J Endocrinol Invest
DOI 10.1007/s40618-017-0740-9
SHORT REVIEW
Polyglandular autoimmune syndromes
G. J. Kahaly1 · L. Frommer1 
Received: 25 July 2017 / Accepted: 3 August 2017
© Italian Society of Endocrinology (SIE) 2017
Abstract  physicians to take appropriate action in order to prevent full-
Background  In recent years, scientific knowledge pertain-
ing to the rare ORPHAN polyglandular autoimmune syn-
drome (registered code ORPHA 282196) has accumulated.
Objective  To offer current demographic, clinical, serologi-
cal and immunogenic data on PAS.
Methods  Review of the pertinent and current literature.
Results  Polyglandular autoimmune syndromes (PAS) are
multifactorial diseases with at least two coexisting autoim-
mune-mediated endocrinopathies. PAS show a great hetero-
geneity of syndromes and manifest sequentially with a large
time interval between the occurrence of the first and second
glandular autoimmune disease. PAS cluster with several
non-endocrine autoimmune diseases. In most endocrinopa-
thies of PAS, the autoimmune process causes an irrevers-
ible loss of function, while chronic autoimmune aggressions
can simultaneously modify physiological processes in the
affected tissue and lead to altered organ function. The rare
juvenile PAS type I is inherited in a monogenetic manner,
whereas several susceptibility gene polymorphisms have
been reported for the more prevalent adult types. Relevant
for a timely diagnosis at an early stage is the screening for
polyglandular autoimmunity in patients with monoglandular
autoimmune disease and/or first degree relatives of patients
with PAS. The most prevalent adult PAS type is the combi-
nation of type 1 diabetes with autoimmune thyroid disease.
Conclusions  Early detection of specific autoantibodies
and latent organ-specific dysfunction is advocated to alert
* G. J. Kahaly
Kahaly@ukmainz.de
1
Department of Medicine I, Johannes Gutenberg University
Medical Center, 55101 Mainz, Germany
blown PAS disease.
Keywords  Polyglandular autoimmune disease · Clinical
picture · Diagnosis · Epidemiology · Treatment
Definition and classification
Polyglandular autoimmune syndromes (PAS) are defined by
the coexistence of at least two autoimmune-mediated endo-
crinopathies [1, 2]. Specific clustering of monoglandular
autoimmune diseases depends on genetic and non-genetic
environmental factors and differs considerably at the time
of presentation allowing distinguishing between two major
subtypes of PAS. The juvenile PAS type I shows a mono-
genetic inheritance, whereas multiple genes contribute to
the etiopathogenesis of the adult PAS [3, 4]. Based on the
various combinations of autoimmune endocrinopathies, the
adult PAS is subdivided into the types II–IV [5, 6]. Patients
with PAS are at high risk for developing non-glandular auto-
immune diseases [7] (Table 1).
A disproportionately high co-occurrence of glandular dis-
eases was described 1908 for the first time and was defined
as a separate entity [8]. In 1978, genetic analysis and defini-
tion of susceptibility genes led to the classification of PAS
with different subtypes, that was modified several times in
consideration of continuously more profound comprehen-
sion of the pathogenesis [9–11]. The current classification
distinguishes between four PAS types.
PAS type I, also known as autoimmune polyendocrinop-
athy, candidiasis and ectodermal dystrophy (APECED) or
multiple endocrine deficiency autoimmune candidiasis syn-
drome is a rare disease characterized by the manifestation of
autoimmune endocrinopathies in a peculiar sequence during
13
Vol.:(0123456789)

Table 1  Characteristics of juvenile and adult PAS
Juvenile PAS
Age of manifestation Childhood
Incidence [1/a] <1:100,000
Gender ratio [M:F] 3:4
Inheritance Monogenic
Serology Interferon α/ω-Ab
Autoimmune endocrinopathies Hypoparathyroidism (80–85%)
Addison’s disease (60–70%)
Type 1 diabetes (2–33%)
Hypogonadism (12%)
Autoimmune thyropathy (10%)
Additional non-glandular auto- Mucocutaneous candidiasis (70–80%); autoimmune
immune diseases hepatitis; atrophic gastritis; alopecia areata; vitiligo,
keratoconjunctivitis
infancy. In most affected children, chronic mucocutaneous
candidiasis caused by Candida albicans occurs before the
age of 5 years affecting up to 5% of the body surface. During
the following years, a primary hypoparathyroidism manifests
as the first autoimmune-induced endocrine disease compo-
nent. The clinical phenotype is a hypocalcemia tetany in
approximately 75%. The complete clinical picture of PAS
type I usually occurs prior to the age of 15 years with a
primary autoimmune-induced adrenal insufficiency (Addi-
son’s disease, AD) as second autoimmune endocrinopathy.
Incomplete subclinical forms make it difficult to timely diag-
nose and provide early treatment. There is a high number of
undetected cases, thus up to 15% of children with autoim-
mune adrenalitis may be PAS I positive [12]. Additionally
non-endocrine autoimmune diseases such as malabsorption
syndromes, necrotizing hepatitis or mucocutaneous candid-
iasis-related carcinomatosis have been observed in PAS I
patients [5, 13–15].
The adult forms of PAS show a great heterogeneity, differ
in prevalence and genetic background as well as in disease
associations and therefore are subdivided into PAS types
II–IV. The major endocrine component of PAS II is AD. In
approximately 40–50% of cases with AD, additional autoim-
mune endocrine diseases occur. Up to 1 year after onset of
AD, less than 50% of those patients only are detected due to
the broad range of unspecific symptoms and the long time
interval between the occurrences of the different endocrine
components [16]. With a relative prevalence of approxi-
mately 40%, PAS type III is the most frequent subtype and
encompasses type 1 diabetes (T1D) and an autoimmune
thyroid disease, AITD [1]. T1D may occur with an autoim-
mune-induced hypothyroidism (generally caused by chronic
lymphocytic Hashimoto’s thyroiditis, HT) or hyperthyroid-
ism (caused by Graves’ disease, GD) differing in genetic,
serologic, and clinical presentation [17]. Additional (non-)
13
J Endocrinol Invest
Adult PAS
Adulthood
1–2:100,000
1:3
Polygenic
Organ-specific Ab
Autoimmune thyropathy (70–75%)
Type 1 diabetes (40–60%)
Addison’s disease (40–50%)
Hypoparathyroidism (≤5%)
Hypogonadism (≤3%)
Hypopituitarism (≤2%)
Atrophic gastritis; pernicious anemia; atopic eczema;
alopecia areata; myasthenia gravis; systemic lupus
erythematosus; rheumatoid arthritis; autoimmune
hepatitis
glandular autoimmune diseases are common in PAS III. In
comparison, PAS type IV is very heterogeneous involving a
large variety of glandular autoimmune diseases that are not
considered within PAS II–III. Being less well defined it is
often incorrectly described as a combination of monoglandu-
lar autoimmune disease with one non-glandular autoimmune
disease. In fact, PAS type IV including various combinations
of autoimmune hypopituitarism, hypergonadotropic hypo-
gonadism or hypoparathyroidism with T1D or an immune
thyropathy is rarely described in the literature [18, 19].
Further autoimmune polyendocrine syndromes exist, such
as the immunodysregulation polyendocrinopathy enteropa-
thy X-linked syndrome (IPEX) or the polyneuropathy orga-
nomegaly endocrinopathy monoclonal protein skin changes
syndrome (POEMS), which are extremely rare and shall only
be mentioned for completeness.
Epidemiology
The prevalence of PAS I is estimated at 1:100,000 ranging
from 1:43,000 (Slovenia) and 1:80,000 (Norway) up to
1:130,000 (Poland/Ireland). In populations with rather low
genetic diversity, higher prevalence has been described,
e.g., Iranian Jews (1:9000), Sardinians (1:14,000) or Finns
(1:25,000). The prevalence of PAS I is lower in Japanese
populations (1:10,000,000) [20–23]. The female/male ratio
of PAS I is 0.8–2.4 showing a slight female predominance
[7, 24]. The manifestation peak is in infancy. In contrast,
with a prevalence of 1:20,000, the adult form of PAS is far
more prevalent with an annual incidence of 1–2:100,000.
Further, the prevalence of subclinical incomplete forms
is estimated to be 150:100,000. The gender ratio of PAS
II–IV shows a female predominance with a female per-
centage of 75% [11, 25]. Due to its sequential course, the
J Endocrinol Invest
adult form of PAS is usually diagnosed beyond an age of
20 years with a manifestation peak in the 4th and 5th dec-
ade depending on the combination of the various autoim-
mune endocrinopathies [1, 26].
Etiology
Juvenile PAS
PAS I is one of the very rare monogenetic autoimmune
diseases. The underlying genetic defect is in the auto-
immune regulator (AIRE) gene located on chromosome
21q22.3. Over 60 different mutations are known varying,
in their frequency of occurrence, on region, ethnicity, and
genetic pool [27]. Most frequent mutations of AIRE are
R257X in exon 6 and 67–979del13 bp in exon 8 [20, 28].
The coded protein is a transcriptional factor primarily
found in medullary thymic epithelial cells where central
self-tolerance is provided via negative or positive selec-
tion, respectively [29]. By upregulating the number of
expressed and presented self-antigens in healthy individu-
als, the transcription factor protects against autoimmune
diseases by eliminating autoreactive T cells. Thus, muta-
tions in the AIRE gene leading to dysfunctional proteins
are strongly susceptible for autoimmunity. Patients with
the same mutations can differ in their phenotype empha-
sizing the impact of environment or other susceptibility
genes such as human leucocyte antigen (HLA) class I
and II modifying the clinical course of PAS I, i.e., HLA-
DQB1*0301 correlating positively with PAS I severity
[30, 31].
Adult PAS
The adult PAS shows a multifactorial etiology with genes
determining a general susceptibility but not eventual dis-
ease manifestation with a concordance in monozygotic
twins being less than 100%. With respect to the polygen-
etic inheritance, genes on chromosome 6 play a predomi-
nant role [1]. By encoding the major histocompatibility
complex for the presentation of self- and foreign antigens,
those genes have a great impact on the occurrence of auto-
immunity in this context, too. Furthermore, several poly-
morphisms carry susceptibility for PAS. Immunogenet-
ics and epidemiologic patterns differentiate between both
mono- and polyglandular autoimmunity as well as between
the subgroups of adult PAS types [32, 33]. Further envi-
ronmental risk factors i.e., nicotine consumption, infec-
tions or hormonal influence have been postulated.
Pathomechanism
In most endocrine components of PAS, the autoimmune pro-
cess causes an irreversible and progressive loss of function as
in T1D, HT or AD. However, chronic autoimmune aggres-
sions can also simultaneously modify physiological processes
in the affected tissue and therefore lead to an altered specific
organ function as seen in patients with GD. Non-endocrine
autoimmune diseases, frequently accompanying PAS, can
show a systemic distribution pattern with unspecific, varying
tissue damage. Each of those forms of autoimmune processes
mainly depends on the underlying pathomechanism that led
to the loss of self-tolerance. The PAS shows exemplary fea-
tures of both cellular and serologic autoimmunity. While
the cellular immunologic response is primarily analyzed for
academic purposes, the serologic markers provide a tool for
screening and monitoring, respectively. But organ-specific
autoantibodies can also be detected in healthy subjects. The
difference between pathologic and physiologic autoantibod-
ies is found in the quantity as well as quality of the segments.
In general, natural antibodies show low serum titers with
the predominance of µ-isotypes and low antigen specificity,
while the V antibody region is characterized by non-mutated
germ line V gene segments (34). On the other side, patho-
genic autoantibodies are predominantly γ-isotype with high
antigen specificity and an alteration in V region due to a T ×
stimulation of B cells in the context of an adaptive immune
response [34]. The serum titers are generally high though the
duration and progress must be considered in this regard, since
the serum titer of an organ-specific autoantibody declines in
the course of time and often correlates with the severity/level
of histopathological destruction [35].
Origin and signaling pathway leading to occurrence
and manifestation of endocrine autoimmunity are not fully
understood. Several concepts may be hypothesized as expla-
nations for the breakdown of self-tolerance on level of T-
and B cells.
(a) Failure of deletion/suppression of autoreactive cells: a
low number of autoreactive T- and B clones is consid-
ered to be physiologic with regulation due to T cells
with immunomodulatory activity [34].
(b) Molecular mimicry: microbial antigens being similar to
self-antigens cause immune reactions directed against
human body cells.
(c) Abnormal presentation of (non-)self-antigens: com-
plexes of self-antigens with foreign antigens can lead
to an aberrant presentation with inadequate T-cell acti-
vation.
(d) Epitope spreading: epitope-specific immune responses
lead to the release of antigens with occasional process-
ing, presentation, and immunization against further
13

epitopes as reported in stroke-induced adaptive auto-
immune responses to novel neuronal antigens [36].
(e) Polyclonal lymphocyte activation: polyclonal B-cell
activation resulting in serum hypergammaglobulinemia.
While alternatives a-d can be considered as general patho-
mechanisms of autoimmune (endocrine) diseases, polyclonal
lymphocyte activation plays a minor part in organ-specific
autoimmunity.
Immunogenetics
The genetic risk factors of the adult PAS and their relevance
for disease manifestation and course of each autoimmune
component are still matter of current research. Several poly-
morphisms have been reported as susceptibility genes and
others are assumed to be involved. Genes that have already
been identified to confer susceptibility encompass several
HLA class I and II alleles which show concordant influence
on both mono- and polyglandular autoimmunopathies but
simultaneously differentiate between PAS types II and III
[32, 33, 37]. In addition, the HLA genes on chromosome 6
have the highest implications. PAS II-defining disorders are
associated with an increased frequency of the HLA haplotype
A1, B8, DR3, DQA1*0501, DQB1*0201 [38]. AD, in par-
ticular, shows a strong association with DR3 and DR4 with a
relative risk of 6.0, 4.6, and 26.5 for DR3, DR4, and DR3/4,
respectively. Both as mono and as component of PAS II, AD
is also correlated with DQ2/DQ8 with DRB1*0404 [39,
40]. In contrast, in patients with PAS III, HLA-DRB1*03,
*04, -DQA1*03 and -DQB1*02 are increased compared to
patients with isolated AITD, also allowing to distinguish
between HT and GD as PAS III components [33]. Numer-
ous population studies indicate that both HLA haplotypes
DR3-DQB1*0201 and DR4-DQB1*0302 contribute to PAS
III with DR3 conferring the susceptibility for T1D to a large
extent [38]. However, the polymorphisms −2221 Msp (C/T)
and −23 Hphl (A/T) in the insulin gene are frequently found
in T1D as monoglandular disease but not within the scope of
PAS. Additionally, polymorphisms in the cytotoxic T-lym-
phocyte-associated antigen 4 (CTLA-4), protein tyrosine
phosphatase non-receptor type 22 (PTPN22), and the fork-
head box P3 (FOXP3) have been identified as risk factors
for PAS emphasizing the relevance of the immunological
synapse [41]. It represents the concept of molecular interac-
tions underlying regulation of the immune response between
antigen presenting cells and T-cell receptors, while different
HLA class II alleles vary in subsequent receptor affinities for
peptides such as self-antigens, an alteration in the length of
CTLA-4 genes leads to an impaired inhibitory function of
T-cell activation. In line with this, the limitation of immuno-
logic response to antigens via lymphoid tyrosine phosphatase
encoded by PTPN22 and expressed in immature as well as
13
J Endocrinol Invest
mature B and T lymphocytes is associated with several auto-
immune disorders. FOXP3 on the other hand regulates the
differentiation of regulatory T cells and therefore might pro-
mote the development of autoimmune endocrinopathies and
PAS III, in particular (41).
Clinical phenotype
Juvenile PAS
Juvenile PAS type I is characterized by the co-occurrence
of at least two of the three main component AD, primary
hypoparathyroidism, and candidiasis. Most patients suf-
fer from additional (non-) glandular autoimmunopathies.
Approximately 70% of all patients with APECED have
three to five diseases associated with PAS I [42]. While
primary hypoparathyroidism is found in about 75–90% and
AD in about 65–80%, the prevalence of (transient) chronic
mucocutaneous candidiasis varies from 95–100% in Finish
or Sardinian patients to 20% in Iranian Jews [43]. Further
ectodermal diseases such as alopecia, keratopathies, gingival
hyperplasia, dental enamel defects, and nail dystrophies are
observed [44]. Up to 24% patients with PAS I were reported
to suffer from intestinal dysfunction other than atrophic gas-
tritis or pernicious anemia (e.g., steatorrhea or constipation)
with unknown etiology. A few patients have also endocrine
and exocrine pancreas insufficiency [13]. Autoimmune hepa-
titis is often referred to as rare component of PAS I and
is detected in 10–20% of the Finish and in 20–30% of the
Sardinian populations, respectively. Varying from asymp-
tomatic to fulminant clinical course, autoimmune hepatitis
caused death in 25% of the Finish patients with PAS I. Fur-
ther glandular autoimmune diseases such as T1D or AITD
occur in about 10–20%, while hypogonadism is found in
15–30% of male and 60–65% of female patients. Hypopi-
tuitarism is a rare component being found in less than 5%.
Adult PAS
The adult PAS is not associated with chronic mucocutaneous
candidiasis, keratinopathies or other dystrophies and differs in
the prevalence of glandular components by definition. Over-
all, AITD (45–46) represent the most frequent autoimmune
endocrinopathies within the scope of PAS and are present
in 70–75% of the patients [15]. AITD within PAS can occur
with or without Graves’ orbitopathy [45–47].The second most
prevalent endocrine autoimmune disease in the adult PAS
type is T1D with 50–60% [48]. Combination of both diseases
defines PAS type III, whereas AD, essential for PAS II, occurs
in 40–50% of all cases with PAS. In contrast to the juvenile
PAS, primary hypogonadism is diagnosed in 4–11% and both
primary hypoparathyroidism and hypopituitarism are found
J Endocrinol Invest
in 1–5% only of the patients with adult PAS [49]. The adult
PAS manifests sequentially with a large time interval between
occurrence of the first and second glandular autoimmune dis-
ease. Additional non-glandular autoimmune diseases manifest
in the course of time and are observed in 40–50% [50].
Associated non‑glandular autoimmune diseases
The prevalence of additional non-glandular autoimmune
diseases associated with PAS I differs from the prevalence
in patients suffering from adult PAS. Especially autoim-
mune diseases with cutaneous manifestation appear to
cluster in patients with a mutation in the AIRE gene, i.e.,
vitiligo (8–25%) and alopecia (16–40%), and are diagnosed
more often than in the adult type with 5–10 and 3–10%,
respectively [51, 52]. Type A autoimmune, atrophic gastritis
(potentially associated with pernicious anemia) is found in
4–10% (1–2%) with PAS II–IV and in 10–20% (1–6%) twice
as often in the juvenile PAS. This holds true for autoim-
mune hepatitis diagnosed in 5–20% of PAS I patients but in
less than 10% of the adult PAS patients. Sjögren syndrome
occurs equally often in both juvenile and adult types (1–3%).
Diagnosis and screening
Early diagnosis of the rare PAS I is difficult because of its
clinical variability and inter-individual differences in pres-
entation with sequential occurrence of associated diseases.
Except for the detection of at least two of the three major
components mentioned above, the manifestation of one major
component in a sibling of a patient diagnosed with PAS I
allows diagnosis, too. PAS I should be considered in patients
with chronic mucocutaneous candidiasis, adrenal insuffi-
ciency or hypoparathyroidism in young age combined with
at least one minor component such as chronic diarrhea/severe
constipation, keratitis/enamel hypoplasia, periodic rash with
fever, autoimmune hepatitis, vitiligo or alopecia [13].
Crucial for the diagnosis of PAS II–IV at an early stage
is considering the presence of polyglandular autoimmun-
ity in patients with still uncomplete syndrome. Screening
and regular follow-up examinations should be performed
to detect endocrine insufficiencies before the occurrence of
potentially severe acute (e.g., AD crisis) or chronic com-
plications (e.g., long-term damages in T1D). In fact, the
consideration of an increased prevalence of non-glandular
autoimmune diseases in patients with PAS can help to avail
missing the therapeutic window of opportunity for early
treatment (e.g., rheumatoid arthritis in patients with PAS
suffering from joint problems).
Besides clinical symptoms, serological testing is indis-
pensable for the screening of patients with polyglandular
autoimmunity. Concerning PAS I, interferon-ω and -α anti-
bodies show the highest prevalence (95–100%) with early
emergence and have been proposed for confirmation of
diagnosis [13, 20]. Most organ-specific autoantibodies can
be found in both PAS I and the respective isolated autoim-
mune disease. Additionally, NACHT leucine-rich repeat
protein 5 (NALP 5) correlating with primary hypoparathy-
roidism and ovarian insufficiency, tryptophan hydroxylase
antibodies (TPH) correlating with intestinal malabsorption
and autoimmune hepatitis as well as aromatic l-amino acid
decarboxylase antibodies (AADC) correlating with autoim-
mune hepatitis and vitiligo can be found in patients with juve-
nile PAS. Each of these above stated antibodies is present in
approximately 50% of the patients with NALP5 showing high
specificity but low sensitivity and TPH/AADC showing high
sensitivity but low to medium specificity. In contrast to the
adult PAS with polygenic dominant inheritance, patients at
high risk for PAS I can theoretically be screened by genetic
testing of the AIRE gene. Further specific autoantibodies e.g.,
against IL-22, IL-17F, and IL-17A have been identified and
allow to distinguish isolated autoimmune diseases from those
occurring in association with PAS I [53, 54].
Patients with monoglandular autoimmune diseases should
be clinically and serologically screened further for both glan-
dular autoimmune diseases as well as non-endocrine auto-
immune disorders (Fig. 1). As an example, TSH receptor
antibody testing is useful to diagnose AITD and untreated
autoimmune hyperthyroidism in particular [55]. Because of
familial autoimmunity with autoimmune diseases clustering
in relatives due to common pathomechanism, first-degree
relatives and members of multiplex families (at least two
family members suffering from monoglandular autoimmune
disease) should also be screened [56]. Since overt (non-)
glandular autoimmune diseases are defined by insufficiency
or complete loss of function of the affected organ, following
functional testing is needed to confirm diagnosis.
Therapy
Treatment of glandular autoimmune diseases consists
primarily of substitution of hormones, modification of
endocrine function, symptomatic therapy, and preven-
tion of potential complications. Since autoimmune patho-
mechanisms cause chronic mucocutaneous candidiasis,
immunomodulators have become of interest in the treat-
ment of PAS I. Topical and systemic application of der-
matologic medications with symptomatic treatment is
combined with immunosuppression adjusted to the overt
autoimmune disease and individual response. In PAS I,
the most important life-threatening complications occur
during childhood and require immediate aggressive immu-
nosuppression. Successful treatment of gastrointestinal
13
 J Endocrinol Invest

Transglutamin
Serological screening
TPO- / TG- / 17-OH Ab CaSR - Ab PC-Ab / IF-Ab
Ab / C-peptide 21-OH Ab ase - Ab
TSH-R-Ab

positive

positive

positive

positive
positive

positive

positive
Functional screening

Endoscopy /
LH / FSH PTH / Ca. / Endoscopy /
OGTT TSH / fT4 Cortisol / ACTH biopsy
E/T Phosphate RBC

positive
positive

positive
positive
positive

positive

positive
Therapy

Iron / vitamin
Insulin LT4 / MMI Hydrocortisone E/T Vitamin D Gluten-free diet
B12

Fig. 1  The serologic and functional screening for associated auto-
immune diseases in patients with a monoglandular autoimmune dis-
ease performed at the onset of endocrinopathy and during follow-up
appointments every 2  years. After diagnosis of type 1 diabetes, thy-
roid dysfunction, adrenal failure, primary hypogonadism, hypopar-
athyroidism, type A autoimmune gastritis with or without pernicious
anemia, and celiac disease, substitution proceeds with levothyroxine,
hydrocortisone, estradiol (E) or testosterone (T), vitamin D, iron tab-
lets, and vitamin B12 intramuscularly, with a strict gluten-free diet.
In contrast, hyperthyroidism due to the autoimmune Graves’ disease
will be managed first with the administration of anti-thyroid drugs
(e.g., methimazole, MMI). Ab antibody, OGTT oral glucose tolerance
test, ACTH adrenocorticotropic hormone, Ca-Sensor calcium-sensing
receptor, E estradiol, FSH follicle-stimulating hormone, fT4 free thy-
roxine, Hypo hypothyroidism, Hyperthyr hyperthyroidism, IF intrin-
sic factor, LH luteinizing hormone, PC parietal cell, PTH parathyroid
hormone, RBC red blood cell count, T total testosterone, transglutam-
inase antibodies, TG thyroglobulin, TPO thyroid peroxidase, TSH-R
TSH receptor, TSH thyrotropin, Vit vitamin, 17-OH 17-hydroxylase,
21-OH 21-hydroxylase

dysfunction, alopecia, and keratoconjunctivitis with cyclo-
sporine has been reported, while autoimmune hepatitis
responded to steroids and azathioprine in several patients
[31, 57]. Additionally, gastrointestinal dysfunction and
exocrine pancreatic insufficiency showed remission and
partial amelioration, respectively, in immunosuppressive
regimes including tacrolimus and mycophenolate mofetil
or oral methotrexate, respectively [58, 59]. Experimental
therapy with either anti-CD52 (Alemtuzumab) or anti-
CD20 monoclonal antibodies (rituximab) was effective
on treatment-resistant components of PAS I.
In overt endocrine insufficiency, substitution therapy
depends on the residual glandular function and is admin-
istered in accordance to monoglandular autoimmune dis-
eases. In patients with the adult PAS, immunomodulatory
therapy does not take a central role and is restricted to
special indications such as Graves’ orbitopathy (47) or
additional non-glandular autoimmune diseases.
Especially during immunosuppressive therapy in patients
with PAS I, an aggravation of chronic mucocutaneous
candidiasis can be observed requiring adequate antimicro-
bial or virustatic drugs (e.g., septrin, itraconazole, and acy-
clovir). Especially systemic application of azole antifungals
may lead to severe liver damage and should be avoided in
patients with autoimmune hepatitis. With regard to immu-
nosuppressive drugs, severe side-effects such as sirolimus-
associated acute interstitial nephritis must be considered and
regular controls must be performed at close intervals.
In patients with PAS, physiologic interactions of hor-
mones need to be considered. levothyroxine, for instance,
increases hepatic metabolism of cortisol and might lead to
acute AD failure in patients with PAS type II. Furthermore,
AD causes both a reduction of insulin requirement as well as
TSH increase due to absence of glucocorticoid-transmitted
inhibition of TSH secretion [1, 60]. Because of the complex-
ity of hormonal therapy, patients need to be instructed and
informed about these interactions to avoid complications
when taking the drug (e.g., simultaneous intake of levothy-
roxine and vitamin D/calcium) and/or side effects (gastric
ulceration during steroid therapy).

13
J Endocrinol Invest
Compliance with ethical standards  17. Horie I, Kawasaki E, Ando T, Kuwahara H, Abiru N, Usa T,
Conflict of interest  The authors have no conflicts of interest to de-
clare.
18. Yoshioka K, Ohsawa A, Yoshida T, Yokoh S (1993) Insulin-
Ethical approval  This review does not contain any studies with
human participants or animals performed by any of the authors.
Informed consent  No informed consent needed.
References
1. Kahaly GJ (2009) Polyglandular autoimmune syndromes. Eur
J Endocrinol Eur Fed Endocr Soc 161(1):11–20. doi:10.1530/
eje-09-0044
2. Eisenbarth GS, Gottlieb PA (2004) Autoimmune polyendocrine
syndromes. N Engl J Med 350(20):2068–2079. doi:10.1056/
NEJMra030158
3. Cutolo M (2014) Autoimmune polyendocrine syndromes. Autoim-
mun Rev 13(2):85–89. doi:10.1016/j.autrev.2013.07.006
4. Martinez Lopez MM, Gonzalez Casado I, Alvarez Doforno R, Del-
gado Cervino E, Gracia Bouthelier R (2006) AIRE gene mutation in
polyglandular syndrome type 1. Anales de pediatria 64(6):583–587
5. Hansen MP, Kahaly GJ (2013) Autoimmune polyglandular syn-
dromes. Deutsche medizinische Wochenschrift 138(7):319–326.
doi:10.1055/s-0032-1327355 (quiz 327-318)
6. Forster G, Krummenauer F, Kuhn I, Beyer J, Kahaly G (1999)
Polyglandular autoimmune syndrome type II: epidemiology and
forms of manifestation. Dtsch Med Wochenschr 124(49):1476–
1481. doi:10.1055/s-2008-1035684
7. Hansen MP, Matheis N, Kahaly GJ (2015) Type 1 diabetes and
polyglandular autoimmune syndrome: a review. World J Diabetes
6(1):67–79. doi:10.4239/wjd.v6.i1.67
8. Claude HGH (1908) Insuffisance pluriglandulaire endocrinienne.
J Physiol Pathol Gen 10:469–480
9. Eisenbarth GS, Wilson PW, Ward F, Buckley C, Lebovita H
(1979) The polyglandular failure syndrome: disease inheritance,
HLA type, and immune function. Ann Intern Med 91(4):528–533
10. Muir A, She JX (1999) Advances in the genetics and immunology
of autoimmune polyglandular syndrome II/III and their clinical
applications. Ann Med Interne 150(4):301–312
11. Betterle C, Zanchetta R (2003) Update on autoimmune polyendo-
crine syndromes (APS). Acta bio-medica: Atenei Parm 74(1):9–33
12. Arlt W, Allolio B (2003) Adrenal insufficiency. Lancet
361(9372):1881–1893. doi:10.1016/S0140-6736(03)13492-7
13. Husebye ES, Perheentupa J, Rautemaa R, Kampe O (2009) Clini-
cal manifestations and management of patients with autoimmune
polyendocrine syndrome type I. J Intern Med 265(5):514–529.
doi:10.1111/j.1365-2796.2009.02090.x
14. Bensing S, Brandt L, Tabaroj F, Sjoberg O, Nilsson B, Ekbom A,
Blomqvist P, Kampe O (2008) Increased death risk and altered
cancer incidence pattern in patients with isolated or combined
autoimmune primary adrenocortical insufficiency. Clin Endo-
crinol 69(5):697–704. doi:10.1111/j.1365-2265.2008.03340.x
15. Dittmar M, Kahaly GJ (2003) Polyglandular autoimmune syn-
dromes: immunogenetics and long-term follow-up. J Clin Endo-
crinol Metab 88(7):2983–2992. doi:10.1210/jc.2002-021845
16. Quinkler M (2012) Addison’s disease. Medizinische Klinik, Inten-
sivmedizin und Notfallmedizin 107(6):454–459. doi:10.1007/
s00063-012-0112-3
Yamasaki H, Ejima E, Kawakami A (2012) Clinical and genetic
characteristics of autoimmune polyglandular syndrome type
3 variant in the Japanese population. J Clin Endocrinol Metab
97(6):E1043–E1050. doi:10.1210/jc.2011-3109
dependent diabetes mellitus associated with Graves’ disease
and idiopathic hypoparathyroidism. J Endocrinol Investig
16(8):643–646
19. Lupi I, Raffaelli V, Di Cianni G, Caturegli P, Manetti L, Ciccarone
AM, Bogazzi F, Mariotti S, Del Prato S, Martino E (2013) Pitui-
tary autoimmunity in patients with diabetes mellitus and other
endocrine disorders. J Endocrinol Investig 36(2):127–131
20. Kisand K, Peterson P (2015) Autoimmune polyendocrinopathy
candidiasis ectodermal dystrophy. J Clin Immunol 35(5):463–478.
doi:10.1007/s10875-015-0176-y
21. Myhre AG, Halonen M, Eskelin P, Ekwall O, Hedstrand H,
Rorsman F, Kampe O, Husebye ES (2001) Autoimmune poly-
endocrine syndrome type 1 (APS I) in Norway. Clin Endocrinol
54(2):211–217
22. Sato K, Nakajima K, Imamura H, Deguchi T, Horinouchi S,
Yamazaki K, Yamada E, Kanaji Y, Takano K (2002) A Novel
Missense Mutation of <I>AIRE</I> gene in a patient with
autoimmune polyendocrinopathy, candidiasis and ectodermal
dystrophy (APECED), accompanied with progressive muscular
atrophy: case report and review of the literature in Japan. Endocr
J 49(6):625–633. doi:10.1507/endocrj.49.625
23. Dominguez M, Crushell E, Ilmarinen T, McGovern E, Collins
S, Chang B, Fleming P, Irvine AD, Brosnahan D, Ulmanen I,
Murphy N, Costigan C (2006) Autoimmune polyendocrinopathy-
candidiasis-ectodermal dystrophy (APECED) in the Irish popula-
tion. J Pediatr Endocrinol Metab 19(11):1343–1352
24. Betterle C, Dal Pra C, Mantero F, Zanchetta R (2002) Autoim-
mune adrenal insufficiency and autoimmune polyendocrine syn-
dromes: autoantibodies, autoantigens, and their applicability in
diagnosis and disease prediction. Endocr Rev 23(3):327–364.
doi:10.1210/edrv.23.3.0466
25. Betterle C, Lazzarotto F, Presotto F (2004) Autoimmune polyglan-
dular syndrome type 2: the tip of an iceberg? Clin Exp Immunol
137(2):225–233. doi:10.1111/j.1365-2249.2004.02561.x
26. Fatma M, Mouna E, Raouf H, Hajer F, Hatem M, Mohammed
A (2014) Autoimmune polyglandular syndrome type II: epide-
miological, clinical and immunological data. J Endocrinol Metab
4(4):101–109
27. Waterfield M, Anderson MS (2010) Clues to immune tolerance:
the monogenic autoimmune syndromes. Ann N Y Acad Sci
1214:138–155. doi:10.1111/j.1749-6632.2010.05818.x
28. Wolff AS, Erichsen MM, Meager A, Magitta NF, Myhre AG,
Bollerslev J, Fougner KJ, Lima K, Knappskog PM, Husebye ES
(2007) Autoimmune polyendocrine syndrome type 1 in Norway:
phenotypic variation, autoantibodies, and novel mutations in the
autoimmune regulator gene. J Clin Endocrinol Metab 92(2):595–
603. doi:10.1210/jc.2006-1873
29. Chan AY, Anderson MS (2015) Central tolerance to self revealed
by the autoimmune regulator. Ann N Y Acad Sci 1356(1):80–89.
doi:10.1111/nyas.12960
30. Halonen M, Eskelin P, Myhre AG, Perheentupa J, Husebye ES,
Kampe O, Rorsman F, Peltonen L, Ulmanen I, Partanen J (2002)
AIRE mutations and human leukocyte antigen genotypes as
determinants of the autoimmune polyendocrinopathy-candidi-
asis-ectodermal dystrophy phenotype. J Clin Endocrinol Metab
87(6):2568–2574. doi:10.1210/jcem.87.6.8564
31. Meloni A, Willcox N, Meager A, Atzeni M, Wolff AS, Husebye
ES, Furcas M, Rosatelli MC, Cao A, Congia M (2012) Autoim-
mune polyendocrine syndrome type 1: an extensive longitudinal
13

study in Sardinian patients. J Clin Endocrinol Metab 97(4):1114–
1124. doi:10.1210/jc.2011-2461
32. Barkia Beradhi S, Flesch BK, Hansen MP, Matheis N, Kahaly GJ
(2015) HLA class II differentiates between thyroid and polyglan-
dular autoimmunity. Horm Metab Res 48(4):232–237. doi:10.10
55/s-0035-1559622
33. Flesch BK, Matheis N, Alt T, Weinstock C, Bux J, Kahaly GJ
(2014) HLA class II haplotypes differentiate between the adult
autoimmune polyglandular syndrome types II and III. J Clin Endo-
crinol Metab 99(1):E177–E182. doi:10.1210/jc.2013-2852
34. Bellone M (2001) Autoimmune disease: pathogenesis. In: eLS.
Wiley. doi:10.1038/npg.els.0004000
35. Kang SY, Oh JH, Song SK, Lee JS, Choi JC, Kang JH (2015) Both
binding and blocking antibodies correlate with disease severity in
myasthenia gravis. Neurol Sci: Off J Ital Neurol Soc Ital Soc Clin
Neurophysiol 36(7):1167–1171. doi:10.1007/s10072-015-2236-8
36. Ortega SB, Noorbhai I, Poinsatte K, Kong X, Anderson A,
Monson NL, Stowe AM (2015) Stroke induces a rapid adaptive
autoimmune response to novel neuronal antigens. Discov Med
19(106):381–392
37. Ramos-Lopez E, Lange B, Kahles H, Willenberg HS, Meyer G,
Penna-Martinez M, Reisch N, Hahner S, Seissler J, Badenhoop
K (2008) Insulin gene polymorphisms in type 1 diabetes, Addi-
son’s disease and the polyglandular autoimmune syndrome type
II. BMC Med Genet 9:65. doi:10.1186/1471-2350-9-65
38. Huang W, Connor E, Rosa TD, Muir A, Schatz D, Silverstein
J, Crockett S, She JX, Maclaren NK (1996) Although DR3-
DQB1*0201 may be associated with multiple component dis-
eases of the autoimmune polyglandular syndromes, the human
leukocyte antigen DR4-DQB1*0302 haplotype is implicated only
in beta-cell autoimmunity. J Clin Endocrinol Metab 81(7):2559–
2563. doi:10.1210/jcem.81.7.8675578
39. Maclaren NK, Riley WJ (1986) Inherited susceptibility to autoim-
mune Addison’s disease is linked to human leukocyte antigens-
DR3 and/or DR4, except when associated with type I autoimmune
polyglandular syndrome. J Clin Endocrinol Metab 62(3):455–459.
doi:10.1210/jcem-62-3-455
40. Robles DT, Fain PR, Gottlieb PA, Eisenbarth GS (2002) The
genetics of autoimmune polyendocrine syndrome type II. Endo-
crinol Metab Clin North Am 31(2):353–368
41. Dittmar M, Kahaly GJ (2010) Genetics of the autoimmune pol-
yglandular syndrome type 3 variant. Thyroid: Off J Am Thyroid
Assoc 20(7):737–743. doi:10.1089/thy.2010.1639
42. Brabant G, Manns MP, Vogel A, Strassburg CP (2002) Autoim-
mun polyglanduläre Syndrome: Aspekte zu Pathogenese, Prog-
nose und Therapie. Dtsch Arztebl Int 99(21):1428
43. Zlotogora J, Shapiro MS (1992) Polyglandular autoimmune syn-
drome type I among Iranian Jews. J Med Genet 29(11):824–826
44. Ahonen P, Myllarniemi S, Sipila I, Perheentupa J (1990) Clinical
variation of autoimmune polyendocrinopathy-candidiasis-ectoder-
mal dystrophy (APECED) in a series of 68 patients. N Engl J Med
322(26):1829–1836. doi:10.1056/NEJM199006283222601
45. Bartalena L, Chiovato L, Vitti P (2016) Management of hyper-
thyroidism due to Graves’ disease: frequently asked questions
and answers (if any). J Endocrinol Invest 39(10):1105–1114.
doi:10.1007/s40618-016-0505-x
46. Bartalena L, Masiello E, Magri F, Veronesi G, Bianconi E, Zerbini
F, Gaiti M, Spreafico E, Gallo D, Premoli P, Piantanida E, Tanda
ML, Ferrario M, Vitti P, Chiovato L (2016) The phenotype of
newly diagnosed Graves’ disease in Italy in recent years is milder
than in the past: results of a large observational longitudinal
study. J Endocrinol Investig 39(12):1445–1451. doi:10.1007/
s40618-016-0516-7
47. Bartalena L, Veronesi G, Krassas GE, Wiersinga WM, Marcocci
C, Marino M, Salvi M, Daumerie C, Bournaud C, Stahl M, Sassi
L, Azzolini C, Boboridis KG, Mourits MP, Soeters MR, Baldeschi
13
J Endocrinol Invest
L, Nardi M, Curro N, Boschi A, Bernard M, von Arx G, Per-
ros P, Kahaly GJ, European Group on Graves O (2017) Does
early response to intravenous glucocorticoids predict the final
outcome in patients with moderate-to-severe and active Graves’
orbitopathy? J Endocrinol Investig 40(5):547–553. doi:10.1007/
s40618-017-0608-z
48. Van den Driessche A, Eenkhoorn V, Van Gaal L, De Block C
(2009) Type 1 diabetes and autoimmune polyglandular syndrome:
a clinical review. Neth J Medicine 67(11):376–387
49. Kobayashi I, Inukai T, Takahashi M, Ishii A, Ohshima K, Mori
M, Shimomura Y, Kobayashi S, Hashimoto A, Sugiura M (1988)
Anterior pituitary cell antibodies detected in Hashimoto’s thyroid-
itis and Graves’ disease. Endocrinologia japonica 35(5):705–708
50. Wallaschofski H, Meyer A, Tuschy U, Lohmann T (2003) HLA-
DQA1*0301-associated susceptibility for autoimmune pol-
yglandular syndrome type II and III. Hormone and metabolic
research=Hormon- und Stoffwechselforschung=Hormones et
metabolisme 35(2):120–124. doi:10.1055/s-2003-39059
51. Betterle C, Greggio NA, Volpato M (1998) Clinical review 93:
autoimmune polyglandular syndrome type 1. J Clin Endocrinol
Metab 83(4):1049–1055. doi:10.1210/jcem.83.4.4682
52. Betterle C, Volpato M, Greggio AN, Presotto F (1996) Type 2 pol-
yglandular autoimmune disease (Schmidt’s syndrome). J Pediatr
Endocrinol Metab 9(Suppl 1):113–123
53. Puel A, Doffinger R, Natividad A, Chrabieh M, Barcenas-Morales
G, Picard C, Cobat A, Ouachee-Chardin M, Toulon A, Bustamante
J, Al-Muhsen S, Al-Owain M, Arkwright PD, Costigan C, McCo-
nnell V, Cant AJ, Abinun M, Polak M, Bougneres PF, Kumararatne
D, Marodi L, Nahum A, Roifman C, Blanche S, Fischer A, Bode-
mer C, Abel L, Lilic D, Casanova JL (2010) Autoantibodies against
IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous
candidiasis and autoimmune polyendocrine syndrome type I. J Exp
Med 207(2):291–297. doi:10.1084/jem.20091983
54. Kisand K, Boe Wolff AS, Podkrajsek KT, Tserel L, Link M,
Kisand KV, Ersvaer E, Perheentupa J, Erichsen MM, Bratanic N,
Meloni A, Cetani F, Perniola R, Ergun-Longmire B, Maclaren N,
Krohn KJ, Pura M, Schalke B, Strobel P, Leite MI, Battelino T,
Husebye ES, Peterson P, Willcox N, Meager A (2010) Chronic
mucocutaneous candidiasis in APECED or thymoma patients cor-
relates with autoimmunity to Th17-associated cytokines. J Exp
Med 207(2):299–308. doi:10.1084/jem.20091669
55. Diana T, Wuster C, Kanitz M, Kahaly GJ (2016) Highly variable
sensitivity of five binding and two bio-assays for TSH-receptor
antibodies. J Endocrinol Invest 39(10):1159–1165. doi:10.1007/
s40618-016-0478-9
56. Cardenas-Roldan J, Rojas-Villarraga A, Anaya JM (2013) How do
autoimmune diseases cluster in families? A systematic review and
meta-analysis. BMC Med 11:73. doi:10.1186/1741-7015-11-73
57. Ward L, Paquette J, Seidman E, Huot C, Alvarez F, Crock P, Delvin
E, Kampe O, Deal C (1999) Severe autoimmune polyendocrinop-
athy-candidiasis-ectodermal dystrophy in an adolescent girl with a
novel AIRE mutation: response to immunosuppressive therapy. J
Clin Endocrinol Metab 84(3):844–852. doi:10.1210/jcem.84.3.5580
58. O’Gorman CS, Shulman R, Lara-Corrales I, Pope E, Marcon M,
Grasemann H, Schneider R, Upton J, Sochett EB, Koltin D, Cohen
E (2013) A child with autoimmune polyendocrinopathy candidi-
asis and ectodermal dysplasia treated with immunosuppression:
a case report. J Med Case Rep 7:44. doi:10.1186/1752-1947-7-44
59. Abinun M, Hodges S, Cheetham T, Ognjanovic M, Hopper N,
Burt A, Wood K, Lilic D (2014) ESID-0264 immunomodulatory
therapy for severe autoimmune polyendocrinopathy type-1 (APS-
1). J Clin Immunol 34(Suppl 2):139–515
60. Michels AW, Eisenbarth GS (2009) Autoimmune polyendocrine
syndrome type 1 (APS-1) as a model for understanding autoim-
mune polyendocrine syndrome type 2 (APS-2). J Intern Med
265(5):530–540. doi:10.1111/j.1365-2796.2009.02091.x