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Rev Med Int Sindr Down. 2011;15(1):8-13
international
medical review
on down’S syndrome
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CASE REPORT
Pediatrics, Down’s syndrome and allergic disease
F. Muñoz-López
Former Chief of Pediatric Allergology Service, Hospital Clínic-Sant Joan de Déu, Faculty of Medicine, Barcelona, Spain
Received on July 19, 2010; accepted on October 20, 2010
KEYWORDS
Allergy;
Atopy;
Genetics;
Hygiene hypothesis;
Down’s syndrome;
Trisomy 21
Abstract
Allergic diseases have a genetic basis (atopy), meaning that inheritance is a determining
factor in the development of these processes. Respiratory pathologies are the most
common, although reactions to foods and drugs also occur. The most common clinical
manifestations occur in the skin and digestive tract, and generalised reactions
(anaphylaxis) can often occur that can be severe or even fatal. The increase in respiratory
pathologies in recent years has been linked to a reduction in infectious diseases in
developed countries. The activity of Th1/Th2 lymphocytes has become imbalanced,
leaning towards the Th2 that are responsible for producing antibodies against allergens
(“hygiene hypothesis”). In spite of this, children with trisomy 21, with the wide gamut of
altered genes responsible for many of the processes associated with this syndrome, rarely
suffer from allergic diseases. This is reflected in the small number of publications on this
field. In contrast, immune response to pathogens is constantly affected (greater incidence
of infections requiring the production of specific antibodies produced by Th1 lymphocyte
activity) along with other processes (auto-immune, leukaemia) related to patient
immunity, and this could be the cause of the reduced possibility for allergic reactions.
© 2010 Fundació Catalana Síndrome de Down. Published by Elsevier España, S.L. All rights
reserved.
E-mail: [email protected] (F. Muñoz).
1138-011X/$ - see front matter © 2010 Fundació Catalana Síndrome de Down. Published by Elsevier España, S.L. All rights reserved.
Pediatrics, Down’s syndrome and allergic disease
PALABRAS CLAVE
Alergia;
Atopia;
Genética;
Hipótesis higiénica;
Síndrome de Down;
Trisomía 21
9
Pediatría, síndrome de Down y patología alérgica
Resumen
Las enfermedades alérgicas tienen una base genética (atopia), por lo que la herencia es
determinante para presentar estos procesos, en los que la enfermedad respiratoria es
predominante, aunque no faltan las reacciones frente a alimentos o medicamentos, cuyas manifestaciones clínicas más comunes tienen lugar en la piel y el aparato digestivo,
con reacciones generales en no pocas ocasiones (anafilaxia) que pueden ser graves, incluso mortales. El aumento de la afección respiratoria en los últimos años se ha relacionado
con la disminución de las enfermedades infecciosas en los países desarrollados, con un
desequilibrio en la actuación de los linfocitos Th1/Th2, inclinada hacia los Th2, encargados de la producción de anticuerpos frente a alérgenos (“hipótesis higiénica”). A pesar de
esto, en los niños con trisomía 21, con gran alteración de genes encargados de otros
muchos de los procesos asociados a la entidad, en pocas ocasiones presentan enfermedades de causa alérgica, como refleja la escasez de publicaciones que se ocupen de este
tema. Por el contrario, la afectación de la respuesta inmunitaria frente a patógenos
(mayor incidencia de infecciones con necesidad de producción de anticuerpos específicos
a cargo de los linfocitos Th1) y otros procesos (autoinmunes, leucemia) relacionados con
la inmunidad, se mantienen de forma constante, lo cual puede ser la causa de la menor
posibilidad de reacciones alérgicas.
© 2010 Fundació Catalana Síndrome de Down. Publicado por Elsevier España, S.L. Todos
los derechos reservados.
Introduction
Among those diseases that are common during paediatric
ages, allergic pathologies are, without a doubt, the most
prevalent. Respiratory pathologies are the most predominant
(rhinitis, rhinosinusitis, asthma, eosinophilic bronchitis),
but other organs are also involved, such as the conjunctiva
(conjunctivitis/rhinoconjunctivitis), the skin (eczema,
urticaria, angio-oedema), and the digestive tract
(eosinophilic oesophagitis, gastroenteritis). All these come
as a consequence of the sensitivity to certain substances,
normally well-tolerated in humans, which behave in these
people as allergens (pneumoallergens, foods, drugs).
Several different studies have also demonstrated a
progressive increase observed in recent years, showing that
respiratory pathologies are most common. The ISAAC study
(International Study of Asthma and Allergies in Childhood),
the largest of its kind, covered a large geographical area
(66 centres in 37 countries), covering two different age
groups (6-7 and 13-14 years), and has been repeated three
times to date with an interval of 7 years between phase I
and phase III. An increase in these pathologies has been
observed in all countries.1 In Spain during this time, asthma
has increased from occurring in 6.2% of the population to
9.6%, with differences in both age groups, whereas
rhinoconjunctivitis and eczema have maintained similar
values throughout.1,2 Similar results have been described in
other countries, although the differences in percentages
are very varied.1,3
The causes of this increase in allergic pathologies, above
all those affecting the respiratory system, can be debated.
There are various factors that could influence results, from
the level of awareness in professionals from various
countries with different levels of development, to the
concept or definition of asthma, which varies often in the
different therapeutic guidelines available. This could lead
to the inclusion of a greater number of patients within the
umbrella of this diagnosis. However, what appears to be the
most highly supported theory is the influence of the changes
in T helper lymphocyte activity (Th), which are activated as
a consequence of the stimulus of pathogenic or allergenic
agents. Th1 lymphocytes activated by bacteria or virus
produce antibodies specific to these pathogens using various
different cytokines (IL-2, IFNγ, TNFβ, etc.) that act on the
corresponding B-lymphocytes. Meanwhile, Th2 cells are
responsible for the production of antibodies against
parasites and allergens, with other cytokines involved (IL-4,
IL-13, etc.). The Th1/Th2 response is balanced, such that
the production of antibodies against pathogens is guaranteed
by the superior activity of Th1. The production of allergenspecific IgE by Th2 cells is fundamentally due to the atopic
predisposition of the patient. This is inherited or even
caused by the decreased activity of Th1 as a result of a
decreased risk of pathogens.4
Regarding the atopic predisposition of the patient,
approximately 12% of children born to non-atopic parents
suffer from allergies, whereas if one of the parents suffers
from allergies, 19% of offspring are at risk of allergies,
increasing to 42% if both parents are atopic, and 72% if both
parents suffer from the same allergic disease (asthma, for
example). Therefore, the atopic predisposition of the
patient is due to the alteration of certain genes responsible
for the immune response related to the production of
specific IgE, allergic inflammation, and broncholability.
A viewpoint known as the “hygiene hypothesis” has been
established regarding the Th1/Th2 imbalance in favour of
10
F. Muñoz López
Th2.5 The improved quality of life and hygienic conditions,
the influence of vaccinations, and above all, the reduced
risk of infection in developed countries appear to have an
important influence on the increase in the prevalence of
allergies as the need for Th1 activity is reduced. Therefore,
when atopic predisposition is of little importance and there
is a greater risk of infection, Th1 cells dominate the
situation, and these levels decrease to a minimum when
this risk is minimised (Th2 activity). However, the
predomination of Th2 can also occur due to over-exposure
to environmental contaminants or allergens, through an
epigenetic mechanism since the mechanisms for genetic
regulation does not cause the DNA sequences to change.6,7
In any case, other coadjuvant possibilities, such as obesity
and physical activity, cannot be ruled out in the appearance
of respiratory pathologies, above all in developed
countries.8
Incidence of Down’s Syndrome
Few studies have broached the topic of the incidence of
allergic pathologies in these children, which probably
indicates the low probability of these conditions appearing
in children with this disease. In a recent publication, Mannan
et al9 presented an interesting study that could serve as the
basis for other larger studies with the same goal: screening
of the population with Down’s syndrome in order to
understand the existence or risk of allergic pathologies.
This was a retrospective study that included 39 children
with Down’s syndrome (aged between 0.75 years and 17
years) that had been referred to the allergy departments at
various North American hospitals with symptoms suggestive
of allergies: chronic rhinitis, chronic or recurring sinusitis,
cough and/or dyspnoea, and other undetermined symptoms.
These results were compared with a control group, with the
same number of children of similar ages studied in the same
hospitals for similar clinical reasons. In all cases, cutaneous
tests were performed (prick test) with common
pneumoallergens (mites, pollen, fungi). Positive results
were found in 7 of the children (18%) and 21 (54%) of the
control patients (it was not recorded how many allergens
they were allergic to in each case). Obviously, this is a
notable difference between the two groups, made even
more interesting by the fact that 30 of the 39 patients with
Down’s syndrome had first-degree relatives with allergic
conditions (asthma, rhinitis, atopic dermatitis). These
results are significant when compared with the above
mentioned values of the risk of children suffering from an
allergy when parents are affected by this pathology.
In another study, Forni et al10 researched the existence of
asthma in Down’s syndrome children in a total of 545
families in which 294 siblings were included in the study as
well. The prevalence of asthma in children with Down’s
syndrome was significantly lower (P<.001) than in their
siblings, in which the incidence of asthma was similar to
that of the general population on the date of publication.
Furthermore, in 30 of the 545 families, at least one of the
parents had a history of asthma, and the same disease was
detected in 12 of the children from these families. Only one
of the children with Down’s syndrome studied, a 10 year-old
boy, had suffered mild symptoms of asthma between the
age of 2 and 5 years old, with positive cutaneous and IgE
tests for mites, whereas his 12 year old brother had severe
asthma.
These results were different to those obtained by Shieve
et al11 in a study that took place between 1997 and 2005
with 146 children with Down’s syndrome aged between 3–17
years old and a control group of 95 454 children of the same
age. This study also included 604 patients with various
unspecified mental conditions; however, these results have
not been included here. The authors studied respiratory
processes (asthma, rhinitis), digestive/food conditions, and
eczema, as well as other conditions not related to atopy.
They found that over twice as many suffered from food/
digestive allergies compared to the control group and there
was a slight increase in respiratory conditions (Table 1). By
age group, the frequency of these processes decreases with
age, which is typical in the general allergic population,
possibly due to the reasons laid out further on.
Table 1 Probable allergic pathology in children with Down’s syndrome, between 3 and 17 years old, compared to a similaraged healthy general population
Disorder
Asthma (at some point)
Asthma (attack in the last 12 months)
Allergic rhinitis (in the last 12 months)
Any type of allergic respiratory disorder
(in the last 12 months)
Digestive/food allergy (in the last
12 months)
Eczema/allergic dermatitis (in the last
12 months)
Schieve et al11.
Down’s syndrome population
General population
Total no. of
cases (%)
3-5 years
old (%)
6-10 years
old (%)
11-17 years
old (%)
No. of cases (%)
29 (19.4)
12 (8.7)
19 (12,7)
28 (19.9)
46.0
29.4
10,6
28.2
19.2
  9.2
15,2
28.0
  9.4
  2.1
11.9
11.8
12 967 (13.2)
  5 586 (5.8)
10 779 (11.4)
12 210 (12.8)
17 (7.8)
11.7
  6.6
  7.1
  3 301 (4.4)
20 (9.2)
12.6
  8.7
  8.2
  7 478 (8.2)
Pediatrics, Down’s syndrome and allergic disease
Genetic Determinants
Trisomy 21
It is currently known that over 400 genes exist on chromosome
21, 139 more than were observed in the first sequencing of
the chromosome, published by Hattori et al12 in 2000. Of
these, at least 83 are exclusive to the human species, while
the other 140 are shared with mice. This animal has been
used as a model for understanding their activity.13 The
relationship between these genes and immunoallergic
pathology is not well known, except for the fact that the
triplication of the chromosome results in the RNA being
somewhat modified or mutated, whose levels increase by
50%.14,15 The genes that participate in the immune response
due ti interferon and those that regulate some aspect of
cell adhesion molecules are the ones that are most probably
involved.
In a study on the genetic basis of atopic dermatitis, Bu et
al16 observed that a series of genes on different chromosomes,
one of these on the 21q21chromosome, could be involved in
the severity of the process, above all in asthma patients.
This finding suggests a possible relationship between trisomy
21 and the incidence of allergic processes.
Immunity
An intricate immune system is involved in the defence
against pathogens, which ranges from the elements that
make up “innate immunity”, such as skin and mucosal
barriers, and the complement system, to the various cells
involved in “adaptive immunity”. These achieve their
objective using mediators (cytokines), different cell
receptors, the production of antibodies, and other elements
that participate in cell dynamics (cell adhesion molecules)
and inflammation (chemokines). The process starts with the
pathogen being engulfed by antigen-presenting cells
(dendritic cells, macrophages), this then leads to
intracellular processing (fragmentation), the pathogen is
then presented to various lymphocytes, B lymphocytes are
stimulated, and it is then passed on to antibody-producing
plasma cells (immunoglobulins M, G, and A and their
subclasses). Many different genes, which are present in
most chromosomes, intervene in the functioning of this
complicated system; even the different fragments that
make up the immunoglobulins (two light chains and two
heavy chains) are encoded by different genes.17 The
aggressiveness of the pathogen or the circumstances of the
patient (social, environmental, pathological) may mean
that these defence mechanisms fail but, above all, the
existence of mutations or other genetic abnormalities leads
to many known immunodeficiencies. Over a hundred
different genetic abnormalities have already been identified
as being responsible for these.18
The higher frequency of potentially severe infectious
diseases in patients with Down’s syndrome has been linked
in part to the altered development of the thymus, which is
smaller with an abnormal structure in these patients. This
leads to a marked decrease in various subclasses of
lymphocytes and a possible increase in NK cells (natural
killers), as well as a deficient or altered production of
11
immunoglobulins that can be linked to a lower production
of B lymphocytes. Some of these abnormalities, along with
a greater incidence of autoimmune disorders and tumours,
which are more frequent at later ages, have led to
characterising the immune system in Down’s syndrome as
early-aging.19
Atopy
Allergic reactions occur due to the predominance of the
activity of Th2 lymphocytes and the subsequent increase of
specific IgE, such as in the case of asthma with bronchial
hyperreactivity.20,21 Chromosome 11 (11q13) was the first in
which researchers attempted to identify genes involved in
the production of IgE; this chromosome is responsible for
the synthesis of the β-chain in high-affinity IgE receptors
(FcεRI-β). The role of these receptors in the allergic
response has not been well established.
To date, about twenty loci have been identified on several
different chromosomes, but the relationship of some of
them with the development of atopy is still to be confirmed
(Table 2). Chromosome 5 (5q31-q33) has sparked the most
interest. This contains genes that modulate the production
of interleukins secreted by Th2 lymphocytes, such as IL-4
and IL-13, which are responsible for the atopic response as
they are involved in the secretion of IgE by B lymphocytes
(plasmocytes), as well as other interleukins (IL-3, IL-5, and
Table 2 Chromosomes involved in the allergic reaction
Chromosome
Mediators of atopy
1q23
2q12
2q33
3p24.2p22
4q35
5q23-q33
Total IgE
Eosinophilia
CD28: activated T cells
Chemokine receptors
Interferon regulatory factor
IL-4 IL-13, IL-3, IL-5, IL-9; colonystimulating factor; CD14: bacterial
lipopolysaccharide-ligand
TNF- : Tumour necrosis factor-alpha
HLA class II Ag
Eosinophilia. IL-33, IL-1-ligand
T cell receptors; IL-6
-chain in high-affinity IgE receptors
(Fc RI- )
Interferon gamma (IFN- ) stem cell
factor
Heavy chain IgG
6p21.1-p23
7p15.2
9q24
11q13
12q14-q24.23
13q14.3
14q32
16p12.1
17p11.1-q11.2
17q-12, 17q21
19q13
20p13
Xq28-Xq28-q29
Cell receptor /
IL-4 receptor
Transmembrane proteins bound to the
endoplasmic reticulum
Chemokine receptor
Metalloproteinase
CD22: Mature B cells. IL-9 receptor
HLA: histocompatibility leukocyte antigen; Ig: immunoglobulin;
IL: interleukin.
12
IL-9) that are also involved in the pathogenesis of asthma
(eosinophilia, inflammation). The IL-4 receptor in Th2 cells
appears to depend on a gene located on chromosome 16
(16p12.1). Genes that could control other elements involved
in the pathogenesis of atopy are also found on this
chromosome. IgE production also seems to depend on other
genes located on chromosomes 7, 14, and 6. This controls
the major histocompatibility complex (HLA II) and has been
linked to a possible increased individual susceptibility to
certain allergens.
Allergic asthma is caused by the combination of atopic
predisposition and the existence of bronchial hyperreactivity.
The early appearance of the disease suggests the existence
of congenital bronchial hyperreactivity, which could be due
to polymorphisms or possible mutations. The frequent
coexistence of these two conditions led to the belief that
the genes responsible could lie on chromosome 5, where
loci had already been identified that encode the production
of interleukins that work in the production of IgE. This was
later confirmed.
To date, 9 different mutations have also been discovered
in the β2-adrenergic receptors of bronchial smooth muscle.
One of these is the substitution of glycine for arginine in
position 16 of the protein chain of the receptor which has
been linked to the severity of asthma due to a reduced
response to the administration of β2-agonists. The
substitution of glutamate for glutamine in position 27
aggravates the situation, while it is also believed that the
substitution of threonine for isoleucine is also involved.
The gene ADAM33, located on the short arm of chromosome
20 (20p13), has been discovered in lung fibroblasts and
bronchial smooth muscle, but not in epithelial cells.
Metalloproteinase, a group of enzymes that have been
related to bronchial hyperreactivity and the process of
bronchial remodelling, is encoded by this gene.
Comments
The reduced incidence of allergic diseases in these children
is undoubtedly related to this genetic structure and above
all, to the greater incidence of infections due to the defects
in the genes responsible for the body’s defence against
infections. This increased risk of infection would be in
accordance with the “hygiene hypothesis”, since the
immune system must predominate, although with difficulty,
over pathogens in these cases in an “effort” to overcome its
deficiencies.
In the work by Schieve et al,11 a clear pattern of “allergic
pathology” existed in these children, with respect to the
general population. The diagnosis was based on the
information provided by the child’s parents, without
requiring confirmation by a professional, which could have
led to incorrect or uncertain diagnoses. In the case of
asthma, rates of incidence described in the general
paediatric population normally decrease in a similar way to
that described here according to the various phenotypes.22
The cause is almost always a viral infection (human
respiratory syncytial virus [RSV], rhinovirus, parainfluenza,
and others) which recurr due to the immature immune
system in the youngest patients. This often leads to cases
F. Muñoz López
being erroneously labelled as asthma, instead of bronchiolitis
or wheezy bronchitis. The same could have occurred in the
cases included in the study, given the increased susceptibility
to respiratory viral infections.23,24
In conclusion, given that there are few publications on
the incidence of allergic processes of any kind in children
with Down’s syndrome, with greater emphasis being placed
on the prevalence of infections and other processes related
to the deficient immune system (auto-immune, leukaemia,
neoplasia, etc.), it is evident that allergic diseases are rare
in these patients.
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