Chapter 586

Autoimmune Polyglandular Syndromes

Christina M. Astley, Jessica R. Smith, Ari J. Wassner

An autoimmune polyglandular syndrome (APS) occurs when autoimmunity is directed at multiple glands and/or nonendocrine organs, sometimes in association with immunodeficiency. Endocrine glands and other organs commonly affected by APS have unique autoantigens that increase these tissues’ susceptibility to damage by an untamed immune response. Most autoimmune endocrinopathies are caused by cell-mediated immunity from autoreactive T cells. Although antibodies to 1 or more autoantigens are commonly associated with specific autoimmune endocrinopathies, in most cases these autoantibodies are not directly pathogenic but rather are markers of immune dysregulation. A notable exception is Graves disease, which is caused by autoantibodies that directly activate the thyrotropin hormone receptor (TSHR).

APS, due to monogenic disorders of immune dysregulation (including APS type 1 [APS-1]), have heritable lesions in key aspects of immune tolerance (Table 586.1 ). Polygenic disorders associated with APS (APS type 2 [APS-2]) and some chromosomal abnormalities (e.g., trisomy 21) also result in an aberrant immune response that produces multiorgan autoimmunity. Finally, nongenetic factors (e.g., immune checkpoint inhibitors for cancer therapy) may lead to autoimmune polyglandular disease. While APS is uncommon, patients can experience significant lifetime morbidity, particularly if the syndrome is not identified early and managed appropriately. There may be 1-2 decades between the presentations of the first and subsequent endocrinopathy. The presence of primary hypoparathyroidism, primary adrenal insufficiency, neonatal type 1 diabetes mellitus, chronic mucocutaneous candidiasis, or a family history should raise particular suspicion for APS.

Table 586.1

Autoimmune Polyglandular Syndromes

AUTOIMMUNE POLYGLANDULAR SYNDROME	MONOGENIC APS
	APS-1	IPEX	CTLA4	LRBA	ITCH	STAT1	STAT5b	CD25
EPIDEMIOLOGY AND GENETICS
Incidence	<1 : 100,000	Rare	Rare	Rare	Rare	Rare	Rare	Rare
Onset	Infancy	Infancy	Infancy	Infancy	Infancy	Infancy	Infancy	Infancy
Male-to-female ratio	1 : 1	Males only
Inheritance	Autosomal recessive (most)	X-linked	Autosomal dominant	Autosomal recessive	Autosomal recessive	Autosomal dominant	Autosomal recessive	Autosomal recessive
Genetic abnormality	AIRE	FOXP3	CLTA4	LRBA	ITCH	STAT1	STAT5b	IL2RA
Mechanism of disease	Central tolerance	Treg development	Treg suppression	Treg suppression	Treg suppression	Treg suppression	Immune signaling	Immune signaling
CLINICAL FEATURES
Classic Phenotype	Candidiasis	Enteropathy	Enteropathy	Enteropathy	Dysmorphic features	Candidiasis	Enteropathy	Enteropathy
	Hypoparathyroidism	Type 1 diabetes mellitus in infancy	Cytopenia	Respiratory tract disease	Developmental delay	Recurrent infections	Respiratory tract disease	Type 1 diabetes mellitus in infancy
	Addison disease	Eczematous dermatitis	Lymphocytic aggregates	Organomegaly	Organomegaly	Multiple autoimmunity	Recurrent infections	Recurrent infections
			Hypogammaglobulinemia	Hypogammaglobulinemia	Autoimmune infiltrates	Cerebral aneurysm	Growth failure
Endocrinopathies
Adrenal insufficiency	60–90%					Rare
Thyroid	10–40%	Common	15%	10%	40%	20%	20%	Common
Type 1 diabetes mellitus	5–20%	Common	Rare	5%	10%	5%		Common
Hypoparathyroidism	80–90%
Gonadal insufficiency	5–60%
Hypophysitis	Rare
Hypothalamic dysfunction
Hyperprolactinemia							Common
GH axis, skeletal					Dysmorphic, growth failure		GH resistance
Nonendocrine Disease
Immune Dysregulation
Candida infection	75–100%	Rare				Common		Common
Other infections	Asplenism (10–20%)	Bacterial (rare)	Common	Common respiratory	Rare bacterial	Common	Common (esp. VZV)	Common (esp. EBV, CMV)
Gastrointestinal
Malabsorption, enteropathy	10–20%	Common	80%	60%	20%	Common	Common	Common
GI autoimmunity	10–15%			10%		5%
Autoimmune hepatitis	10–15%	Rare			30%	Rare
Integumentary/Rheumatologic			Psoriasis or other skin (20%)			Psoriasis, vitiligo, or other skin (20%)
Vitiligo	5–15%			5%
Eczema, allergic disease		Common		10%	Common	20%	80%	Common
Alopecia	25%
Ectodermal dysplasia	75%
Arthritis		Rare	15%	10%
Other	Keratoconjunctivitis (5–20%) Periodic fever (15%)	Cytopenias (common) Nephritis (rare)	Cytopenia (60%) Lung disease (60%)	Cytopenia (70%) Myasthenia gravis (rare)	Lung disease (80%)	Cytopenia (5%) Vascular (5%)	Cytopenia (20%)	Cytopenia (common)

AUTOIMMUNE POLYGLANDULAR SYNDROME	OTHER APS AND APS-LIKE CONDITIONS
	APS-2	TURNER SYNDROME	KLINEFELTER SYNDROME	DOWN SYNDROME	DIGEORGE SYNDROME	ROHHAD
EPIDEMIOLOGY AND GENETICS
Incidence	1-2/10,000	1 : 2,500 females	1 : 1,000 males	1 : 700	1 : 4,000	Rare
Onset	Adulthood	Congenital	Congenital	Congenital	Congenital	Early childhood
Male-to-female ratio	1 : 3	Females only	Males only
Inheritance	Polygenic	N/A	N/A	N/A (most)	Autosomal dominant	N/A
Genetic abnormality	HLA, MICA, PTPN22, CTLA4, NALP1	46, X	47, XXY	Trisomy 21	22q11.2 del	None identified
Mechanism of disease	Multifactorial	Multifactorial	Multifactorial	Multifactorial	T-cell development defects	Possible autoimmunity
CLINICAL FEATURES
Classic Phenotype	Addison disease	Short stature	Tall stature	Hypotonia	Absent thymus	Rapid-onset obesity
	Autoimmune thyroid disease	Ovarian insufficiency	Testicular insufficiency	Epicanthal folds	Congenital heart disease	Hypothalamic dysfunction
	Type 1 diabetes mellitus	Webbed neck	Gynecomastia	Brushfield spots	Hypocalcemia	Autonomic dysregulation
		Coarctation of the aorta		Single palmar crease	Developmental delay	Neuroendocrine tumor
				Developmental delay
Endocrinopathies
Adrenal insufficiency	70–100%		Rare
Thyroid	70%	15–20%	1%	15%	5%
Type 1 diabetes mellitus	40–50%	2%	2%	1–10%	Rare
Hypoparathyroidism	None				30%
Gonadal insufficiency	3–10%	90%	Common
Hypophysitis	Rare
Hypothalamic dysfunction						Present
Hyperprolactinemia						Common
GH axis, skeletal		Short stature	Tall stature	Short stature	Short stature
Nonendocrine disease
Immune Dysregulation
Candida infection	None
Other infections					Thymic dysplasia/aplasia
Gastrointestinal		IBD (1%)
Malabsorption, enteropathy	Rare
GI autoimmunity	2–25%	Rare		5%
Autoimmune hepatitis	Rare
Integumentary/Rheumatologic		Psoriasis (rare)
Vitiligo, other skin	4–5%	Rare
Eczema, allergic disease
Alopecia	2%	Rare		Rare
Ectodermal dysplasia	None
Arthritis		Rare	1%		Rare
Other		Lymphedema	Lupus, Sjogren and multiple sclerosis (rare)	Congenital heart disease	Congenital heart disease T-cell deficiency Cytopenias (rare)	Autonomic dysregulation

CMV, cytomegalovirus; EBV, Epstein-Barr virus; GH, growth hormone; GI, gastrointestinal; IBD, inflammatory bowel disease; VZV, varicella zoster virus.

Modified from Nambam B, Winter WE, Schatz DA: IgG4 antibodies in autoimmune polyglandular disease and IgG4-related endocrinopathies: pathophysiology and clinical characteristics. Curr Opin Pediatr 26:493–499, 2014, Table 1, p. 494 and Verbsky JW, Chatila TA: Immune dysregulation, polyendocrinopathy, enteropathy, X–linked (IPEX) and IPEX–related disorders: an evolving web of heritable autoimmune diseases. Curr Opin Pediatr 25:708–715, 2013, Table 1, p. 709.

Monogenic Autoimmune Polyglandular Syndromes

The number of recognized monogenic defects of immune regulatory mechanisms leading to APS has grown substantially in the past decade (see Table 586.1 ). The best-characterized monogenic APS are caused by mutations that primarily affect central immune tolerance (APS-1) or regulatory T cell development (immune dysregulation polyendocrinopathy enteropathy X-linked, or IPEX). Other monogenic APS (the so-called IPEX-like disorders) are due to defects in regulatory T cell suppression or signaling.

Autoimmune Polyglandular Syndrome Type 1

APS-1, the archetypal monogenic polyendocrinopathy syndrome, is caused by loss of function mutations in the autoimmune regulator gene (AIRE) on chromosome 21q22.3. AIRE plays a critical role in the presentation of self-antigens to developing T cells in the thymus, which normally leads to central immune tolerance by inducing apoptosis of T cells specific for these autoantigens (negative selection). AIRE also plays a role in the development of regulatory T cells (see Chapter 149 ). Therefore patients with APS-1 develop autoreactive T cells and autoantibodies directed at multiple tissues. APS-1 is a rare disorder but is more common in certain founder populations, including Iranian Jews, Sardinians, Finns, and Norwegians, with a reported prevalence ranging from 1 in 9,000 to 1 in 90,000. It is inherited in an autosomal recessive pattern, although sporadic and autosomal dominant cases have been reported. APS-1 is also referred to by the clinically descriptive name autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).

APS-1 is defined by the presence of at least 2 of the 3 primary clinical features (Whitaker's triad) of chronic mucocutaneous candidiasis, primary hypoparathyroidism and primary adrenal insufficiency. These three conditions tend to emerge over time—candidiasis before around 5 yr of age, hypoparathyroidism around 10 yr, and adrenal insufficiency around 15 yr—but the precise order and age of onset of each component are highly variable. Most patients develop additional autoimmune manifestations over time, with skin and gastrointestinal disorders tending to emerge before age 20 yr and other endocrine disorders after the 2nd decade (see Table 586.1 ). Sex, ancestry, and specific AIRE mutations may correlate with an increased risk for certain manifestations.

Nearly every endocrine gland may be affected by immune dysregulation in APS-1. The most commonly affected glands include the parathyroids and adrenals (about 80% each), with less frequent involvement of the gonads (ovarian insufficiency in 70% of females; testicular insufficiency in 30% of males), thyroid (20%), pancreatic beta-cells (10%), and pituitary (less than 5%). Nonendocrine autoimmunity affects a wide range of tissues and may appear before the first endocrinopathy is detected clinically. The most commonly affected tissues are the teeth and nails, with ectodermal dystrophy present the majority of patients (80%). Other affected tissues include the gastrointestinal tract (about 15% each for malabsorption, autoimmune hepatitis, and pernicious anemia), skin (vitiligo in 15%), and hair follicle (alopecia in 25%). APS-1 patients are at increased risk of infections, possibly related to a combination of cytokine autoantibodies, splenic dysfunction, and poor gut integrity. Mucocutaneous candidiasis is very common (70–100%) and can lead to esophageal cancer if not detected and treated. Esophageal cancer, autoimmune hepatitis, adrenal crisis, and severe hypocalcemia are important causes of mortality in APS-1 patients.

The diagnosis of APS-1 is generally made clinically. Patients with APS-1 should have regular screening for the development of new autoimmune manifestations. The importance of such screening is illustrated by reports of unexplained death in APS-1 patients or their siblings, presumably due to undiagnosed autoimmune manifestations (such as adrenal insufficiency). Multiple autoantibodies may be detectable in patients with APS-1 (Table 586.2 ). While some of these are also present in the corresponding single-organ autoimmune endocrinopathy (e.g., 21-hydroxylase autoantibodies in adrenal insufficiency), other antibodies are unique to APS-1. Moreover, the clinical utility of measuring organ-specific autoantibodies for predicting the onset of endocrine gland failure in APS-1 is variable. Therefore clinical suspicion, laboratory screening, and education about symptoms of evolving endocrinopathies and other autoimmune disease are paramount regardless of autoantibody status.

Table 586.2

Autoantibodies Present in Autoimmune Polyglandular Syndromes and in Isolated Autoimmune Endocrinopathies

TISSUE OR GLAND	AUTOANTIGEN	DISEASE MANIFESTATION	NOTE
AUTOIMMUNE ENDOCRINOPATHIES
Adrenal	CYP21A2, CYP11A1, CYP17A1	Primary adrenal insufficiency	Of the adrenal autoantibodies, CYP21A2 most strongly associated with adrenal insufficiency. Higher risk of progression to adrenal insufficiency in children with positive adrenal autoantibodies (over 80%) compared to adults (near 20%). Adrenal autoantibodies detected in 50% pediatric hypoparathyroidism and 1% pediatric type 1 diabetes mellitus.
Thyroid	TPO, Tg	Hashimoto thyroiditis (hypothyroidism)	Frequently positive without clinical thyroid disease
	TSHR	Graves disease (hyperthyroidism)	Only endocrine autoantibody that directly causes autoimmune endocrinopathy
Pancreatic beta cell	IA-2, GAD65, insulin, ZnT8	Type 1 diabetes mellitus	Risk of type 1 diabetes mellitus increases with the number of positive autoantibodies; IA-2, but not GAD65, autoantibodies associated with time to type 1 diabetes mellitus diagnosis in APS-1
Parathyroid	NALP5, CaSR	Hypoparathyroidism	NALP5 antibodies are present only in hypoparathyroidism due to APS-1
Gonad	CYP11A1, CYP17A1, NALP5, and TSGA10	Gonadal insufficiency	CYP11A1 antibodies associated with gonadal insufficiency in APS-1
Pituitary	TDRD6	Hypophysitis	Poorly predictive of clinical pituitary disease
NONENDOCRINE DISEASE
Cytokines	IFN-ω, IFN-α, IL-22, IL-17F	APS-1	IFN-ω autoantibodies are 100% sensitive and 99% specific for APS-1; IL-22 autoantibodies associated with time to diagnosis and diagnosis of candidiasis in APS-1
Gastric	IF, H+/K+ ATPase	Pernicious anemia, autoimmune gastritis	IF autoantibodies associated with time to B12 deficiency in APS-1
Small intestine	TTG, gliadin	Celiac disease
Gastrointestinal	TPH, GAD65	Intestinal dysfunction	TPH autoantibodies associated with time to intestinal dysfunction in APS-1. Both autoantibodies associated with diagnosis of intestinal dysfunction in APS-1.
Liver	CYP1A2, TPH, AADC	Autoimmune hepatitis	TPH autoantibodies associated with diagnosis of autoimmune hepatitis in APS-1
Skin melanocytes	Tyrosinase, SOX9, SOX10, AADC	Vitiligo
Hair follicle	Tyrosine hydroxylase	Alopecia
Lung	KCNRG, BPIFB1	Interstitial lung disease	Both autoantibodies present in 90–100% of APS-1 patients with interstitial lung disease, and are associated with time to diagnosis.

AADC, aromatic L-amino acid decarboxylase; BPIFB1, bactericidal/permeability-increasing fold-containing B1; CaSR, calcium sensing receptor; CYP11A1, side chain cleavage enzyme; CYP17A1, 17-α-hydroxylase; CYP1A2, cytochrome P450 1A2; CYP21A2, 21-hydroxylase; GAD65, glutamic acid decarboxylase; IA-2, islet antigen-2; IF, intrinsic factor; IFN, interferon; IL, interleukin; KCNRG, potassium channel-regulating protein; NALP5, NACHT leucine-rich-repeat protein 5; TDRD6, tudor domain containing protein 6; Tg, thyroglobulin; TPH, tryptophan hydroxylase; TPO, thyroid peroxidase; TSGA10, testis-specific gene 10 protein; TSHR, thyroid-stimulating hormone receptor; TTG, tissue transglutaminase; ZnT8, zinc transporter 8.

Three autoantibodies may eventually prove to have diagnostic value in APS-1, although they are not yet in clinical use. Autoantibodies to NALP5 are associated with hypoparathyroidism only in patients with APS-1 but not in isolated autoimmune or idiopathic hypoparathyroidism. Therefore patients with hypoparathyroidism and NALP5 antibodies should be further evaluated for APS-1. Autoantibodies to Th17 cytokines (especially interleukin-22 and interleukin-17F) are correlated with and may play a pathogenic role in APS-1 associated candidiasis. Autoantibodies to interferons (particularly interferon-ω and interferon-α) are present in virtually all patients with clinical APS-1 and are highly specific for the diagnosis, making this potentially an optimal diagnostic test for APS-1 itself. At present, confirmation of the diagnosis can be obtained by sequencing the AIRE gene, which is indicated for any patient with classic features, or an incomplete picture with supportive evidence. AIRE mutations can be detected by genetic testing in the majority of patients with clinical APS-1. Knowledge of the causative mutation facilitates genetic counseling and testing of family members.

Treatment of individual endocrinopathies, other autoimmune diseases, and associated infections are reviewed separately in the relevant chapters. Immunosuppression for the underlying immune dysregulation of APS-1 is problematic because of the coexistence of candidiasis and immunodeficiency, but this has been used in selected patients with specific autoimmune manifestations.

Immune Dysregulation-Polyendocrinopathy-Enteropathy X-Linked

IPEX is caused by loss-of-function mutations in the FOXP3 gene, which is located on the X-chromosome (Xp11.23) (see Chapter 152 ). The inactivation of FOXP3 results in impaired peripheral immune tolerance due to impaired development of regulatory T cells and the emergence of autoreactive T cells. The endocrinopathies most commonly associated with IPEX are early-onset type 1 diabetes mellitus and autoimmune thyroiditis. Any diagnosis of type 1 diabetes mellitus before 6-9 mo of age should prompt consideration of a monogenic APS or a genetic cause of beta-cell dysfunction. Patients with IPEX often have autoimmune enteropathy and eczematous dermatitis; they may also have other autoimmunity (e.g., liver, kidney, cytopenias) and allergic dysregulation (e.g., food allergy, peripheral eosinophilia). Therapy of IPEX consists of immune modulation with immunosuppressants (e.g., glucocorticoids, tacrolimus), novel therapeutics (e.g., abatacept), or stem cell transplantation.

Other Monogenic Immune Dysregulation Disorders

Several other disorders involve failure of peripheral tolerance and emergence of autoimmunity, often with some degree of immunodeficiency. These disorders include loss-of-function mutations in CD25 (IL2RA), LRBA , CTLA4 , STAT5b , and gain-of-function mutations in STAT1 that are pathophysiologically similar to IPEX. Broadly, patients with these IPEX-like disorders tend to be at high risk of type 1 diabetes mellitus and autoimmune thyroiditis (see Table 586.1 ). They also have multiple nonendocrine diseases, especially autoimmunity and immunodeficiency affecting the skin, lungs, and gastrointestinal tract. STAT5b participates in the IL2/STAT5 signal transduction axis necessary for growth hormone signaling, and may also affect prolactin secretion; therefore patients with STAT5b defects may have nonautoimmune growth hormone insensitivity and hyperprolactinemia in addition to immune dysregulation, hypergammaglobulinemia, and multiple autoimmunity. STAT1 gain-of-function mutations inhibit the normal production of Th17 cytokines, which leads to chronic mucocutaneous candidiasis. These patients also have increased risk of infection, squamous cell cancer, enteropathy, and arterial aneurysms. Patients with CD25 defects are also at increased risk of infection due to the role of IL-2 signaling in Th17 responses.

Polygenic Autoimmune Polyglandular Syndrome (APS-2)

APS-2 is a clinical syndrome defined by the presence of two or more syndrome-specific endocrinopathies: autoimmune primary adrenal insufficiency (Addison disease), autoimmune thyroid disease (Hashimoto thyroiditis or Graves disease) and/or type 1 diabetes mellitus. Some classification systems subdivide APS-2 according to the particular glands affected (e.g., subtype 2, 3, and 4 if adrenal, thyroid, or neither gland) or other autoimmune manifestations present (e.g., subtype 3A, 3B, and 3C if additional endocrine, gastrointestinal, or systemic autoimmunity). However, because there is no clear pathophysiological distinction between these subtypes, we consider them collectively as APS-2. Still, when describing the characteristics of APS-2, it is important to acknowledge some degree of overlap between patients with clinical APS-2 and those with a single clinical endocrinopathy but evidence of additional autoimmunity (such as autoantibodies) who may go on to be classified APS-2.

Unlike monogenic APS, which generally manifest by early childhood with a mendelian inheritance pattern, APS-2 usually becomes apparent after the 2nd decade in a patient with a personal history of autoimmune endocrinopathy and a family history of autoimmune disease. APS-2 is most common in middle-aged females (prevalence near 1 : 20,000). Primary gonadal insufficiency, vitiligo, alopecia, and chronic atrophic gastritis (with or without pernicious anemia) can occur, but autoimmune hypoparathyroidism and candidiasis are not typical of APS-2.

While Addison disease is uncommon (prevalence near 1 : 10,000), patients with this condition are at high risk of developing additional endocrine autoimmunity constituting APS-2, with evidence of additional subclinical or clinical autoimmunity reported in up to two thirds. About half of patients with Addison disease have comorbid autoimmune thyroid disease (Schmidt syndrome), and 15% have type 1 diabetes mellitus (Carpenter syndrome). Other autoimmune manifestations each affecting 5–10% of patients include Graves disease, ovarian insufficiency, alopecia, vitiligo, pernicious anemia, or positive celiac autoantibodies. APS-2 develops less frequently in patients with type 1 diabetes mellitus than in those with Addison disease, but additional autoimmunity is still frequent. In these patients, autoimmune thyroid disease and gastrointestinal autoimmunity (each in about 20% of patients) are much more common than comorbid adrenal disease (in <1%). Because thyroxine and cortisol affect insulin sensitivity, metabolism, and appetite, unexplained hypoglycemia or deterioration in glycemic control may be the first clinical sign of APS-2 in a patient with preexisting type 1 diabetes mellitus. Unexplained hypoglycemia may also signal the onset of celiac disease. Indeed, celiac disease often precedes the onset of autoimmune endocrinopathies including type 1 diabetes mellitus, hypothyroidism, and Addison disease.

The development of APS-2 among those with isolated autoimmune thyroid disease is relatively infrequent. Nevertheless, the clinician should consider the possibility of adrenal insufficiency prior to treating autoimmune primary hypothyroidism in a patient with features suggestive of APS-2, as thyroid hormone replacement may precipitate adrenal crisis in this setting. As in APS-1, autoantibodies to specific tissues may be detectable and may prompt functional screening prior to the onset of overt clinical disease (see Table 586.2 ); however, the predictive value of these autoantibodies for the development of clinical disease is variable.

Aberrant T cell responses likely play a role in pathogenesis of multiple gland destruction seen in APS-2. Risk of autoimmunity directed against the adrenal glands, thyroid gland, and islet cells appears to be shared across certain human leukocyte antigen (HLA) haplotypes and other immune-related genetic loci, though the magnitude of this risk varies substantially for each endocrinopathy. The prevalence of HLA-D3 and HLA-D4 alleles is increased in patients with APS-2, and they appear to confer an increased risk for development of this disease. Particular alleles of the major histocompatibility complex class I chain–related genes A and B (MICA and MICB) also are associated with APS-2. Polymorphisms in other genes (e.g., PTPN22 , CTLA4 ) have been associated with individual autoimmune endocrinopathies that constitute APS-2, but the contribution of these genes to the pathogenesis of APS-2 itself is uncertain. Although not well defined, there are also likely environmental factors that predispose to or promote the development of autoimmunity in genetically susceptible individuals, and many of the risk factors associated with endocrine and nonendocrine autoimmunity overlap (see individual chapters on these diseases for more detailed discussions of risk factors).

Chromosomal Abnormalities Associated With Autoimmune Polyglandular Syndrome

Many genetic syndromes involving chromosomal deletions, duplications, and other copy number variations are associated with an increased risk of autoimmunity, and especially endocrine autoimmunity affecting the thyroid and pancreatic beta cells (see Table 586.1 ). These include Turner syndrome, Klinefelter syndrome, DiGeorge (22q11.2 deletion) syndrome, and trisomy 21. Males with Klinefelter syndrome and females with Turner syndrome have an increased risk of autoimmunity in multiple systems, including autoimmune endocrine disease. The mechanism of autoimmunity in trisomy 21 remains unclear, although differences in AIRE gene expression, HLA-susceptibility, and autoantibody profiles have been described. Thymic dysplasia is a typical feature of DiGeorge syndrome, and the resulting immune dysregulation may play a role in the increased risk of autoimmunity in this disorder. Patients with genetic syndromes and chromosomal abnormalities may have nonautoimmune endocrinopathies such as abnormal growth, primary gonadal failure, and primary hypoparathyroidism.

Mitochondrial disease has been rarely associated with autoimmune endocrinopathy/polyendocrinopathy syndromes. Kearns-Sayre syndrome (progressive external ophthalmoplegia, retinal pigmentation, cardiac conduction defects) has been associated with autoimmune thyroid, adrenal disease, and diabetes. Other mitochondrial gene mutations including MELAS (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes) are associated with single endocrine disorders such as gonadal failure, hypogonadism, hypoparathyroidism, Addison disease, and type 1 diabetes mellitus.

Nongenetic Autoimmune Causes of Multiple Endocrinopathy

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD ) is a rare pediatric syndrome diagnosed by its cardinal clinical features. ROHHAD usually presents with rapid weight gain in a previously healthy child (age of onset between 1 and 9 yr). The clinical picture evolves to include autonomic deficits (e.g., ophthalmologic findings, gastrointestinal dysmotility, thermal dysregulation, bradycardia), central hypoventilation, and variable hypothalamic dysfunction that may include central hypothyroidism, growth hormone deficiency, hyperprolactinemia, or hyponatremia (Chapter 60.1 ). The hypothesis that ROHHAD has an autoimmune paraneoplastic etiology is supported by the presence of markers of immune-mediated injury, its response to immunosuppressive therapy in some patients, and its association with neuroendocrine tumors (NETs). However, such tumors are present in only 40% of patients and tumor removal may not affect disease progression. To date, a genetic cause of ROHHAD has not been discovered.

Novel immune-modulating biological compounds are used increasingly in the treatment of malignancies and immune disorders. Antitumor drugs that inhibit immune checkpoints such as CLTA4, PD1, and PDL1 are associated with acute onset of multiple autoimmune endocrinopathies including hypophysitis with hypopituitarism, type 1 diabetes mellitus, primary adrenal insufficiency, and thyroiditis. Anti-CD52 antibodies used in the treatment of multiple sclerosis have been linked to the development of Graves disease and other antibody-mediated autoimmune diseases (e.g., immune thrombocytopenic purpura). Preexisting autoimmunity may be a risk factor for developing autoimmune disease after exposure to a wide range of immunomodulatory therapies.

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