescent-shaped, the head is often small, the teeth are widely spaced, and the ears are low-set. The hands are often deformed with a proximally positioned thumb and metacarpophalangeal deformities. It is stated that the middle phalanx of the index finger is always hypoplastic. Other limb abnormalities of both upper (95%) and lower extremities are common. Urinary tract abnormalities have been found in 41% of patients. Middle ear effusions often lead to conductive hearing loss but 80% of patients have a sensorineural hearing deficit.

Genetics

This disorder is caused by mutations in genes encoding components of the cohesion complex. Most cases occur sporadically but numerous familial cases suggest autosomal dominant inheritance. However, since at least three genes code for components of the cohesion complex including one located on the X-chromosome (610759), familial cases reported earlier without genotyping have created some confusion. Hence, even autosomal recessive inheritance has been suggested in some families. Genetic counseling should be family-specific based on the genotype and family pattern.

About 50% of cases result from mutations in the NIPBL gene (122470; 5p13.1) but less than 1% have an affected parent and the recurrence risk for sibs is similar. The X-linked form of CDLS (300590; Xp11.22-p11.21) is caused by a mutation in the SMC1A gene, and a mild form (610759) results from mutations in the SMC3 gene (10q25). Mutations in RAD21 (8q24) have been found in patients with milder disease and atypical presentations (614701).

A CDLS phenotype can also result from a specific duplication of a 3q 26-27 band.

Pedigree:

Autosomal dominant

Autosomal recessive

Treatment

Treatment Options:

No genetic treatment is available.

References

Article Title:

Two novel RAD21 mutations in patients with mild Cornelia de Lange syndrome-like presentation and report of the first familial case

Minor A, Shinawi M, Hogue JS, Vineyard M, Hamlin DR, Tan C, Donato K, Wysinger L, Botes S, Das S, Del Gaudio D. Two novel RAD21 mutations in patients with mild Cornelia de Lange syndrome-like presentation and report of the first familial case. Gene. 2013 Dec 27. [Epub ahead of print].

PubMed ID:

24378232

Mutation Spectrum and Genotype-Phenotype Correlation in Cornelia de Lange Syndrome

Mannini L, Cucco F, Quarantotti V, Krantz ID, Musio A. Mutation Spectrum and Genotype-Phenotype Correlation in Cornelia de Lange Syndrome. Hum Mutat. 2013 Aug 29. [Epub ahead of print].

PubMed ID:

24038889

X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations

Musio A, Selicorni A, Focarelli ML, Gervasini C, Milani D, Russo S, Vezzoni P, Larizza L. X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations. Nat Genet. 2006 May;38(5):528-30.

PubMed ID:

16604071

de Lange syndrome: a clinical review of 310 individuals

Jackson L, Kline AD, Barr MA, Koch S. de Lange syndrome: a clinical review of 310 individuals. Am J Med Genet. 1993 Nov 15;47(7):940-6.

PubMed ID:

8291537

Ophthalmologic findings in the Cornelia de Lange syndrome

Levin AV, Seidman DJ, Nelson LB, Jackson LG. Ophthalmologic findings in the Cornelia de Lange syndrome. J Pediatr Ophthalmol Strabismus. 1990 Mar-Apr;27(2):94-102.

PubMed ID:

2348318

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