The Ophthalmology Department,  Universiti Malaysia Sarawak (UNIMAS), Kuching, Sarawak.

The Ophthalmology Department, Sarawak General Hospital, Kuching, Sarawak, East Malaysia.



Case 35a

by Dr. Ngo Chek Tung, Dr. Mahadhir Alhady & Professor Chua Chung Nen


A 3-year-old girl with dysmorphic features was referred to the ophthalmology unit because her mother noticed a right leukocoria which had been present for 2 months. There was no history of retinoblastoma in the family. She was diagnosed with Cornealia de Lange’s syndrome based on her facial features:  prominent eyebrows, anteverted nostrils, long philtrum, thin lips, and hirsutism (Figure 1 a and b). She was noted to have mental retardation however there was no growth problem or any skeletal anomalies seen.


Figure 1 a and b. Dysmorphic features seen from the front and side.


CT scan showed calcification and a mass which was confined to the globe. Examination of the right eye under general anaesthesia revealed a large white mass measuring 1.5 cm in its widest diameter located in the macula. The features were consistent with retinoblastoma. The left eye was normal. Lumbar puncture and bone marrow biopsy showed no evidence of tumour spread. Enucleation was performed. Histology showed the tumour was confined to the retina and the cut end of the optic nerve was clear.


She recovered well post-operatively underwent regular orbital and brain MRI scans for any recurrence. She remained disease free at one year review.  Her chromosomal analysis revealed chromosome 13q deletion involving band 14 (Figure 3 and 4).


Figure 2. Karyotypes showing46, XX, del(13)(q14.2q31).


Figure 3. Close-up view of the deleted chromosome 13.


a. What is Cornelia de Lange's syndrome?


Cornelia de Lange’s syndrome also known as Brachmann-de Lange Syndrome was first reported in 1916 by Brachmann on a child whom he performed an autopsy. In 1933, Cornelia de Lange described 2 unrelated infant girls with mental retardation and similar dysmorphic features. The dysmorphic features are characterized by bushy eyebrows, long curly eyelashes, hirsutism, long philtrum, thin upper lip and down turned angles of the mouth. Late eruption of widely spaced teeth. Limb anomalies are common and consisted of micromelia, phacomelia and oligodactyly.  There are growth and mental retardations. The syndrome is estimated to affect about 1:50,000 of the population. Most cases are sporadic and numerous chromosomal rearrangements have been reported in individuals with CdLS1

It is now recognized that CdLS also shows clinical variability. Van Allen2 classified the syndrome into three types based on these variations:


a. type I (or classic) syndrome shows the characteristic facial and skeletal changes as mentioned above.


b. type II syndrome have facial and minor skeletal abnormalities similar to those seen in  type I but with less severe psychomotor retardation and milder growth deficiency.


c. type III (phenocopies) refers to patients with phenotypic manifestations resembling Cornelia de Lange’s syndrome but may be related to chromosomal aberrations or teratogenic exposures.


These classification is useful as it shows that identification of syndrome using only facial features can be misleading as chromosomal aberrations such as deletion can exhibit similar facial characters. The chromosomal abnormality in our patients shows that our patient belong to type III.


b. What are the dysmorphic features of chromosome 13Q deletion?


The tumour suppressor gene of retinoblastoma (RBI gene) is located on the long arm of the chromosome 13 band 14. Patients with chromosome 13q14 deletion are associated with a high risk (90 to 95%) of developing retinoblastoma3. In addition, depending on the amount of deletion of the adjacent chromosome a variety of dysmorphic features may occur ranging from mild to severe collectively known as chromosome 13q deletion syndrome. Motegi4 reported facial characteristics in patients with an interstitial deletion of 13q consisting of prominent eyebrows, broad nasal bridge, bullous tip of the nose, a thin upper lip, and long philtrum. Other workers5 noted anteverted ear lobes, high broad forehead, and prominent philtrum. However, all these features are not specific to chromosome 13q deletion as they are also found in other clinical syndromes such as Cornelia de Lange’s syndrome (CdLS). These overlapping of facial phenotypes explain why our patient with chromosome 13q deletion was initially misdiagnosed as a case of CdLS.


Our report suggests that chromosome 13q deletion syndrome cannot be diagnosed based on dysmorphic feature only. Chromosomal analysis is warranted in all infants with facial dysmorphism suggestive of Cornelia de Lange syndrome so that those with chromosome 13q deletion can be identified early.  Early ocular screening of such patients may reduce the mortality from retinoblastoma and allow preservation of the eye as smaller tumour may be treated with laser or cryotherapy.



1. Buad O, Cormier-Daire V, Lyonnet S, Desjardins L, Turleau C, Doz F. Dysmorphic phenotype and neurological impairment in 22 retinoblastoma patients with
constitutional cytogenetic 13q deletion. Clin Genet 1999;55:478–482.

2. DeScipio C, Kaur M, Yaeger D, Innis JW, Spinner NB, Jackson LG, Krantz ID. Chromosome rearrangements in Cornelia de Lange syndrome (CdLS): report of a der(3)t(3;12)(p25.3;p13.3) in two half sibs with features of CdLS and review of reported CdLS cases with chromosome rearrangements. Am J Med Genet A. 2005 Sep 1;137(3):276-82.

3. Van Allen MI, Filippi G, Siegel-Bartelt J Clinical variability within Brachmann-de Lange syndrome: a proposed classification system. Am J Med Genet. 1993 Nov 15;47(7):947-58.


4. Pakakasama S, Tomlinson GE. Pediatr Clin N Am 49 (2002) 1393-1413.

5. Motegi T, Kaga M, Kadowaki H, et al. A recognizable pattern of the midface of retinoblastoma patients with interstitial deletion of 13q. Hum Genet 1983;64:160–162.