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The natural course of childhood food allergy
depends on the food protein causing symptoms.
Some food allergies have a high rate of resolution
in childhood, such as milk (>50% by age
5–10 years), egg (approximately 50% by ages
2–9years), wheat (50% by age 7years) and soy
(45% by age 6years), with continued resolution
into adolescence. Other food allergies typically
persist or have low rates of childhood resolution:
peanut allergy (approximately 20% by age
4 years), tree nut allergy (approximately 10%)
and allergy to seeds, sh and shellsh are also
considered persistent, but studies are lacking to
dene the course.
Alcoholic Drinks andtheNose
Alcoholic beverages, notably red and white
wines, are known to produce bronchial symptoms
in certain individuals [83–85]. Alcohol- induced
nasal symptoms (ANS) can also occur after wine
intake [83, 86]. ANS are about twice as common
in women than in men [87].
Nasal blockage is the dominating symptom of
ANS, but sneezing and nasal discharge can also
occur. Alcohoic drinks I can trigger migraine and
induce acute onset symptoms of nasal congestion, clear watery rhinorrhoea, and pressure over
the forehead and cheeks.
Red wine is the most frequently described
cause of acute-onset symptoms compared to
other alcoholic beverages. Red wine is also associated with rhinorrhoea and a corresponding
increase of fucose, a carbohydrate present in
mucin glycoproteins, that can be measured in
nasal lavage uid [86], and reects altered mucinous secretion [88]. Sulphite and histamine are
constituents of wine and both have been suggested to induce airway symptoms [84, 85, 89].
Patients with Aspirin-exacerbated respiratory
disease (AERD) have a predilection for alcohol
intolerance and respiratory reactions. Reactions
are most likely to occur with red wine, beer and
sometimes white wine. It has been suggested
that the reaction is induced by polyphenols that
inhibit the COX-1 enzyme. Polyphenols occur in
red wine grape skin, barley and hops used in
brewing beer and oak barrels used to age white
wine.
Patients should be advised to limit or avoid
alcohol, or try clear liquor such as vodka that is
free from polyphenols. In patients with AERD,
aspirin desensitisation has been shown to
improve alcohol intolerance. Loratidine has been
shown to reduce nasal blockage after drinking
red wine [86]. Wine produced with ecological
methods has been suggested to give less nasal
blockage than wine not labelled as ecologically
produced [90].
The Principles ofManagement
Allergic diseases are chronic and often variable
in degree of severity. Environmental factors often
play a major role in the development of allergic
disorders and in the symptom prole. Once
allergy is recognized, symptom control is dependent on identifying allergens, minimizing exposure and appropriate medication. Patient
information leaets and web links, adjusting the
environmental exposure and clinical review to
assess impact of treatment, are all important
components to consider.
Allergen Avoidance Allergen avoidance is the
rst line in management but is not always practically possible or sufcient.
Medication The drug treatment for allergic rhi-
nitis (and conjunctivitis) is based on local treatment for the nose and/or oral treatment with
antihistamines and/or local nasal corticosteroids,
depending on the degree of discomfort and
patient preference. Many recommended preparations can be bought without a prescription (OTC)
and can be used for self-care in case of temporary
or mild symptoms. The combination of treatments
may achieve additive effects. Pronounced symptoms in adolescents and adults may require a
short course of oral steroids to allow more rapid
symptomatic relief.
Immunotherapy In cases of poor symptom
control despite allergen avoidance, optimal medi-
76
Based on ARIA 2017
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C. A. Emanuelsson and N. Makwana
Anti
IgE
Allergen
immunotherapy
Peroral
corticosteroid
Topical nasal
corticosteroid +
antihistamine
Antihistamine
Anti-leukotrienea
Antihistamine eye drops
Nasal corticosteroid
Allergen avoidance
Fig. 6.7 Treatment of allergic rhinitis
cal treatment and good compliance, the patient
should be considered for allergen immunotherapy (AIT) (see Chap. 20) (Fig.6.7).
Key Learning Points
• Symptoms of rhinitis including rhinorrhoea,
nasal obstruction or blockage, nasal itching,
sneezing and postnasal drip exclude allergic
rhinitis.
• Histamine is acute released by the allergic
reaction and gives rise to the symptoms of rhinorrhoea, nasal obstruction and sneezing.
• The inspection in the nose, after decongestion,
with endoscope is obligated by patient with
rhinitis.
• Many people with allergic rhinitis also have
asthma.
• A majority of people with asthma also have
rhinitis.
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Genetics andDisorders oftheNose
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andSinuses
EmilyAnderson andVictoriaMcKay
7
Introduction
Humans have 46 chromosomes in almost every
cell, arranged into 23 pairs. One homologue, or
copy, of each pair is paternally inherited (from
the father), and the other is maternally inherited
(from the mother). Chromosomes are numbered
from pair 1 to 22; chromosome 1 is the largest
chromosome, and 22 is the smallest. The 23rd
pair forms the sex chromosomes: XX in females
and XY in males.
Within the chromosomes sit around 20,000
individual genes. Some have been extensively
studied, and their role in human development and
disease is well-understood; others remain poorly
characterised with no clearly dened links to
human disease. Each gene is comprised of exons,
the coding sections of the gene. Between the exons
are the introns, or non-coding sections of deoxyribonucleic acid (DNA). The joining regions
between introns and exons are called splice sites.
The basic structure of DNA is the doublestranded helix, rst identied back in the 1950s.
The DNA itself consists of a series of bases,
known as adenine (A), guanine (G), cytosine (C)
and thymine (T). Adenine on one strand pairs
with guanine on the complementary strand and
cytosine with guanine.
E. Anderson (*) · V. McKay
Liverpool Centre for Genomic Medicine, Liverpool
Women’s Hospital, Liverpool, UK
e-mail: Emily.anderson@lwh.nhs.uk
When referring to the DNA sequence, it is the
order of these four bases, A, C, T and G, that is
important. When a cell requires the production
of a specic protein, a process called transcription occurs. This is the ‘reading’ of the DNA
sequence to produce ribonucleic acid (RNA), a
single- strand replica of the DNA sequence for
that gene, as shown in Fig. 7.1. An important
step following transcription is called splicing,
whereby the introns (non-coding sections) are
removed, so that the nal, mature RNA only contains the code of the exons, as shown in Fig.7.2.
The mRNA is then transported out of the
nucleus to the cytoplasm, where it interacts with a
ribosome. This allows for translation, the process
by which the genetic code is read, three bases at a
time. Small molecules known as transfer RNAs
align to the mRNA.The transfer RNAs are each
attached to an amino acid, and the combination of
these amino acids leads to the formation of the
nal protein product, as shown in Fig.7.3.
Changes to the original (or germline) DNA
sequence can result in changes to the mRNA and
subsequent amino acid and protein structure.
There are many ways that the DNA sequence can
be disrupted including:
• Substitution of a base
• Deletion of one or more bases, or one or more
exons
• Insertion of one or more bases, or one or more
exons
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
A. C. Swift et al. (eds.), Contemporary Rhinology: Science and Practice,
https://doi.org/10.1007/978-3-031-28690-2_7
81
82
Splice sites
RN
mRNA
C
A
RNA
r
Growing chain
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E. Anderson and V. McKay
G
U
A
Fig. 7.1 Gene transcription. The double-helix DNA
unwinds in the region to be transcribed. The two complementary strands separate, and free-oating nucleotides
(shown in green) align to the coding strand (shown in
A
C
T
A
A
U
T
A
U
C
C
G
G
C
G
G
C
G
black). Note that adenine (A), cytosine (C) and guanine
(G) exist as in DNA; thymine (T) is replaced by uracil (U).
An enzyme called RNA polymerase causes the freeoating nucleotides to form a strand of RNA
U
G
C
C
G
A
U
T
G
A
Exon 1 Intron Exon 2 Intron Exon 3 Intron Exon 4
Exon 1 Exon 2 Exon 3 Exon 4
Fig. 7.2 Splicing. Introns are spliced out, forming mature messenger RNA (mRNA) containing only the coding
sequence
of amino acids
Amino
acid
Transfe
RNA
A
A
C
A
C
A
Ribosome
U
C
A
A
Fig. 7.3 Gene translation. The mature messenger RNA
(mRNA) is transported out of the nucleus to the cell cytoplasm, where it interacts with a ribosome. The mRNA is
‘read’ three bases at a time. Transfer RNA molecules
C
U
(shown in blue) align to the mRNA, attached to specic
amino acids. The amino acids then link to form the nal
protein product
G
Messenger
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• Substitution, deletion or insertion of the splice
site bases
• Whole gene deletion or insertion
• Contiguous gene deletion, where multiple
adjacent genes are deleted
In addition, there are other factors that can
affect the function of a gene and can result in
human disease. These include disruption or alteration of gene regulators and epigenetic factors
such as imprinting, although these will not be
discussed in detail here.
Genetic Testing
Genetic testing is constantly evolving. It is helpful to understand the basis of some of the more
commonly requested tests.
General Sample Information
Most genetic tests are carried out on germline
DNA, i.e. the constitutional DNA created at conception and present in almost every cell of the
body. Germline DNA is usually obtained from a
blood sample, although in some circumstances it
may be necessary to consider alternate sources
such as saliva, buccal swab or skin biopsy.
In certain types of cancer, it may be appropri-
ate to offer testing on tumour tissue, i.e. the DNA
contained within the tumour itself. During the
process of tumorigenesis, the tumour DNA will
accumulate many new variants and chromosomal
changes. Genetic changes present in a tumour
may not be present in the germline DNA, and
therefore the results need to be interpreted with
caution by an experienced clinician.
Karyotype
A karyotype is an assessment of the number and
structure of the chromosomes. It will detect any
whole extra or missing chromosomes, e.g. trisomy 21 (Down syndrome), and will also detect
large structural changes such as deletions, dupli-
cations and translocations, where material from
one chromosome becomes attached to a different
chromosome. Karyotyping is rarely used as a routine clinical test and has largely been superseded
by new technologies such as microarray (see
below).
Microarray
A microarray is a more detailed analysis of the
chromosomes, specically looking for any deletions or duplications. It will detect missing or
additional genetic material much more sensitively than a karyotype. Microarray is usually
used as the rst-line genetic test for individuals
with learning difculties, developmental delay
and/or multiple congenital anomalies.
Single Gene Testing
Historically, most genetic testing involved analysis of a single gene at a time. Nowadays, this is
far less commonly requested, as it is more costeffective and efcient to analyse large groups of
genes simultaneously. Single gene testing is still
appropriate in some circumstances, usually when
the patient’s phenotype is highly suggestive of a
single disorder. For example, a baby with meconium ileus, failure to thrive and recurrent respiratory infections may undergo single gene testing
of the CFTR gene for cystic brosis.
Gene Panels
A gene panel involves simultaneous analysis of
multiple genes linked to a given disorder or phenotype (clinical feature or collection of features).
Panels may be small, with only a handful of
genes linked to that condition, e.g. hereditary
haemorrhagic telangiectasia. Other panels may
be very large, with hundreds or thousands of
genes linked to a particular characteristic, e.g.
hearing loss.
The advantages and disadvantages of using a
panel-based approach are outlined in Table7.1.
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E. Anderson and V. McKay
Table 7.1 Advantages and disadvantages of gene panels
Advantages Disadvantages
More efcient and
cost-effective than
testing a single gene at
a time
Useful when there is no
obvious clinical
diagnosis but a high
suspicion of an
underlying genetic
cause
Increased chance of
nding a clinically
relevant variant
compared to single
gene testing
Generally takes longer for a
result than a single gene
test
Increased chance of
receiving uncertain or
incidental ndings, due to
the large number of genes
being analysed
Whole Exome/Genome Sequencing
Recent advances in genetic technology have
enabled the advent of whole exome sequencing
(WES) and whole genome sequencing (WGS).
These approaches involve sequencing either the
exome (the coding sections of all genes) or the
genome (all of the DNA). By analysing a much
larger proportion of the DNA, new variants and
even new genes are being discovered, and the
diagnostic rate for individuals with rare diseases
is going up. The cost of WES/WGS approaches
is falling rapidly, and results are now able to be
reported in a clinically relevant timeframe. This
means these technologies are becoming more
accessible in every day clinical practice.
However, the number of variants generated
from these approaches can be vast, and it can be
challenging to classify their pathogenicity (see
variant interpretation below). This can be particularly relevant in WGS when variants are found
outside the coding region of a gene. With the
increase of WES and WGS, it is likely that many
more patients will be found to have uncertain
genetic results, which may increase anxiety and
may not always be clinically helpful.
Ethics ofGenetic Testing
Diagnostic genetic testing, where a patient with
symptoms of a genetic disorder undergoes testing
to try to conrm a diagnosis, is usually fairly
straightforward from an ethical viewpoint. A
diagnostic test can be offered to a child or adult,
if it is felt that this would contribute to their clinical care. Some genetic tests can be requested by
clinicians outside of Clinical Genetics; others can
only be requested following consultation with a
Clinical Geneticist.
Predictive genetic testing, where an asymptomatic person is offered a test for a genetic condition known about in the wider family, is
ethically more complex. Predictive testing is
often not carried out in children, unless there is a
specic reason why this result would change
clinical care in childhood. Undergoing a predictive test can have insurance implications for the
patients and, in almost all circumstances, can
only be requested by clinicians working within
the eld of Clinical Genetics.
Variant Interpretation
Current nomenclature states that any change to the
genetic code is described as a ‘variant’. Historically,
genetic changes were called ‘mutations’, but this
term is no longer preferred for two reasons: rstly,
the term mutation or mutant may have negative
connotations for patients, and secondly, it implies
that the genetic change is disease- causing. The
human genome is subject to a wide range of variation between individuals, but most of these variants will not be associated with disease.
Variants can be classied using a ve-point
scale of pathogenicity (as summarised in
Table7.2), according to published guidelines [1]:
The key message is that not every variant identied on genetic testing is causative of disease.
When the result of a genetic test is reported,
the clinical scientist will classify any variants
identied using standard criteria. The variant classication is usually clearly stated on the report.
If a pathogenic or likely pathogenic variant is
identied in a gene linked to the patient’s phenotype, this can be regarded as a molecular
conrmation that the patient has the disease with
which the gene is associated. If there is uncertainty about the phenotype, e.g. the patient has a
likely pathogenic variant found on a panel but the
phenotype does not entirely t, then this should
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Table 7.2 Summary of variant classication (adapted
from ACMG guidelines) [1]
Class 1 Benign Not clinically relevant
Class 2 Likely benign
Class 3 Uncertain
signicance
Class 4 Likely
pathogenic
Class 5 Pathogenic
Not clinically actionable
but may be appropriate to
discuss with a clinical
geneticist
Clinically actionable, i.e.
likely to be causative of
disease
be discussed with the reporting laboratory or the
patient should be referred to a Clinical Geneticist.
In most circumstances, the laboratory will not
report variants classied as benign or likely
benign, as these are regarded as part of the normal variation between individuals and are not
clinically relevant.
Where a variant is classed as being of uncertain signicance, the decision on whether or not
to report the variant will lie with the reporting
laboratory, often in conjunction with input from
Clinical Geneticists. If a patient is reported to
have a variant of uncertain signicance, it is
sometimes appropriate to discuss with the local
Clinical Genetics service for further evaluation.
In some scenarios, it would be appropriate to test
other family members for the variant; this may
glean further information to reclassify the variant
as likely benign or likely pathogenic. Family
studies are usually only requested from within
the Clinical Genetics service.
ease. This means that an affected person has one
working copy of the gene and one altered copy.
When that person has children, there is a 50%
chance of passing on the altered copy of the gene,
and the child inheriting the genetic condition.
Autosomal Recessive
A genetic disorder that shows autosomal recessive (AR) inheritance requires both copies of a
gene to be altered to cause the condition. An individual who has one working copy and one altered
copy of a gene linked to an AR disorder is said to
be a ‘carrier’ of that condition. In most circumstances, being a carrier for an AR condition does
not cause any health concerns for that individual.
Indeed, it is believed that we are all carriers for
multiple rare, recessive disorders.
If two people who are both carriers for the
same AR disorder have a baby, they have a 25%
chance of a healthy child, 50% chance of a (usually healthy) carrier and 25% chance of an affected
child. The chance of both partners being a carrier
for the same disorder is generally low; however,
this chance is increased if the couple is consanguineous (i.e. genetically related to each other). It
is sometimes possible to offer carrier testing for
diseases known to be common in a given population, e.g. cystic brosis carrier testing in Northern
European White Caucasian populations.
Inheritance Patterns
There are different patterns of inheritance for
genetic disorders. It is important to correctly
identify the inheritance pattern within a family in
order to understand the risk of other family members being affected by the condition. Table 7.3
summarises some of the key ndings in a family
to help identify the inheritance pattern.
Autosomal Dominant
An autosomal dominant (AD) genetic disorder
only requires a single variant in order to cause dis-
X-Linked (Dominant andRecessive)
An X-linked condition is one in which the associated gene is located on the X chromosome. Females
have two copies of the X chromosome, whereas
males have one X and one Y chromosome.
Some X-linked disorders show X-linked
recessive inheritance, meaning that females can
be carriers and males are usually affected. This is
because males with a variant associated with an
X-linked recessive condition do not have a second copy of that gene to compensate and, therefore, tend to develop the disease. In some
X-linked recessive conditions, carrier females
can be at risk of developing features, but usually
more mildly than affected males.
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