CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 2, March 2012
e4
AFRICA
Discussion
This syndrome was first described by Holt and Oram in 1960.
1
It
is a rare genetic disorder which is inherited as autosomal domi-
nant with near-complete penetrance but with variable expression.
In nearly 40% of cases there are new mutations. Other cases of
Holt–Oram syndrome are sporadic, and result from new muta-
tions in the TBX5 gene that occurs in people with no history of
the disorder in their family.
The Holt–Oram syndrome is estimated to affect one in
100 000 individuals The responsible gene has been mapped to
band 12q24.1 which codes for human transcription factor TBX5.
The T box gene family is a group of related genes that plays
a critical role in human embryonic development.
2,3
All people
with this disorder have at least one limb abnormality that affects
bones in the wrist (carpal bones). Often, these wrist bone abnor-
malities can be detected only by X-ray. Affected individuals may
have additional bone abnormalities that can include a missing
thumb or a thumb that looks like a finger, partial or complete
absence of bones in the forearm, an underdeveloped bone of
the upper arm, and abnormalities that affect the collar bone and
shoulder blades.
4
Bone abnormalities may affect each arm differ-
ently, and the left side can be affected more than the right side. In
some cases, only one arm and/or hand is affected.
About 75% of individuals with Holt–Oram syndrome have
heart problems. The most common problem is a defect in the
muscular wall, or septum, that separates the right and left sides
of the heart. Atrial septal defects (ASD) are caused by a hole in
the septum between the left and right upper chambers of the heart
(atria), and ventricular septal defects (VSD) are caused by a hole
in the septum between the left and right lower chambers of the
heart (ventricles).
Sometimes people with Holt–Oram syndrome have cardiac
conduction disease, which is caused by abnormalities in the elec-
trical system that coordinates contractions of the heart chambers.
Cardiac conduction disease can lead to problems such as a slow
heart rate (bradycardia) or a rapid and ineffective contraction of
the heart muscles (fibrillation). Cardiac conduction disease can
occur along with other heart defects (such as septal defects) or
as the only heart problem in people with Holt–Oram syndrome.
5
Although Holt–Oram syndrome bears some resemblance to the
VATER association, the clear Mendelian nature and lack of
more extensive organ system involvement of the Holt–Oram
indicate that the two conditions do not represent a pathogenetic
spectrum.
6
In any sporadic case of ASD, the patient and the parents
should be carefully examined for limb malformations. Detection
of a subtle limb defect alters the recurrence risk in offspring of
the proband from the empirical risk of an isolated septal defect
of 3% to nearly 50% of an autosomal dominant trait.
7
Our case
had a rare cardiac defect VSD with PDA along with upper limb
abnormality. This increases the spectrum of presentation for this
rare genetic disorder.
References
1.
Basson CT, Cowley GS, Solomon SD,
et al
. The clinical and genetic
spectrum of the Holt Oram syndrome (heart-hand syndrome).
N Engl J
Med
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330
(13): 885–891.
2.
Li QY, Newbury-Ecob RA, Terrett JA,
et al
. (January 1997). Holt-Oram
syndrome is caused by mutations in TBX5, a member of the Brachyury
(T) gene family.
Nat Genet
1997;
15
(1): 21–29.
3.
Fan C, Liu M, Wang Q. Functional analysis of TBX5 missense muta-
tions associated with Holt Oram syndrome.
J Biol Chem
2002;
23
:
55–58.
4.
Alizard A, Seward JB. Echocardiographic features of genetic diseases.
J Am Soc Echocardiogr
2000;
13
: 248–253.
5.
Voshtani SH, Hossein-Akbar M, Khalili-Joafshani H. Holt–Oram
syndrome revisited. Two patients in the same family.
Arch irn Med
2001;
4
(2): 99–100
6.
McGurirk CH, Westgate MN, Holmes LB. Limb deficiencies in
newborn infants.
Pediatrics
2001;
108
(4): 104–105.
7.
Jones KL. Holt–Oram syndrome. In: Jones KL, ed.
Smith’s Recognizable
Patterns of Human Malformation
. 5th edn. Philadelphia: WB Saunders,
1997; 316–317.
Fig. 4. Echocardiography showing subaortic ventricular
septal defect with extra tissue over the right ventricular
side and small PDA.
Fig. 3. Pulmonary plethora with left ventricular pattern
cardiomegaly.
