IMMUNOGLOBULIN - G SUBCLASS PATTERN

AMONG CHILDREN WITH DOWN`S SYNDROME

Eman Marzouk*, Akram Degeidi**, Maha Youssef*, Basma
Moustafa Kamel Mohammed*
* Department of Pediatrics, Faculty of Medicine, University of Alexandria
** Department of Clinical Pathology, Faculty of Medicine, University of
Alexandria

ABSTRACT:
Down syndrome is the most common and best known chromosomal
disorder. The possible relation between DS predisposition to recurrent respiratory
infection and IgG subclasses have been infrequently addressed in children. All
previous studies showed IgG1 and IgG3 were significantly raised among children
with Down's syndrome whereas IgG2 and IgG4 were deficient.

INTRODUCTION 57 years in 1989,today probably

Down syndrome (DS) also
known as trisomy 21, is a genetic
disorder caused by the presence of
all or part of a third copy of
chromosome 21. DS is the most
common and best known
chromosomal disorder and is the
single most common genetic cause
of mental retardation. It affects over
300,000 people in USA and 30,000 in
UK.(1) In Egypt, although
governmental care of this syndrome
has increased tremendously in the
past few years, prenatal diagnosis is
still inaccessible to most of the
families and almost all cases of DS
are diagnosed postnatal.
In the last decades great
changes have taken place in the
management of children with DS. In
addition to the advances in neonatal
care, new surgical techniques and
the development of new medical
drugs ,a change in attitude toward
these children has taken place. The
result is an increase in their life
expectancy, from 9 years in 1929 to
even longer.(2)
Globally, as of 2010, DS occurs
in about 1 per 1000 births and results
in about 17,000 deaths. The
incidence of DS is estimated 1.4 per
1000 live births in the United States.
(3)
El Sobky and Elsayed estimated
risk of 2285
DS births among 1.6 million
births annually.(4) Approximately 95%
of the diagnosed DS cases have pure
trisomy 21 from non dysjunction
error of chromosome 21. Advanced
maternal age is by far the strongest
epidemiological variable associated
with DS due to increased mutagenic
exposures upon some older mother's
reproductive cells. Maternal age
affects the chances having a
pregnancy with DS, at age 20 the
chance 1 in 1441; at age 30 it is 1 in
959; at age 40 it is 1 in 84; and at
age 50 it is 1 in 44.(5) Although the
probability increases with maternal

1
age, 70% of children with DS are
born to women 35 years of age and
younger, reflecting the fact that
younger people have more children.
The father's older age is also a risk
factor in women older than 35 but
not in women younger than 35, and
may partly explain the increase in
risk as women age.(6) Besides the
known risk factors, consanguinity,
region (rural/urban) of residence of
parents, exposure of parents to
chemicals, educational status of
parents, smoking habits of father,
prenatal scanning reproductive
performance of mother are possible
risk factors for DS in Egypt.(7)
Individuals with DS have a
higher risk of death than the general
population. This is most often from
heart problems or infections.
Following improved medical care,
particularly for heart and
gastrointestinal problems, the life
expectancy has increased. This
increase has been from 12 years in
1912, to 25 years in the 1980s, to 50
to 60 years in the developed world in
the 2000s. Currently between 4 and
12% of DS babies die in the first year
of life. The probability of long-term
survival is partly determined by the
presence of heart problems. In those
with congenital heart problems 60%
survive to 10 years and 50% survive
to 30 years of age. In those without
heart problems 85% survive to
10 years and 80% survive to
30 years of age. About 10% live to 70
year Children with DS have an
increased risk of infections,
especially respiratory tract infections,
which can be of diverse pathogenic
origin (e.g. viral, bacterial, fungal or
a combination of these).2 This
increased susceptibility to infections
has been linked to abnormal
2
parameters of the immune system,
as DS is the most common
recognizable genetic syndrome
associated with immune defects.(48)
Infections of the respiratory
tract, particularly otitis media, have
been identified as one of the most
significant health problems in DS
children of school age by their
parents, with a higher frequency than
in the general population. This
increased susceptibility to infections
have been linked to abnormal
parameters of the immune system
for more than 30 years, and DS is the
most common recognizable genetic
syndrome associated with immune
(48)
defects . Although multiple
differences between the immune
system of DS children and that of the
general population have been
described, the clinical relevance of
these differences is less clear.
Various medical and anatomical co-
morbidities commonly associated
with DS increase the susceptibility to
infections and might also affect the
immune responses. We reviewed the
infectious disease burden in DS
children and the mechanisms of
innate and adaptive immunity
defective in this conditions of age. (30)
IgG subclasses was studied by G
Annern, C G Magnusson, G Lilja,
and S L Nordval in 1992, on 38
children with Down's syndrome aged
1-12 years. An age matched group of
50 healthy children served as
controls. The serum concentrations
of IgG1 and IgG3 were significantly
raised among children with Down's
syndrome in all three age groups
studied (that is 1-2.5, 4-8, and 9-12
years). The serum concentrations of
IgG2 were normal in the first two
groups but significantly reduced in
the third age group. In contrast, the
concentrations of IgG4 among
Aims and Objectives of
children with Down's syndrome were
significantly reduced in all three age
the Study:
The study aimed at estimating
groups. Moreover, among the
the level of Ig G subclasses level in
children with Down's syndrome aged
children with Down syndrome and
4-12 years 68% (15/22) had IgG4
proving relation between different
concentrations below 2 SDs of the
levels of IgG subclasses and
geometrical mean of the controls.
recurrent upper respiratory infection
The results may partially explain the
if any.
proneness of children with Down's
syndrome to infections with Materials and Methods:
encapsulated bacteria.[123]
Study settings:
In another study made by C. Study was conducted in the
Barradasa, J. Charltona, P. Mendoaa, A genetic clinic of Alexandria
I. Lopesa, M. Palhaa, J C. Trindadea in University children`s Hospital.
University Clinic of Paediatrics.
Target Population:
Hospital of Santa Maria, Lisboa
Group1 : 30 children with
,Portugal, Serum total IgG and
Down syndrome .
subclasses were determined in three
Group2: 30 apparently
different groups of children: with
healthy , age and sex matched
Down syndrome, their siblings and children taken as control
general pediatric population. Several group.
cases of IgG2 and IgG4 deficiency
were identified, predominantly in Inclusion criteria:
children with Down syndrome. The Age range : 4-18 years, confirmation
differences, considering three age of diagnosis of Down syndrome was
groups, were statistically significant done by Karyotyping.
for both groups in relation to the
general population group, with an Exclusion criteria:
Children with:
increase of IgG1 and IgG3 and a
decrease in serum concentrations of 1-Immunocompromised status
IgG2 and IgG4. Down syndrome secondary to other disease as: HBV-
HCV-HIV positive.
children and their siblings tend to
have a similar variation of the IgG4 2-Patient on long term steroid
serum concentration levels (P < therapy.
0.05). The mechanisms of this
3-Associated complications such as
concordance are not well understood. Diabetes Mellitus, leukemia,
The results point out that an malignancy, hypothyroidism, and
adequate strategy to improve the systemic lupus erythematosus.
immune status of Down syndrome
METHODS
children could have a positive
manifestation in the immune profile Study Design:
of their brothers.[124]

3
Case control study comparing the IgG
subclasses values in both Down and
Control groups.Informed consent was
taken from parents of all subjects
included in this study. An ethical
approval was obtained from the
Research and Ethics committee of
Alexandria Faculty of Medicine.
Collected Data:
History-Age-Sex-Maternal Age-history
of repeated upper respiratory tract
infection -family history of DM CBC-
ELISA for estimation of the levels of
IgG subtypes: gG1,IgG2,IgG3,IgG4
RESULTS
The study was conducted on 30
children diagnosed with Down
syndrome, coming for follow up at
the genetics clinic of Alexandria
University children`s Hospital. Total
30 apparently healthy, age and sex
matched children were taken as
control group.
The comparison between the
two studied groups regarding age,
the mean age in control cases (group
I) was 11.473.28, while the cases
age was 11.563.83, on comparing
the two groups regarding age it was
found that there was no significant
difference between the two groups
regarding age (p > 0.05).
The comparison between the
two studied groups regarding sex,
the male represent 56.7% in control
and 53.3% in group II (cases), there
was no significant difference
between the two groups regarding
sex.
The comparison between the
two studied groups regarding
maternal age at delivery, the mean
age of maternal in control group was
32.944.86, and in cases the
maternal age was 35.285.60, there
was a significant increase in maternal
age in cases more than control (p <
0.05).
4
The comparison between the
two studied groups regarding mode
of delivery, there was no significant
difference between the two groups
regarding the mode of delivery (p >
0.05).
The comparison between the
two studied groups regarding history
of more than 4 repeated upper
respiratory tract infections per year.,
it was found that there was a
significant increase in history of
repeated upper respiratory tract
infection in cases (76.7%) more than
the control group (6.7%) (p < 0.05).
The comparison between the
two studied groups regarding FBG,
the mean fasting blood glucose in
group I was 87.387.22, while in
cases was 79.005.44, there was a
significant decrease in FBS in cases
than the control group (p < 0.05).
The comparison between the
two studied groups regarding Hb, the
mean Hb level in control group was
11.031.08, while in cases the mean
Hb level was 11.020.89, there was
no significant difference between the
two groups regarding Hb level (p >
0.05).
The comparison between the
two studied groups regarding IgG1,
the level of IgG1 in control groups
was 11.283.35, while in cases the
mean level was 13.033.25, there
was a significant increase in IgG1 in
cases than the control (p < 0.05).
The comparison between the
two studied groups regarding IgG2,
the mean IgG2 in group I (control)
was 4.281.40, while in cases group
was 1.661.40, there was a
significant increase in IgG2 in group I
than the cases (p <0.01).
The comparison between the
two studied groups regarding IgG3,
the level of IgG3 in group I was
0.970.45, while in cases was
1.210.45, there was a significant
increase in IgG3 in group II (cases)
than control (p <0.05).
 The comparison between the
two studied groups regarding IgG4,
the level of IgG4 in control group was
1.220.11, while in cases was
0.130.11, there was a significant
increase in IgG4 in control than the
cases group (p < 0.05).
the distribution of study patients with
DS according to their karyotyping,
the majority of the patients had non
dysjunction karyotype, while
translocation and mosaicim was
found in one patient for each.
The relation between IgGs and
repeated URTI in Downs patients, it
was found that there was a
significant increase in IgG1 in
repeated URTI patients more the
patients without repeated URTI, the
IgG2 show a signficiant increase in
patients with repeated URTI. The
IgG3 show no significant difference
between the two groups, while the
IgG4 show significant increase in the
patients with repeated URTI more
than patients without.
The correlation between
different IgGs showed no significant
correlation between the different
values.
DISCUSSION:
Susceptibility to infections is a
feature of Down's syndrome, and is
likely to be due to abnormalities of
host defence, that is, of the immune
response. Reported defects include
components of cell mediated and
humoral immunity, the inflammatory
response, and interferon production.
[123]
Several studies have established an
association between the deficiency of
certain IgG subclasses and the
predisposition for recurrent infections
of the respiratory airways . The
antibodies for virus are specially IgG1
and IgG3 associated subclasses. The
response to bacterial polysaccharide
antigens is predominantly an IgG2
and IgG4 reaction.[124]
5
One study published by : G
Anneren, C G M Magnusson, G
Lilja, S L Nordvall in 1992 , stated
a possible relation between
predisposition to infection and the
serum concentrations of the IgG
subclasses. The results of the studies
of serum immunoglobulin
concentrations in subjects with
Down's syndrome have been
conflicting. In adults with Down's
syndrome the serum concentrations
of IgG2 and IgG4 have been found to
be significantly reduced and those of
IgG1, and IgG3 to be normal or
raised. Based on this study,it has
been claimed that about half of the
children with Down's syndrome are
deficient in IgG4. [123]
In 2002 , C. Barradas, J. Charlton,
P. Mendoa, A. I. Lopes, M. Palha,
and J. C. Trindade in University
Clinic of Paediatrics, Hospital of
Santa Maria, Lisboa, Portugal studied
serum total IgG and subclasses in
three different groups of children:
with Down syndrome, their siblings
and general pediatric population.
The results of that study pointed out
that an adequate strategy to improve
the immune status of Down
syndrome children could have a
positive manifestation in the immune
profile of their brothers.[124]
In the study done by G Anneren et
al; 38 children with Down's
syndrome aged 1-12 years were
taken as cases. The 38 cases with
chromosomally verified Down's
syndrome were 16 girls and 22 boys.
The children were split into three age
groups: 1-2 5, 4-8, and 9-12 years.
Total of 50 age matched healthy
children served as controls.[123] There
were no significant age differences
between controls and children with
Down's syndrome in the two
youngest groups, but the children
with Down's syndrome were slightly
older than the controls in the oldest
age group (p=0.04). [123]
In the study done by C. Barradas et
al, 206 caucasian children were
included, divided in three different
groups. One group included children
with trisomy 21, another formed by
their siblings and a third with
otherwise considered normal
children. statistical significant
differences between the three groups
were found. The Trisomy 21 group
was constituted by 79 individual, 39
girls and 40 boys, with an average
age (SD) of 4.6 (3.0) years and a
variation between 1 and 14 years.
Fifty-four normal children formed a
control group, 31 girls and 23 boys
with an average age (SD) of 3.9 (3.5)
years, variation between 1 and 12
years .[124]
In our study the mean age in control
(group I) was 11.473.28, while the
cases age was 11.563.83. On
comparing the two groups regarding
age it was found that there was no
significant difference between the
two groups regarding age (p > 0.05).
The comparison between the two
studied groups regarding sex, male
represented 56.7% in control and
53.3% in cases, there was no
significant difference between the
two groups regarding sex.
In the study done by C. Barradas et
al, it was mentioned that Children
from mothers with an age below 25
years have 1:2,000 risk of having the
problem, increasing with the
maternal age until an incidence of
1:50 at the 40 years. [124]
In this study it was found that,
the mean age of maternal in control
group was 32.944.86, and in cases
the maternal age was 35.285.60,
there was a significant increase in
maternal age in cases more than
control (p < 0.05).
Frequent respiratory tract infections
is considered a significant
component of the morbidity of DS
children; however, few studies help
to define the current epidemiology of
infections in the DS population. It
appears that the incidence of
respiratory infections has declined in
the last decade, due most probably
to the progress in the management
6
of infections and the awareness of
the medical problems that are
common to DS patients. While the
incidence of respiratory infections
may not be too high compared to
non-DS children, it appears that DS
children suffer a prolonged period of
illness time and need additional
treatment to overcome the same
infections compared to non-DS
children.[129]
In our study, it was found that there
was a statistically significant increase
in history of repeated upper
respiratory tract infection in DS cases
(76.7%) more than the control group
(6.7%). (p < 0.05).
In the study done by G Anneren et
al; the concentrations of the
subclasses of IgG were determined
(ELISA) .The individual values and
the geometrical mean concentrations
and 1 SD of the four IgG subclasses
in the controls and children with
Down's syndrome showed no
significant age differences between
controls and children with Down's
syndrome in the two youngest
groups, but the children with Down's
syndrome were slightly older than
the controls in the oldest age group
(p=0.04). The children with Down's
syndrome had significantly higher
concentrations of IgG1 and IgG3
than the controls in all three age
groups. In contrast, the serum
concentrations of IgG2 were normal
in the children with Down's syndrome
in the two youngest age groups but
significantly reduced among the
oldest children with Down's
syndrome . The IgG4 concentrations
were significantly reduced in all three
age groups of children with Down's
syndrome . While IgG4 deficiency
was found in Down's syndrome at all
ages, IgG2 deficiency tended to
develop later in life among children
with Down's syndrome. The study
concluded that the IgG4 deficiency is
not accompanied by an IgG2
deficiency in childhood in Down's
syndrome. Even though the serum
concentration of IgG4 is low, it may
play a part in mucosal defense
because of its higher relative
[123]
concentration in secretions.
C. Barradas et al mentioned that
Down syndrome children showed
tendency to present higher values of
total IgG, with statistical significance
above four years old in relation to the
other two groups (P < 0.05). In
relation to IgG1, Down syndrome
children and their siblings show
statistically higher values to the
normal population in all age groups.
Above four years old, trisomy 21
group has a significant difference to
the rest (P < 0.01). Down syndrome
children present statistically lower
values of IgG2 to the normal
population below eight years old (P <
0.05) . Down syndrome children
present statistically higher values of
IgG3 to the normal population above
four years old (P < 0.01). In relation
to IgG4,Down syndrome group
revealed statistically lower values,
compared with normal population
below 8 years old (P < 0.01).There
was a significant difference in the
number of cases of Down syndrome
with low levels of IgG4 compared to
the other two groups (p < 0.05) [124]
C. Barradas et al concluded that
total IgG concentration should not be
a form to identify IgG subclass
deficiency, mainly because the IgG2
and IgG4 represent a small ratio of
the total IgG. In children the
concentrations of IgG subclasses are
lower, requiring quantification with
methods that are more sensible. [124]
In our study , IgG subclasses
were detected using Human IgG total
ELISA Sandwitch technique ,Ready-
SET-Go! Catalog Number: 88-
50550,comparing both cases to
control groups concentrations of Ig G
subclasses (IgG1,IgG2,IgG3,IgG4).
The study showed that in comparison
between the two studied groups
regarding IgG1, the level of IgG1 in
control groups was 11.283.35,
while in cases the mean level was
13.033.25, there was a significant
increase in IgG1 in cases than the
control (p < 0.05). on the other
7
hand , the mean IgG2 control was
4.281.40, while in cases group was
1.661.40, there was a significant
increase in IgG2 in the controls ,than
the cases (p <0.01). With
comparison between the two studied
groups regarding IgG3, the level of
IgG3 in controls was 0.970.45,
while in cases was 1.210.45, there
were a significant increase in IgG3 in
(cases) than control (p <0.05). the
comparison between the two studied
groups regarding IgG4, the level of
IgG4 in control group was 1.220.11,
while in cases was 0.130.11, there
was a significant increase in IgG4 in
control than the cases group (p <
0.05). , It was found that there was a
significant increase in IgG1 in
repeated URTI patients compared to
patients without repeated URTI, the
IgG2 show a signficiant increase in
patients with repeated URTI. The
IgG3 show no significant difference
between the two groups, while the
IgG4 show significant increase in the
patients with repeated URTI more
than patients without.
CONCLUSION:
There is a statistically
significant relation between
the history of repeated upper
respiratory tract infection and
Down syndrome.
There is a statistically
significant tendency to have
decreased levels of IgG2,IgG4
in patients with Down
syndrome compared to
normal.
There is a statistically
significant tendency to have
increased levels of IgG1 ,IgG3
in patients with Down
syndrome compared to
normal.
There is statistically significant
relationship between elevated
IgG1,IgG2,IgG4 subtypes and
repeated upper respiratory
tract infection in Down
children.
REFERENCES: Romina Krebel, Croatia 1st ed
1. Patterson D. Molecular 2011; 1: 1-21.
genetic analysis of Down 10. Lyle R, Ben F, Gagos S,
syndrome. Human genetics Gehrig C, Lopez G, Schinzel et
2009; 126 (1): 195214. al. Genotypephenotype
2. Megarbane, A., Ravel, correlations in Down syndrome
A., Mircher, C., et al. The 50th identified by array CGH in 30
anniversary of the discovery cases of partial trisomy and
oftrisomy 21: the past, present, partial monosomy chromosome
and future of research and 21. European Journal of human
treatment of ...down genetics 2009;17: 454-66.
syndrome,Genet 11. Davidson MA. Primary
Med,2009,11(9):611-6. care for children and
3. Gardner RJM, Sutherland adolescents with Down
GR, Shaffer LG. Chromosome syndrome. Pediatr Clin
Abnormalities and Genetic North Am. 2008;55:1099-111
Counseling. USA: Oxford 12. Piro E, Pennino C,
University Press; 2011. Cammarata M, Corsello G,
4. El-Sobky ES, Elsayed Grenci A, Lo Giudice C, et al.
SM. Down Syndrome in Egypt. Growth charts of Down
The Egyptian J Med Hum Genet syndrome in Sicily: evaluation of
2004; 2: 67-78. 382 children 0-14 years of age.
Am J Med Genet Suppl 1990;7:
5. Morris JK, Mutton DE, 6670.
Alberman E. Revised estimates
of the maternal age specific live 13. Roizen NJ, Patterson D.
birth prevalence of Down's Down's syndrome. Lancet 2003;
syndrome. J Med Screen 2002; 361(9365) 12819.
9(1): 26. 14. Pope BD, Gilbert DM.
6. Carrell DT (ed) Paternal Genetics: up and down in
influences on human Down's syndrome. Nature 2014;
reproductive success. UK: 508(7496):323-4 .
Cambridge University Press; 15. Shalaby HM. A study of
2013. new potential risk factors for
7. Mokhtar MM, Abd el-Aziz Down syndrome in Upper Egypt.
AM, Nazmy NA, Mahrous HS. The Egyptian J Med Hum Genet
Cytogenetic profile of Down 2011; 12: 15-9.
syndrome in Alexandria, 16. Marzouk IM, Kassem HS,
Egypt.East Mediterr Health j. Mostafa MA, Abdelhamid HS.
2003; 9: 37-44. Clinical characteristics of Down
8. Summar K, Lee B. Down syndrome patients through a
syndrome and other decade in Alexandria University
abnormalities of chromosome Hospitals, Alexandria Faculty of
number. In: St Geme JW III, Medicine, Egypt. 3rd National
Schor N, Kliegman RM, Stanton Congress of the Egyptian
B, Behrman RE (eds). Nelson Society of Phoniatrics and
textbook of pediatrics. 19thed. Logaoedics. 6th March 2013.
Philadelphia: Saunders; 2011. 17. Shaffer RJ, Gardner M,
399-403. Grant R, Lisa G. Chromosome
9. Eggermann T, Thomas, abnormalities and genetic
Schwanitz G. Genetics of Down counseling. 4thed. Oxford:
Syndrome. Genetics and Oxford University Press; 2012.
aetiology of Down syndrome,

8
18. Sambrook J, Russell DW, Reprod Update 2013; 19 (4):
Sambrook J. The condensed 31829. Cite uses deprecated
protocols from Molecular parameters (help)2
cloning: a laboratory manual.
2nded. Philadelphia: Lippincott 25. National Down
Williams & Wilkins; 2006. syndrome Society (NDSS).
Inclusion: Educating students
19. Hickey F, Hickey E, with Down syndrome with their
Summar KL. Medical update for non-disabled peers. NDSS;
children with Down syndrome 2013. Available from:
for the pediatrician and family http://www.kcdsg.org/files/conte
practitioner. Advances in nt/Educating%20Students
pediatrics 2012; 59 (1): 137 %20with%20Down
57. Cite uses deprecated %20Syndrome%20With
parameters (help) %20Their%20Typical
%20Peers.pdf [Accessed On: 5
20. Natoli JL, Ackerman DL, Feb, 2014].
McDermott S, Edwards JG.
Prenatal diagnosis of Down 26. Weijerman ME, de
syndrome: a systematic review Winter JP. Clinical practice: the
of termination rates (1995 care of children with Down
2011). Prenatal Diagnosis 2012; syndrome. Eur J Pediatr 2010;
32 (2): 14253. Cite uses 169(12): 144552..
deprecated parameters (help)
27. Mohan M, Bennett C,
21. Canick J. Prenatal Carpenter PK. Memantine for
screening for trisomy 21: recent dementia in people with Down
advances and guidelines. Clin syndrome. Cochrane Database
Chem Lab Med 2012;50 (6): Syst Rev 2009; 1:CD007657.
10038.
28. Hickey, F; Hickey, E;
22. Agathokleous M, Summar, KL. Medical update for
Chaveeva P, Poon LC, Kosinski children with Down syndrome
P, Nicolaides KH. Meta-analysis for the pediatrician and family
of second-trimester markers for practitioner. Advances in
trisomy 21. Ultrasound Obstet pediatrics 2012; 59 (1): 13757.
Gynecol 2013; 41(3):247-61.
Cite uses deprecated 29. Richard Urbano. Health
parameters (help) Issues among Persons With
Down Syndrome. Academic
23. Noninvasive prenatal Press. p. 129. ISBN 2010: 978-0-
diagnosis of fetal aneuploidy 12-374477-7.
using cell-free fetal nucleic
acids in maternal blood". 30. Tintinalli, Judith E. "The
Oxford: United Healthcare; Child with Special Health Care
2014. Available from: Needs". Emergency Medicine: A
https://www.oxhp.com/secure/p Comprehensive Study Guide
olicy/noninvasive_prenatal_diag (Emergency Medicine
nosis_fetal_aneuploidy.pdf. (Tintinalli)). New York: McGraw-
[Accessed On: 25 Mar, 2014]. Hill Companies. pp. Chapter
138. ISBN 2010: 0-07-148480-9.
24. Mersy E, Smits LJ, van
Winden LA, de Die-Smulders CE, 31. skotko B.capone
South-East NIPT, Macville Mv, et G,kishnani S,postnatal diagnosis
al. Noninvasive detection of of Downsyndrome;synthesis of
fetal trisomy 21: systematic evidence on how best to deliver
review and report of quality and the news ,Pediatr.2009;124:751-
outcomes of diagnostic 8
accuracy studies performed 32. Moore, SW. "Down
between 1997 and 2012. Hum syndrome and the enteric

9
 nervous system." Pediatric introduction to clinical medicine
surgery international 24 (8): (6th ed.ed.). New York: McGraw-
87383..2008: PMID 18633623. Hill Medical. pp. Chapter 2. ISBN
2010: 978-0-07-162167-0.
33. Kent RD, Vorperian HK.
Speech impairment in Down 41. Weijerman, ME; de
syndrome: a review. J Speech Winter, JP. "Clinical practice. The
Lang Hear Res 2013; 56 (1): care of children with Down
178210. syndrome.". European journal of
pediatrics 169 (12):2010: 1445
34. Reilly C. Behavioral 52. Cite uses deprecated
phenotypes and special parameters (help)
educational needs: is etiology
important in the classroom? J 42. Sam Goldstein, ed.
Intellect Disabil Res 2012; Handbook of
56(10):929-46. neurodevelopmental and
genetic disorders in children
35. Weksler ME, Szabo P, (2nd ed. Ed.). New York: Guilford
Relkin NR, Reidenberg MM, Press. p. 365. ISBN 2011: 978-
Weksler BB, Coppus AM. 1-60623-990-2.
Alzheimer's disease and Down
syndrome: treating two paths to 43. Rodman, R; Pine, HS.
dementia. Autoimmun Rev "The otolaryngologist's
2013; 12 (6): 6703. Cite uses approach to the patient with
deprecated parameters (help) Down syndrome."
Otolaryngology clinics of North
36. Howard Reisner . America 45 (3): 2012: 599629,
Essentials of Rubin's Pathology. viiviii.
Lippincott Williams & Wilkins.
pp. 129131. ISBN 2013: 978-1- 44. Pradhan, M; Dalal, A;
4511-8132-6. Khan, F; Agrawal, S. "Fertility in
men with Down syndrome: a
37. David Wright. case report". Fertil Steril 86 (6):
Downs:The history of a 2006: 1765.e13.
disability: The history of a
disability. Oxford University 45. Batshaw, Mark, ed.
Press. p. 145. ISBN 2011: 978-0- Children with disabilities (5th
19-956793-5. Retrieved 25 ed). Baltimore [u.a.]: Paul H.
August 2012. Brookes. p. 308. ISBN
2005: 978-1-55766-581-2.
38. Gamis, AS; Smith, FO.
"Transient myeloproliferative 46. Jackson AS, Stanforth
disorder in children with Down PR, Gagnon J, Rankinen T, Leon
syndrome: clarity to this AS, Rao DC, et al. True.
enigmatic disorder.". British International Journal of Obesity
journal of haematology 2012: 2002; 26 (6): 78996.
159 (3): 27787.
47. Szabo L. Life with Down
39. Graber, E; Chacko, E; syndrome is full of possibilities.
Regelmann, MO; Costin, G; USA Today [Cited On: 9 May,
Rapaport, R. "Down syndrome 2013]. Available from:
and thyroid function.".
Endocrinology and metabolism 48. Cruz NV, Mahmoud SA,
clinics of North America 41 Chen H, Lowery-Nordberg M,
(4):2012: 73545. Berlin K, Bahna SL. Follow up
study of immune defects in
40. Hammer, edited by patients with dysmorphic
Stephen J. McPhee, Gary D. disorders. Ann Allergy Asthma
"Pathophysiology of Selected Immunol. 2009;102:42631.
Genetic Diseases". [PubMed]
Pathophysiology of disease: an

10
49. Bloemers BL, van Furth old? What's new? Acta Paediatr.
AM, Weijerman ME, Gemke RJ, 2010;99:16028. [PubMed]
Broers CJ, van den Ende K,
Kimpen JL, Strengers JL, Bont LJ: 56. Bertrand P, Navarro H,
Down syndrome: a novel risk Caussade S, Holmgren N,
factor for respiratory syncytial Sanchez I. Airway anomalies in
virus bronchiolitisa prospective children with Down syndrome:
birth-cohort study. Pediatrics. endoscopic findings. Pediatr
2007, 120 (4): e1076-e1081. Pulmonol. 2003;36:13740.
10.1542/peds.2007-0788. [PubMed]

50. Bloemers BL, van Furth 57. Dyken ME, Lin-Dyken

AM, Weijerman ME, Gemke RJ, DC, Poulton S, Zimmerman MB,
Broers CJ, Kimpen JL, Bont L: Sedars E. Prospective
High incidence of recurrent polysomnographic analysis of
wheeze in children with Down obstructive sleep apnea in
syndrome with and without Down syndrome. Arch Pediatr
previous respiratory syncytial Adolesc Med. 2003;257:65560.
virus lower respiratory tract [PubMed]
infection. Pediatr Infect Dis J. 58. Sheikh S, Allen E, Shell
2010, 29 (1): 39-42. R, et al. Chronic aspiration
10.1097/INF.0b013e3181b34e52 without gastroesophageal reflux
. as a cause of chronic respiratory
51. McDowell KM, Craven symptoms in neurologically
DI: Pulmonary complications of normal infants. Chest.
Down syndrome during 2001;120:119095. [PubMed]
childhood. J Pediatr. 2011, 158 59. Brumbaugh DE, Accurso
(2): 319-325. FJ. Persistent silent aspiration in
10.1016/j.jpeds.2010.07.023. a child with trisomy 21. Curr
52. Weijerman ME, Brand Opin Pediatr. 2002;14:2313.
PL, van Furth MA, Broers CJ, [PubMed]
Gemke RJ: Recurrent wheeze in 60. Weir K, McMahon S,
children with Down syndrome: is Barry L, Ware R, Masters IB,
it asthma?. Acta Paediatr. 2011, Chang AB. Oropharyngeal
100 (11): e194-e197. aspiration and pneumonia in
10.1111/j.1651- children. Pediatr Pulmonol.
2227.2011.02367.x. 2007;42:102431. [PubMed]
53. Day SM, Strauss DJ, 61. Shott SR. Down
Shavelle RM, Reynolds RJ: syndrome: common
Mortality and causes of death in otolaryngoloic manifestations.
persons with Down syndrome in Am J Med Genet Part C Semin
California. Dev Med Child Med Genet. 2006;142:13140.
Neurol. 2005, 47 (3): 171-176. [PubMed]
10.1017/S0012162205000319.
62. General care. Immune
54. Verstegen RH, van Deficiency Foundation.
Gameren-Oosterom HB, Fekkes http://primaryimmune.org/about
M, Dusseldorp E, de Vries E, van -primary-
Wouwe JP: Significant impact of immunodeficiencies/relevant-
recurrent respiratory tract info/general-care/. Accessed
infections in children with Down Nov. 3, 2014.
syndrome. Child Care Health
Dev. 2013, 39 (6): 801-9. 63. Kusters MAA, Verstgen
RHJ, Gemen EFA, deVries E.
55. Don M, Canciani M, Intrinsic defect of the immune
Korppi M. Community-acquired system in children with Down
pneumonia in children: what's syndrome: a review. Clin Exp

11
 Immunol. 2009;156:18993. Different profiles of wheat
[PMC free article] [PubMed] antigens are recognised by
patients suffering from coeliac
64. Junqueira, Luiz C.; Jose disease and IgE-mediated food
Carneiro (2003). Basic Histology. allergy. Int Arch Allergy
McGraw-Hill. ISBN 0-8385-0590- Immunol. 2005 Nov. 138(3):257-
2. [page needed] 66. [Medline].
65. Mallery DL, McEwan WA, 71. Janeway CA Jr; Travers
Bidgood SR, Towers GJ, Johnson P; Walport M; et al. (2001). "Ch3
CM, James LC (2010). Antigen Recognition by B-Cell
"Antibodies mediate and T-cell Receptors".
intracellular immunity through Immunobiology: The Immune
tripartite motif-containing 21 System in Health and Disease
(TRIM21)". Proc. Natl. Acad. Sci. (5th ed.). New York: Garland
U.S.A. 107 (46): 1998519990. Science.
doi:10.1073/pnas.1014074107.
PMC 2993423 . 72. Stadlmann J, Pabst M,
PMID 21045130. Kolarich D, Kunert R, Altmann F
(2008). "Analysis of
66. Cai C, Shen J, Zhao D immunoglobulin glycosylation
(2004). "Sierological by LC-ESI-MS of glycopeptides
investigation of food specific and oligosaccharides".
immunoglobulin G an Jump up ^ Proteomics. 8 (14): 28582871.
Cai C, Shen J, Zhao D (2004). doi:10.1002/pmic.200700968.
"Sierological investigation of PMID 18655055.
food specific immunoglobulin G
antibodies in patients with 73. Bonilla FA Immuno
infiammatory bowel disease.". Allergy Clin N Am 2008; 803-
PLOS ONE. 819
67. Speciani AF, Piuri G, 74. Collins, Andrew M.;
Ferrazzi E (2014). "IgG levels to Katherine J.L. Jackson (2013-08-
food correlate with nutritional 09). "A temporal model of
exposure to food antigens but a human IgE and IgG antibody
methodological weakness of this function". Frontiers in
research prevents the Immunology. 4: 235.
recognition of Yeast.related doi:10.3389/fimmu.2013.00235.
foods as a possible cause of
Irritable Bowel Syndrome ( IBS). 75. Gao, ZH; McAlister, VC;
Comment to IgG and IgG4 Wright Jr., JR; McAlister, CC;
antibodies in subjects whith Peltekian, K; MacDonald, AS
irritable bowel syndrome: a case (2004). "Immunoglobulin-G
control study in the general subclass antidonor reactivity in
population". BMC transplant recipients". Liver
Gastroenterol. Transplantation. 10 (8): 1055
1059. doi:10.1002/lt.20154.
68. Schur PH.. IgG PMID 15390333.
subclasses. A historical
perspective. Monogr Allergy 76. Azeredo da Silveira S,
(1988) 23:111 [PubMed] Kikuchi S, Fossati-Jimack L, Moll
T, Saito T, Verbeek JS, Botto M,
69. Anantaphruti MT, Walport MJ, Carroll M, Izui S
Nuamtanong S, Dekumyoy P. (2002-03-18). "Complement
Diagnostic values of IgG4 in activation selectively
human gnathostomiasis. Trop potentiates the pathogenicity of
Med Int Health. 2005 Oct. the IgG2b and IgG3 isotypes of
10(10):1013-21. [Medline]. a high affinity anti-erythrocyte
autoantibody". J Exp Med. 195
70. Constantin C, Huber (6): 66572.
WD, Granditsch G, et al.

12
 doi:10.1084/jem.20012024. 82. Latiff AH, Kerr MA.. The
PMC 2193744 . clinical significance of
PMID 11901193. immunoglobulin A deficiency.
Ann Clin Biochem (2007) 44(Pt
77. Lakos G, Sos L, Fekete 2):131
A, Szab Z, Zeher M, Horvth IF, 9.10.1258/00045630778011799
Dank K, Kapitny A, Gyetvai A, 3 [PubMed] [Cross Ref]
Szegedi G, Szekanecz Z (Mar
Apr 2008). "Anti-cyclic 83. von Gunten S, Smith DF,
citrullinated peptide antibody Cummings RD, Riedel S,
isotypes in rheumatoid arthritis: Miescher S, Schaub A, et al.
association with disease Intravenous immunoglobulin
duration, rheumatoid factor contains a broad repertoire of
production and the presence of anticarbohydrate antibodies
shared epitope". Clinical and that is not restricted to the IgG2
Experimental Rheumatology. 26 subclass. J Allergy Clin Immunol
(2): 25360. PMID 18565246. (2009) 123(6):1268
76.10.1016/j.jaci.2009.03.013
78. Teri Shors (August [PMC free article] [PubMed]
2011). "Ch5 Laboratory [Cross Ref]
Diagnosis of Viral Diseases and
Working with Viruses in the 84. Stapleton NM, Andersen
Research Laboratory". JT, Stemerding AM, Bjarnarson
Understanding Viruses (2nd SP, Verheul RC, Gerritsen J, et al.
ed.). Jones & Bartlett Publishers. Competition for FcRn-mediated
pp. 103104. ISBN 978-0-7637- transport gives rise to short
8553-6. half-life of human IgG3 and
offers therapeutic potential. Nat
79. Ferrante A, Beard LJ, Commun (2011)
Feldman RG.. IgG subclass 2:599.10.1038/ncomms1608
distribution of antibodies to [PMC free article] [PubMed]
bacterial and viral antigens. [Cross Ref]
Pediatr Infect Dis J (1990) 9(8
Suppl):S16 85. Brezski RJ, Jordan RE..
24.10.1097/00006454- Cleavage of IgGs by proteases
199008001-00004 [PubMed] associated with invasive
[Cross Ref] diseases: an evasion tactic
against host immunity? MAbs
80. Jefferis R, Kumararatne (2010) 2(3):212
DS.. Selective IgG subclass 20.10.4161/mabs.2.3.11780
deficiency: quantification and [PMC free article] [PubMed]
clinical relevance. Clin Exp [Cross Ref]
Immunol (1990) 81(3):357
67.10.1111/j.1365- 86. Meyts I, Bossuyt X,
2249.1990.tb05339.x [PMC free Proesmans M, Boeck KD..
article] [PubMed] [Cross Ref] Isolated IgG3 deficiency in
children: to treat or not to treat?
81. Schauer U, Stemberg F, Case presentation and review of
Rieger CH, Buttner W, Borte M, the literature. Pediatr Allergy
Schubert S, et al. Levels of Immunol (2006) 17(7):544
antibodies specific to tetanus 50.10.1111/j.1399-
toxoid, Haemophilus influenzae 3038.2006.00454.x [PubMed]
type b, and pneumococcal [Cross Ref]
capsular polysaccharide in
healthy children and adults. Clin 87. Nouri-Aria KT, Wachholz
Diagn Lab Immunol (2003) PA, Francis JN, Jacobson MR,
10(2):202 Walker SM, Wilcock LK, et al.
7.10.1128/CDLI.10.2.202- Grass pollen immunotherapy
207.2003 [PMC free article] induces mucosal and peripheral
[PubMed] [Cross Ref] IL-10 responses and blocking

13
 IgG activity. J Immunol (2004) differentiation from rheumatic
172(5):3252 diseases and other diseases.
9.10.4049/jimmunol.172.5.3252 Mod Rheumatol (2012)
[PubMed] [Cross Ref] 22(3):41925.10.1007/s10165-
011-0532-6 [PubMed] [Cross
88. Jutel M, Akdis CA.. Ref]
Immunological mechanisms of
allergen-specific 94. Mahajan VS, Mattoo H,
immunotherapy. Allergy (2011) Deshpande V, Pillai SS, Stone
66(6):72532.10.1111/j.1398- JH.. IgG4-related disease. Annu
9995.2011.02589.x [PubMed] Rev Pathol (2014) 9:315
[Cross Ref] 47.10.1146/annurev-pathol-
012513-104708 [PubMed]
89. van Helden PM, van den [Cross Ref]
Berg HM, Gouw SC, Kaijen PH,
Zuurveld MG, Mauser- 95. Pan Q, Hammarstrom L..
Bunschoten EP, et al. IgG Molecular basis of IgG subclass
subclasses of anti-FVIII deficiency. Immunol Rev (2000)
antibodies during immune 178:99110.10.1034/j.1600-
tolerance induction in patients 065X.2000.17815.x [PubMed]
with hemophilia A. Br J [Cross Ref]
Haematol (2008) 142(4):644
52.10.1111/j.1365- 96. Vlug A, Nieuwenhuys EJ,
2141.2008.07232.x [PubMed] van Eijk RV, Geertzen HG, van
[Cross Ref] Houte AJ.. Nephelometric
measurements of human IgG
90. van Schouwenburg PA, subclasses and their reference
Krieckaert CL, Nurmohamed M, ranges. Ann Biol Clin (Paris)
Hart M, Rispens T, Aarden L, et (1994) 52(78):5617. [PubMed]
al. IgG4 Production Against
Adalimumab During Long Term 97. Wu TT, Johnson G, Kabat
Treatment of RA Patients. J Clin EA.. Length distribution of
Immunol (2012) 32:1000 CDRH3 in antibodies. Proteins
6.10.1007/s10875-012-9705-0 (1993) 16(1):1
[PubMed] [Cross Ref] 7.10.1002/prot.340160102
[PubMed] [Cross Ref]
91. Adjobimey T, Hoerauf
A.. Induction of immunoglobulin 98. Bruhns P, Iannascoli B,
G4 in human filariasis: an England P, Mancardi DA,
indicator of immunoregulation. Fernandez N, Jorieux S, et al.
Ann Trop Med Parasitol (2010) Specificity and affinity of human
104(6):455 Fcgamma receptors and their
64.10.1179/136485910X127863 polymorphic variants for human
89891407 [PMC free article] IgG subclasses. Blood (2009)
[PubMed] [Cross Ref] 113(16):3716
25.10.1182/blood-2008-09-
92. Sah RP, Chari ST.. 179754 [PubMed] [Cross Ref]
Serologic issues in IgG4-related
systemic disease and 99. Hershfield M. Combined
autoimmune pancreatitis. Curr immune deficiencies due to
Opin Rheumatol (2011) purine enzyme defects. In:
23(1):108 Stiehm ER, Ochs HD,
13.10.1097/BOR.0b013e328341 Winkelstein JA, eds.
3469 [PubMed] [Cross Ref] Immunologic Disorders in
Infants & Children. 5th ed.
93. Yamamoto M, Tabeya T, Philadelphia, PA: Elsevier
Naishiro Y, Yajima H, Ishigami K, Saunders; 2004:480-504.
Shimizu Y, et al. Value of serum
IgG4 in the diagnosis of IgG4- 100. Aucouturier P, Mariault
related disease and in M, Lacombe C, Preud'homme JL.
Frequency of selective IgG

14
 subclass deficiency: a influenza is associated with
reappraisal. Clin Immunol cytokine dysregulation. Clin
Immunopathol 1992; 63:289. Vaccine Immunol 2011; 18:305.
101. Lawton AR. IgG subclass 109. Knutsen AP, Becker BA.
deficiency and the day-care Evolution of IgG subclass
generation. Pediatr Infect Dis J deficiency into common variable
1999; 18:462. immunodeficiency in a child
with pulmonary interstitial
102. Depiero A, Kaminski DA, glycogenosis. Pediatr Asthma
Halsey JF, et al. Immunologic Allergy Immunol 2009; 21:191.
compensation in a patient with
a large IgH constant region 110. de Moraes Lui C,
deletion. J Allergy Clin Immunol Oliveira LC, Diogo CL, et al.
2001; 107:1051. Immunoglobulin G subclass
concentrations and infections in
103. Meulenbroek AJ, children and adolescents with
Zeijlemaker WP. Human IgG severe asthma. Pediatr Allergy
subclasses: Useful diagnostic Immunol 2002; 13:195.
markers for
immunocompetence, 2nd 111. Abrahamian F, Agrawal
edition, CLB, Amsterdam, The S, Gupta S. Immunological and
Netherlands 2000. clinical profile of adult patients
with selective immunoglobulin
104. Javier FC 3rd, Moore CM, subclass deficiency: response to
Sorensen RU. Distribution of intravenous immunoglobulin
primary immunodeficiency therapy. Clin Exp Immunol 2010;
diseases diagnosed in a 159:344.
pediatric tertiary hospital. Ann
Allergy Asthma Immunol 2000; 112. Hill SL, Mitchell JL,
84:25. Burnett D, Stockley RA. IgG
subclasses in the serum and
105. Escobar-Prez X, Dorta- sputum from patients with
Contreras AJ, Interin-Morales bronchiectasis. Thorax 1998;
MT, et al. IgG2 53:463.
immunodeficiency: association
to pediatric patients with 113. Bossuyt X, Marin G,
bacterial meningoencephalitis. Meyts I, et al. Determination of
Arq Neuropsiquiatr 2000; IgG subclasses: a need for
58:141. standardization. J Allergy Clin
Immunol 2005; 115:872.
106. Kalfa VC, Roberts RL,
Stiehm ER. The syndrome of 114. Kato Z, Watanabe M,
chronic mucocutaneous Kondo N. IgG2, IgG4 and IgA
candidiasis with selective deficiency possibly associated
antibody deficiency. Ann Allergy with carbamazepine treatment.
Asthma Immunol 2003; 90:259. Eur J Pediatr 2003; 162:209.
107. Lotz DR, Knutsen AP. 115. Qvarfordt I, Riise GC,
Concomitant selective antibody Andersson BA, Larsson S. IgG
deficiency in pediatric patients subclasses in smokers with
with mannose-binding lectin chronic bronchitis and recurrent
deficiency. Pediatric Allergy, exacerbations. Thorax 2001;
Immunology, and Pulmonology 56:445.
2010; 23:265.
116. Sorensen RU, Leiva LE,
108. Chan JF, To KK, Tse H, et Giangrosso PA, et al. Response
al. The lower serum to a heptavalent conjugate
immunoglobulin G2 level in Streptococcus pneumoniae
severe cases than in mild cases vaccine in children with
of pandemic H1N1 2009 recurrent infections who are

15
 unresponsive to the serum concentrations in a
polysaccharide vaccine. Pediatr population of children with
Infect Dis J 1998; 17:685. Down syndrome: comparative
study with siblings and general
117. Wolpert J, Knutsen AP. population. Allergol
Natural history of selective Immunopathol (Madr). 2002
antibody deficiency to bacterial Mar-Apr;30(2):57-61.
polysaccharide antigens in
children. Pediatr Asthma Allergy 125. Selikowitz M. Health
Immunol 1998; 12:183. problems and health checks in
school-aged children with Down
118. Gutirrez-Tarango MD, syndrome. J Pediatr Child Health
Berber A. Safety and efficacy of 1992; 28:3836.
two courses of OM-85 BV in the
prevention of respiratory tract 126. Hilton JM, Fitzgerald DA,
infections in children during 12 Cooper DM. Respiratory
months. Chest 2001; 119:1742. morbidity of hospitalized
children with trisomy 21.J
119. Karaca NE, Karadeniz C, Pediatr Child Health 1999;
Aksu G, Kutukculer N. Clinical 35:3836.
and laboratory evaluation of
periodically monitored Turkish 127. Bloemers BL, van Furth
children with IgG subclass AM, Weijerman ME et al. Down
deficiencies. Asian Pac J Allergy syndrome: a novel risk factor for
Immunol 2009; 27:43. respiratory syncytial virus
bronchiolitisaprospectivebirth-
120. Abdou NI, Greenwell CA, cohortstudy.Pediatrics
Mehta R, et al. Efficacy of 2007;120:107681.
intravenous gammaglobulin for
immunoglobulin G subclass 128. Bruijn M, van der Aa LB,
and/or antibody deficiency in van Rijn RR, Bos AP, van
adults. Int Arch Allergy Immunol Woensel JB. High incidence of
2009; 149:267. acute lung injury in children
with Down syndrome. Intens
121. Meyts I, Bossuyt X, Care Med 2007; 33:217982.
Proesmans M, De B. Isolated
IgG3 deficiency in children: to 129. Clinical and
treat or not to treat? Case Experimental Immunology
presentation and review of the 2011 British Society for
literature. Pediatr Allergy Immunology, Clinical and
Immunol 2006; 17:544. Experimental Immunology, 164:
916
122. Olinder-Nielsen AM,
Granert C, Forsberg P, et al. 130. Milunsky A, Neurath PW.
Immunoglobulin prophylaxis in Diabetes mellitus in Down's
350 adults with IgG subclass Syndrome. Arch Environ Health
deficiency and recurrent 1968: 372-6.
respiratory tract infections: a
long-term follow-up. Scand J 131. Arquhar JW. Early-onset
Infect Dis 2007; 39:44. diabetes in the general and the
Down's syndrome population.
123. Annern G1, Magnusson Lancet 323-4.
CG, Lilja G, Nordvall SL.
Abnormal serum IgG subclass 132. Bergholdt R et al.
pattern in children with Down's Increased prevalence of Down's
syndrome. Arch Dis syndrome in individuals with
Child. 1992 May;67(5):628-31. type 1 diabetes in DA
nationwide population-based
124. Barradas C1, Charlton study. Diabetologia. 1179-82.
J, MendoCa P, Lopes AI, Palha
M, Trindade JC. IgG subclasses

16
17