Format 2016: masqueradesyndromes in allergicdiseases.

Masquerade syndromes in allergic diseases
Attilio Boner
University of
Verona, Italy
attilio.boner@univr.it
 Introduction
 Eczema or Primary Immunodeficiency (PID)?
 Eczema or Secondary Immunodeficiency?
 Eczema with an exagerated skin barrier defect
 Allergy with musculoskeletal abnormalities
 “Food allergy” without sIgE
 Respiratory Tract Manifestations in PID
 Caution is important
 Summary & Conclusions

The term masquerade syndrome encompasses a group of malignant
diseases that mimic clinical presentations of ocular inflammation.
The following differential diagnoses ought to be considered:
❃ Intraocular:
❃ In the area of the
conjunctiva and eyelids:
Masquerade syndromes’ definiton
lymphoma,
choroid melanoma,
intraocular metastases,
retinoblastoma,
para-neoplastic retinopathy
melanoma of the conjunctiva,
squamous cell carcinoma,
conjunctival lymphoma,
basal cell carcinoma,
sebaceous gland carcinoma of the eyelid,
chalazion.

❃ Intraocular:
lymphoma,
retinoblastoma,
chalazion.
 They are usually poorly, if not at all, responsive to corticosteroid.
 One must be suspicious
when the apparent
intraocular inflammation :
is unilateral
occurs either in very young children
or in the elderly

❃ Intraocular:
lymphoma,
retinoblastoma,
chalazion.
………………….and masquerading as allergic diseases?

Primary Immunodeficiency Masquerading as Allergic Disease
Primary immune deficiencies (PIDs)
have an incidence and prevalence
estimated between:
1:10,000 to 1:2000
from registries
in > 40 countries.
This is likely an underestimation as many cases remain undiagnosed;
a random telephone survey in the United States
estimated the prevalence of all PIDs at 1:2000 to 1:800.
Boyle J, J Clin Immunol 2007;27(5):497–502.
The hallmark clinical pattern is an increased susceptibility to infection

Jeffrey Modell Foundation (JMF):
10 warning signs of primary immunodeficiency (PI)
Hernandez-Trujillo VP. Immunol Allergy Clin N Am 2015;35:625–636
Pediatrics
1. ≥ 4 new ear infections within 1 year
2. ≥ 2 serious sinus infections within 1 year
3. ≥ 2 months on antibiotics with little effect
4. ≥ 2 pneumonias within 1 year
5. Failure of an infant to gain weight or grow normally
6. Recurrent deep skin or organ abscesses
7. Persistent thrush in mouth or fungal infection on skin
8. Need for intravenous antibiotics to clear infections
9. ≥ 2 deep-seated infections including septicemia
10. A family history of PI
≥ 2 months
≥ 2/yr
≥ 2/yr
≥ 4/yr

Clinical characteristics of pediatric patients evaluated
for primary immunodeficiency.
MacGinnitie A, Pediatr Allergy Immunol. 2011;22(7):671-5.
retrospective analysis
of 141 children who
underwent testing for
possible primary
immunodeficiency 30 –
25 –
20 –
15 –
10 –
05 –
00
% children diagnosed
with an underlying
primary
immunodeficiency
23%
published warning
signs were
neither sensitive
nor specific
for primary
immunodeficiency

Clinical characteristics of pediatric patients evaluated
for primary immunodeficiency.
MacGinnitie A, Pediatr Allergy Immunol. 2011;22(7):671-5.
retrospective analysis
of 141 children who
underwent testing for
possible primary
immunodeficiency 30 –
25 –
20 –
15 –
10 –
05 –
00
% children diagnosed
with an underlying
primary
immunodeficiency
23%
published warning
signs were
neither sensitive
nor specific
for primary
immunodeficiency
Patients with
allergy as
determined by the
presence of
antigen-specific
IgE were more
likely to be
diagnosed with
immunodeficiency.

Features of primary immunodeficiencies
Raje N, Immunol Allergy Clin N Am 2015;35:599–623

Common allergic symptoms can also be manifestations
of an underlying and severe Immune Deficiency
the allergic triad
in immunodeficiencies
Allergic diseases share common
factors with primary
immunodeficiencies including:
1) skin rashes such as eczema,
2) increased IgE,
3) eosinophilia.

Primary immune deficiencies with aberrant IgE production
Ozcan E, J Allergy Clin Immunol 2008;122(6):1054–62
Omenn syndrome;
Immunodysregulation, polyendocrinopathy,
enteropathy, X-linked (IPEX);
Wiskott-Aldrich syndrome;
Hyper-IgE syndrome;
Atypical complete DiGeorge syndrome.
PID with
elevated
serum IgE
levels
Increased IgE levels in IPEX, Wiskott-Aldrich syndrome and Omenn syndrome are likely
related to increased T(H)2 cytokine production caused by decreased a number or function
of CD4(+)CD25(+)forkhead box protein P3(+) regulatory T cells.
The link between signal transducer and activator of transcription 3 mutations and elevated
serum IgE levels in hyper-IgE syndrome is unclear.

Primary Immune Deficiency Presenting
with Newborn and Infant Eczema
severe whole body dermatitis
loose stool/diarrhea
standard interventions with
topical steroids and
changing formulas
are helpful only transiently
>

 Originally described in 1965 with reticuloendotheliosis
and eosinophilia. Omenn G. N Engl J Med 1965;273:427–32.
The prevalence is estimated at less than 1/1,000,000.
It is linked to Severe Combined Immune Deficiency (SCID)
and presents in infancy.
Omenn Syndrome
erythroderma,
desquamatous alopecia,
chronic diarrhea,
failure to thrive,
lymphedema,
hepatomegaly.
Omenn syndrome is an
inflammatory condition
characterized by:
Aleman K, Eur J Pediatr
2001;160(12):718–25

Reviewing Omenn syndrome.
Aleman K, Eur J Pediatr 2001;160(12):718–25.
literature search
in the period
1965-1999
68 patients
100 –
090 –
080 –
070 –
060 –
050 –
040 –
030 –
020 –
010 –
000
erythematous
rash
98%
Hepato
Spleno
megaly
88%
lymphadenopathy
80%
alopecia
57%
% infants with

Reviewing Omenn syndrome.
Aleman K, Eur J Pediatr 2001;160(12):718–25.
literature search
in the period
1965-1999
68 patients
100 –
090 –
080 –
070 –
060 –
050 –
040 –
030 –
020 –
010 –
000
erythematous
rash
98%
Hepato
Spleno
megaly
88%
lymphadenopathy
80%
alopecia
57%
% infants with
recurrent infections in 72%

It is an inflammatory phenotype of SCID that has been linked to
mutations in the recombination-activating gene 1 (RAG1) or RAG2,
RNA component of mitochondrial RNA processing endoribonuclease,
adenosine deaminase, interleukin (IL)-2R, IL-7R,
artemis-nuclease-DCLRE1C DNA ligase 4, and 22q11 microdeletion.
It usually presents in an autosomal-recessive pattern.
This is a “leaky” T/B-SCID phenotype where some T or B cells are
present and suggestive of mutations that lead to impairment of the
V(D)J DNA recombination involved in generating immunoglobulins as
well as T-cell receptors.
Omen Syndrome Pathogenesis
Chan SK, Immunol Allergy Clin North Am. 2015 Nov;35(4):767-78
X
X

In contrast to classic SCID, patients have
low, normal or even markedly increased
circulating activated T-lymphocyte levels;
however, they are oligoclonal and associated
with poor antigenic responses.
Typically, B cells are absent with loss of IgG, IgA, IgM,
but increased serum IgE.
Peripheral blood eosinophilia resulting from Th2 skewing.
Skin biopsy of lesions show acanthosis (thickening of the skin)
and parakeratosis (retention of nuclei in the stratum corneum).
Omen Syndrome Diagnosis
Chan SK, Immunol Allergy Clin North Am. 2015 Nov;35(4):767-78

Immunosuppressive treatment for their marked lymphoproliferation
and inflammation targeting the janus kinase/signal transducer and
activator of transcription (JAK/STAT) pathway has been used to
control inflammation. Borie DC, Curr Opin Investig Drugs. 2003;4(11):1297-303
Suppression can result in almost complete resolution of the
dermatitis, alopecia, hepatosplenomegaly, and lymphadenopathy with
significant weight gain. Ege M, Blood 2005;105(11):4179–86.
Care should be taken to treat underlying infections and screening
for opportunistic infections should be initiated before immune
suppression, given the underlying SCID phenotype.
To date, curative treatment and ultimate resolution
requires Hematopoietic stem cell transplantation HSCT.
Gomez L. J Pediatr 1995;127(1):76–81.
Omen Syndrome Management

An X-linked syndrome of diarrhea, polyendocrinopathy,
and fatal infection in infancy.
Powell BR, J Pediatr 1982;100(5):731–7.
Features of 8 patients from a family in which 17 male infants died
in the first years of life.
The features included:
•diarrhea,
•diabetes mellitus,
•hemolytic anemia,
•eczematoid rashes,
•exaggerated responses to viral illnesses,
•pathologic evidence of autodestruction of endocrine glands,
insulitis, and thyroiditis with thyroid autoantibodies.
(IPEX)
X-linked
recessive disease
Immune dysregulation,
Polyendocrinopathy,
Enteropathy,
X-linked (IPEX)
syndrome.

X-linked Immunodysregulation, Polyendocrinopathy,
and Enteropathy (IPEX)
Most commonly, these patients present with:
early onset severe and watery diarrhea,
type 1 diabetes mellitus, and
failure to thrive
Patients with (IPEX)
frequently present with:
Williams KW, Immunol Allergy Clin N Am 2015;35:523–544
eosinophilia
severe atopy.
(+) the classic triad of:
enteropathy, (severe darrhea)
endocrinopathy,
dermatitis.
•usually type 1 diabetes mellitus,
•sometimes thyroiditis
Chan SK, Immunol Allergy Clin North Am. 2015;35(4):767-78

and Enteropathy (IPEX): Pathogenesis
It is a X-linked recessive disease caused by
a mutation in the FoxP3 gene on chromosome Xp11
resulting in absent or dysfunctional Tregs
This transcription factor plays an important role in the development
and function of T regulatory cells that are actively involved in
suppressing the immune system and in self-tolerance.
Ricciardelli I, Immunology 2008;125(2):178–83.
These T regulatory cells (CD41251) control
T- and B-cell inflammatory reactions.
FoxP3 binds to the FOX-binding site within
the IL-2 promoter and suppresses its activity.

and Enteropathy (IPEX): Diagnosis
 Elevated IgE (possible sIgE to foods), IgA, and blood eosinophilia.
 The diagnosis is often
made after endoscopy.
Evaluation for IPEX should follow the diagnosis
of male infant-onset insulin-dependent diabetes mellitus.
Enteric biopsy may reveal villous atrophy
reminiscent of severe gastrointestinal graft
versus host disease or similar to that
described in celiac disease or autoimmune
enteropathy (with the presence of
anti-enterocyte, harmonin, and villin autoantibodies).
normal villous atrophy

and Enteropathy (IPEX): Differential Diagnosis
The triad of endocrine dysfunction, enteropathy, and eczema in infant
males is suggestive of IPEX, although other diseases should be
considered, including:
IPEX-like syndrome in CD25 mutations that affect both genders;
STAT5b mutation;
ITCH syndrome,
Nedd4 family of HECT domain E3 ubiquitin ligase mutation;
Schmidt syndrome/autoimmune polyendocrinopathy syndrome type 1;
autoimmune polyendocrinopathy,
candidiasis,
ectodermal dystrophy;
Wiskott–Aldrich;
STAT1 (gain of function);
X-linked autoimmune enteropathy;
X-linked thrombocytopenia.
(the IL-2 receptor)
No mutations
in FoxP3 gene

and Enteropathy (IPEX): Management
high-dose corticosteroids,
cyclosporine,
tacrolimus,
methotrexate,
infliximab,
rituximab,
Sirolimus has been effective.
the mainstays
of treatment
is supportive care
parenteral nutrition,
blood transfusions,
controlling diabetes
have been used:
Bindl L, J Pediatr 2005;147(2):256–9.
stop
arrests lymphocytes in the late G1 or S-phase
leaving the regulatory T cells relatively
unphased and fully functional.

A challenging undertaking: Stem cell transplantation
for immune dysregulation, polyendocrinopathy,
enteropathy, X-linked (IPEX) syndrome
Kucuk ZY, J Allergy Clin Immunol 2016;137:953-954
Our results suggest
a higher risk of graft failure
compared with
a previous report
or compared with other
immune disorders:
6 of 7 patients experienced
decreasing engraftment
Retrospective analysis
of 7 patients with IPEX
syndrome who underwent
hematopoietic stem
cell transplantation (SCT)
Median age at diagnosis
was 4.5 years
Median age at SCT
was 6.7 years

Pedigree demonstrating a sex-linked recessive condition
characterized by draining ears, eczematoid dermatitis
and bloody diarrhea. Aldrich R, Pediatrics 1954;13(2):133–9.
Wiskott–Aldrich Syndrome
†
†
†
†
†
†
† †
†
†
†
† †
†
†
†
†
†X-linked recessive disease

Wiskott–Aldrich syndrome
Infant males
severe diarrhea,
eczema, and
thrombocytopenia
Because of severe thrombocytopenia
bloody diarrhea
hemorrhagic manifestations
(small platelets and a reduced number of platelets)

Infant males
severe diarrhea,
eczema, and
thrombocytopenia
bloody diarrhea
skin,
nose,
intestine,
brain.spontaneous or as the result of an injury
(approximately 36,000/mm3)

Infant males
severe diarrhea,
eczema, and
thrombocytopenia
bloody diarrhea
skin,
nose,
intestine,
brain.spontaneous or as the result of an injury
(approximately 36,000/mm3)
Symptoms of WAS vary significantly between patients
and even between patients in the same family.
Some patients show symptoms soon after birth whereas
in others, symptoms are only seen in late infancy.

Wiskott–Aldrich Syndrome: Pathogenesis
Wiskott-Aldrich syndrome (WAS) protein (WASp)
belongs to a family of proteins that relay signals
from the surface of the cell to the actin cytoskeleton.
Mutations in the WAS gene have various effects
on the level of WASp, which, in turn, correlates with
the severity of the disease.
The absence of functional WASp leads to a severe clinical phenotype
that can result in death if not diagnosed and treated early in life.
In addition to WAS, mutations in the WAS gene can result in the
mild variant X-linked thrombocytopenia, or in X-linked neutropenia,
characterized by neutropenia with myelodysplasia.
Massaad MJ, Ann N Y Acad Sci. 2013;1285:26-43
The three fibers of the cytoskeleton–
microtubules in blue, intermediate
filaments in red, and actin in green
X
X
XXX
X X X
X
X

Wiskott–Aldrich Syndrome: Pathogenesis
Wiskott-Aldrich syndrome (WAS) protein (WASp)
belongs to a family of proteins that relay signals
from the surface of the cell to the actin cytoskeleton.
Mutations in the WAS gene have various effects
on the level of WASp, which, in turn, correlates with
the severity of the disease.
The absence of functional WASp leads to a severe clinical phenotype
that can result in death if not diagnosed and treated early in life.
In addition to WAS, mutations in the WAS gene can result in the
mild variant X-linked thrombocytopenia, or in X-linked neutropenia,
characterized by neutropenia with myelodysplasia.
The three fibers of the cytoskeleton–
microtubules in blue, intermediate
filaments in red, and actin in green
X
X
XXX
X X X
X
X
All immune cells, B, NK, and T cells are
affected, resulting in a combined
phenotype.

Wiskott–Aldrich Syndrome: Diagnosis
It has a typical triad:
thrombocytopenia,
eczema,
recurrent infections.
eosinophilia
elevated IgE, IgA,
impaired antibody production,
(mainly antipolysaccharide antibodies),
decreased serum IgM levels
with reduced platelet size
and a normal number of
megakaryocytes

The bleeding in the skin is in the form of purpura which are
red or purple discolorations measuring 0.3-1cm, under the skin
or inside the mouth.
Petechiae are purpura which appear as pin-head sized
red or blue dots and measure less than 3 mm.
Ecchymoses are those discolorations from
bleeding that measure greater than 1 cm.
These boys can have prolonged bleeding after circumcision, bleeding from
the gum especially after the loss of a tooth and prolonged bloody noses.
Copious hemorrhage, during infancy is often the presenting symptom.
Internal bleeding, as in the brain, liver or spleen can be life threatening.
Wiskott–Aldrich Syndrome: Clinical Manifestations
Microthrombocytopenia

eczema,
Patients with WAS tend to have allergies.
These can be in the form of food allergies, asthma, hay fever.
Patients with Classic WAS tend to have severe eczema (80% of cases) which can be
persistent and difficult to control.
Eczema usually starts in infancy, and it can manifest as
"cradle cap" on the scalp or a diaper rash.

eczema,
recurrent infections.
Frequent and severe bacterial infections ranging from ear infection
and sinusitis to more severe infections such as pneumonia, meningitis and sepsis.
Those patients are particularly susceptible to infections with bacteria that have a
capsule covering them (encapsulated)
such as the Pneumococcus and Hemophilus influenzae.
The infections usually start between 3-6 months of age
when the defense acquired from the mother prior to birth begins to wane.
The immune function tends to decline over the years
with infections becoming more serious and frequent.
impaired antibody production

eczema,
recurrent infections.T-lymphocytes defects
Frequent and recurrent viral infections such as
with the herpes virus, disseminated varicella
Encephalitis and hepatitis with cytomegalovirus,
Patients are unable to clear the EBV (mononucleosis) completely from their immune
system, and thus they are more susceptible to lymphoma's associated with this virus,
Fungal and opportunistic infections, especially those caused
by Candida and Aspergillus and Pneumocystis jirovecii.

Mutations in the WAS gene result in
a broad range of disease severity:
Patients with X Linked Thrombocytopenia (XLT) who present with
microthrombocytopenia but no other immunologic defects are assigned
a score of 1.
Those who present with platelet defects, mild transient eczema,
and minor infections are assigned a score of 2.
The survival rate of these two groups is similar to healthy individuals,
yet XLT is associated with severe disease-related events such as
serious hemorrhage episodes, life-threatening infections,
autoimmunity, and cancer.
0 1 2 3 4

Mutations in the WAS gene result in
a broad range of disease severity:
Patients who present with thrombocytopenia and small platelets,
persistent but manageable eczema, and/or recurrent infections are
assigned a score of 3.
Those who present with difficult-to-treat eczema
and multiple severe infections are assigned a score of 4.
Because diagnosis could be before the full manifestation of the
disease, patients with XLT should be reevaluated at a later
stage in life and their clinical scores updated accordingly.
0 1 2 3 4

A novel primary human immunodeficiency due to
deficiency in the WASP-interacting protein WIP
Lanzi G. J Exp Med. 2012; 209(1):29–34
A female offspring of consanguineous parents, showed features of
Wiskott-Aldrich syndrome (WAS), including recurrent infections, eczema,
thrombocytopenia, defective T cell proliferation and chemotaxis,
and impaired natural killer cell function.
Cells from this patient had undetectable WAS protein (WASP),
but normal WAS sequence and messenger RNA levels.
WASP interacting protein (WIP), which stabilizes WASP,
was also undetectable. A homozygous c.1301C>G stop codon
mutation was found in the WIPF1 gene, which encodes WIP.
Introduction of WIP into the patient’s T cells restored
WASP expression.
These findings indicate that WIP deficiency should
be suspected in patients with features of WAS in whom
WAS sequence and mRNA levels are normal.
WIP
X
OK
OK

Wiskott–Aldrich Syndrome: Differential Diagnosis
Wiskott-Aldrich syndrome-2 (WAS2) caused by mutations in the
WAS/WASL-interacting protein family member 1 (WIPF1) gene on
chromosome 2q31.1 coding for a protein that stabilizes and prevents
the degradation of WASp, (both male and female can be affected)
Acute or chronic idiopathic thrombocytopenia,
Thrombocytopenia
absent radius syndrome,
X-linked thrombocytopenia
(a mild form of WAS with no other immunologic defects).
radius
ulna

Wiskott–Aldrich Syndrome: Management
The goal is to control bleeding disorder and the autoimmune
manifestations (autoimmune arthritis and anemia), without further
suppressing the immune system.
Patients who are on preventative medication for Pneumocystis
(Bactrim), Aspergillus, Candida (oral anti-fungal agent such as
fluconazole) and herpes virus (Acyclovir) were noticed to have a
reduced rate of infection.
This underscores the importance of starting preventative medication
early on in infancy in patients with severe WAS.

Patients with
Wiskott–Aldrich
syndrome may require
intensive support with parenteral nutrition,
blood transfusions,
platelet transfusions,
intravenous immunoglobulin.
s
p
l
e
n
e
c
t
o
m
y
•increase level and volume of platelets
in patients with X Linked Thrombocytopenia,
•does not decrease the risks of autoimmunity and lymphoproliferative disorders,
•T and B cell function are reduced in patients who undergo HSCT following
splenectomy, making it a less desirable intervention if HSCT is considered.
•Nevertheless, because of the introduction of efficient vaccines and antibiotics,
splenectomy remains a reasonable treatment for XLT patients with mild disease.

The only curative treatment to date is
Hematopoietic stem cell transplantation (HSCT).
The use of HSCT for XLT is still controversial, considering
the excellent long-term survival with conventional treatment.
However, in light of possible severe infections, autoimmunity, and
lymphoproliferative disorders in some XLT patients, HSCT can be considered,
especially if a human leukocyte antigen (HLA)–identical related sibling donor is
available.
The best transplantation outcome has been achieved with
HLA-identical sibling donors and matched unrelated donors when the
age of the recipient is < 5 years at the time of the transplant.

Job’s Syndrome. Recurrent, “cold”, staphylococcal
abscesses. Davis SD, Lancet 1966;1(7445):1013–5.
Job’s syndrome was first described in 1966 with 2 patients
who had recurrent staphylococcal abscesses, similar to the
boils borne by the prophet Job in the Bible.
This clinical syndrome, which was
first characterized as a triad of:
recurrent staphylococcal abscesses,
pulmonary infections,
eczematous dermatitis

Job’s Syndrome. Recurrent, “cold”, staphylococcal
abscesses. Davis SD, Lancet 1966;1(7445):1013–5.
Job’s syndrome was first described in 1966 with 2 patients
who had recurrent staphylococcal abscesses, similar to the
boils borne by the prophet Job in the Bible.
This clinical syndrome, which was
first characterized as a triad of:
recurrent staphylococcal abscesses,
pulmonary infections,
eczematous dermatitis
was later found to be
associated with
increased serum IgE levels,
leading to the name
autosomal dominant
hyper IgE syndrome
(AD-HIES).
Buckley RH. Pediatrics 1972;49:59-70.

Autosomal-Dominant Hyper-immunoglobulin E Syndrome
(Job Syndrome)
it may not
just be atopy
 eosinophilia,
 increased IgE,
 eczema
the prevalence is
estimated between
1 and 9 in 100,000.
≈ 1 in 10,000
most of cases are
de novo mutations

(Job Syndrome)
it may not
just be atopy
primary immune deficiency
presenting with
 eosinophilia,
 increased IgE,
 eczema
chronic eczema starting in newborns,
recurrent staphylococcal skin infections,
increased serum IgE,
eosinophilia.
characteristically
features

Dermatitis and the newborn rash of hyper-IgE syndrome.
Eberting CL. Arch Dermatol. 2004;140(9):1119-25.
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00
% patients
81%
(35/43)
born with
the rash
7 days 14 days 30 days 35 days
acquired the rash within
19%
(8/43)
53%
(23/43)
74%
(32/43)
79%
(34/43)
81%
(35/43)
with rash
within the
first month
43 patients
seen between
January 1998
and August 2003
who had a
clinical
diagnosis
of HIES.

began on the face of this 5-day-old infant (A) and progressed to involve most of the body by
age 2 weeks (B).
The newborn rash of hyper-IgE syndrome

The dermatitis pictured here
is diffuse and affects atypical
areas for atopic dermatitis,
sparing the areas usually
covered by the patient’s socks.
Retroauricular fissures are very
common in hyper-IgE syndrome,
as is
weeping crusted
external otitis.
A virulent Staphylococcus
aureus folliculitis
is common in the
axillae in hyper-IgE
syndrome
extensory areas

Candida paronychia and onychodystrophy as a manifestation of
mucocutaneous candidiasis in hyper-IgE syndrome before (A)
and after (B) long-term therapy with fluconazole.
Fungal susceptibility is apparent, with more than 80% of patients
having chronic mucocutaneous candidiasis

(Job Syndrome)
They are prone to infections:
recurrent “cold” skin abscesses (lacking the classical
feature of red, warm, tender abscesses filled with pus),
pneumonia with pneumatocele formation,
mucocutaneous candidiasis.
Interestingly,
many feel fine
even during
severe
infections
(no dolor).
X
X
X
X X
X
X
X
X
“cold”

(Job Syndrome)
Recurrent sinopulmonary infections generally start in the first
several years of life, with S. aureus being the most common pathogen
implicated in the pneumonias.
Streptococcus pneumoniae and Haemophilus influenzae also occur
frequently, and the first presentation of pneumonia in infancy may be
caused by Pneumocystis jirovecii.
As with the cold abscesses, patients with
AD-HIES with pneumonia lack systemic
signs of inflammation, including fever,
frequently delaying diagnosis leading
to parenchymal lung damage
multiple pneumatoceles, and an
evident aspergilloma (arrows).

Hyper-IgE syndrome with recurrent infections–
an autosomal dominant multisystem disorder.
Grimbacher B, N Engl J Med 1999;340(9):692–702.
30 patients with the
hyper-IgE syndrome
70 of their relatives
histories, physical and
dental examinations,
anthropometric
measurements,
laboratory evaluation.
Nonimmunologic
features
of the hyper-IgE syndrome
were present in all patients
> 8 years.

Characteristic Facial Appearance of Men and Women
of Different Races with the Hyper-IgE Syndrome. Patients had:
facial asymmetry with a
suggestion of
hemihypertrophy;
facial skin is rough,
with prominent pores
prominent forehead;
prominent inferior lip
deep-set eyes;
wide, fleshy nasal tip;
mild prognathism.
broad nasal bridge with
increased distance between
alae.
(carnosa)

hyper-IgE syndrome
anthropometric
measurements,
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00
failure or delay
of shedding of the
primary teeth owing
to lack of root
resorption.
72%
recurrent
fractures
57%
hyperextensible
joints
68%
% of patients with

Failure of Dental Exfoliation in
Patients with the Hyper-IgE
Syndrome.
Panel A shows the lower canines of
Patient 8 (age, 11 years), and Panel B
shows the upper central incisor of
Patient 4 (age, 8 years) and a high
palate. Persistent deciduous teeth
required extraction in both subjects.
Panel C shows a panoramic radiograph
of a patient (aging, 23 years),
revealing retention of 5 primary teeth
with unresorbed roots.
The eruption of upper and lower
premolars has been blocked by
retained primary teeth,

hyper-IgE syndrome
anthropometric
measurements,
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00
scoliosis in
patients
> 16 years
of age
72%
classic triad of
abscesses, pneumonia,
and an elevated IgE
in pts > 8 yrs of age
85%
% of patients with
decline in IgE
levels over time
within the
normal range.
26%

(Job Syndrome): Pathogenesis
Dominant-negative mutations in STAT3 cause AD-HIES.
These mutations are primarily missense or single-codon in-frame
deletions that result in single amino acid changes.
STAT3 is a transcription factor that plays an essential role in the
signal transduction of many cytokines, including
IL-6, IL-10, IL-21, IL-22, IL-23 and generation of Th 17.
Because of its involvement with many cytokines, STAT3 plays a
crucial role in immunity, inflammation, wound healing, cell survival,
embryogenesis, and oncogenesis.

Role of STAT3 and consequences of its dysfunction in the
differentiation of Th17 cells and defence against infection.
Secretion of IL-1 and IL-6 by
dendritic cells (DCs) under
appropriate conditions results
in Th17 differentiation.
Th17 cells secrete
IL-17A, IL17-F and IL-22.
IL-17A and IL-17F stimulate
epithelial cells to produce chemokines
that recruit polymorphonuclear
leukocytes (PMNs) for killing of
pathogens by phagocytosis.
IL-22 secretion triggers the
production of defensins by epithelial
cells for further defence against
extracellular pathogens.
Yong PF, Arthritis Res Ther. 2012;14(6):228.
X

(Job Syndrome): Diagnosis
Serum IgE levels are often > 2000 IU/mL,
Eosinophilia often > 700 cells/µL,
Almost absent Th 17
but
patients usually lack any symptomatic
allergic disease such as allergic rhinitis,
food allergy, or anaphylaxis.

Diminished allergic disease in patients with STAT3 mutations
reveals a role for STAT3 signaling in mast cell degranulation.
Siegel AM, J Allergy Clin Immunol. 2013;132(6):1388-96.
Allergy
incidence
Allergy
incidence
sIgE sIgE
patients with Autosomal-Dominant Hyper-immunoglobulin E Syndrome rarely have sIgE

Grimbacher B, Am J Hum Genet 1999;65:735-44.
A score > 15 indicated that
ADHIES is likely owing to
STAT3 deficiency.
Clinical Scoring Criteria to assess the probability
Autosomal-Dominant Hyper-IgE Syndrome (AD-HIES),

(Job Syndrome): Diagnosis
AD-HIES as a result of STAT3 dominant-negative mutations
lead to eosinophilia and increased serum IgE.
Often, the baseline increased total white blood
cell count does not increase with acute infection.
Neutropenia is rare, but has been reported, as have normal Ig levels.
Numbers of T helper 17 cells assessed by flow cytometry or STAT3
phosphorylation are low.
The gold standard is molecular diagnosis with sequencing of STAT3.
X

(Job Syndrome): Prognosis
Parenchymal lung disease and subsequent chronic infection with
molds, such as Aspergillus, and gram-negative bacteria, such as
Pseudomonas, contribute to most cases of death in AD-HIES.
Because of this situation, pyogenic pneumonias should be
aggressively diagnosed and treated to minimize parenchymal damage.
Lung abscesses may require operative intervention and aggressive
management of possible complications.
Although there is significant mortality,
life expectancy can reach 50 years.

(Job Syndrome): Management
Prevention and management of infections with long-term systemic
antibiotics and antifungals is important.
The dermatitis in HIES is largely driven by ongoing
infection, particularly S. aureus. Consequently, treatment
of the skin includes bleach baths (1 mL/ L of water) or
chlorhexidine washes as well as prophylactic antibiotics
(cotrimoxazole, which targets S. aureus) frequently
leads to minimal dermatitis.
The development of skin abscesses has reduced following the
introduction of prophylactic antibiotics, although these
sometimes require surgical intervention.

A further point of note is that the aberrant tissue healing following
pulmonary infections can result in parenchymal abnormalities that
allow colonisation with P. aeruginosa, fungal infections and
non-tuberculous mycobacteria.
Superinfection with these organisms represents the most challenging
aspect of long-term management. Eradication of these organisms is
difficult and the role of surgery for areas of parenchymal abnormality
is uncertain.
Pulmonary surgery appears to be associated with a
greater risk of complications and should be carefully considered and
only undertaken in a centre with particular experience in the disease.

Because some patients fail to sustain protective vaccination titers,
Ig replacement should be initiated.
Immunoglobulin replacement should be considered in those
patients with impaired specific antibody responses,
bronchiectasis, and breakthrough infections
while on prophylaxis.
HSCT is under investigation, but has been used
in severe disease.

Autosomal recessive hyperimmunoglobulin E syndrome:
a distinct disease entity. Renner ED, J Pediatr 2004;144:93–9.
13 human immunodeficiency
virus-seronegative patients
from 6 consanguineous families
with an autosomal-recessive
form of hyperimmunoglobulin E
syndrome (AR-HIES)
68 of their relatives.
Partial pedigrees and origin of six consanguineous
families with AR-HIES.
Filled symbol, affected subject;
open symbol, unaffected subjet; slash, deceased.

Autosomal recessive hyperimmunoglobulin E syndrome:
a distinct disease entity. Renner ED, J Pediatr 2004;144:93–9.
13 human immunodeficiency
virus-seronegative patients
from 6 consanguineous families
with an autosomal-recessive
form of hyperimmunoglobulin E
syndrome (AR-HIES)
68 of their relatives.
Partial pedigrees and origin of six consanguineous
families with AR-HIES.
Filled symbol, affected subject;
open symbol, unaffected subjet; slash, deceased.
Also known as
Dedicator of Cytokinesis 8
Deficiency
Williams KW,
Immunol Allergy Clin N Am
2015;35:523–544

AR-HIES is also characterized by:
chronic eczema,
recurrent staphylococcal skin infections,
increased serum IgE, and
blood eosinophilia.
Clinically distinct from AD-HIES,
these patients rarely have:
skeletal/dental abnormalities or
coarse facial features
but develop severe allergies
and severe recurrent fungal and viral infections
Autosomal-Recessive Hyper-immunoglobulin E Syndrome
(DOCK8 deficiency): Clinical Manifestation
YES

disseminated
molluscum contagiosum
verrucous and flat warts caused
by human papillomavirus
Cutaneous viral infections seen in DOCK8 deficiency.

The spectrum of cutaneous findings in DOCK8 immunodeficiency.
Pichard DC, J Am Acad Dermatol. 2015;73(3):355-64
A, Severe
herpetic
stomatitis
in a 7-year-old
girl.
B, Generalized
molluscum
contagiosum with
verrucous human
papillomavirus
infection on the
distal fingers of
a 22-year-old
woman.
C, Generalized
verrucosis of
the arm,
D) extensive
thin, pink to red
brown papules
resembling
Epidermo
dysplasia
verruciformis
in a 25-year-old
man.

2) Central nervous system manifestations
(facial paralysis, hemiplegia, ischemic
infarction, and subarachnoid hemorrhage),
3) Autoimmune diseases
4) Vascular disorders (aneurysms)
are variably associated.
5) Poor growth and failure to thrive is common,
6) Malignancy.
autoimmune hemolytic anemia,
hypothyroidism,
vasculitis
They are susceptible to:

The 2 predominant inherited forms of hyper-IgE syndrome
(AD-HIES, autosomal-dominant hyper-IgE syndrome; AR-HIES, autosomal recessive hyper-IgE syndrome)
have overlapping similarities, as well as distinct differences
that can suggest the underlying genetic defect
Autosomal
Recessive
Hyper-IgE
Syndrome:
•dedicator of the
cytokinesis 8
(DOCK8)
and
•tyrosine kinase 2
deficiency
(TYK2)
deficiecies
present with
abnormalities
confined to the
immune system.

(DOCK8 deficiency): Pathogenesis
AR-HIES is a combined immune deficiency where dedicator of the
cytokinesis 8 (DOCK8) gene or the signaling protein tyrosine kinase 2
(TYK2) mutations affect CD4 and CD8 proliferation, B cells, and
memory cells.
Homozygous mutations of DOCK8
(9p24.3) result in its loss of function.
DOCK8 belongs to a subfamily of
guanine nucleotide exchange factors,
which have multiple roles,
Including signal transduction and
activation of small G proteins.
DOCK8 belongs to
the 11-member family of
DOCK180 proteins, which are
involved in cytoskeletal
rearrangement allowing
cell migration,
adhesion and
growth.

(DOCK8 deficiency): Diagnosis
low T-cell numbers (CD4+and CD8+), low serum IgM levels BUT poor
specific responses, (failure to sustain protective titers against vaccination).
Flow cytometry for T helper 17 cells may be low.
T-lymphocyte activation and proliferation are diminished,
particularly in the CD8+ population, thus contributing their increased
viral susceptibility.
elevated total white blood cell counts that
do not increase with acute infection,
Eosinophilia typically > 1000 µL,
high IgE,
Serum IgG levels are normal or increased
Similar to AD-HIES,
AR-HIES patients have:
Diagnosis is confirmed with DOCK8 sequencing
and can be strongly suggested by absence of
expression on flow cytometry.
Zhang Q. N Engl J Med 2009;361(21):2046–55.

(DOCK8 deficiency): Prognosis
There is higher mortality at a younger age in DOCK8
deficiency, with death often occurring before the age of 20.
The prognosis is poor worse than AD-HIES,
with most failing to reach adulthood as a result
of sepsis, neurologic disorders, and malignancies.
Vascular complications (aneurysms) have been
documented,including those secondary
to vaccine-strain varicella zoster.
Sabry A, J Allergy Clin Immunol 2014;133(4):1225–7.

 Specific antibody production in AR-HIES can be variable
(despite normal IgG levels) and replacement immunoglobulin
therapy because of poor specific antibody production has
been used with anecdotal improvement in
respiratory tract infections.
 Viral skin infections have unfortunately not improved
with replacement immunoglobulin therapy.
 Widespread molluscum and human papilloma virus
infection has been difficult to treat - standard therapies
with salicylic acid, cryotherapy and imiquimod have had
limited success; interferon alpha has been used anecdotally
with mixed results.
(DOCK8 deficiency): Management
Yong PF. Arthritis Research & Therapy 2012;14:228

 Specific antibody production in AR-HIES can be variable
(despite normal IgG levels) and replacement immunoglobulin
therapy because of poor specific antibody production has
been used with anecdotal improvement in
respiratory tract infections.
 Viral skin infections have unfortunately not improved
with replacement immunoglobulin therapy.
 Widespread molluscum and human papilloma virus
infection has been difficult to treat - standard therapies
with salicylic acid, cryotherapy and imiquimod have had
limited success; interferon alpha has been used anecdotally
with mixed results.
Acyclovir or valacyclovir should be considered
for prophylaxis to prevent recurrent HSV and
VZV infections.

Haematopoeitic stem cell transplantation has been
reported in DOCK8 deficiency patients.
In all individuals, resolution of recurrent infections
(particularly viral skin infections with molluscum) and eczema
occurred, although one individual continued to suffer from food
allergies.
Improvement in IgE levels and resolution of vasculitis were reported
These initial results suggest that stem cell transplantation
in AR-HIES may represent an excellent curative option given
the high morbidity and mortality seen in the disease.

Autosomal Recessive Hyper-IgE syndrome
with Phosphoglucomutase 3 Deficiency
Mutations in phosphoglucomutase 3 (PGM3) were recently defined,
leading to a multisystem disease sharing some clinical features with
AD-HIES and DOCK8 deficiency.
cutaneous leukocytoclastic vasculitis,
eczema-like rash,
cognitive impairment, myoclonus, ataxia,
dysarthria (motor speech disorder)
delayed visual and sensory hearing evoked potentials,
severe bronchiectasis.
Are all
present
Phosphoglucomutase catalyzes the reversible transfer of a phosphate group
between the I- and 6-positions of glucose and mediates both glycogen formation and
utilization

Autosomal Recessive Hyper-IgE syndrome
with Phosphoglucomutase 3 Deficiency
Mutations in phosphoglucomutase 3 (PGM3) were recently defined,
leading to a multisystem disease sharing some clinical features with
AD-HIES and DOCK8 deficiency.
cutaneous leukocytoclastic vasculitis,
eczema-like rash,
cognitive impairment, myoclonus, ataxia,
dysarthria (motor speech disorder)
delayed visual and sensory hearing evoked potentials,
severe bronchiectasis.
Are all
present
Phosphoglucomutase catalyzes the reversible transfer of a phosphate group
between the I- and 6-positions of glucose and mediates both glycogen formation and
utilization
PGM3 deficiency should be suspected in an
individual with an exaggerated allergic
phenotype, recurrent infections,
and neurologic deficits.

The Diverse Clinical Features of Chromosome 22q11.2
Deletion Syndrome (DiGeorge Syndrome)
Maggadottir SM,J Allergy Clin Immunol Pract 2013;1:589-94
The estimated prevalence for chromosome 22q11.2 deletion
syndrome is 1 in 4000 births.
The inheritance pattern is autosomal dominant.
The prevalence of chromosome 22q11.2 deletion syndrome
will rise because this is a haplosufficiency genetic disorder*,
and, therefore, the chance of an affected parent having
an affected child is approximately 50%.
Spontaneous or de novo mutations account for approximately 90%, of
22q11.2 deletions; only approximately 10% are inherited from an affected
parent.
*Any gene that allows the production of viable adults even when one copy of the gene in diploids is mutant or deleted
from one of the homologous chromosomes.

Presenting phenotype in 100 children with the 22q11
deletion syndrome. Oskarsdottir S, Eur J Pediatr 2005;164:146-53.
most common clinical features that lead to diagnosis:
•Cardiac defects,
•Absent or hypoplastic thymus,
•Hypocalcemia, and
•Characteristic dysmorphic features.
Cardiac defects,
Recurrent infections,
Speech delay,
Developmental delay, or learning difficulties
Characteristic dysmorphic features
in children
younger than
2 years of age
in children
older than 2
years of age

most common clinical features that lead to diagnosis:
•Cardiac defects,
•Absent or hypoplastic thymus,
•Hypocalcemia, and
•Characteristic dysmorphic features.
Cardiac defects,
Recurrent infections,
Speech delay,
developmental delay, or learning difficulties
Characteristic dysmorphic features
in children
younger than
2 years of age
in children
older than 2
years of age
In very few patients, <1% with chromosome 22q11.2 deletion
syndrome, the thymus and the T cells are absent, and this is
referred to as complete DiGeorge syndrome.
In 75% of patients, the immune system is affected to some degree,
which leaves approximately 20% of patients with normal T-cell counts.

Clinical findings at diagnosis of the 22q11DS in 26 infants (< 2 years)
and features leading to the diagnosis.
92%
*Feeding difficulties were not included because of the low age at diagnosis.
Chromosome 22q11.2 deletion syndrome
is the most common cause of
congenital hypoparathyroidism

Clinical findings of the 22q11DS in 74 children (>2 years) and teenagers
at diagnosis and clinical features leading to the diagnosis.
54%
(74%) had a history of feeding difficulties during infancy,
mainly poor sucking and often also nasal regurgitation.

All patients had mild dysmorphic features considered to be typical for 22q11 deletion, such as:
•minor auricular anomalies
(small round ears, posterior rotation of the ears, simple helices, or low-set ears),
•typically shaped nose (thin alae nasae, broad nose tip, tubular form of the nose),
•small, arch-shaped mouth,
•hooded eyelids,
•malar flatness (cheekbones may be flat),
•myotonic-looking face,
•long, slender and/or tapering fingers.
(lunghe e snelle)
OK

All patients had mild dysmorphic features considered to be typical for 22q11 deletion, such as:
•minor auricular anomalies
(small round ears, posterior rotation of the ears, simple helices, or low-set ears),
•typically shaped nose (thin alae nasae, broad nose tip, tubular form of the nose),
•small, arch-shaped mouth,
•hooded eyelids,
•malar flatness (cheekbones may be flat),
•myotonic-looking face,
•long, slender and/or tapering fingers.
(lunghe e snelle)
OK
Images A show normal ear position.
Low set ears are positioned below the horizontal
line as illustrated in B.
Low-set ears are often posteriorly
rotated, reflecting an arrest in the
normal anterior rotation that occurred
during fetal ear development.
Low set
ears
Normal
set
ears

Chromosome 22q11.2 Deletion Syndrome
(DiGeorge Syndrome): Clinical Manifestations
Maggadottir SM,J Allergy Clin Immunol Pract 2013;1:589-94
contributions to recurrent infections in these children:
1) palatal dysfunction (majority of patients will have palatal weakness and a
minority will have submucous clefting, a cleft lip is extraordinarily uncommon
in the syndrome.) with dysfunctional swallowing.
2) Nasal regurgitation is a major problem and together with Eustachian
tube dysfunction and poor drainage contributes to recurrent ear infections.
3) Decreased T-cell responses and proliferation.
(avoid live viral vaccine if CD4+ T-cell count is <400 cells).
However, even if T-cell counts may be low-for-age in infancy but in most
patients typically improves in the first year of life.
Despite poor thymic output of T cells, antiviral defenses and B-cell help by
existing T cells is not greatly impaired,

What is a submucous cleft palate?
A submucous cleft of the soft palate is characterized by a midline deficiency or lack of
muscular tissue and incorrect positioning of the muscles.
A submucous cleft of the hard palate is defined as a bony defect in the midline or center of
the bony palate. This can sometimes be felt as a notch or depression in the bony palate when
the palate is palpated with a finger.
Often a submucous cleft palate is associated with a bifid or cleft uvula.
What are the effects of submucous cleft palate?
When a submucous cleft is present, the muscles of the soft palate may not function properly
and the individual is at risk for speech problems, middle ear disease, and swallowing
difficulties.
How can a submucous cleft palate be identified?
The most common reason that a child is evaluated for a submucous cleft palate
is abnormal nasal speech.
Other symptoms may include persistent middle ear disease
and feeding/swallowing difficulties.
A submucous cleft palate may be identified by the presence of a bifid uvula;
a very thin translucent strip of lining (mucosa) in the middle of the roof of the mouth;
and, a notch at the back edge of the hard palate that can be felt by the fingertip.

Allergies in patients with chromosome 22q11.2 deletion
syndrome (DiGeorge syndrome/velocardiofacial syndrome)
and patients with chronic granulomatous disease.
Staple L, Pediatr Allergy Immunol. 2005;16(3):226-30
Patients with chromosome 22q11.2 deletion syndrome and sibling controls
%
%
%
%
%
DiGeorge syndrome is significantly associated with both eczema and asthma
%
%

IMMUNE DEFICIENCY in Complete DiGeorge Syndrome
Patients with rare complete DiGeorge syndrome have true thymus aplasia
and absence of T cells and severe immune compromise.
This group of patients can be defined by <50 T cells/mm3 and/or <50 naive
(CD45RA+/CD62L+ T cells/mm3). Markert ML, J Allergy Clin Immunol 2004;113:734-41.
These patients need protection from infection and blood products.
Antipneumocystis and antifungal prophylaxis should be promptly initiated and
immunoglobulin replacement therapy in those with hypogammaglobulinemia.
Live viral vaccines should be avoided, and respiratory syncytial virus (RSV)
prophylaxis is provided.
If cardiac surgery is needed these patients should receive
cytomegalovirus negative and irradiated blood products.

Human immunodeficiency virus infection is characterized by a progressive
depletion of helper T-lymphocytes and, like allergic diseases, is associated with
altered T cell regulation.
It is one of the more common immunodeficiencies and should always be excluded
when considering a Primary Immune Deficiency.
Virologic testing with HIV DNA polymerase or HIV RNA assays should be used.
Human Immunodeficiency Virus (HIV)
Infants with HIV infection
(a secondary immunodeficiency)
can present with:
1) eczematous rash,
2) high IgE, and
3) failure to thrive.
Mankahla A,
Am J Clin Dermatol.
2012;13(3):153-66
in about 25%
of children with
HIV infection

HIV and Eosinophilic Pustular Folliculitis
Eosinophilic pustular folliculitis.
a A large erythematous plaque with central
clearing and peripheral clusters of pruritic
follicular pustules arranged in an annular
configuration on the left face. Similar lesions
kept recurring on both cheeks symmetrically for
over 6 weeks.
b Destruction of follicles and dense infiltrate of
eosinophils, lymphocytes and neutrophils in and
around follicles and sebaceous glands in the
dermis (hematoxylin–eosin, original magnification
×40), with formation of eosinophilic
microabscess
(red boxes original magnification ×400)
Eosinophilic pustular folliculitis (EPF), also known as eosinophilic folliculitis, is a
rare, noninfectious inflammatory dermatosis characterized by recurrent episodes of
pruritic follicular papules and pustules involving the trunk, face, and extremities, and
histopathologically associated with folliculo tropic infiltration of eosinophils.
In some patients it is associated with human immunodeficiency virus (HIV)
infection, or a malignancy.

Comel-Netherton Syndrome
Comel-Netherton syndrome is an autosomal-recessive dermatologic
condition associated with an exaggerated allergic phenotype, including:
severe atopic dermatitis,
allergic rhinitis,
peripheral eosinophilia,
increased serum IgE levels.
The hallmark clinical features of Comel-Netherton syndrome are:
severe congenital ichthyosis and
the pathognomonic bamboo hairs,
known as trichorrexis invaginata

The extent of skin involvement varies and may include:
erythroderma or
migrating and scaly plaques.
The skin lesions are usually pruritic secondary to the
profound skin barrier defect and enhanced inflammation.
S aureus skin infections are frequent.
Additional findings include:
failure to thrive,
sparse or absent hair, eyebrows and eye lashes at birth,
chronic diarrhea

The extent of skin involvement varies and may include:
erythroderma or
migrating and scaly plaques.
The skin lesions are usually pruritic secondary to the
profound skin barrier defect and enhanced inflammation.
S aureus skin infections are frequent.
Additional findings include:
sparse or absent hair, eyebrows and eye lashes at birth,
chronic diarrhea
Mortality is highest in the neonatal period
from sepsis, dehydration due to
transepidermal water loss, or malnutrition.
Hovnanian A. Cell Tissue Res 2013;351(2):289–300.

f Partial alopecia predominating on the occiput,
with short, fragile, thin, spiky and broken hair.
Clinical aspects of Netherton syndrome
Hovnanian A. Cell Tissue Res 2013;351(2):289–300.
a Congenital
erythroderma
with scaling.
b Erythroderma with transient alopecia and absence of eyebrows.
c Eczematous-
like lesions
with fine
scaling.
d Severe skin
inflammation
with superficial
desquamation. e
Abnormal
hair shaft
showing
protrusion of its
distal part into
its proximal
part
(trichorrhexis
invaginata or
bamboo hair).
g Ichthyosis
linearis
circumflexa
composed of
serpiginous and
migratory
patches with
red and double-
scaling edges

Comel-Netherton Syndrome:
Genetics and Pathogenesis
Comel-Netherton syndrome stems from loss-of-function mutations
in SPINK5 (serine protease inhibitor Kazal-type 5) , which encodes
the serine protease inhibitor LEKTI (lympho-epithelial kazal type
related inhibitor type 5) that inhibits enzymes having a trypsin or
chymotrypsin-like activity in the skin.
LEKTI is expressed in both the epithelia and the thymus.
Murine models have shown that
LEKTI deficiency leads to unopposed
peptidase activity, causing
impaired epidermal differentiation,
defective cornification, and
poor skin barrier formation.

Comel-Netherton syndrome defined
as primary immunodeficiency.
Renner ED, J Allergy Clin Immunol 2009;124(3):536–43.
9 patients with
Comèl-Netherton
sequenced SPINK5, and LEKTI
expression by
immunohistochemistry.
Immune function assessed by
measuring cognate immunity,
serum cytokine levels, and
natural killer cell cytotoxicity.
intravenous immunoglobulin
replacement therapy.
100 –
090 –
080 –
070 –
060 –
050 –
040 –
030 –
020 –
010 –
000
recurrent skin
infections caused
predominantly by
S. aureus
sepsis and/or
pneumonia
recurrent
gastrointestinal
disease and
failure to thrive
100%
78%
67%
% children with

Comel-Netherton syndrome defined
as primary immunodeficiency.
Renner ED, J Allergy Clin Immunol 2009;124(3):536–43.
Treatment with intravenous immunoglobulin
resulted in remarkable clinical improvement
and temporarily increased natural killer cell
cytotoxicity.
9 patients with
Comèl-Netherton
sequenced SPINK5, and LEKTI
expression by
immunohistochemistry.
Immune function assessed by
measuring cognate immunity,
serum cytokine levels, and
natural killer cell cytotoxicity.
intravenous immunoglobulin
replacement therapy.

Comel-Netherton Syndrome: Management
Management is aimed at systemic and cutaneous
symptom management.
Emollients are essential for their skin,
and adequate nutrition and hydration is critical.
•Renner ED, Comel-Netherton syndrome defined as primary immunodeficiency.
J Allergy Clin Immunol 2009;124(3):536–43.
Intravenous immunoglobulin and anti-TNF-a monoclonal
antibodies have been effective in reducing
skin inflammation.
•Fontao L, Infliximab infusions for Netherton syndrome:
sustained clinical improvement correlates with a reduction of thymic stromal
lymphopoietin levels in the skin. J Invest Dermatol 2011;131(9):1947–50.

Severe Dermatitis, Multiple Allergies,
and Metabolic Wasting Syndrome (SAM)
clinical features
Severe dermatitis, multiple allergies, and metabolic wasting (SAM)
syndrome closely resembles Comel-Netherton syndrome,
Unique to SAM syndrome is:
early and severe development of food allergies
prominent metabolic wasting.
malabsorption
failure to thrive.
are also common

clinical features
Severe dermatitis, multiple allergies, and metabolic wasting (SAM)
syndrome closely resembles Comel-Netherton syndrome,
Unique to SAM syndrome is:
early and severe development of food allergies
prominent metabolic wasting.
malabsorption
failure to thrive.
are also common
Recurrent infections, developmental delay, and
minor cardiac defects,
such as ventricular septal defects,
have also been described

clinical laboratory findings
Increased serum IgE levels and absolute eosinophil counts.
Keratinocytes show upregulation of
proinflammatory cytokine genes, such as IL5,
which likely contributes to the eosinophilia.
Skin biopsy shows abnormally formed desmosomes
and loss of cell-cell adhesion.
Samuelov L, Nat Genet 2013; 45(10):1244–8.
+IL-5

genetics and pathogenesis
Homozygous loss-of-function mutations in desmoglein-1 (DSG-1)
were identified in 2 consanguineous families with SAM syndrome.
DSG-1 plays a crucial role in cell-cell adhesion in keratinocytes, as
well as in myocardial cells. Amagai M. J Invest Dermatol 2012;132(3 Pt 2):776–84.
DSG-1 deficiency leads to absent
cell-cell adhesion and abnormally
formed epidermal desmosomes with
consequent epidermal barrier dysfunction.

Loeys-Dietz Syndrome: Clinical features
Loeys-Dietz syndrome (LDS) is a connective tissue disorder with a
great clinical overlap with Autosomal Dominant Hyper IgE Syndrome.
Musculoskeletal
abnormalities
are variable
and can include:
craniosynostosis,
retained primary dentition,
facial asymmetry,
pectus deformity,
scoliosis,
flat feet,
joint hyperextensibility,
high arched or cleft palate,
abnormal uvula,
hypertelorism.

Their skin is classically thin and translucent, and
easy bruising and poor wound healing are not uncommon.
Vascular anomalies are a prominent feature of LDS.
Diffuse arterial abnormalities, such as aneurysms and tortuosity, put
patients at great risk for dissection or hemorrhages.
Patients with LDS have an exaggerated
allergic phenotype, which can include:
 asthma,
 food allergy,
 atopic dermatitis,
 allergic rhinitis

Their skin is classically thin and translucent, and
easy bruising and poor wound healing are not uncommon.
Vascular anomalies are a prominent feature of LDS.
Diffuse arterial abnormalities, such as aneurysms and tortuosity, put
patients at great risk for dissection or hemorrhages.
Patients with LDS have an exaggerated
allergic phenotype, which can include:
 asthma,
 food allergy,
 atopic dermatitis,
 allergic rhinitis
Not present in theAutosomal Dominant Hyper IgE Syndrome
But present in the Autosomal Recessive Hyper IgE Syndrome

Gastrointestinal complaints, such as:
chronic abdominal pain,
poor growth,
constipation,
vomiting,
Eosinophilic gastrointestinal disease
(eosinophilic esophagitis, colitis, or gastritis)
Elimination diets seem to be beneficial in reducing clinical symptoms.
are common
is often diagnosed
pathologically.

Loeys-Dietz Syndrome: Genetics and pathogenesis
Four genetic mutations have been identified in LDS.
These mutations include heterozygous mutations
in TGFBR1, TGFBR2, SMAD3, and TGFB2.
Each mutation results in
altered TGF-β signaling, yielding
abnormal collagen and connective tissue growth,
and effects on lymphocyte differentiation.

Loeys-Dietz Syndrome: Management
Despite the genetic and phenotypic variation
seen in the LDS types,
medical management is similar and very complex:
Cardiovascular care
Orthopedic care
Allergies care
Gastroenterology and nutrition care

Food Protein-Induced Enterocolitis Syndrome.
Leonard SA, Pediatr Clin North Am. 2015;62(6):1463-77
Food protein-induced enterocolitis syndrome (FPIES) is a rare,
non-IgE-mediated gastrointestinal food allergy primarily diagnosed in
infancy, but has also been reported in older children and adults.
Acute FPIES reactions
typically present within
1 to 4 hours of
food ingestion with:
Chronic FPIES
typically presents with:
delayed, repetitive vomiting,
lethargy,
pallor
collapse
protracted vomiting and/or diarrhea,
weight loss or poor growth.

1 to 4 hours of
Chronic FPIES
lethargy,
pallor
collapse
Common foods triggering
FPIES include:
•cow's milk,
•soy,
•rice,
•oats,
•fish,
•egg.

1 to 4 hours of
Chronic FPIES
lethargy,
pallor
collapse
most Cow Milk or Soy FPIES presented with
chronic symptoms, such as diarrhea, colitis, reflux, or
failure to thrive, occurring shortly after CM or soy
formula introduction, which resolved with avoidance.

1 to 4 hours of
Chronic FPIES
lethargy,
pallor
collapse
Owing to nonspecific symptoms
and the lack of diagnostic testing,
FPIES is often
initially misdiagnosed, leading
to a delay in diagnosis and
increased morbidity from
extensive workups and
hospitalizations.

Many FPIES patients have an atopic background.
Eczema was reported in 9% to 57%,
Wheezing or asthma was reported in 3% to 25%,
Allergic rhinitis was reported in 38%,
IgE-mediated food allergy to other foods in 11% to 30%,
A family history of allergic disease was reported in 20% to 77%,
A family history of FPIES in 6% and of food allergy in 34%.
less than 10% of subjects had a positive SPT to trigger foods, and
between 11% and 24% had detectable sIgE levels.

The pendulum between food protein-induced enterocolitis
syndrome and IgE-mediated milk allergy.
Kessel A, Acta Paediatr. 2011;100(10):e183-5.
The transition from milk protein-induced enterocolitis syndrome
to IgE-mediated milk allergy is uncommon.
Herein, we describe three infants that suffered from recurrent vomiting
and restlessness in response to cow's milk formula with negative skin prick to
milk and therefore diagnosed as milk protein-induced enterocolitis syndrome.
After recovering and reintroducing cow's milk formula, they developed
disseminated urticaria and positive skin prick test to cow milk compatible
with IgE-mediated milk allergy.
CONCLUSION:
An infant that recovers from cow milk food-induced enterocolitis syndrome
might develop afterward IgE-mediated cow milk allergy.
IgE
FPIES

Unusual shift from IgE-mediated milk allergy to food
protein-induced enterocolitis syndrome.
Banzato C, Eur Ann Allergy Clin Immunol. 2013;45(6):209-11
In children with FPIES, the presence of sIgE to the causative food,
either at presentation or during follow-up, defines an "atypical form"
of FPIES characterized by a lesser probability of developing tolerance
and a potential progression to typical IgE-mediated hypersensitivity.
Although it is uncommon, the shift from non-IgE-mediated milk-
protein induced enterocolitis syndrome to IgE-mediated milk allergy
has recently been described.
We report the first case, to our knowledge, of a shift from IgE-
mediated cow's milk allergy to pure non-IgE-mediated FPIES,
in a 4-month-old male infant. IgE
FPIES

Pulmonary Manifestations
of Primary Immunodeficiency Disorders
Nonas S. Immunol Allergy Clin North Am. 2015;35(4):753-66.
Pulmonary complications of primary
immunodeficiency disorders (PIDDs) are
common and contribute significantly to
morbidity and mortality in these patients.
Recurrent pulmonary infections are often the
first warning sign of PIDD and remain a leading cause of death
from infectious causes in adults with PIDD.
Recurrent pulmonary infections, including pneumonia,
lung abscess, and/or empyema formation, account for
significant morbidity and mortality in PIDD, accounting
for 29% to 44% of deaths.

Pulmonary Manifestations
of Primary Immunodeficiency Disorders
The mortality from infectious complications of PIDD has
significantly decreased in the past several decades, following
the widespread standard use of immunoglobulin replacement
therapy starting in the 1980s.
With this increased longevity came an increasing prevalence
in, and mortality from, noninfectious complications in PIDD.
In short, patients now live long enough to develop
chronic noninfectious complications, particularly
in the lungs including bronchiectasis,
interstitial lung disease (ILD) ,
pulmonary malignancy, and autoimmunity.

Obstructive Airway Disease and Bronchiectasis
In CVID the prevalence of bronchiectasis
is greater than 70%. Thickett KM, QJM 2002;95:655–62.
classic tram-track
appearance.
Obstructive airway disease, including asthma,
bronchiolitis, and bronchiectasis, is extremely
common in primary immunodeficiency.
Obstructive spirometry is noted in 50% to 94% of patients
with primary immunodeficiency disease (PIDDs).
Touw CM, Pediatr Allergy Immunol 2009;21:793–805.
Asthma is particularly common in patients with antibody deficiency,
with rates between 15% and 42% of patients with common variable
immune deficiency (CVID), selective immunoglobulin (Ig) A deficiency,
and X-linked agammaglobulinemia (XLA). Agondi RC, Allergy 2010;65:510–5.
Ozcan C, Allergol Immunopathol (Madr) 2015;43:57–61.

Primary Immunodeficiency Disorders: Epidemiology
Primary immunodeficiency disorders
are usually considered to
be “rare diseases.”
However, as a whole, this group
of diseases may not be as rare
as once thought.
Common Variable Immunodeficiency is the most common symptomatic
primary immunodeficiency
(estimated at between 1:100,000 and 1:10,000 of the population).

Common Variable Immunodeficiency:
Diagnosis, Management, and Treatment.
Abbott JK, Immunol Allergy Clin North Am. 2015;35(4):637-58
CVID occurs equally in males and females, although,
among children, boys predominate.
CVID age of onset is variable, but it peaks in early childhood
(34% < 10 years of age) and around the third decade of life.
Several noninfectious complications
are commonly reported, including:
splenomegaly,
chronic gastrointestinal (GI) disease,
bronchiectasis,
chronic lung disease,
autoimmune cytopenia, and
other autoimmune, malignant, and granulomatous diseases.
0 5 10 20 30
age years

Common variable immunodeficiency (CVID) is a grouping of
heterogeneous diseases with the common finding of
impaired antibody production.
the following criteria for probable CVID were proposed:
1) > 2 years of age,
2) IgG, IgA, IgM < 2 standard deviations from the mean for age,
3) either absent isohemagglutinin* or absent vaccine responses, and
4) no other defined causes of hypogammaglobulinemia.
* Isohemagglutinin is the naturally occurring anti-A and anti-B antibodies against the antigens
present on red blood cells.

* Isohemagglutinin is the naturally occurring anti-A and anti-B antibodies against the antigens
present on red blood cells.
*
In children with
recurrent
infections check
also for
blood group
and
isohemagglutinin

Common variable immunodeficiency disorders in children:
delayed diagnosis despite typical clinical presentation.
Urschel S, J Pediatr. 2009;154(6):888-94.
retrospectively
investigated clinical
findings in 32
children with
primary CVID
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00
% children at presentation with
88%
recurrent or chronic
respiratory tract
infections
sinusitis
78%
Allergic
disorders
38%

retrospectively
investigated clinical
findings in 32
children with
primary CVID
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00
% children at presentation with
28%
16%
34%
Bronchiectasis Growth
retardation
Retarded
mental
development

IgG (circles), IgM (triangles), and IgA (diamonds) serum level
in each patient at first diagnosis.
The line in the left chart shows age-related third percentile of normal IgG values, in the right chart
normal values for IgM (green line) and IgA (dark line) for each age. Uffelmann JA, Clin Chim Acta 1970 Apr;28(1):185-92.
3° percentile of normal IgG values
3° percentile of normal IgA values
3° percentile of
normal IgA values

IgG (circles), IgM (triangles), and IgA (diamonds) serum level
in each patient at first diagnosis.
The line in the left chart shows age-related third percentile of normal IgG values, in the right chart
normal values for IgM (green line) and IgA (dark line) for each age. Uffelmann JA, Clin Chim Acta 1970 Apr;28(1):185-92.
3° percentile of normal IgG values
3° percentile of normal IgA values
3° percentile of
normal IgA values
Mean time between symptoms and induction of
immunoglobulin substitution therapy was 5.8 years

Common Variable Immunodeficiency: Treatment.
Effective treatment of CVID depends on adequate treatment of
both infectious and noninfectious medical issues.
IgG replacement is generally effective in preventing further
infections, although, for patients who have bronchiectasis, aggressive
pulmonary physiotherapy should also be implemented.
Antibiotic prophylaxis is frequently used in patients with persistent
infections.
Treatment of noninfectious complications requires specific
management approaches tailored to the specific problem. Medications
can include immunosuppressives and even cytotoxic therapies.

Adenosine Deaminase–Severe Combined Immunodeficiency
Peripheral eosinophilia is a commonly encountered
clinical manifestation seen in adenosine deaminase
(ADA)-SCID.
Because of the profound T-cell, B-cell, and
NK-cell lymphopenia seen in ADA-SCID,
affected individuals typically present in infancy
with severe opportunistic infections, such as
with Pneumocysti jirovecii pneumonia.
Recurrent or severe respiratory infections
typically occur within the first few months of life, along with
failure to thrive, frequent thrush, and chronic diarrhea.
Cysts of Pneumocystis jiroveci
in smear from bronchoalveolar
lavage. Methenamine silver stain

Atopy is a common feature in ADA-SCID,
found in about half of those with early onset disease.
Of the atopic manifestations:
wheezy bronchitis, asthma,
food allergy,
mild atopic dermatitis,
urticaria.
were the most
common identified
in this population
(+) sIgE

Atopy is a common feature in ADA-SCID,
found in about half of those with early onset disease.
Of the atopic manifestations:
wheezy bronchitis, asthma,
food allergy,
mild atopic dermatitis,
urticaria.
were the most
common identified
in this population
(+) sIgE
Without early recognition
and treatment, ADA-SCID
is often fatal within the
first year of life.

Diagnosis
Profound deficiency of circulating T lymphocytes, B lymphocytes,
and NK cells.
Serum IgG levels are usually normal at presentation as a result of
maternal transfer of IgG but decrease soon after.
Serum IgA and IgM levels are variable, although more commonly
IgM levels are low.
Serum eosinophilia and IgE levels are frequently increased among
both those with early and delayed onset, presumably because of their
increased CD4+ Th2 cytokine production and their clinical features of atopy.

ADA-SCID results from
autosomal recessive mutations in the ADA gene.
ADA is an enzyme that is crucial in the purine
salvage pathway, catalyzing the deamination of
deoxydenosine and adenosine to deoxyinosine and inosine.

In an ADA-deficient state,
there is buildup of deoxydenosine,
S-adenosylhomocysteine, and
deoxyadenosine triphosphate
in the intracellular and extracellular
compartments, leading to
impaired T-lymphocyte and B-lymphocyte development.

Newborn Screening for SCID
Newborn screening for SCID
begins with analysis of a dried
blood spot collected at birth.
Babies with a positive result
should have additional
confirmatory tests.
Current estimates suggest the
incidence of this group of
immunodeficiency disorders is as
high as 1 in 40,000 births.
T-cell receptor excision circle (TREC) serves as a helpful marker of naive T-cell
development and production in the thymus, especially in the neonate.
Since these excision circles are extra-chromosomal, they are diluted by cell division in
peripheral circulation (blood); therefore, caution must be used when using TREC as a primary
diagnostic marker for recent thymic emigration.
T-cell receptor excision circle (TREC)
by real-time PCR
While TREC analysis has been very useful in identifying many types of SCID and
other T-cell lymphopenias in newborns, researchers have reported that some forms
of partial SCID are missed by this method, specifically ADA deficiency.
Mass spectrometric analysis of adenosine metabolites, including
2'-deoxyadenosine in dried blood spots, identified those cases.

that can be helped with some type
of corticosteroid therapy.
The majority of patients with
eczema, eosinophilia, elevated IgE
are likely to be atopic individuals
oral corticosteroids
have long been the mainstay of
therapy to treat
severe flares of allergic diseases.
inhibit production of proinflammatory cytokines,
chemokines, arachidonic acid metabolites, and
adhesion molecules while concurrently
upregulating anti-inflammatory mediators.

immune suppression by administered corticosteroids
can lead to detrimental effects if
an underlying PID goes unrecognized
patients with the PIDs rely on the remaining functioning parts of their
immune system to control latent infections and combat opportunistic
diseases
Pneumocystis jirovecii,
Mycobacterium avium complex,
fungi

immune suppression by administered corticosteroids
can lead to detrimental effects if
an underlying PID goes unrecognized
patients with the PIDs rely on the remaining functioning parts of their
immune system to control latent infections and combat opportunistic
diseases
Pneumocystis jirovecii,
Mycobacterium avium complex,
fungi
practitioners should exercise prudence before
using elective systemic corticosteroids or
other immune suppressants
if there is a history of recurrent or
opportunistic infection(s).

PIDs are rare diseases that
can be masked or not
considered because of the
predominant clinical
features of atopy.
The differential diagnosis of eosinophilia and Hyper IgE is broad
and includes disorders of immune deficiency or dysfunction.
Since there is a great deal of overlap in many of these disorders,
and thus, clinical and laboratory evaluation is warranted.
Summary & Conclusions

An underlying PID should be considered especially in severe cases of
atopic disease with concurrent signs of:
severe whole body dermatitis starting in the first few weeks of life,
diarrhea,
frequent thrush,
recurrent infections or unusual infections,
characteristic facial appearance
autoimmunity (early onset diabetes, thrombocytopenia)

An underlying PID should be considered especially in severe cases of
atopic disease with concurrent signs of:
severe whole body dermatitis starting in the first few weeks of life,
diarrhea,
frequent thrush,
recurrent infections or unusual infections,
characteristic facial appearance
autoimmunity (early onset diabetes, thrombocytopenia)
Without considering an underlying PID,
some individuals will remain undiagnosed
and untreated, and this risk impacts their
morbidity and mortality, especially when
exposed to agents that further reduce
immune competence.

19° FORMAT Verona 12-13/05/2017

Grazie per la vostra
attenzione alla storia che vi
ha raccontato il mio nonno.
Ciao a tutti.
Mia Charlize Powell

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