CHAPTER I

INTRODUCTION
Holt-Oram syndrome (HOS) is a rare inherited disorder involving the hands, arms, and
the heart.1 This syndrome was defined for the first time in 1960. HOS syndrome is an
autosomal dominant trait with high rate of interference and different variants. The
position of gene disrupted on chromosome 12 (12q24.1) and it is caused by a mutation in
the TBX5 gene located on chromosome 12, however sporadic cases have also been
reported. Although the disease is congenital, the diagnosis may only be made later in life.
Holt-Oram syndrome is clinically characterized by morphological abnormalities of upper
limbs and congenital heart defects. Upper limb involvement as aplasia, hypoplasia,
fusion or anomalous development of carpal, radial and thenar bones which may arise in
variety forms and with relative frequency of 1:100000. Cardiac anomalies are present in
approximately 75% of patients mostly atrial or ventricular septal defect and conduction
defect.2 Cardiac defects include mainly atrial septal or ventricular septal defect, the
electrocardiographic abnormalities ranges from asymptomatic conduction disturbance to
variable degree of atrioventricular block. Rare but other cardiac associations include
pulmonary stenosis, mitral valve prolapse, and arrhythmias in the form of
atrioventricular blocks.More complex cardiac lesions such as tetralogy of Fallot,
endocardial cushion defects, and total anomalous pulmonary venous return are also noted
in these subjects. The cardiac disease may manifest as an emergency necessitating
prompt intervention.1
The prevalence of HOS in United States 1 of 100.000 live births, and it occurs
with wide ethnic and geographic distribution. All patients with HOS have upper limb
anomaly and about 85% to 95% have cardiac malformation. 3 The results of European
study show that HOS is a very rare condition with an average prevalence of 0.7 per
100.000 births and a high regional variation. The prevalence is higher in registries were
familial cases are recorded. The mean prevalence of 1: 135615 births represents a
minimum figure and refers to a group of patients with obvious clinical presentation. The
only population-based study on HOS was conducted in Hungary covering the 19751988
period. The established prevalence of 0.95 per 100.000 births is in agreement with the
prevalence of 1.0 per 100.000 births recorded in our dataset for 19902000. Interestingly,
1

there is a significant decrease in the prevalence rate for 20012011 period, for which
there is no obvious explanation and requires further monitoring.4
The aim of this report are to discuss about patient Holt-Oram syndrome with
Patent Ductus Arteriosus (PDA) and how to manage patient HOS when hospitalize and
after being discharged.

CHAPTER II
CASE REPORT
A 10 years old male child with name FA, he had a weight 16 kg. He lives in
Sinanggul, Mlonggo, Jepara. He was admitted to hospital on 26 th may 2015. He was
came with a referral from one of hospital in Jepara with Myelodisplastic Syndrome
(MDS) hypocellular and PDA.
Patients came to hospital with Chief complaint of pallor. Since 4 days before
hospital admission, he looked paler than usual, lethargic, lazy to play and drowsy. He
complained of occasional dizziness, starry vision, difficulty in concentrating on studies.
Complaints of nausea and vomiting were denied, hemorrhages such as red dots on skin,
nosebleed, gum bleeding, black or brownish vomit, red or black feces, and red urine
were denied. Complaints of fever (+) 2 days before hospital admission, fever went away
on its own, and was not accompanied by cough, cold, throat pain, ear pain, stomach pain,
or pain on urination. Complaints of shortness of breath, cyanosis, lump joints, neck
underarms, abdomen and inguinal were denied. The patients was also came for
evaluation of BMP.
Past history of illness: Patient was diagnosed with aplastic anemia in April 2013
from Bone Marrow Puncture (BMP) examination and received continuous therapy of
siklosforin and danazole for 6 month. In October 2013 patient had BMP evaluation
which showed improvement result of aplastic anemia. In January 2015 patient had
second BMP evaluation that showed a different result compared to the previous BMP,
which were MDS with hypocellular, and also had echocardiography examination that
shows PDA 3mm. The patients are often hospitalized for blood transfusions due to
anemia and thrombocytopenia. The patients also had right hand right hand congenital
malformation.
.

Figure.1. Pedigree
3

Developmental history: Smile: 2 months old, tilting: 3 months old, proning: 4

months old, sit: 7 months, teeth 8 months old, crawl: 8 months old, stand: 11 months old
and walk 14 months old. Impression: development of this patient is accordance with the
Milestones.
Growth history: Weight at delivery 2400 gram, weight 4 months ago 19 kg,
weight last month 19 kg, weight on admission 16 kg and his height 120 cm. Impression:
short stature, flat of growth, nutritional status can not be assessed
Intake history: Breast milk until 2,5 years old. Formula milk since 13 months old
2-3 times/day 150 ml. Banana or papaya 2-3 times/week. Porridge at age 6-10 months
old 2-3 times/day. Steamed rice at age 9 months- 1 years old 2-3 times/day. Daily food
menu: rice, fish, egg, 3 times/day. Impression: quality and quantity are adequate.
Physical examination: A 10 years old male child, 19 kg of weight, 120 cms of
height. General condition: composmentis, spontaneous respiration. Vital sign: heart rate
115 beats/min, temperature 36,8C, respiratory rate 24 breaths/mnt. Eyes conjunctiva are
anemic, no up slanting eyes. Mouth looks anemic and no cyanosis. Thorax is symmetric,
no retraction. Cor: heart sounds I-II normal, continuous murmur (+) grade III/6 2nd left
infraclavicular, gallop (-). Lung: vesicular +/+, rales -/-. Abdomen: flat, no venectation,
intestine sound normal. Liver: unpalpable, lien: S0. Extremity cyanosis (-), capp refill
<2, The patients also had right hand right hand congenital malformation in the form of
radial deviation at the wrist, complete thumb agenesis, and shortening of the forearm.

Table 1. Laboratory Finding

Hemoglobin
Hematocrit
Erythrocytes
Lekocytes
Trombocytes
Ureum
Creatinine
Glucose
SGOT
SGPT
Uric Acid
Calcium
Anorganic
Phospat
Sodium
Potassium
Chloride

Normal

26/5/15

11-13 g/dL
36-44 %
3-5,4 jt/uL
5.5-15.5 ribu/uL
150-400 ribu/uL
15-39 mg/dL
0,6-1,3 mg/dL
80-60 mg/dL
15-34 U/L
15-60 U/L
3,5-7,2 mg/dL
2,12-2,52 mmol/L
2,4-5,1 mg/dL

4,4
12,4
1,3
2,6
22,7
28
0,6
117
54
92
3,8
2,4
4,6

136-145 mmol/L
3,5-5,1 mmol/L
98-107 mmol/L

141
4,2
111

Blood Count
Eosinophils (1-5 %)
Basophils (0-2 %)
Neutrophil rod (2-5 %)
Neutrophil segment (25-70)
Limfocytes (20-40)
Monocytes (4-8)
Others

30/5/15
Time 07.16
12,9
36,4
4,01
2,94
22
28
0,6

26/5/15
1
0
1
45
41
0
AMC 10%
Metamielocytes 2%
Nucleated eritrocytes 4/100 leucocyte

30/5/15
Time 11.27
12,8
35,6
3,98
2,75
52

30/5/15
2
1
1
38
49
3
AMC 5%
Mielocytes1%

Peripheral blood test result (30/5/2015): Eritrocytes : moderate anisocitosis

(normocytes, mikrocytes, makrocytes), mild poikilocitosis (anulocytes, ovalocytes,
fragmentocytes, pear shape cell), young eritrocytes (+), polikromasi (+), distribution of
eritrocytes looks rare.
Trombocytes : quantity looks decreasing, normal shape.

Leukocytes : quantity looks decreasing, atypical mononuclear cell shape 10%

from core ratio. Big cytoplasma, small nucleus not clear, bluish cytoplasma
Impression: interference of myeloproliferation.
5

Table 2. Bone marrow punction

Impression:

28th January 2015

Bone marrow

June 2015
Bone marrow hyposeluler.

aplastic

improvement

hyposeluler with

Decreased of hematopoietic

anemia

aplastic

moderate eritroid

activity cell. There are sign

anemia

hyperplasia. There

of bilineage dysplasia.

April 2013
Impression:

October 2013

are sign of dysplasia

such as myeloblast

Impression: MDS

1% and limfoblast

diagnostic with bone

1%.

marrow hypoplasia and

refractory cytopenia

Impression: MDS

multilineage dysplasia

diagnostic with

(RCMD)

bone marrow
hypoplasi

Figure 2. X ray Antebrachii Dextra (April 10th 2015)

Impression: Shortening radius with fusion radioulnar joint proksimal; abscent
phalang and metacarpal 1st digiti (thumb aplasia); and absent os schapoid and os
trapezoid.

Figure 3. E Echocardigraphy (January 23rd 2015)

-

Atrial situs solitus, AV-VA concordance

Normal pulmonary venous estuary

ASD (-)

VSD (-)

PDA (+) with 3mm diameter

Chambers of the heart is balance

Normal major blood vessels

Normal valve

Arkus aorta sinistra, CoA (-)

Contractility of miocard is good

The function of LV is good with EF 75%

Impression: PDA (+) with 3mm diameter

Diagnose
This patient was diagnosed as MDS dd/ aplastic anemia, malnutrition, patent ductus
arteriosus, suspect holt-oram syndrome
Therapy
During hospitalized he received infusion infusion

D5 1/4 NS 15 cc/ min,

paracetamol 180 mg/ 8 hours, captopril 6,25 mg/ 12 hours. He got transfusion three
packed red cell and six unit of trombocyte concentrate. He should control to nutrition
metabolic division, rehabilitation medic and social pediatric division.
CHAPTER III
7

DISCUSSION
3.1.

HOLT ORAM SYNDROME

3.1.1. Definition
The Holt-Oram syndrome (HOS) was first mentioned in 1960 by Mary Clayton Holt and
Samuel Oram, who detected an ASD in members of 4 generations of a family associated
with a congenital anomaly of the thumbs.
HOS is defined as combination of a cardiac septal defect or conduction defect and
an upper extremity anomaly. This syndrome has also been referred to as atriodigital
dysplasia and heart-hand syndrome.5, 6
3.1.2. Etiology
HOS in an autosomal dominant disorder with complete penetrance. The underlying
genetic defect was found on the long arm of chromosome 12 (12q2). Mutation in the
TBX3 and TBX5 genes lead a wide range of phenotypes typical of HOS. These gene
play an important role in cardiac and skeletal development. Mutation in these T-box
genes on chromosome 12q2 give an embryologic basis for prevalence of ASD, VSD and
left-sided malformations observed in patients with HOS (Level of evidence 2).5, 7
Currently, 37 mutations in TBX5 have been found in patients with HOS. These
include 12 frameshift mutations, 11 missense mutations, seven nonsense mutations, four
splice acceptor site mutations, two small microdeletions (one of which is in frame), and
one large deletion that removes exons 3-9. Although these mutations are found
distributed throughout TBX5, the majority are found within the T-box DNA-binding
domain (21 of 37 mutations, including seven of 11 missense mutations) (Level of
evidence 2).7

Figure 4. TBX5 gene

Source: Mori AD, Bruneau BG.7
In this patient there was no history of similar finding in the family. The mutation
of genetic defect of gene TBX5 on the long arm of chromosome 12not yet to be found
because gen chromosome examination did not done yet.
3.1.3. Clinical manifestation and Diagnose
1. Upper limb
The clinical presentation of limb deficiency in Holt Oram syndrome is variable, but
most patients are on the spectrum of Radial Longitudinal deficiency (RLD). The
thumb is often involved although not universally. When affected, the thumb is
typically either absent or hypoplastic, but may be different from other hypoplastic
thumbs and often is not classifiable by traditional grading systems. The thumb may
be triphalangeal, syndactylized to the index ray, or have a finger-like appearance (5finger hand), resting in the plane of the fingers. Other upper extremity anomalies are
even more variable. The forearm is often involved, the most common finding of

which is a deficient or completely absent radius; radioulnar synostosis may also be

encountered. (Level of evidence 2). 6

Figure 5. Upper Limb Malformation of HOS

Source: Charles A. Goldfarb M, Lindley B. Wall, MD.6

Figure A: clinical photograph of left radial longitudinal deficiency. Note the partial
syndactyly between the index and middle fingers.
Figure B: Radiograph of the same patients left hand. The index ray is hypoplastic.
Figure C: Radiograph of severe radial longitudinal deficiency (absent radius) with
complete syndactyly of the thumb and index finger. The thumb is notably
hypoplastic. There is a clinodactyly of the little finger, an atypical finding in
Holt-Oram syndrome.

10

Figure 6. Upper Limb Malformation of HOS

Source: Charles A. Goldfarb M, Lindley B. Wall, MD.6
Abnormalities within the carpus, such as the presence of additional carpals, have
also been reported.There may be brachydactyly,polydactyly,or clinodactyly (small
finger). Often, but not always, the upper extremity deficiencies are bilateral.Both the
RLD and the thumb anomaly in Holt Oram syndrome may be more severe than
nonsyndromic forms. (Level of evidence 2). 7
2. Lower limb
Lower limb anomalies in Holt-Oram syndrome are infrequently reported. In 1 report,
a single patient was described with bilateral findings of a bifid distal phalanx of the
third toe, an absent distal phalanx of the fourth toe, and hypoplasia of the second,
third, and fourth toe phalanges. (level of evidence 3).6
3. Cardiac
Holt and Oram first reported arrhythmias in this syndrome since then various
electrocardiographic abnormalities such as right bundle branch block, wandering
pacemaker,

sinus

node

dysfunction,

atrial

fibrillation/flutter,

paroxysmal

supraventricular tachycardia, and WolffParkinsonWhite syndrome are described.

Only electrocardiographic abnormalities are found in 39 % of the patients with Holt
Oram syndrome with no anatomical heart anomalies (Level of evidence 2).5, 8
Table 3. ECG abnormality in HOS

11

Source: Tidake A, Gangurde P, Shaikh Z, Mahajan A.8

Ostium secundum atrial septal defect is the most common heart abnormality in
patients with HoltOram syndrome followed by ventricular septal defect. The
severity of the cardiac spectrum is not always proportional to that of the upper limb
deformity. Anomalies of the great vessels have also been associated with HoltOram
syndrome (persistent left-sided superior vena cava, replaced subclavian artery,
coarctation of the aorta, and hypoplastic aortic arch) (Level of evidence 2).8
Newbury-Ecob et al found a significant positive correlation between severity of
the limb and cardiac defects. Patients with HoltOram syndrome and atrial septal defects
had more severe limb abnormalities than patients with HoltOram syndrome without any
heart defect. The correlation between sibs was greater than that between parent and
offspring. (Level of evidence 3).8
Table 4. Cardiac defect in HOS

12

Source: Tidake A, Gangurde P, Shaikh Z, Mahajan A.8

It is important to know that hypoplastic peripheral vessels of the upper limbs have
not been frequently observed, since this might lead to difficulties in cardiac
catheterization. Anomalies of vena cava, subclavian artery, coronary arteries and other
great vessels like coarction and hypoplastic aortic arch have been described.5
A scoring system to assess severity has been recommended by Gall et al and
modified by Gladstone and Sybert, as follows: (Level of evidence 1)9
a. Skeletal Abnormalities
1

No abnormality on physical or radiological examination

Minor abnormalities, including reduced thenar eminence, clinodactyly, or

hypoplasia of the thumb

Triphalangeal or aplastic thumbs, radial/ulnar hypoplasia

Arms and forearms present, but with bone(s) missing

Phocomelia

b. Cardiac Abnormalities
1

Asymptomatic, with no abnormal physical findings

Innocent murmur or conduction defect

Structural heart abnormality not requiring surgery

Structural heart abnormality requiring surgery, but not life threatening

Potentially lethal malformation

In this patient the clinical manisfestation that appear are malformation of upper

limb which supported from x-ray antebrachii that showed shortening radius with fusion
radioulnar joint proksimal and abscent phalang and metacarpal digiti 1 (thumb aplasia)
and abscent os schapoid and os trapezoid and cardiac defect as PDA with diameter 3
mm from echocardiograph examination. Based on severity scoring system of HOS, the
patients had score 7 of 10.
Holt oram Syndrome was diagnosed by using clinical manisfestation that appear
in this patient which shows congenital malformations of the hand and heart. Those were:
-

Malformations of the hand: shortening of the radius with fusion of the proximal
radioulnar joint with absence of phalanx and metacarpal digiti 1 (thumb aplasia)
and absence of os. scaphoid and os. Trapezoid.
13

Malformation of the heart:PDA (+) with diameter 3 mm

Confirmed the chromosome examination more adecuately to diagnosis holt-oram

syndrome.
However, gold standard diagnose of holt oram syndrome have nat done yet,
because genetic defect examination of gene TBX5 on the long arm of chromosome 12 did
not done yet due to this examination is not available in Semarang.
3.1.4. Differential Diagnose
Other congenital malformations reported with cardiac malformation and upper limb
anomalies, include lung hypoplasia and cardiomyopathy, postaxial or central polydactyly,
arachnodactyly, thoracic scoliosis, hemiatrophy of the body, high myopia, Hirschsprung
disease, malformations of the urinary system, the Rokitansky-Kuster-Hauser syndrome,
cryptorchidism, malformations of renal and cerebral arteries, hypoplastic peripheral
upper extremity vasculature, hypoplasia of the left radial artery, pulmonary hypertension,
multiple strokes and end-stage renal failure, and malignant tumors. These reports
probably reflect fortuitous occurrences or represent different conditions. To date, no
mutations in TBX5 have been found in individuals with atypical phenotypes.3
The following autosomal-dominant conditions need to be considered for
differential diagnosis:3
1. Fanconi anemia syndrome is characterized by congenital abnormalities. These
abnormalities include malformations of the thumbs, forearms, and heart; progressive
bone marrow failure with pancytopenia, typically in the first decade; and increased
risk for myelodysplasia or acute myelogenous leukemia. The diagnosis of Fanconi
anemia syndrome relies on detection of chromosomal breakage or rearrangements in
the presence of diepoxybutane or mitomycin C.
2. Thrombocytopenia-absent radius: both radii are always absent; the thumbs are
always present. By contrast, radial aplasia in HOS is invariably associated with
hypoplasia or absence of the thumb. Phocomelia occasionally occurs. The lower
limbs can be involved, including club foot and instability of the knee.
Thrombocytopenia, present in infancy, generally improves with time. Heart defects
can be present.
3. Heart-hand syndrome II (Tabatznik): type D brachydactyly (shortening of the distal
phalanx of the thumb with or without shortening of the fourth and fifth metacarpals),

14

sloping shoulders, short upper limbs, bowing of the distal radii, and absence of the
styloid process of the ulna with supraventricular tachycardia. Patients can also have
mild facial dysmorphism and mild mental retardation.
4. Heart-hand syndrome III: type C brachydactyly (shortening of the middle phalanges)
with an accessory wedged-shaped ossicle on the proximal phalanx of the index
fingers with sick sinus syndrome.
5. Okihiro syndrome: Duane syndrome (a congenital eye-movement disorder resulting
from abnormal development of cranial nerve VI and characterized by absence of
abduction of the globe and narrowing of the palpebral fissure on adduction of the
globe), upper extremity reduction defects, and cardiac malformation.
6. Long thumb brachydactyly syndrome: elongation of the thumb distal to the proximal

interphalangeal joint, often associated with index finger brachydactyly, clinodactyly,

narrow shoulders, secondary short clavicles, and pectus excavatum. Occasionally,
rhizomelic limb shortening occurs. The cardiac abnormality is often a conductive
defect.
7. Vertebral, anal, cardiac, tracheal, esophageal, renal, and limb (VACTERL) anomalies
association: radial defects are usually unilateral and accompanied by characteristic
other malformations (imperforate anus, tracheoesophageal fistula).

3.1.5. Treatment
No specific medications are indicated for this condition. The orthopedic team may be
able to guide individuals in decisions regarding surgery for improved upper-limb and
hand function as well as physical and occupational therapy options. Those individuals
born with severe upper-limb malformations may be candidates for surgery to improve
function, such as pollicization (creation of a thumb-like digit by moving another digit
into the thenar position) in the case of thumb aplasia/hypoplasia. Children with severe
limb shortening may benefit from prostheses as well as from physical and occupational
therapy. Individuals and families are also likely to benefit from programs providing
social support to those with limb anomalies. (Level of evidence 2).9
PDA cardiac abnormalities can not close spontaneously except for premature
babies, because in term infants DAP result from structural abnormalities ductal smooth
muscle. Great PDA untreated can lead to congestive heart failure, recurrent pneumonia,
15

pulmonary hypertension, and PVOD. While on a small PDA frequent endocarditis.

Therefore the main principles of handling PDA, regardless of the size and type of shape
PDA, PDA closure was done. Management closure of PDA with indomethasin is
ineffective, and only useful for premature babies. PDA closure actions in general are in
ADO or surgically (Level of evidence 1).2
Requirements to be taken for closure of PDA ADO are:2
1. The diameter of PDA> 2 mm
2. Body weight 5 kg
3. Without another heart disorder
4. PARI <8 HRU / m2
If the terms of the action ADO are not fulfilled or anatomical abnormalities in the
PDA should be performed by surgical closure of PDA ligation of the PDA. PDA closure
ideal time is between the ages of 6 -12 months, or when the DAP was found in a large
child. Other therapy is given antibiotic prophylaxis against endocarditis or therapeutic
antibiotics if they have evidence of endocarditis (Level of evidence 1).1
In these cases, children are routinely treated with physiotherapy and occupational
therapy so that the child has been able to adapt to using the hand that had
malformations in daily activities such as writing, eating, holding a spoon and fork, bring
light objects such as books, bags, scoop shower , toothbrushes, and so that the child can
remain independent and schools as an ordinary child without limitations. Centralization
and prosthesis surgery can not be done because the children always experience
thrombocytopenia that complicate surgery. Closing act either ADO PDA or PDA ligation
also can not be done because the children always experience trombositopeni. The child
did not have a drug to heart failure because they do not have heart failure, and children
are programmed routine echocardiography to monitor endocarditis, and increase the
size of the PDA. Antibiotics are also not given because there are no endocarditis.
3.1.6. Prognosis
Prognosis is generally good, however it depends on the severity of the cardiac
malformations. Structural lesions are present at birth. Prognosis depends on the severity
of the cardiac lesions. Significant intracardiac shunts can be associated with sudden
death or the development of pulmonary hypertension and Eisenmenger syndrome. The
16

first clinical manifestation of the disease may be heart failure, cardiac arrhythmias
(including heart block), or infective endocarditis. Considerable physical and psychologic
morbidity may be associated with limb abnormalities, particularly in severe cases(Level
of evidence 2).9
3.2.

MYELODYSPLASTIC SYNDROME

3.2.1. Definition
Myelodysplastic syndrome is a problem of hematopoietic stem cells marked by
manifestations of bone marrow failure accompanied by dysplasia seen on the blood
smear and bone marrow.11
3.2.2. Incidence
The highest incidence of MDS occurs in the geriatric (above 65 years) with 3.3
cases/100,000 population. Meanwhile in children, incidence of MDS is very rare. A
retrospective study in India in 2015 showed that out of 1094 children with hematologic
malignancies, MDS was only found in 0.6%.11 (Level of Evidence 3) Another study in
USA in 2014 also showed a similar figure, where they found 1.16 cases/1,000,000
population per year. Based on age, MDS in children most often occur in in children < 1
year old. Based on gender, the incidence of MDS in boy to girls is 1.2:1.0. 12,13 Level of
Evidence 3)
3.2.3. Risk Factors

The etiology of MDS is not yet confirmed. On the big picture there are two types of risk
factors for MDS. Which are:14
1. Non-preventabe risk factors:
Age
Sex
Congenital inherited illnesses (familial MDS)
Immune system dysfunction
DNA mutation
2. Preventable risk factor:
Chemotherapy drugs (doxorubicin, etopusid, cyclophosphamide, chlorambucil)
Environmental exposure like pollution, cigarette smoke, alcohol, canned food
Radiation

17

A case-control study in Texas in 2005 showed a multivariate analysis for family

history of hemotologic malignancy (OR 1.92) and exposure to farming chemicals (OR
4.55) increases the risk of MDS in children. 15(Level of Evidence 3) A case control study
frm China in 2010 showed that exposure to benzene (OR 3.72), pesticide (OR 2.92) and
herbicide (OR12.0) increases risk for MDS.16(Level of Evidence 3) This is similar with a
multicenter study in 2012 that showed that cumulative benzene exposure increases risk
of MDS (OR 6.32).17(Level of Evidence 3) For the pesticide factor, a meta analyisis in
2014 shwoed that insecticides increased the risk of MDS (OR1.71), not
herbicide/fungicide. Risk of MDS is higher in children exposed to pesticide with a
history of refractory anemia.18 (Level of Evidence 1)
In this case, the child does not live in a farm environment with no chronic exposure to
pesticide (from birth to now), history of malignancy or cancer in the family was denied.
Risk factor in the patient is possibly the exposure to cigarette smoke (+) and the child is
used to or often consumes instant noodles as well as canned food (preservatives).
3.2.4. Pathophysiology

Pathophysiology of MDS is an interaction of several factors. The following are 5 theories

that are implicated in MDS pathophysiology:14
1. Cellular damage due to toxin exposure and cell aging.
Mechanisms that icrease the incidence of MDS may be genotoxic and non-genotoxic.
Genotoxic mechanism is caused by formation of free oxygen radicals from toxic
environmental exposures such as tobacco, alcohol, and infection. One of the
examples proven through cohort is benzene metabolite and DNA damage. This is
proven by the presence of abnormalitied in chromosomes +9 (trisomy), -5 or -7
(deletion) and t(8,21) (translocation).
Non-genotoxic mechanism is caused by the lowering of the immune system
which may be caused due to radiation exposureand chemotherapy , especially
therapy using Inhibitor Topoisomerase II andanthracycline may cause changes in
chromosome 11q23 (Mixed Lineage leukemia, MLL gene), meanwhile exposure to
alkylating agents may cause changes in chromosomes 5 and 7.

2. Cell damage caused by cytogenetic and gene abnormalities.

18

One of the effects of environmental exposure is DNA damage and changes in gene
expression. Following is a table of cytogenetic abnormalities in MDS.
Table 5. Cytogenetic abnormalities in MDS

Source: Niemeyer CM.14

3. Changes in micro environment of the bone marrow
In MDS there are changes occurring in the micro environement of the bone marrow,
indicated by increase in TNF alpha production, gamma interferon, beta TGF,
interleukin 6 and interleukin 11. Those raised cytokines cuses changes in growth,
differentiation and angiogenesis of cell. Increased YNF alpha affects tumor necrosis
factors 1 and 2 which causes increase in cell apoptosis followed by hypercellularity
of the bone marrow but cytopenia in the peripheral blood.
4. Immune system dysregulation
Immune system dysregulation that occurs in MDS are changes in T cell in the form
of increase of cytotoxic T cell which cause increase in CD8, CD28, and CD57,
causing extensive damage of the hematopoietic system in the bone marrow. In MDS
abnormaldifferentiation of blood cells also occur causing failure of cells to mature,
which causes cytopenia.
QystemQystem

19

Figure 7. Pathophysiology of MDS

Source: Niemeyer CM.14
3.2.5. MDS Classification
MDS Classification based on WHO is as follows:20 (tabel 6)
Tabel 6.Classification of MDS in children according to WHO 2008
WHO Classification
% Blast % Blast
(BM)
(PB)

Refractory anemia (RA)/Refractory anemia with

<5
Rare
ringed sideroblasts (RARS)

Refractory cytopenia (RC)

<5
<2

Refractory anemia with excess balsts (RAEB)

5 19
2 19

RAEB in transformation (RAEBt)

20 29
20 29
20
Source: Alberta Health Services.
Refractory cytopenia with unlineage dysplasia (RCUD)
In cases of RCUD, usually refractory Anemia (RA) is also found. Anemia is commonly
macrocytic. Blasts are not found in blood, with a maximum of 1% found on differential
count. Bone marrow is usually hypercellular due to erythroid dysplasia. This dysplasia is
also indicated by the presence of megakaryocyte and granulocytic cells. Anemia paling
sering jenis makrositik.Tidak ditemukan blast pada darah, bahkan maksimal hanya 1%
yang dapat saat differential count. There are no Auer Rods, on history the patient usually
complains of tanemia that doesntresolve for as long as 6 months.
Refractory anemia with ring sideroblast (RARS)
RARS in MDS has a characteristic anemia of unknown origin, erythroid dysplasia, and
sideroblast rings in > 15% erythroid precursors and bone marrow. Erythrocytes are
dysmorphic (a mix of macrocytic, normochromic and hyperchromic)
Refractory cytopenia with multilineage dysplasia (RCMD)
20

RCMD characteristically has one or more cytopenia in peripheral blood with two or
more dysplasia in myeloid precursors (erythroid, granulocytic, and/or megakaryocyte).
There is <1% blast in blood and <5% blast in bone marrow, and no Auer Rods.
Refractory anemia with excess blasts (RAEB 1 dan RAEB-2)
RAEB is a form of MDS with 5%-19% blasts in bone marrow or blood. RAEB-1 has a
characteristid of <5% blast in the bone marrow and 2%-4% blasts in theperipheral blood.
Meanwhile RAEB-2 is when there is >10% blasts in the bone marrow and %% in blood.
Patients with RAEB-2 has poor prognosis which is less than 2 years survival, and 3040% develop into acute leukemia.
3.2.6. Diagnosis
Diagnosis of MDS is formed based on diagnosis, physical examination and
supportive tests. Clinical manifestation of MDS patients is divided into general
symptoms (weakness, anorexia, loss of weight) and specific symptoms which are: 14
-Anemia due to suppression and ineffective erythropoiesis system, causing pallor,
lethargy and dizziness.
-Infection due to neutropenia and granulocyte dysfunction, causing recurrent infection
and fevers.
-Hemorrhaging due to thrombocytopenia, whether overt or occult.
From physical examination there may be clinical signs of anemia (pale conjunctiba
and palpebral), nleeding signs (epistaxis, gum bleed, ptechiae, purpura, melena) and
organomegaly (hepatomegaly, splenomegaly, lymphadenopathy). Study in India
presented the clinical characteristics of an MDS patient in the following graphic:11

Figure 8. Graphic of Clinical characteristics of MDS patients.

Source: Lingegowda A, Kuntegowdenahalli L, Komarancchath A, Devi L, Kumari
P, Kamath M. 1
21

Laboratory analysis based on a study in Hasan Sadikin Hospital Bandung shows: 19

(Level of Evidence 3)
Tabel 7. Routine peripheral blood analysis
No Routine blood analysis

Cases

Pancytopenia

57,1 %

Anemia dan thrombocytopenia

21,5%

Anemia and leucopenia

14,3 %

Anemia without leukopenia or

thrombocytopenia

7,1 %

Source: Oehadian A, Fianza PI, Fadjari TH, Sumantri R, Supandiman I.19

Tabel 8.Analysis of peripheral blood smear

No

Peripheral blood smear

Erythrocyte

Leukocyte

Thrombocyte

Normochromic
Hypochromic
Polychromation
Poikilocytosis
Promyelocyte
Myeloblast
Myelocyte
Shift to the left
Decreased amount

Amount of
cases
21,5 %
7,1 %
71,4 %
64,3 %
7,1 %
21,4 %
35,7 %
78,6 %

source: Oehadian A, Fianza PI, Fadjari TH, Sumantri R, Supandiman I. 19

Table 9.Analysis of bone marrow aspiration (BMP)
No

BMP Image

Number of cases
22

Normocellular

64,3 %

Hypocellular

14,3 %

3
4

Dry tap
Erythropoietic hyperplasia

21,4 %
14,3 %

Megakaryocyte hyperplasia

7,1 %

Source: Oehadian A, Fianza PI, Fadjari TH, Sumantri R, Supandiman I.19

In diagnosing MDS, three examinations are required: (1) clinical and laboratory,
(2) cytology, and (3) cytogenetic. In conditions where facilities are limited, there are two
criterias to be fulfilled, which are (1) cytopenia, (2) BMP analysis with blast cells 5%.
In cases of bone marrow hyperproliferation cytopenia may be found without increase in
number of blast cell.23
In this patient, the diagnosis of MDS was setbased n the history of recurrent pallor with
intial Hb at 4 mg/dk. The child often felt tired, lethargic, anorexic, and headaches.
Manifestation of bleeding was also found such as epistaxis and petechia. Physical
examination showed anemia and heatosplenomegaly. Supportive examination in the
form of BMP and immunohistochemical staining showed MDS with RCMD
classification.
3.2.7. Management
Therapy for MDS is divided into 2, which are definitive and supportive. Definitive
therapy is with Hematopoietic Stem Cell Transplantation (HSCT). 14,20 Whereas
supportive therapy includes :20.21
1) Transfusion
Red blood cell transfusion is used to incrase the concentration of hemoglobin in
blood. However, transfusion too oftn has a side effect of iron accumulation.
Transfusion of other componenets may be done as indicated.
2) Hemorrhaging
Adminisration of tranexamic acid may be considered in patients with severe
thrombocytopenia manifesting in profuse bleeding. It is important to note the use
of anticoagulants, acetylsalycilic acid and NSAIDs.
3) Iron chelation therapy
Iron accumulation in MDS occure due to increased absorption in the guts, (2)
ineffective hematopoiesis, and (3) PRC transfusion (each unit of PRC contains
200-250 mg iron, while the body excreted only 1-2mg iron per day). Chelation
23

therapy has been proved to reduce iron levels in thebody. The principles od
providing iron chelationare:
Iron chelation therapy is considered in patients with life expectancy > 1 year,
ferritin levels > 1000, history of transfusion > 20 times or proven to have iron
accumulation in several organs.
Iron chelation therapy is indicated in patients with iron accumulation planned

for HSCT.
Iron chelation: defeoxamine (20-50 mg/kgBB/day) subcutaneously or infusion

every 8-12 hours, or deferasirox 20-30 mg/day per-oral.

4) Chemotherapy
Chemotherapy is given to patients with RAEB or RAEBt towards leukemia. It is
also given as an adjuvant in patients pro HSCT.
Infection
Antibiotic therapy is indicated in cases of neutropenic fever or fever due to
bacterial infection. Neutropenic fever is defined as increase in body temperature >
38 degree celcius accompanied with ANC < 500. Antibiotic in neutropenic fever is
stopped when (1) ANC >500, ( no fever in 48 hours, and (3) proven sterile on
blood culture.
In this patient,management given was transfusion of PRC and TC in accordance with
the patients laboratory results. Ferritin levels should have been tested as the patient has
been treated 8 times in the ward and was given PRC transfusion. If ferritien levels wer
high, iron chelation could be given. In the 14 times the patient has been admitted, he had
not experienced fevers of febrile neutropenia, therefore antibiotics have not been given.
3.2.8. Prognosis
Prognosis of MDS in children without bone marrow transplant is poor. The most
common cause of death is infection due to pancytopenia. A prospective study showed 2030% of patients with MDS develop AML. 20 Prognosis of MDS based on International
Prognosti System (IPSS) is viewd from 3 aspects, which are: number of cell blasts in
bone marrow, cytogenetic analysis, and prove of cytopenia.20,21
Table 10. Prognosis of MDS based on IPSS

24

Risk criteria: low risk (score 0), intermediate-1 (score 0.5-1.0), intermediate-2 (score
1.5-2.0), high (score2.5).
Source: MDS Foundation.21

Table 11.Prognosis of MDS based on modified IPSS14

Risk groups
Very low
Low
Intermediate
High
Very high

Duration to AML
(in years)
NR
10,8
3,2
1,4
0,7

Median survival
(in years)
8,8
5,3
3,0
1,6
0,8

Source: Malcovati L, Porta MG, Pascutto C, Invernizzi R, Boni M, Travaglino E, et al. 24

In this patient, prognosis based on IPSS criteria is difficult to implement because of the
lack of cytogenetic analysis. Score without cytogenetic test are % blast in bone marrow
0, haemoglobine level 1.5,absolute neutrofil count 0, and platelet count 1=total score 2.5
concluding a very high score which means lower life expectancy and bigger chance to
develop AML. The expected chance fo this patient to develop AML is in 1.4 years with a
life expectancy of 1.6 years, as patient experiences recurrent pancytopenia although
25

given component transfusion. Therefore the prognosis of this patient is quo ad vitam ad
malam, quo ad sanam ad malam and quo ad fungsionam dubia ad malam.

26

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