Peculiarities of autoimmune polyglandular syndromes in children and adolescents.

BACKGROUND: no reviews have specifically addressed , to now, whether autoimmune polyglandular syndromes (APSs) may have a peculiar epidemiology and phenotypical expression in pediatric age
Objectives: to review the most recent literature data about the specific epidemiological and clinical peculiarities of APSs in childhood and adolescenceDesign: the main features of the different APSs in pediatric age were compared among them.
CONCLUSIONS: 1) Among the different APSs, the one that is most typical of pediatric age is APS-1; 2) APS-1 is not characterized only by the classical triad (chronic moniliasis-hyposurrenalism-hypoparathyroidism) and its clinical spectrum is enlarging over time; 3)APS-2 may have a different epidemiological and clinical expression according to two different nosological classifications.

Background

The autoimmune polyglandular syndromes (APSs) are characterized by the association of multiple autoimmune disorders and, in some cases, immunodeficiency (1). They include both monogenic illnesses, such as APS-1 and IPEX (immune dysfunction, polyendocrinopathy, X-linked) syndrome, as well as more complex genetic disorders, such as APS-2, APS-3 and APS-4.

The term “polyglandular” itself may be misleading, since some patients have multiple endocrine diseases, whereas others have many non-endocrine disorders (2). Some disorders, such as autoimmune thyroid diseases (AITDs) and type 1 diabetes mellitus (T1DM), occur very often in all APSs, whilst other disorders, such as Addison’s disease (AD) and myasthenia gravis are much more infrequent (1). In patients at risk for APSs, who have a single autoimmune disease, the prevalence of other autoimmune disorders is 30 to 50 times more elevated than in the general population (3). It has been estimated that one fourth of individuals with one autoimmune illness will develop another one throughout their lives (4).

APSs may occur at any age, with a different epidemiology between APS-1 and the other forms: whereas APS-1 is more common in childhood, APS-2 occurs most commonly in patients 30 to 40 years of age (5). However, to the best of our knowledge, no reviews have specifically addressed, to now, this interesting point, i.e. whether APSs may have a peculiar epidemiology and phenotypical expression in pediatric age.

Aim of this commentary is to review the most recent literature data concerning the specific epidemiological and clinical peculiarities of APSs in childhood and adolescence.

Peculiarities of APS-1 in childhood

APS-1, also called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome, is a rare autosomal recessive monogenic disorder caused by mutations in the autoimmune regulator (AIRE) gene (6-8). More than 60 different mutations of this gene had been reported until 2012 (9, 10), but their number is progressively increasing over time (11). Some specific mutations are described to be associated with the geographical distribution of patients (10, 11), thus suggesting a potential founder effect (9). This might explain why APS-1 occurs worldwide, but its prevalence is distinctly higher among genetically isolated ethnic groups and particularly among Finnish (6), Sardinian (12), and Iranian Jewish populations (13).

It is a T-cell mediated disease with increased frequencies of CD8+ effector and reduction of FoxP3+T regulatory cells. In addition, APECED patients show a significant alteration of the B-cell phenotype and a dysregulation of B-cell function involving peripheral innate immune mechanisms; such alterations become more evident with increasing disease duration (14).

Clinical picture of APECED syndrome is mainly characterized by the classic triad: chronic mucocutaneous candidiasis, hypoparathyroidism and AD. These are the most common components of this syndrome, two of which are required for diagnosis (diagnostic dyad). Apart from these classic manifestations, however, many other endocrine and non-endocrine autoimmune disorders may occur in this condition, whose clinical spectrum has been reported to be progressively enlarging over time (15). The novel autoimmune disorders that have been described during the last years in individuals with APECED syndrome are : interstitial lung disease (16, 17), chronic inflammatory demy elinating polineuropathy (18) and gastrointestinal dysfunction (19). For each of them the respective autoantigens and autoantibodies have been also identified (19-21).

Table 1 summarizes the main features of APS-1, APS-2, as defined according to the most recent nosological classification (1,2) and IPEX syndrome.

Table 1

Epidemiological, genotypical and phenotypical peculiarities of autoimmune polyendocrine syndromes (APSs) as defined according to a recent nosological classification (References 1 and 2)

Features	APS-1	APS-2	IPEX syndrome °
Prevalence	Rare	Common	Very rare
Preferential age at clinical onset	Infancy	Adolescence and childhood	Neonatal period
Inheritance	Monogenic	Polygenic	Monogenic
HLA genotype	No association	DQ2 and DQ8	No association
Common phenotype	Candidiasis, hyposurrenalism, hypoparathyroidism	Thyropathies, diabetes, hyposurrenalism, celiac disease	Immunodeficiency, malabsorption, diabetes, dermatitis
Other manifestations	Malabsorption, Vitiligo, polyneuropathy, lung disease, gastrointestinal dysfunction,	Vitiligo, pernicious anemia, myasthenia gravis, alopecia others	Diabetes, dermatitis
Clinical expressivity	Very severe	Severe	Often fatal

Immune dysfunction, polyendocrinopathy, enteropathy, X-linked

Peculiarities of APS-2 in childhood

This autoimmune polyendocrine syndrome may be defined according to two different nosological classification.

According to the original classification of Neufeld and Blizzard (22), this condition is characterized by the mandatory presence of AD (100% of cases), which may be associated with either AITDs (Schmidt’s syndrome) or T1DM (Carpenter’s syndrome). The association with AITDs (69-82% of cases) is more frequent than that with T1DM (30-52% of cases) (23). The association with other autoimmune disorders (Table 2) is much less frequent and, however, non-mandatory.

Table 2

Epidemiological and phenotypical peculiarities of autoimmune polyendocrine syndromes (APSs) type 2, 3 and 4, as defined according to the classic classification of Neufeld and Blizzard (Reference 22)

Features	APS-2	APS-3	APS-4
Prevalence	Very rare	Common	Very rare
Preferential age of clinical onset	Middle age	Adolescence and early adulthood	From childhood to adulthood
Inheritance	HLA mutations	HLA mutations	HLA mutations
Mandatory component	Addison’s disease	Thyropathy	Addison’s disease
Excluded component	------------------	Addison’s disease and hypoparathyroidism	------------------
Minor autoimmune disorders °	Infrequent	Common	Very common

V itiligo, alopecia, atrophic gastritis, pernicious anemia, hypophysitis

According to the same classification (22), APS-2 is a specific clinical entity, which differs from APS-3 and APS-4 and is very rare: 1.4-2.0/100000 inhabitants (23). APS-2 may occur at any age and in both sexes, although it is especially common in middle-aged women and very infrequent in childhood (23).

APS3 is another clinical entity, which is characterized by the mandatory presence of AITDs (22). Other less frequent autoimmune disorders are: T1DM (APS3a), atrophic gastritis and pernicious anemia (APS3b), vitiligo, alopecia and myasthenia gravis (APS3c). AD and hypoparathyroidism are absent by definition (23). This condition would be less rare than APS-2 and it may present even in pediatric age (23).

According to the same classification of Neufeld and Blizzard (22), APS-4 is a further and very rare syndrome, that is characterized by the combination of autoimmune disorders not falling into APS-1 and APS-3 (chronic candidiasis, hypoparathyroidism, AITDs and T1DM). AD is a mandatory component of APS-4 and a positivity of autoantibodies against adrenal cortex/21-hydroxylase is absolutely required for diagnosis (23). In individuals with suspicious APS-4 it is also important to exclude the coexistence of chronic moniliasis and/or signs of latent hypocalcemia, in order to exclude the possibility of a subclinical APS-1 (23).

According to another and more recent classification, which has been diffusely adopted in the last years (1, 2, 24-26), APS-2, APS-3 and APS-4 should not be considered as separate entities and could be included in the context of a single syndrome, which has been named as APS-2 (1, 2, 24-26). According to this recent view, APS-2 is the most frequent polyglandular syndrome (incidence 1-2:10000/year), that occurs more often in females (ratio 3:1) and may present from childhood to adulthood (25). Its inheritance is polygenic, with genes on chromosome 6 playing a predominant role (1). AITDs represent the most frequent clinical component of this condition (70-75%), followed by T1DM (50-60%), AD (40%) and other autoimmune disorders: celiac disease, vitiligo, pernicious anemia, myasthenia gravis and alopecia. Individual comorbidities may manifest even many years later, which reinforces the necessity of a widespread knowledge of this syndrome (1). This is particularly important considering that also first-degree relatives of children with APS-2 are at high risk of autoimmune diseases (1). In the light of all these considerations and the relatively high frequency of APS-2, it is important to recommend that children with AITDs or T1DM or AD or celiac disease are periodically monitored for other autoimmune disorders, although the optimal screening interval is not defined.

The main features of APS-2, APS-3 and APS-4, as defined according to the nosological classification of Neufeld and Blizzard (22), are summarized in Table 2, whereas the main features of APS-2, as defined according to the more recent nosological classification (1, 2), are given in Table 1.

Peculiarities of IPEX

This monogenic syndrome of X-linked polyendocrinopathy, immune dysfunction and enteropathy is very rare, may present very early and may be often fatal (1, 2). It results from mutations in the forkhead box protein P3 gene, that controls the normal function of regulatory T cells.

Clinically this syndrome presents during the first few months of life with chronic diarrhea and malabsorption, dermatitis, failure to thrive, T1DM and other autoimmune disorders (Table1). Due to the severe malnutrition degree and the recurrent infections which result from immunosuppressive therapies, children with this condition usually die during the first two years of life (1, 2). Supportive care and management of underlying clinical problems are mandatory and restoration of normal T-cell function may improve the overall clinical picture. The immunosuppressive medications that have been tried in the management of this syndrome are: ciclosporin, methotrexate, highdose glucocorticoids, tacrolimus, infliximab and rituximab (27-31). It is very important to suspect and recognize this condition as soon as possible, since an early bone marrow transplantation, with the development of mixed chimerism in the recipient, could stop the natural evolution of this very sever disorder (2). The main peculiarities of this condition in pediatric age are summarized in Table 1.

Conclusions

1) Among the different APSs, the one that is most typical of pediatric age is APS-1; 2) APS-1 is not characterized only by the classical triad (chronic moniliasis-hyposurrenalism-hypoparathyroidism) and its clinical spectrum is enlarging over time; 3)APS-2 may have a different epidemiological and clinical expression according to two different nosological classifications.

Addison’s disease

autoimmune polyglandular syndromes

autoimmune thyroid diseases

immune dysfunction, polyendocrinopathy, X-linked

type 1 diabetes mellitus