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,
Figure 3. Close-up view of the deleted
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
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.
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
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 et.al. 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