Académique Documents
Professionnel Documents
Culture Documents
Faculty of Medicine
Post graduate Medical Studies Board
By
Dr. Gubartella Mohammed Zein Babiker
M.B.B.S (University of Khartoum)
Supervisor
Dr. El Tahir Medani El Shibly
Associate Prof.- Consultant Pediatrician
M.P.H (Harvard, America)
M.D (U. of K.)
FRCPCH (London)
M.P.C.H and M.B.B.S (U. of K.)
(
)(78
To
my lovely parents,
my family
&
all innocent, happy, friendly children with Down's syndrome
whom I love
ABBREVIATIONS
ACHT
Acquired hypothyroidism
CHD
CHT
Congenital hypothyroidism
CNS
DIT
Di-iodotyrosine
DM
Diabetes mellitus
DNA
Deoxyribonucleic acid
DS
Down's syndrome
FT4
Free T4
MID
Monoiodotyrosine
mu/L
IQ
Intellectual quotient
PCR
rT3
Reverse Tri-iodothyronine
T3
Tri-iodothyronine
T4
Thyroxin
TSH
TBG
TRH
T3RU
UE3
Unconjugated estriol
ABSTRACT
.
.
2002/4/1 2003/3/31.
16
96
: .1 : 1.34
: ) (TSH
) (T4, T3 (%39.6 ) 38
) (% 20.8 (%17.7)17
.
.
.
:
.
LIST OF FIGURES
Page No.
Fig. 3.1
Fig. 3.2
Fig. 3.3
Fig. 3.4
Fig. 3.5
59
60
Fig. 3.7
58
Fig. 3.6
56
61
62
LIST OF TABLES
Page No.
Table 3.1: Distribution of mothers' age at time of conception
of the study group
63
64
65
66
67
68
69
70
70
71
Table 3.11: TSH and T4 levels for the study group compared to
the age specific range
72
Table 3.12: Frequencies of TSH ranges in the study group with high
TSH and normal T4 levels
72
Table 3.13: Frequencies of TSH ranges in the study group with high
TSH and low T4 levels
73
73
74
Table 3.16: TSH level of the different age groups of the children
in the study
74
75
75
76
77
TABLE OF CONTENTS
Page
Dedication....I
AcknowledgmentII
List of Abbreviations.....III
English Abstract....V
Arabic Abstract.........VI
List of Figures.....VII
List of Tables ....VIII
CHAPTER ONE
1. INTRODUCTION AND LITERATURE REVIEW......1
1.1. Historical background
1.2. Epidemiology
1.3. Incidence
1.4.1.2. Translocation
1.5. Pathophysiology
1.6.1. Abnormalities
1.6.2. Occasional abnormalities
8
10
11
12
12
14
14
15
15
15
15
1.7.6. Growth
16
16
18
18
19
20
20
21
21
22
22
23
23
23
24
25
25
25
26
27
28
1.8.9.3. Hyperthyroidism
28
29
1.8.10.1. Hypothyroidism
29
1.8.10.2. Hyperthyroidism
30
30
30
30
32
33
34
1.9.1.3. Hyperthyroidism
35
36
36
JUSTIFICATION
38
OBJECTIVES
39
CHAPTER TWO
2. PATIENTS AND METHODS
40
40
40
41
41
41
41
41
2.8. Sample
42
2.8.1. Size
42
2.8.2. Design
42
42
2.9.1. Consent
42
43
43
43
43
44
2.11. Budget
44
45
CHAPTER THREE
3. RESULTS
3.1. Socio-demographic characteristic
46
46
46
46
47
47
47
48
48
48
49
49
49
49
49
49
49
49
49
50
50
51
51
51
3.4.3. T 4 levels
52
3.4.5. T3 levels
52
52
53
53
55
CHAPTER FOUR
4. DISCUSSION
78
78
79
79
82
CONCLUSION
84
RECOMMENDATIONS
85
REFERENCES
87
APPENDIX (Questionnaire)
in
institulized
retardation,
hypotonia,
mentally
dysmorphic
retarded
facial
children.(4)Mental
features
and
other
1.2. Epidemiology:
It occurs in all areas of the world, no known ethnic predilection
exists.(20)There is an increased male to female ratio (1.15 : 1) in new
born with DS(21).
1.3. Incidence:
The incidence of DS is approximately one in 600-800 live
births(2,5). The incidence is estimated to be more than twice as high
among all conceptions than it is among live births. More than half of
the trisomy 21 conceptions abort early in pregnancy(2). The
occurrence of trisomy 21 increases with advancing maternal age(2)
(see the table).
Incidence of trisomy 21 at birth in relation to maternal age(5).
Maternal age
Incidence
15-29
1:1500
30-34
1:800
35-39
1:270
40-44
1:100
>45
1:50
1.4.1. Types of defects:1.4.1.1. Regular trisomy 21 or (non-dysjunction):The majority of cases (95%) have 3 fine standing copies of
chromosome 21, usually arises from the failure of paired (replicated)
chromosomes to separate (mitotic non-dysjunction) one cell end with
only one copy (monosomic) and the other with 3 copies (trisomic) of
the specific chromosome(1,2,5). Occasionally, normal separation
occurs but one member fails to migrates, this is known as (anaphase
log)(22). The risk of having a child with extra chromosome 21
increases with advancing maternal age. This risk rises dramatically
after 35 years of age. Most children with trisomy 21 are born to
women younger than 35 years of age, however, because most
women give birth before 35 years of age(23).
The mechanism of increased incidence of trisomy 21 in
foetuses of older mothers is not understood. The extra chromosome
come from the father in only a small percentage of cases.
The
recurrence risk for parent of children with trisomy 21 increases to 1%2% (unless age-related risk is greater) (23).
1.4.1.2. Translocation:
2 - 4% are due to the transfer of a chromosome material to
form one chromosome to another chromosome. It may be centre
fusion (Robertsonian) or reciprocal. The majority of translocation that
give rise to DS involve the translocation of the third number 21
chromosome to another chromosome (Fusion at the centromere)
usually a D-group (number 13,14 or 15) or a G-group (number 21 or
22) chromosome(5,23).
(i)
(ii)
(iii)
Mosaicism:
cells trisomic.
The
growth,
maturation,
bone
development
and
dental
eruption(1,24,25).
The presence of an extra copy of the proximal part of 21 and
22, 3 region appear to result in the typical physical phenotype: mental
retardation, characteristic facial features, hand anomalies and
congenital heart defects. Molecular analysis revealed that 21& 22, 1922, 3 region appears to contain gene(s) responsible for the
congenital heart disease observed in DS(24,26,27). The new gene
(DSCR1); identified from region 21 & 22, 1-922, 2 is highly expressed
Abnormal
Diabetes
- Hypotonia.
Small
open
protruded tongue.
-
Diastasis recti.
mouth
and
Hyperflexibility of joints.
Short stature.
CNS:
- Mental deficiency.
Craniofacial:
- Brachycephaly.
Flat occipit.
Microcephaly.
Thin
cranium
with
wide
Hypoplasia
to
aplasia
of
frontal sinuses.
-
Dentation:
art:
Neck:
- Short neck.
Hands:
Clinodactyly (50%).
Distal
position
of
palmar
Ulnar
loop
dermal
ridge
Open
field
dermal
ridge
- Hypoplasia.
septal
defect,
patent
ductus
Hair:
Genitalia:
apnea,(29)
dementia,(30)
atlantoaxial
instability.(31)Thyroid
80%.
85%.
Hyperflexibility of joints
80%.
80%.
90%.
80%.
Anomalous auricles
60%.
Dysplasia of pelvis
70%.
60%.
Simian crease
45%.
Mothers blood is
said to be 25-50.
It is therefore, particularly
the males are considered infertile and have relatively low serum
testosterone values(5,42).
1.7.5. Speech development:
It is slower than motor activity. The DS child uses words and
possibly phrases at 3 years but rarely speaks in sentences before 4-6
years. Coordination is often poor, and the voice tends to be
raucous(5).
1.7.6. Growth:
Growth in children with DS differs markedly from that of
normal children(44,45). Short stature is a cardinal feature of DS(45).
The growth retardation of children with DS commences prenatally(46).
After birth growth velocity is most reduced between 6 months and 3
years of age(45,47). Puberty generally occurs somewhat early and is
associated with an impaired growth spurt(45,48). During the first eight
years secondary centres of ossification are often late in development.
During the later childhood the osseous maturation is more normal
and final height is usually attained around 15 years of age(5).
Statural growth is a well known indicator of health during childhood.
As growth and final height differs markedly between children with DS
and
healthy
children,
standard
growth
charts
have
been
hormone
deficiency,(57,58)and
nutritional
T3 and rT3
the level of TBG can result in a significant change in the level of total
circulating hormone, although the free (i.e. metabolically available,
not protein pound) hormone remain the same. For the same reason,
TBG acts as a buffer to protect the tissues from fluctuations in T4
levels. Disorder of TBG have been described(66).
Thyroid hormones
thyroid
hyperthyroidism.(66)
1.8.9.1. Hypothyroidism:
functions
may
be
hypothyroidism
or
II.
Prolonged jaundice
Umbilical hernia
Constipation
Macroglosia
Lethargy
Difficulty feeding
Hypotonia
Hypothermia
Abdominal distension
Hoarse cry
Goiter
Respiratory distress
II.
Autoimmune thyroiditis.
Central acquired hypothyroidism is caused by pituitary or
hypothalamus dysfunction. Symptoms and signs of AHT are listed in
table (1.2) below:
Table (1.2): signs and symptoms of AHT
Short stature
Obesity
Delay reflexes
Goiter
Bradycardia
Cold intolerance
Delayed puberty
Constipation
Loss of memory
improvement
in
cognitive
(77)
re-growth of
functioning(79)and
social
functioning.(20)
1.8.10.2. Hyperthyroidism: is treated with measures to reduce
thyroxine activity, medically with carbimazole, propylthyiouracil or
radioactive
iodine,
while
surgical
intervention
involve
partial
thyroidectomy.(80,81)
1.8.10.3. Subclinical hypothyroidism: treatment of subclinical
hypothyroidism is contraversal see under management in DS.
Year
No. of
Age range
sub. in
year
M/F
study
No. of
Abnormality
patients
in one or
with thyroid
more of
dysfunction
values of
TSH, T4, T3 %
Pearse et al
1963
151
6-21
25
17
Samuel et al
1981
54
9-12 day
20/34
10
18
Fort et al
1984
1130
3-16 day
12
1.0
Ziai et al
1984
62
5-16
40/22
11
Coleman
& 1984
206
<18
16
& 1985
151
3-21
92/59
41
27
Abassi
Pueschel
Pezzullo
Cutler et al
1986
49
4/12 -3
24/25
18
37
Toledo et al
1997
105
3/12 - 20
50/55
54
51
Jaruratansiri-
1998
112
<1
17
15
kul et al
process
account
for
much
of
the
acquired
32.7%
had
hypothyroidism,
subclinical
1.7%
hypothyroidism,
hyperthyroidism
and
1.7%
1.7%
correlation
between
clinical
hypothyroidism
and
biochemical
hypothyroidism.
1.9.1.3. Hyperthyroidism:
Hyperthyroidism
occurs
much
less
frequently
than
e.g.
abnormal
electrocardiogram
consistent
with
thyroid
hormone
supplementation
remains
in
doubt.(108)
JUSTIFICATION
1-
2-
3-
4-
5-
OBJECTIVES
1-
2-
ii.
Eltagwa
Institute,
Elthawra
18,
Omdurman City.
iii.
iv.
v.
vi.
vii.
i.
ii.
iii.
iv.
v.
vi.
Alban
Jadid
Hospital,
Elhaj
Yousif,
Khartoum North.
2.3. Study duration: Data were collected in the period from 1st of
April 2002 to 31st of March 2003.
2.
d2
(0.1)2
Where:
N = sample size.
Z = statistical certainty (1.96 at 95%, level of confidence).
P = Probability of success.
Author.
2. Laboratory
technician.
2.9.3. Input of the author:
Input of the author was to:
1.
2.
3.
4.
5.
(recurrent
infections,
other
diseases,
and
medical
examinations
and
clinical
assessment
were
obtained. For children whom consent had been given venous blood
was obtained. Height and weight of the study children were compared
to the American centiles.(109)
2.9.4.2. Laboratory tests:
b. IRMA assay
buffer.
c. Wash buffer.
d. Tracer solution I -125 monoclonal anti TSH.
e. Standards.
f. Coated beads.
Methods:
T4: sufficient test tubes were labelled in duplicate for the
standard set quality control pools and the samples. 10 l of
standard, quality control and sample were pipetted into the
corresponding tubes, 200 l of T4 tracer were added, mixed,
one bead was added to each tube and tubes were added to
each tube and aspirated, washing step was repeated twice and
the beads were counted in the gamma counter for 100 seconds.
The same steps were done to TSH and T3 tests.
2.10. Data entry and statistical methods:
The data obtained from the questionnaire was entered into
the computer and analysed using Statistical Package Social Sciences
(SPSS), chi-square was used to 95% significant level.
2.11. Budget: The author without external funds financed this
research.
2.12. Encountered difficulties: The anticipated difficulties in doing
this study were the difficulties in attempted venous sampling,
we found venepuncture is difficult to perform in some cases,
but the uptake of screening in the study has been excellent,
that no patient was unscreened. Other things which needed
more effort was to convince families of children about
importance of screening. These problems had been resolved
and at the end all of them accepted to be enrolled in the study.
2.13. Ethical points:
RESULTS
A total of 96 children with DS were enrolled in this study.
They included 55 boys and 41 girls aged less than 16 years for whom
clinical data were obtained, and they were investigated for thyroid
function.
Weight centile for the study group was shown in Fig. 3.5.
3.1.18. Height centile for children in the study:
Height centile for the study group was shown in Fig. 3.6.
in
40(41.7%),
constipation
in
23(24%),
tiredness
diseases
were
found
in
the
remaining
38(39.5%).
3.4.3. T4 levels:
Table 3.14 shows T4 levels in the study group compared to
the age specific range. T4 (SD) was 87.6 (29.4) u/ml.
3.4.4. T3 levels:
Table 3.15 shows T3 levels in the study group compared to
the age specific range. T3 (SD) was 1.2 ( 0.4) u/ml.
10(18.2%)
of
males
were
found
to
have
3.20
shows
associated
condition
with
thyroid
No. of children
20
17
Male
Female
15
12
11
10
10
5
6
3
7
3
0
0-<2 month
1-<5 y ear
5-<10 y ear
10-16 y ear
Age group
P = 0.766
High
11(11.5%)
Low
39(40.6%)
Moderate
46(47.9%)
1(1%)
44(45.80%)
51(53.20%)
First degree
18(18.8%)
Not related
44(45.8%)
Second degree
18(18.8%)
Third degree
16(16.7%)
30
26
25
22
22
18
20
13
15
10
5
0
< 3rd
3rd - <5th
50th -<75th
75th - <95th
>95th
Weight (centile)
35
30
25
20
15
12
12
15
12
10
10
5
0
3rd - <5th
50th -<75th
Height centile
75th - <95th
>95th
Hypothyroidism
20(20.8%)
Normal thyroid
function
58(60.4%)
Compensated
hypothyroidism
17(17.7%)
Hyperthyroidism
1(1%)
Frequency
Percentage
Cumulative percentage
15 - 29
24
25%
25%
30 - 34
14
14.6%
39.6%
35 - 39
29
30.3%
69.8%
40 - 45
28
29.2%
99%
> 45
1.0%
100%
Total
96
100%
100%
Frequency
Percentage
25 - 30
3.1%
30 - 34
10
10.5%
35 - 39
23
24%
40 - 44
21
21.9%
45- 49
19
19.8%
50 - 55
20
20.8%
Total
96
100%
Educational level
Frequency
Percentage
Illiterate
6.3%
Primary
12
12.5%
Secondary
47
49%
University
22
22.9%
Postgraduate
9.4%
Total
96
100%
Educational level
Frequency
Percentage
Illiterate
7.3%
Primary
26
27.1%
Secondary
44
45.8%
University
18
18.8%
Postgraduate
1.0%
Total
96
100%
Occupation
Frequency
Percentage
Professional
13
13.5%
Businessman
23
24%
Governmental employee
33
34.4%
Skilled labourer
14
14.6%
Unskilled labourer
11
11.5%
Unemployed
2.1%
Total
96
100%
Frequency
Percentage
Professional
5.2%
Governmental employee
11
11.5%
Skilled labourer
2.1%
Unskilled labourer
3.1%
Housewives
75
78.1%
Total
96
100%
Frequency
Percentage
16
16.7%
10
10.4%
12
12.5%
16
16.7%
11
11.5%
8.3%
52%
9.4%
3.1%
10
3.1%
12
2.1%
13
1.0%
Total
96
100%
Frequency
Percentage
No sibs
4.2%
1-4
35
36.5%
5 - 10
36
37.5%
> 10
21
21.9%
Total
96
100%
Frequency
Percentage
30 - 36
13
13.5%
37 - 40
79
82.3%
42
4.2%
Total
96
100%
Frequency
Percentage
Hypotonia
90
93.8%
Heat intolerance
40
41.7%
Constipation
23
24%
Tiredness
21
21.9%
Dry skin
20
20.8%
Umbilical hernia
19
19.8%
Irritability
18
18.8%
15
15.8%
Change in mood
10
10.4%
Loss of memory
7.3%
Diarrhoea
6.3%
Total
96
100%
Table 3.11: TSH and T4 levels for the study group compare to
the age specific range
Level
Frequency
Percentage
58
60.5%
17
17.7%
20
20.8%
1%
Total
96
100%
Range u/ml
Frequency
6 - < 10
13
10 - < 15
15
Total
17
Frequency
13
10 - < 15
15
Total
20
Frequency
Percentage
Normal
75
78.2%
Low
20
20.8%
High
1%
Total
96
100%
Frequency
Percentage
66
67.7%
Low
31
32.3%
High
Total
96
100%
Age groups
0 -<2 mon. 2 mon.- <1 yr.
1- <5 yr.
Total
Normal
2 (2.1%)
16 (16.7%)
5(5.2%)
5(5.2%)
30 (24%)
58(52%)
Low
0 (0.0%)
0 (0.0%)
1 (1.0%)
0 (0.0%)
0 (0.0%)
1 (1.0%)
High
4(4.3%)
7(7.4%)
10(10.4%)
5(5.2%)
Total
6(6.3%)
23(24%)
11(11.5%) 37(38.5%)
X2 = 0.938
P. value = 0.905
Age groups
levels
1- <5 yr.
Total
Normal
4(4.2%)
17(17.2%)
10(10.4%)
7(7.4%)
Low
2(2.1%)
6(6.3%)
5(5.2%)
3(3.1%)
4(4.2%)
20(20.8%)
High
0(0.0%)
0(0.0%)
1(1.0%)
0(0.0%)
0(0.0%)
1(1.0%)
Total
6(6.3%)
23(24%)
X2 = 0.207
37(38.5%) 75(78.2%)
P. value = 0.275
Thyroid status
Male
Female
Total
33 (34.4%)
25(26%)
58(60.4%)
Hypothyroidism
12(12.5%)
8 (8.3%)
20(20.8%)
Hyperthyroidism
0(0.0%)
1(1.0%)
1(1.0%)
Compensated hypothyroidism
10(10.4%)
7(7.3%)
17(17.7%)
Total
55 (57.3%)
41 (42.7%)
96 (100%)
X2 = 0.395
P. value = 0.335
Thyroid
Normal thyroid
disturbance
function
12
13
25
Diabetes mellitus
Alopecia
Goitre
Cataract
Total
18
15
33
DISCUSSION
4.1. Frequencies and sociodemographic characters:
Total
so
early
detection
of
thyroid
disorder
especially
(77,92,93,94)
disturbances,
it
was
found
in
four
children
with
This
showed
that
the
majority
of
symptoms
of
Associated
condition
in
DS
children
with
thyroid
CONCLUSION
The
study
population
were
children
with
Down's
RECOMMENDATIONS
Recognizing the increased frequency of thyroid dysfunction in
children with DS and the difficulty in clinical diagnosis, regular
screening for thyroid dysfunction is recommended by TSH and T4
estimation.
Normal thyroid levels are necessary for growth and cognitive
functioning, therefore, early detection of hypothyroidism in any
individual, and especially in children who already have growth
impairment and mental disability is needed, so screening has been
recommended at birth for any newborn with Down's syndrome.
Additional thyroid screening at six months and 12 months should
be performed.
Concerning the increase incidence of thyroid disturbances with
age and the rapid progression of thyroid dysfunction in children
with Down's syndrome suggest that screening should be performed
on an annual basis.
In infants and young children with Down's syndrome a common
transient condition known as idiopathic hyperthyrotropinaemia with
high TSH and normal T4 levels, for these cases repeating the TSH
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2-
3-
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E.
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6-
7-
8-
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Philip
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Benda CE. Mongolism and cretinism, 2nd ed. New York: Grune
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Maranon
G,
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Gochi
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Kennedy RL, Jones TH, Cuckle HS. Down's syndrome and the
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Suzanne BC, David AH. Birth defects and genetic disorders. In:
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Fuentes TJ, Pritchard MA, Planas AM. A new human gene from
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In: Roizen NJ (ed). Down syndrome Ment Retard Dev Disab Res
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1966; 5: 4 - 23.
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Down's syndrome with the quadruple test. Lancet 2003; 361: 835 36.
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Krantz DA, Larsen JW, Buchanan PD, Macri JN. First trimester
42-
50-
932-5.
58-
Prasher
VP.
Overweight
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obesity
amongst
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Werner and Ingbars (editors) The thyroid, 4th ed. London: Harper
and Row; 1978. P. 147 -78.
65-
Particia AD. Thyroid gland. In: Julia AM, Cathrine DD, Ralph
its disease, 5th ed. New York: Wiley 1984. P. 658 - 63.
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Blackwell
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