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Autoimmune Polyendocrine Syndromes

Chapter 401 | Part 12: Endocrinology and Metabolism · Part 12 – Endocrinology & Metabolism

Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition

🔑 Key Clinical Points

  1. APS-1 (APECED) is caused by AIRE gene mutations (chromosome 21), autosomal recessive, onset in infancy.
  2. APS-2 is polygenic (HLA-DR3/DR4), onset in adulthood (20-60 years), females > males (3:1).
  3. APS-1 Diagnosis: Two of three major components (Candidiasis, Hypoparathyroidism, Addison's) + AIRE mutation or anti-interferon antibodies.
  4. APS-2 Diagnosis: Two or more endocrine deficiencies (Addison's, Thyroid, T1DM, Gonadal).
  5. Adrenal insufficiency in APS-1/2 can be masked by primary hypothyroidism; treat adrenal before thyroid hormone.
  6. Hypocalcemia in APS-2 is more likely due to malabsorption (celiac) than hypoparathyroidism.
  7. ICI-induced T1D is permanent and requires lifelong insulin; onset is rapid with DKA.
  8. IPEX (FOXP3 mutation) requires hematopoietic stem cell transplantation for cure.
  9. POEMS syndrome median survival <3 years; treat with lenalidomide/thalidomide.
  10. Anti-21-hydroxylase antibodies confirm Addison's risk in APS-1/2.
  11. Anti-interferon alpha/omega antibodies identify nearly 100% of APS-1 cases.

📑 Table of Contents

1. DEFINITION & OVERVIEW

Autoimmune polyendocrine syndromes (APS) are a group of disorders characterized by the presence of multiple autoimmune endocrine deficiencies. They are divided into two major categories: APS type 1 (APS-1) and APS type 2 (APS-2). Some groups further subdivide APS-2 into APS-3 and APS-4 depending on the type of autoimmunity involved. These syndromes often include nonendocrine disease associations.

1.1 APS-1 (Autoimmune Polyendocrinopathy–Candidiasis–Ectodermal Dystrophy)

APS-1, also called autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), is a rare autosomal recessive disorder caused by mutations in the AIRE gene (autoimmune regulator gene) found on chromosome 21. The classical form develops very early in life, often in infancy. The three major components are mucocutaneous candidiasis, hypoparathyroidism, and Addison's disease. Many other organ systems can be involved over time.

Table 1 — Table 401-1 Disease Associations with Autoimmune Polyendocrine Syndromes

Syndrome Type 1 Syndrome Type 2 Other Autoimmune Polyendocrine Disorders
Addison's disease Addison's disease Thymic tumors
Hypoparathyroidism Type 1 diabetes Anti-insulin receptor antibodies
Hypogonadism Graves' disease or autoimmune thyroiditis POEMS syndrome
Graves' disease or autoimmune thyroiditis Hypogonadism Insulin autoimmune syndrome (Hirata's syndrome)
Type 1 diabetes Adult combined pituitary hormone deficiency (CPHD) with anti-Pit1 autoantibodies Kearns-Sayre syndrome
Celiac disease, dermatitis herpetiformis DIDMOAD syndrome
Pernicious anemia Nonendocrine associated with thyroiditis
Vitiligo Congenital rubella
Alopecia Myasthenia gravis
IgA deficiency Idiopathic thrombocytopenia
Parkinson's disease Asplenism

1.2 APS-2

APS-2 (OMIM 269200) is more common than APS-1, with a prevalence of 1–2 in 100,000. It has a gender bias and occurs more often in female patients, with a ratio of at least 3:1 compared to male patients. In contrast to APS-1, APS-2 often has its onset in adulthood, with a peak incidence between 20 and 60 years of age. It shows a familial, multigenerational heritage. The presence of two or more of the following endocrine deficiencies in the same patient defines the presence of APS-2: primary adrenal insufficiency (Addison's disease; 50–70%), Graves' disease or autoimmune thyroiditis (15–69%), type 1 diabetes mellitus (T1D; 40–50%), and primary hypogonadism.

Table 2 — Table 401-2 Comparison of APS-1 and APS-2

Feature APS-1 APS-2
Onset Early onset: infancy Later onset
Inheritance Monogenic: AIRE gene, chromosome 21, autosomal recessive Polygenic: HLA, MICA, PTNP22, CTLA4
Sex Distribution Equivalent sex distribution Females > males affected
Autoantibodies Autoantibodies to type 1 interferons and IL-17 and IL-22 Autoantibodies to specific target organs
Nonendocrine Associations Mucocutaneous candidiasis, Ectodermal dysplasia, IgA deficiency, Asplenism, Malabsorption syndromes Celiac disease, Dermatitis herpetiformis, Pernicious anemia, Vitiligo, Alopecia, Myasthenia gravis, Idiopathic thrombocytopenia, Parkinson's disease, Serositis, Stiff man syndrome, IgA deficiency, Myocarditis, Hypophysitis, Cerebellar ataxia, Chronic inflammatory demyelinating polyneuropathy, Idiopathic heart block, Serositis, Stiff man syndrome, Vitiligo

1.3 IPEX Syndrome

Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked disease (IPEX; OMIM 304790) is a rare X-linked recessive disorder. The disease onset is in infancy and is characterized by severe enteropathy, T1D, and skin disease, as well as variable association with several other autoimmune disorders. Many infants die within the first days of life, but the course is variable, with some children surviving for 12–15 years. IPEX is caused by mutations in the FOXP3 gene, which is also mutated in the Scurfy mouse. The FOXP3 transcription factor is expressed in regulatory T cells designated CD4+CD25+FOXP3+ (Treg). Lack of this factor causes a profound deficiency of this Treg population and results in rampant autoimmunity due to the lack of peripheral tolerance normally provided by these cells.

Table 3 — Table 401-4 APS-2 and Other Polyendocrine Disorder Associations

Disease HLA Association Initiating Factor Mechanism Autoantigen
Graves' disease DR3 Iodine Antibody TSH receptor
Myasthenia gravis DR3, DR7 Thymoma Antibody Acetylcholine receptor
Penicillamine ? SLE or other autoimmune disease Antibody Insulin receptor
Insulin autoimmune syndrome DR4, DRB1*0406 Methimazole Antibody Insulin
Celiac disease DQ2/DQ8 Gluten diet T cell Transglutaminase
Type 1 diabetes DR3/DR4 ? T cell Insulin, GAD65, IA-2, ZnT8, IGRP
Addison's disease DR3/DR4 Unknown T cell 21-Hydroxylase
Thyroiditis DR3/DQB1*0201 Iodine T cell Thyroglobulin
Vitiligo ? Melanoma Antigen Immunization ? Melanocyte
Hypophysitis ? Pit-1, TDRD6 ? Pituitary, Pit-1

2. EPIDEMIOLOGY

APS-1 is rare, with <500 cases reported in the literature. APS-2 has a prevalence of 1–2 in 100,000. APS-1 incidence rates for many disorders peak in the first or second decade of life. APS-2 shows a familial, multigenerational heritage. The presence of two or more endocrine deficiencies defines APS-2. The overwhelming risk factor for APS-2 has been localized to the genes in the human lymphocyte antigen (HLA) complex on chromosome 6. Primary adrenal insufficiency in APS-2, but not APS-1, is strongly associated with both HLA-DR3 and HLA-DR4.

2.1 APS-1 Epidemiology

APS-1 is rare, with <500 cases reported in the literature. The disease associations found in APS-1 and APS-2 are summarized in Table 401-1. Understanding these syndromes and their disease manifestations can lead to early diagnosis and treatment of additional disorders in patients and their family members. Siblings of individuals with APS-1 should be considered affected even if only one component disorder has been detected due to the known inheritance of the syndrome.

2.2 APS-2 Epidemiology

APS-2 is more common than APS-1, with a prevalence of 1–2 in 100,000. It has a gender bias and occurs more often in female patients, with a ratio of at least 3:1 compared to male patients. In contrast to APS-1, APS-2 often has its onset in adulthood, with a peak incidence between 20 and 60 years of age. It shows a familial, multigenerational heritage. The presence of two or more of the following endocrine deficiencies in the same patient defines the presence of APS-2: primary adrenal insufficiency (Addison's disease; 50–70%), Graves' disease or autoimmune thyroiditis (15–69%), type 1 diabetes mellitus (T1D; 40–50%), and primary hypogonadism.

3. ETIOLOGY & PATHOPHYSIOLOGY

APS-1 is an autosomal recessive disorder caused by mutations in the AIRE gene (autoimmune regulator gene) found on chromosome 21. This gene is most highly expressed in thyroid medullary epithelial cells (mTECs) where it controls the expression of tissue-specific self-antigens (e.g., insulin). Deletion of this regulator leads to decreased expression of tissue-specific self-antigens and is hypothesized to allow autoreactive T cells to avoid central deletion, which normally occurs during T-cell maturation in the thymus. The AIRE gene is also expressed in epithelial cells found in peripheral lymphoid organs, but its role in these extrathymic cells remains controversial. To date, >100 mutations have been described in this gene, and there is a higher frequency within certain ethnic groups including Iranian Jews, Sardinians, Finns, Norwegians, and Irish. Recently, several autosomal dominant mutations have been identified and are localized primarily in the PHD1 domain of the AIRE gene, rather than the CARD region, where the autosomal recessive mutations have been found. Individuals with this nonclassical form of APS-1 may have a later onset of symptoms and less aggressive disease, without the full spectrum of autoimmune components being expressed.

3.1 APS-2 Pathophysiology

The overwhelming risk factor for APS-2 has been localized to the genes in the human lymphocyte antigen (HLA) complex on chromosome 6. Primary adrenal insufficiency in APS-2, but not APS-1, is strongly associated with both HLA-DR3 and HLA-DR4. Other class I and class II genes and alleles, such as HLA-B8, HLA-DQ2 and HLA-DQ8, and HLA-DR subtypes such as DRB1*04:04, appear to contribute to organ-specific disease susceptibility. HLA-B8- and HLA-DR3-associated illnesses include selective IgA deficiency, juvenile dermatomyositis, dermatitis herpetiformis, alopecia, scleroderma, autoimmune thrombocytopenia purpura, hypophysitis, metaphyseal osteopenia, and serositis. Several other immune genes have been proposed to be associated with Addison's disease and therefore with APS-2. The "5.1" allele of a major histocompatibility complex (MHC) gene is an atypical class I HLA molecule MIC-A. The MIC-A5.1 allele has a very strong association with Addison's disease that is not accounted for by linkage disequilibrium with DR3 or DR4. Its role is complicated because certain HLA class I genes can offset this effect. PTPN22 codes for a polymorphism in a protein tyrosine phosphatase, which acts on intracellular signaling pathways in both T and B lymphocytes. It has been implicated in T1D, Addison's disease, and other autoimmune conditions. CTLA4 is a receptor on the T-cell surface that modulates the activation state of the cell as part of the signal 2 pathway (i.e., binding to CD80/86 on antigen presenting cells). Polymorphisms of this gene appear to cause downregulation of the cell surface expression of the receptor, leading to decreased T-cell activation and proliferation. This appears to contribute to Addison's disease and potentially other components of APS-2. Allelic variants of the IL-2Rα are linked to development of T1D and autoimmune thyroid disease and could contribute to the phenotype of APS-2 in certain individuals.

3.2 IPEX Pathophysiology

IPEX is caused by mutations in the FOXP3 gene, which is also mutated in the Scurfy mouse, an animal model that shares much of the same phenotype of IPEX patients. The FOXP3 transcription factor is expressed in regulatory T cells designated CD4+CD25+FOXP3+ (Treg). Lack of this factor causes a profound deficiency of this Treg population and results in rampant autoimmunity due to the lack of peripheral tolerance normally provided by these cells. Certain mutations may lead to varying forms of expression of the full syndrome, and there are rare cases where the FOXP3 gene is intact but other genes involved in this pathway (e.g., CD25, IL-2Rα) may be causative.

3.3 Other Genetic Associations

Wolfram's syndrome (OMIM 222300, chromosome 4; OMIM 598500, mitochondrial) is a rare autosomal recessive disease that is also called DIDMOAD. The disease is caused by defects in the Wolfram syndrome 1 (WFS1) gene, which encodes a 100-kDa transmembrane protein that has been localized to the endoplasmic reticulum and is found in neuronal and neuroendocrine tissue. Its expression induces ion channel activity with a resultant increase in intracellular calcium and may play an important role in intracellular calcium homeostasis. Down's syndrome, or trisomy 21 (OMIM 190685), is associated with the development of T1D, thyroiditis, and celiac disease. Patients with Turner's syndrome also appear to be at increased risk for the development of thyroid disease and celiac disease.

4. CLINICAL FEATURES

Clinical manifestations vary by syndrome type. APS-1 classical form develops very early in life, often in infancy. Chronic mucocutaneous candidiasis without signs of systemic disease is often the first manifestation. It affects the mouth and nails more frequently than the skin and esophagus. Chronic oral candidiasis can result in atrophic areas suggestive of leukoplakia, which can pose a risk for future carcinoma. The etiology is associated with anticytokine autoantibodies (anti-interleukin [IL] 17A, IL-17F, and IL-22) related to T helper (Th) 17 T cells and depressed production of these cytokines by peripheral blood mononuclear cells. Hypoparathyroidism usually develops next, followed by adrenal insufficiency. The time from development of one component of the disorder to the next can be many years, and the order of disease appearance is variable. Other endocrine disorders that occur less frequently include type 1 diabetes (23%) and autoimmune thyroid disease (18%). Nonendocrine manifestations that present less frequently include alopecia (40%), vitiligo (26%), intestinal malabsorption (18%), pernicious anemia (31%), chronic active hepatitis (17%), and nail dystrophy. An unusual and debilitating manifestation of the disorder is the development of Addison's disease refractory diarrhea/obstipation that may be related to autoantibody-mediated destruction of enterochromaffin or enterochromaffin-like cells. The incidence rates for many of these disorders peak in the first or second decade of life, but the individual disease components continue to emerge over time. Therefore, prevalence rates may be higher than originally reported.

4.1 APS-1 Clinical Features

Chronic mucocutaneous candidiasis is nearly always present and is not very responsive to treatment. Hypoparathyroidism is found in >85% of cases, and Addison's disease is found in nearly 80%. Gonadal failure appears to affect women more than men (70 vs 25%, respectively), and hypoplasia of the dental enamel also occurs frequently (77% of patients). Specific physical examination findings of hyperpigmentation, vitiligo, alopecia, tetany, and signs of hyper- or hypothyroidism should be considered as signs of development of component disorders. The development of disease-specific autoantibody assays can help confirm disease and also detect risk for future disease. For example, where possible, detection of anticytokine antibodies to IL-17 and IL-22 would confirm the diagnosis of mucocutaneous candidiasis due to APS-1. The presence of anti-21-hydroxylase antibody or anti-17-hydroxylase antibody (which may be found more commonly in adrenal insufficiency associated with APS-1) would confirm the presence or risk for Addison's disease. Other autoantibodies found in type 1 diabetes (e.g., anti-GAD65), pernicious anemia, and other component conditions should be screened for on a regular basis (6- to 12-month intervals depending on the age of the subject). Myocarditis, Serositis, Stiff man syndrome, Idiopathic heart block, Myasthenia gravis, Cerebellar ataxia, Chronic inflammatory demyelinating polyneuropathy, Hypophysitis, IgA deficiency, Vitiligo, Alopecia, Parkinson's disease, Asplenism, Malabsorption syndromes, Pernicious anemia, Splenic atrophy, Type 1 diabetes, Ovarian failure, Obstipation, Hypothyroidism/Graves' disease, Hepatitis, Hypoparathyroidism, Ectodermal dysplasia, Diarrhea, Addison's disease are all potential features.

4.2 APS-2 Clinical Features

APS-2 often has its onset in adulthood, with a peak incidence between 20 and 60 years of age. It shows a familial, multigenerational heritage. The presence of two or more of the following endocrine deficiencies in the same patient defines the presence of APS-2: primary adrenal insufficiency (Addison's disease; 50–70%), Graves' disease or autoimmune thyroiditis (15–69%), type 1 diabetes mellitus (T1D; 40–50%), and primary hypogonadism. Frequently associated autoimmune conditions include celiac disease (3–15%), myasthenia gravis, vitiligo, alopecia, serositis, and pernicious anemia. These conditions occur with increased frequency in affected patients but are also found in their family members. The development of a rarer form of autoimmunity, such as Addison's disease, should prompt more extensive screening for other linked disorders, as ~50% of Addison's disease patients develop another autoimmune disease during their lifetime.

4.3 ICI-Induced Endocrine Autoimmunity

Therapies that block immune checkpoints, such as programmed cell death protein 1 (PD-1), its ligand (PD-L1), or CTLA-4, are beneficial immunotherapies for many advanced-stage cancers. These immune checkpoint inhibitors (ICIs) block negative immune regulation, thereby allowing for an immune response directed against tumor cells. However, immune-related adverse events also occur, especially autoimmunity directed toward self-tissues. ICI-induced T1D, thyroid disease, hypophysitis, and adrenal insufficiency have all been reported with these therapies and in combination. Hypothyroidism occurs in ~10% and T1D in 1–2% of those receiving monoclonal anti-CD3 monoclonal antibody, to delay the clinical onset of diabetes. These autoimmune side effects can develop during or after therapy, mostly within a few weeks to months following the start of therapy. ICI-induced T1D has a very rapid onset, presents with diabetic ketoacidosis, is permanent, and requires lifelong exogenous insulin therapy for treatment. There is a strong genetic association, with HLA-DR4 being present in ~70% of patients, and islet autoantibodies may be present at diagnosis. The pathogenesis is immune mediated as T lymphocyte infiltration has been documented in the pancreatic islets of an ICI-T1D patient.

4.4 Other Syndromes

POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes; also known as Crow-Fukase syndrome; OMIM 192240) patients usually present with a progressive sensorimotor polyneuropathy, diabetes mellitus (50%), primary gonadal failure (70%), and a plasma cell dyscrasia with sclerotic bony lesions. Associated findings can be hepatosplenomegaly, lymphadenopathy, and hyperpigmentation. Patients often present in the fifth to sixth decade of life and have a median survival after diagnosis of 100,000 units of insulin to be given daily with only partial control of hyperglycemia. Patients can also have severe hypoglycemia due to partial activation of the insulin receptor by the antibody. The course of the disease is variable, and several patients have had spontaneous remissions. A therapeutic approach that targets B lymphocytes, including rituximab, cyclophosphamide, and pulse steroids, has been validated in follow-on case reports to induce remission of the disease.

5. DIFFERENTIAL DIAGNOSIS

Differential diagnosis is based on the specific component disorders and the presence of autoantibodies. For APS-1, the differential includes other causes of mucocutaneous candidiasis, hypoparathyroidism, and Addison's disease. For APS-2, the differential includes sporadic Addison's disease, sporadic T1D, sporadic autoimmune thyroid disease, and sporadic gonadal failure. IPEX must be distinguished from other causes of early-onset T1D and enteropathy. Thymoma must be distinguished from other causes of myasthenia gravis. Insulin autoimmune syndrome must be distinguished from other causes of hypoglycemia. POEMS syndrome must be distinguished from other causes of polyneuropathy and organomegaly.

5.1 APS-1 Differential

Differential diagnosis for the components of APS-1 includes: Chronic mucocutaneous candidiasis (other immunodeficiencies), Hypoparathyroidism (genetic causes, parathyroidectomy), Addison's disease (adrenal hemorrhage, tuberculosis, other autoimmune causes). The presence of anti-interferon α and anti–interferon ω antibodies can identify nearly 100% of cases with APS-1, distinguishing it from other causes of these component disorders.

5.2 APS-2 Differential

Differential diagnosis for the components of APS-2 includes: Addison's disease (adrenal hemorrhage, tuberculosis, other autoimmune causes), Graves' disease or autoimmune thyroiditis (iodine-induced, drug-induced), Type 1 diabetes (idiopathic, other genetic syndromes), Primary hypogonadism (Kallmann syndrome, other genetic causes). The presence of two or more of the following endocrine deficiencies in the same patient defines the presence of APS-2, distinguishing it from sporadic autoimmune endocrine diseases.

5.3 IPEX Differential

Differential diagnosis for IPEX includes: Other causes of early-onset T1D, other causes of severe enteropathy, other causes of skin disease. The presence of FOXP3 mutation confirms the diagnosis. The disease onset is in infancy and is characterized by severe enteropathy, T1D, and skin disease, as well as variable association with several other autoimmune disorders.

6. INVESTIGATIONS & DIAGNOSIS

Diagnosis of APS-1 is usually made clinically when autoantibodies to two of the three major component disorders are found in an individual patient. Genetic analysis of the AIRE gene should be undertaken to identify mutations. Detection of anti–interferon α and anti–interferon ω antibodies can identify nearly 100% of cases with APS-1. The autoantibody arises independent of the type of AIRE gene mutation and is not found in other autoimmune disorders. Diagnosis of each underlying disorder should be done based on their typical clinical presentations. Laboratory tests, including a complete metabolic panel, phosphorous and magnesium, thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH; morning), hemoglobin A1c, plasma vitamin B12 level, and complete blood count with peripheral smear looking for Howell-Jolly bodies (asplenism), should also be performed at these time points. Detection of abnormal physical findings or test results should prompt subsequent examinations of the relevant organ system (e.g., presence of Howell-Jolly bodies indicates need for ultrasound of spleen).

6.1 APS-1 Diagnostic Workup

Diagnosis of APS-1 is usually made clinically when autoantibodies to two of the three major component disorders are found in an individual patient. Siblings of individuals with APS-1 should be considered affected even if only one component disorder has been detected due to the known inheritance of the syndrome. Genetic analysis of the AIRE gene should be undertaken to identify mutations. Detection of anti–interferon α and anti–interferon ω antibodies can identify nearly 100% of cases with APS-1. The autoantibody arises independent of the type of AIRE gene mutation and is not found in other autoimmune disorders. Diagnosis of each underlying disorder should be done based on their typical clinical presentations (Table 401-3). Mucocutaneous candidiasis may present throughout the gastrointestinal tract, and it may be detected in the oral mucosa or from stool samples. Evaluation by a gastroenterologist to examine the esophagus for candidiasis or secondary stricture may be merited based on symptoms. Other gastrointestinal manifestations of APS-1, including malabsorption and obstipation, may also bring these young patients to the attention of gastroenterologists for first evaluation. Specific physical examination findings of hyperpigmentation, vitiligo, alopecia, tetany, and signs of hyper- or hypothyroidism should be considered as signs of development of component disorders. The development of disease-specific autoantibody assays can help confirm disease and also detect risk for future disease. For example, where possible, detection of anticytokine antibodies to IL-17 and IL-22 would confirm the diagnosis of mucocutaneous candidiasis due to APS-1. The presence of anti-21-hydroxylase antibody or anti-17-hydroxylase antibody (which may be found more commonly in adrenal insufficiency associated with APS-1) would confirm the presence or risk for Addison's disease. Other autoantibodies found in type 1 diabetes (e.g., anti-GAD65), pernicious anemia, and other component conditions should be screened for on a regular basis (6- to 12-month intervals depending on the age of the subject).

Component Disease Recommended Evaluation (APS-1) Recommended Evaluation (APS-2)
Addison's disease Sodium, potassium, ACTH, cortisol, 21- and 17-hydroxylase autoantibodies 21-Hydroxylase autoantibodies, ACTH stimulation testing if positive
Diarrhea History History
Ectodermal dysplasia Physical examination Physical examination
Hypoparathyroidism Serum calcium, phosphate, PTH Serum calcium, phosphate, PTH
Hepatitis Liver function tests Liver function tests
Hypothyroidism/Graves' disease TSH; thyroid peroxidase and/or thyroglobulin autoantibodies and anti-TSH receptor Ab TSH; thyroid peroxidase and/or thyroglobulin autoantibodies, anti-TSH receptor Ab
Male hypogonadism FSH/LH, testosterone FSH/LH, testosterone
Malabsorption Physical examination, anti-IL-17 and anti-IL-22 autoantibodies Physical examination, anti-IL-17 and anti-IL-22 autoantibodies
Mucocutaneous candidiasis Physical examination, mucosal swab, stool samples Physical examination, mucosal swab, stool samples
Obstipation History History
Ovarian failure FSH/LH, estradiol FSH/LH, estradiol
Pernicious anemia CBC, vitamin B12 levels Anti–parietal cell autoantibodies; CBC, vitamin B12 levels if positive
Splenic atrophy Blood smear for Howell-Jolly bodies; platelet count; ultrasound if positive Blood smear for Howell-Jolly bodies; platelet count; ultrasound if positive
Type 1 diabetes Glucose, hemoglobin A1c, diabetes-associated autoantibodies (insulin, GAD65, IA-2, ZnT8) Glucose, hemoglobin A1c, diabetes-associated autoantibodies (insulin, GAD65, IA-2, ZnT8)
Alopecia Physical examination Physical examination
Autoimmune hyper- or hypothyroidism TSH; thyroid peroxidase and/or thyroglobulin autoantibodies, anti-TSH receptor Ab TSH; thyroid peroxidase and/or thyroglobulin autoantibodies, anti-TSH receptor Ab
Celiac disease Transglutaminase autoantibodies; small intestine biopsy if positive Transglutaminase autoantibodies; small intestine biopsy if positive
Cerebellar ataxia Dictated by signs and symptoms of disease Dictated by signs and symptoms of disease
Chronic inflammatory demyelinating polyneuropathy Dictated by signs and symptoms of disease Dictated by signs and symptoms of disease
Hypophysitis Dictated by signs and symptoms of disease, anti-Pit1 autoantibody Dictated by signs and symptoms of disease, anti-Pit1 autoantibody
Idiopathic heart block Dictated by signs and symptoms of disease Dictated by signs and symptoms of disease
IgA deficiency IgA level IgA level
Myasthenia gravis Dictated by signs and symptoms of disease, antiacetylcholinesterase Ab Dictated by signs and symptoms of disease, antiacetylcholinesterase Ab
Myocarditis Dictated by signs and symptoms of disease Dictated by signs and symptoms of disease
Serositis Dictated by signs and symptoms of disease Dictated by signs and symptoms of disease
Stiff man syndrome Dictated by signs and symptoms of disease Dictated by signs and symptoms of disease
Vitiligo Physical examination, NALP-1 polymorphism Physical examination, NALP-1 polymorphism

6.2 APS-2 Diagnostic Workup

Diagnosis of APS-2 is based on the presence of two or more of the following endocrine deficiencies in the same patient: primary adrenal insufficiency (Addison's disease; 50–70%), Graves' disease or autoimmune thyroiditis (15–69%), type 1 diabetes mellitus (T1D; 40–50%), and primary hypogonadism. Circulating autoantibodies, as previously discussed, can precede the development of clinical disease by many years but would allow the clinician to follow the patient and identify the disease onset at its earliest time point (Tables 401-3 and 401-4). For each of the endocrine components of the disorder, appropriate autoantibody assays are listed and, if positive, should prompt physiologic testing to diagnose clinical or subclinical disease. For Addison's disease, antibodies to 21-hydroxylase antibodies are highly diagnostic for risk of adrenal insufficiency. Screening of 21-hydroxylase antibody–positive patients can be performed measuring morning ACTH and cortisol on a yearly basis. Rising ACTH values over time or low morning cortisol in association with signs or symptoms of adrenal insufficiency should prompt testing via the cosyntropin stimulation test (Chap. 398). T1D can be screened for by measuring autoantibodies directed against insulin, GAD65, IA-2, and ZnT8. Risk for progression to disease is based on the number of antibodies (≥2 islet autoantibodies with normal glucose tolerance is now defined as stage 1 of T1D as the lifetime risk for developing clinical symptoms is nearly 100%) and metabolic factors (impaired oral glucose tolerance test). Many efforts are ongoing and underway to screen relatives of T1D patients and those in the general population for islet autoantibodies to identify individuals with preclinical disease who may elect to have treatment with teplizumab, to delay the clinical onset of diabetes. Screening tests for thyroid disease can include anti–thyroid peroxidase (TPO) or anti-thyroglobulin autoantibodies or anti-TSH receptor antibodies for Graves' disease. Yearly measurements of TSH can then be used to follow these individuals. Celiac disease can be screened for using the anti–tissue transglutaminase (tTg) antibody test. For those <20 years of age, testing every 1–2 years should be performed, whereas less frequent testing is indicated after the age of 20 because the majority of individuals who develop celiac disease have the antibody earlier in life. Positive tTg antibody test results should be confirmed on repeat testing, followed by small-bowel biopsy to document pathologic changes of celiac disease. Many patients have asymptomatic celiac disease that is nevertheless associated with osteopenia and impaired growth. If left untreated, symptomatic celiac disease has been reported to be associated with an increased risk of gastrointestinal malignancy, especially lymphoma, and osteoporosis later in life. A complete history and physical examination should be performed every 1–3 years including complete blood count, metabolic panel, TSH, and vitamin B12 levels to screen for most of the possible abnormalities. More specific tests should be based on specific findings from the history and physical examination.

6.3 IPEX Diagnostic Workup

Diagnosis of IPEX is based on the presence of severe enteropathy, T1D, and skin disease, as well as variable association with several other autoimmune disorders. Many infants die within the first days of life, but the course is variable, with some children surviving for 12–15 years. Early onset of T1D, often at birth, is highly suggestive of the diagnosis because nearly 80% of IPEX patients develop T1D. Although treatment of the individual disorders can temporarily improve the situation, treatment of the underlying immune deficiency is required and includes immunosuppressive therapy generally followed by hematopoietic stem cell transplantation. Transplantation is the only life-saving form of therapy and can be fully curative by normalizing the imbalanced immune system found in this disorder. IPEX is caused by mutations in the FOXP3 gene, which is also mutated in the Scurfy mouse, an animal model that shares much of the same phenotype of IPEX patients. The FOXP3 transcription factor is expressed in regulatory T cells designated CD4+CD25+FOXP3+ (Treg). Lack of this factor causes a profound deficiency of this Treg population and results in rampant autoimmunity due to the lack of peripheral tolerance normally provided by these cells. Certain mutations may lead to varying forms of expression of the full syndrome, and there are rare cases where the FOXP3 gene is intact but other genes involved in this pathway (e.g., CD25, IL-2Rα) may be causative.

7. MANAGEMENT & TREATMENT

Treatment of individual disease components is carried out as outlined in other relevant chapters. Replacement of deficient hormones (e.g., adrenal, pancreas, ovaries/testes) will treat most of the endocrinopathies noted. Several unique issues merit special emphasis. Adrenal insufficiency can be masked by primary hypothyroidism by prolonging the half-life of cortisol. The caveat therefore is that replacement therapy with thyroid hormone can precipitate an adrenal crisis in an undiagnosed individual. Hence, all patients with hypothyroidism and the possibility of APS should be screened for adrenal insufficiency to allow treatment with glucocorticoids prior to the initiation of thyroid hormone replacement. Treatment of mucocutaneous candidiasis with ketoconazole in an individual with subclinical adrenal insufficiency may also precipitate adrenal crisis. Furthermore, mucocutaneous candidiasis may be difficult to eradicate entirely. Severe cases of disease involvement may require systemic immunomodulatory therapy, but this is not commonly needed. With the exception of Graves' disease, the management of each endocrine component of APS-2 involves hormone replacement and is covered in detail in the chapters on adrenal (Chap. 398), thyroid (Chap. 394), gonadal (Chaps. 403 and 404), and thyroid diseases (Chap. 422). As noted for APS-1, adrenal insufficiency can be masked by primary hypothyroidism and should be considered and treated as discussed above. In patients with T1D, decreasing insulin requirements or hypoglycemia, without obvious secondary causes, may indicate the emergence of adrenal insufficiency. Hypocalcemia in APS-2 patients is more likely due to malabsorption, potentially from undiagnosed celiac disease, than hypoparathyroidism. Immunotherapy for autoimmune endocrine disease has been reserved for T1D, for the most part, reflecting the lifetime burden of the disease for the individual patient and society. Although several immunotherapies (e.g., modified anti-CD3, rituximab, abatacept, alefacept, low-dose antithymocyte globulin, TNF-α inhibitors, and JAK inhibitors) can prolong the honeymoon phase of T1D, none has achieved long-term success. Notably, the anti-CD3 monoclonal antibody (teplizumab) does delay the onset of clinical diabetes by an average of 3 years when administered to individuals with stage 2 T1D (e.g., those with autoantibodies and impaired glucose tolerance) and is now approved for clinical use in the United States. Active basic and clinical research using novel therapies and combinations may change the treatment landscape of this disease and other autoimmune conditions that share similar pathways. Therapies that block immune checkpoints, such as programmed cell death protein 1 (PD-1), its ligand (PD-L1), or CTLA-4, are beneficial immunotherapies for many advanced-stage cancers. These immune checkpoint inhibitors (ICIs) block negative immune regulation, thereby allowing for an immune response directed against tumor cells. However, immune-related adverse events also occur, especially autoimmunity directed toward self-tissues. ICI-induced T1D, thyroid disease, hypophysitis, and adrenal insufficiency have all been reported with these therapies and in combination. Hypothyroidism occurs in ~10% and T1D in 1–2% of those receiving monoclonal anti-CD3 monoclonal antibody, to delay the clinical onset of diabetes. These autoimmune side effects can develop during or after therapy, mostly within a few weeks to months following the start of therapy. ICI-induced T1D has a very rapid onset, presents with diabetic ketoacidosis, is permanent, and requires lifelong exogenous insulin therapy for treatment. There is a strong genetic association, with HLA-DR4 being present in ~70% of patients, and islet autoantibodies may be present at diagnosis. The pathogenesis is immune mediated as T lymphocyte infiltration has been documented in the pancreatic islets of an ICI-T1D patient. Determining the mechanisms of autoimmune disease development following ICI therapies and developing biomarkers to stratify risk for autoimmune side effects prior to therapy are active areas of research. POEMS patients have been treated with thalidomide, and more recently lenalidomide, leading to a decrease in vascular endothelial growth factor. Hyperglycemia responds to small, subcutaneous doses of insulin. The hypogonadism is due to primary gonadal disease with elevated plasma levels of follicle-stimulating hormone and luteinizing hormone. Temporary resolution of the features of POEMS, including normalization of blood glucose, may occur after radiotherapy for localized plasma cell lesions of bone or after chemotherapy, lenalidomide and dexamethasone, or autologous stem cell transplantation. Anti-insulin receptor antibodies cause severe insulin resistance (type B) associated with acanthosis nigricans, which can also be associated with other forms of less severe insulin resistance. About one-third of patients have an associated autoimmune illness such as systemic lupus erythematosus or Sjögren's syndrome. Therefore, the presence of anti-nuclear antibodies, elevated erythrocyte sedimentation rate, hyperglobulinemia, leukopenia, and hypocomplementemia may accompany the presentation. The presence of anti-insulin receptor autoantibodies leads to marked insulin resistance, requiring >100,000 units of insulin to be given daily with only partial control of hyperglycemia. Patients can also have severe hypoglycemia due to partial activation of the insulin receptor by the antibody. The course of the disease is variable, and several patients have had spontaneous remissions. A therapeutic approach that targets B lymphocytes, including rituximab, cyclophosphamide, and pulse steroids, has been validated in follow-on case reports to induce remission of the disease. The insulin autoimmune syndrome, associated with Graves' disease and methimazole therapy (or other sulfhydryl-containing medications), is of particular interest due to a remarkably strong association with a specific HLA haplotype. Such patients with elevated titers of anti-insulin antibodies frequently present with hypoglycemia. In Japan, the disease is restricted to HLA-DR4-positive individuals with DRB104:06, while Caucasian patients predominantly have DRB104:03 (which is related to DRB1*04:06). In Hirata's syndrome, the anti-insulin antibodies are often polyclonal. Discontinuation of the medication generally leads to resolution of the syndrome over time. There are very rare cases of insulin autoimmune syndrome not associated with sulfhydryl-containing medications that result in profound, life-threatening hypoglycemia. Treatment involves treating the underlying condition that causes anti-insulin antibodies, such as a B lymphocyte lymphoma (tend to have monoclonal insulin antibodies) or systemic lupus erythematosus. As hypoglycemia is profound when elevated titers of high-affinity insulin antibodies bind secreted insulin and then release it into circulation, treatment that begins with high-dose glucocorticoids and rituximab to target B lymphocytes has been shown to be effective. Other diseases can exhibit polyendocrine deficiencies, including Kearns-Sayre syndrome, DIDMOAD syndrome (diabetes insipidus, diabetes mellitus, progressive bilateral optic atrophy, and sensorineural deafness; also termed Wolfram's syndrome), Down's syndrome, or trisomy 21 (OMIM 190685), Turner's syndrome (monosomy X, 45,X0), and congenital rubella. Kearns-Sayre syndrome (OMIM 530000) is a rare mitochondrial DNA disorder characterized by myopathic abnormalities leading to ophthalmoplegia and progressive weakness in association with several endocrine abnormalities, including hypoparathyroidism, primary gonadal failure, diabetes mellitus, and hypopituitarism. Crystalline mitochondrial inclusions are found in muscle biopsy specimens, and such inclusions have also been observed in the cerebellum. Antiparathyroid antibodies have not been described; however, antibodies to the anterior pituitary gland and striated muscle have been identified, and the disease may have autoimmune components. These mitochondrial DNA mutations occur sporadically and do not appear to be associated with a familial syndrome. Wolfram's syndrome (OMIM 222300, chromosome 4; OMIM 598500, mitochondrial) is a rare autosomal recessive disease that is also called DIDMOAD. Neurologic and psychiatric disturbances are prominent in most patients and can cause severe disability. The disease is caused by defects in the Wolfram syndrome 1 (WFS1) gene, which encodes a 100-kDa transmembrane protein that has been localized to the endoplasmic reticulum and is found in neuronal and neuroendocrine tissue. Its expression induces ion channel activity with a resultant increase in intracellular calcium and may play an important role in intracellular calcium homeostasis. Wolfram's syndrome appears to be a slowly progressive neurodegenerative process, and there is nonautoimmune selective destruction of the pancreatic beta cells. Diabetes mellitus with an onset in childhood is usually the first manifestation. Diabetes mellitus and optic atrophy are present in all reported cases, but expression of the other features is variable. Treatments targeting endoplasmic reticulum dysfunction are being tested and may be a bridge until gene therapy can be developed to treat the most severely affected cases. Down's syndrome, or trisomy 21 (OMIM 190685), is associated with the development of T1D, thyroiditis, and celiac disease. Patients with Turner's syndrome also appear to be at increased risk for the development of thyroid disease and celiac disease. It is recommended to screen patients with trisomy 21 and Turner's syndrome for associated autoimmune diseases on a regular basis. Identification of these syndromes requires access to central laboratories with the ability to detect unique autoantibodies and to sequence the specific genes that may underlie these disorders. Early recognition of the clinical features of these disorders and timely referral and/or consultation with tertiary care centers to confirm the diagnosis and initiate therapy are important to improving outcomes. The AIRE recessive gene mutations found in APS-1 were originally described in high frequency in several populations including Finns, Iranian Jews, Sardinians, Norwegians, and Irish. Although individuals from many other countries have now been found to have these mutations and the newly identified dominant AIRE gene mutations, understanding the frequency in the background population may raise the clinician's level of suspicion for these rare disorders. Hirata's syndrome was originally reported in Japanese populations but also may be found in other populations, as noted.

7.1 APS-1 Management

Treatment of individual disease components is carried out as outlined in other relevant chapters. Replacement of deficient hormones (e.g., adrenal, pancreas, ovaries/testes) will treat most of the endocrinopathies noted. Several unique issues merit special emphasis. Adrenal insufficiency can be masked by primary hypothyroidism by prolonging the half-life of cortisol. The caveat therefore is that replacement therapy with thyroid hormone can precipitate an adrenal crisis in an undiagnosed individual. Hence, all patients with hypothyroidism and the possibility of APS should be screened for adrenal insufficiency to allow treatment with glucocorticoids prior to the initiation of thyroid hormone replacement. Treatment of mucocutaneous candidiasis with ketoconazole in an individual with subclinical adrenal insufficiency may also precipitate adrenal crisis. Furthermore, mucocutaneous candidiasis may be difficult to eradicate entirely. Severe cases of disease involvement may require systemic immunomodulatory therapy, but this is not commonly needed.

7.2 APS-2 Management

With the exception of Graves' disease, the management of each endocrine component of APS-2 involves hormone replacement and is covered in detail in the chapters on adrenal (Chap. 398), thyroid (Chap. 394), gonadal (Chaps. 403 and 404), and thyroid diseases (Chap. 422). As noted for APS-1, adrenal insufficiency can be masked by primary hypothyroidism and should be considered and treated as discussed above. In patients with T1D, decreasing insulin requirements or hypoglycemia, without obvious secondary causes, may indicate the emergence of adrenal insufficiency. Hypocalcemia in APS-2 patients is more likely due to malabsorption, potentially from undiagnosed celiac disease, than hypoparathyroidism.

7.3 Immunotherapy

Immunotherapy for autoimmune endocrine disease has been reserved for T1D, for the most part, reflecting the lifetime burden of the disease for the individual patient and society. Although several immunotherapies (e.g., modified anti-CD3, rituximab, abatacept, alefacept, low-dose antithymocyte globulin, TNF-α inhibitors, and JAK inhibitors) can prolong the honeymoon phase of T1D, none has achieved long-term success. Notably, the anti-CD3 monoclonal antibody (teplizumab) does delay the onset of clinical diabetes by an average of 3 years when administered to individuals with stage 2 T1D (e.g., those with autoantibodies and impaired glucose tolerance) and is now approved for clinical use in the United States. Active basic and clinical research using novel therapies and combinations may change the treatment landscape of this disease and other autoimmune conditions that share similar pathways.

7.4 ICI-Induced Autoimmunity Management

Therapies that block immune checkpoints, such as programmed cell death protein 1 (PD-1), its ligand (PD-L1), or CTLA-4, are beneficial immunotherapies for many advanced-stage cancers. These immune checkpoint inhibitors (ICIs) block negative immune regulation, thereby allowing for an immune response directed against tumor cells. However, immune-related adverse events also occur, especially autoimmunity directed toward self-tissues. ICI-induced T1D, thyroid disease, hypophysitis, and adrenal insufficiency have all been reported with these therapies and in combination. Hypothyroidism occurs in ~10% and T1D in 1–2% of those receiving monoclonal anti-CD3 monoclonal antibody, to delay the clinical onset of diabetes. These autoimmune side effects can develop during or after therapy, mostly within a few weeks to months following the start of therapy. ICI-induced T1D has a very rapid onset, presents with diabetic ketoacidosis, is permanent, and requires lifelong exogenous insulin therapy for treatment. There is a strong genetic association, with HLA-DR4 being present in ~70% of patients, and islet autoantibodies may be present at diagnosis. The pathogenesis is immune mediated as T lymphocyte infiltration has been documented in the pancreatic islets of an ICI-T1D patient. Determining the mechanisms of autoimmune disease development following ICI therapies and developing biomarkers to stratify risk for autoimmune side effects prior to therapy are active areas of research.

7.5 POEMS Syndrome Management

POEMS patients have been treated with thalidomide, and more recently lenalidomide, leading to a decrease in vascular endothelial growth factor. Hyperglycemia responds to small, subcutaneous doses of insulin. The hypogonadism is due to primary gonadal disease with elevated plasma levels of follicle-stimulating hormone and luteinizing hormone. Temporary resolution of the features of POEMS, including normalization of blood glucose, may occur after radiotherapy for localized plasma cell lesions of bone or after chemotherapy, lenalidomide and dexamethasone, or autologous stem cell transplantation.

7.6 Insulin Autoimmune Syndrome Management

In Hirata's syndrome, the anti-insulin antibodies are often polyclonal. Discontinuation of the medication generally leads to resolution of the syndrome over time. There are very rare cases of insulin autoimmune syndrome not associated with sulfhydryl-containing medications that result in profound, life-threatening hypoglycemia. Treatment involves treating the underlying condition that causes anti-insulin antibodies, such as a B lymphocyte lymphoma (tend to have monoclonal insulin antibodies) or systemic lupus erythematosus. As hypoglycemia is profound when elevated titers of high-affinity insulin antibodies bind secreted insulin and then release it into circulation, treatment that begins with high-dose glucocorticoids and rituximab to target B lymphocytes has been shown to be effective.

7.7 Anti-Insulin Receptor Antibodies Management

Anti-insulin receptor antibodies cause severe insulin resistance (type B) associated with acanthosis nigricans, which can also be associated with other forms of less severe insulin resistance. About one-third of patients have an associated autoimmune illness such as systemic lupus erythematosus or Sjögren's syndrome. Therefore, the presence of anti-nuclear antibodies, elevated erythrocyte sedimentation rate, hyperglobulinemia, leukopenia, and hypocomplementemia may accompany the presentation. The presence of anti-insulin receptor autoantibodies leads to marked insulin resistance, requiring >100,000 units of insulin to be given daily with only partial control of hyperglycemia. Patients can also have severe hypoglycemia due to partial activation of the insulin receptor by the antibody. The course of the disease is variable, and several patients have had spontaneous remissions. A therapeutic approach that targets B lymphocytes, including rituximab, cyclophosphamide, and pulse steroids, has been validated in follow-on case reports to induce remission of the disease.

8. PROGNOSIS & COMPLICATIONS

Prognosis varies by syndrome. APS-1 is rare, with <500 cases reported in the literature. The incidence rates for many of these disorders peak in the first or second decade of life, but the individual disease components continue to emerge over time. Therefore, prevalence rates may be higher than originally reported. APS-2 is more common than APS-1, with a prevalence of 1–2 in 100,000. IPEX: Many infants die within the first days of life, but the course is variable, with some children surviving for 12–15 years. POEMS: Patients often present in the fifth to sixth decade of life and have a median survival after diagnosis of <3 years. ICI-induced T1D: ICI-induced T1D has a very rapid onset, presents with diabetic ketoacidosis, is permanent, and requires lifelong exogenous insulin therapy for treatment. Wolfram's syndrome: The disease appears to be a slowly progressive neurodegenerative process, and there is nonautoimmune selective destruction of the pancreatic beta cells. Down's syndrome: Associated with the development of T1D, thyroiditis, and celiac disease. Turner's syndrome: Patients with Turner's syndrome also appear to be at increased risk for the development of thyroid disease and celiac disease.

8.1 APS-1 Prognosis

APS-1 is rare, with <500 cases reported in the literature. The incidence rates for many of these disorders peak in the first or second decade of life, but the individual disease components continue to emerge over time. Therefore, prevalence rates may be higher than originally reported. The time from development of one component of the disorder to the next can be many years, and the order of disease appearance is variable.

8.2 APS-2 Prognosis

APS-2 is more common than APS-1, with a prevalence of 1–2 in 100,000. It has a gender bias and occurs more often in female patients, with a ratio of at least 3:1 compared to male patients. In contrast to APS-1, APS-2 often has its onset in adulthood, with a peak incidence between 20 and 60 years of age. It shows a familial, multigenerational heritage. The presence of two or more of the following endocrine deficiencies in the same patient defines the presence of APS-2: primary adrenal insufficiency (Addison's disease; 50–70%), Graves' disease or autoimmune thyroiditis (15–69%), type 1 diabetes mellitus (T1D; 40–50%), and primary hypogonadism. Frequently associated autoimmune conditions include celiac disease (3–15%), myasthenia gravis, vitiligo, alopecia, serositis, and pernicious anemia. These conditions occur with increased frequency in affected patients but are also found in their family members. The development of a rarer form of autoimmunity, such as Addison's disease, should prompt more extensive screening for other linked disorders, as ~50% of Addison's disease patients develop another autoimmune disease during their lifetime.

8.3 IPEX Prognosis

IPEX: Many infants die within the first days of life, but the course is variable, with some children surviving for 12–15 years. Early onset of T1D, often at birth, is highly suggestive of the diagnosis because nearly 80% of IPEX patients develop T1D. Although treatment of the individual disorders can temporarily improve the situation, treatment of the underlying immune deficiency is required and includes immunosuppressive therapy generally followed by hematopoietic stem cell transplantation. Transplantation is the only life-saving form of therapy and can be fully curative by normalizing the imbalanced immune system found in this disorder.

8.4 POEMS Prognosis

POEMS: Patients often present in the fifth to sixth decade of life and have a median survival after diagnosis of <3 years. The high frequency of the syndrome is assumed to be secondary to circulating immunoglobulins, but patients have excess vascular endothelial growth factor as well as elevated levels of other inflammatory cytokines such as IL-1β, IL-6, and tumor necrosis factor α.

9. SPECIAL CONSIDERATIONS

Identification of these syndromes requires access to central laboratories with the ability to detect unique autoantibodies and to sequence the specific genes that may underlie these disorders. Early recognition of the clinical features of these disorders and timely referral and/or consultation with tertiary care centers to confirm the diagnosis and initiate therapy are important to improving outcomes. The AIRE recessive gene mutations found in APS-1 were originally described in high frequency in several populations including Finns, Iranian Jews, Sardinians, Norwegians, and Irish. Although individuals from many other countries have now been found to have these mutations and the newly identified dominant AIRE gene mutations, understanding the frequency in the background population may raise the clinician's level of suspicion for these rare disorders. Hirata's syndrome was originally reported in Japanese populations but also may be found in other populations, as noted. Down's syndrome, or trisomy 21 (OMIM 190685), is associated with the development of T1D, thyroiditis, and celiac disease. Patients with Turner's syndrome also appear to be at increased risk for the development of thyroid disease and celiac disease. It is recommended to screen patients with trisomy 21 and Turner's syndrome for associated autoimmune diseases on a regular basis. Kearns-Sayre syndrome (OMIM 530000) is a rare mitochondrial DNA disorder characterized by myopathic abnormalities leading to ophthalmoplegia and progressive weakness in association with several endocrine abnormalities, including hypoparathyroidism, primary gonadal failure, diabetes mellitus, and hypopituitarism. Crystalline mitochondrial inclusions are found in muscle biopsy specimens, and such inclusions have also been observed in the cerebellum. Antiparathyroid antibodies have not been described; however, antibodies to the anterior pituitary gland and striated muscle have been identified, and the disease may have autoimmune components. These mitochondrial DNA mutations occur sporadically and do not appear to be associated with a familial syndrome. Wolfram's syndrome (OMIM 222300, chromosome 4; OMIM 598500, mitochondrial) is a rare autosomal recessive disease that is also called DIDMOAD. Neurologic and psychiatric disturbances are prominent in most patients and can cause severe disability. The disease is caused by defects in the Wolfram syndrome 1 (WFS1) gene, which encodes a 100-kDa transmembrane protein that has been localized to the endoplasmic reticulum and is found in neuronal and neuroendocrine tissue. Its expression induces ion channel activity with a resultant increase in intracellular calcium and may play an important role in intracellular calcium homeostasis. Wolfram's syndrome appears to be a slowly progressive neurodegenerative process, and there is nonautoimmune selective destruction of the pancreatic beta cells. Diabetes mellitus with an onset in childhood is usually the first manifestation. Diabetes mellitus and optic atrophy are present in all reported cases, but expression of the other features is variable. Treatments targeting endoplasmic reticulum dysfunction are being tested and may be a bridge until gene therapy can be developed to treat the most severely affected cases.

9.1 Genetic Considerations

The overwhelming risk factor for APS-2 has been localized to the genes in the human lymphocyte antigen (HLA) complex on chromosome 6. Primary adrenal insufficiency in APS-2, but not APS-1, is strongly associated with both HLA-DR3 and HLA-DR4. Other class I and class II genes and alleles, such as HLA-B8, HLA-DQ2 and HLA-DQ8, and HLA-DR subtypes such as DRB1*04:04, appear to contribute to organ-specific disease susceptibility (Table 401-4). HLA-B8- and HLA-DR3-associated illnesses include selective IgA deficiency, juvenile dermatomyositis, dermatitis herpetiformis, alopecia, scleroderma, autoimmune thrombocytopenia purpura, hypophysitis, metaphyseal osteopenia, and serositis. However, individuals may take many years to develop overt symptoms. Several other immune genes have been proposed to be associated with Addison's disease and therefore with APS-2 (Table 401-3). The "5.1" allele of a major histocompatibility complex (MHC) gene is an atypical class I HLA molecule MIC-A. The MIC-A5.1 allele has a very strong association with Addison's disease that is not accounted for by linkage disequilibrium with DR3 or DR4. Its role is complicated because certain HLA class I genes can offset this effect. PTPN22 codes for a polymorphism in a protein tyrosine phosphatase, which acts on intracellular signaling pathways in both T and B lymphocytes. It has been implicated in T1D, Addison's disease, and other autoimmune conditions. CTLA4 is a receptor on the T-cell surface that modulates the activation state of the cell as part of the signal 2 pathway (i.e., binding to CD80/86 on antigen presenting cells). Polymorphisms of this gene appear to cause downregulation of the cell surface expression of the receptor, leading to decreased T-cell activation and proliferation. This appears to contribute to Addison's disease and potentially other components of APS-2. Allelic variants of the IL-2Rα are linked to development of T1D and autoimmune thyroid disease and could contribute to the phenotype of APS-2 in certain individuals.

9.2 Screening Recommendations

A complete history and physical examination should be performed every 1–3 years including complete blood count, metabolic panel, TSH, and vitamin B12 levels to screen for most of the possible abnormalities. More specific tests should be based on specific findings from the history and physical examination. Detection of abnormal physical findings or test results should prompt subsequent examinations of the relevant organ system (e.g., presence of Howell-Jolly bodies indicates need for ultrasound of spleen). For those <20 years of age, testing every 1–2 years should be performed, whereas less frequent testing is indicated after the age of 20 because the majority of individuals who develop celiac disease have the antibody earlier in life. Positive tTg antibody test results should be confirmed on repeat testing, followed by small-bowel biopsy to document pathologic changes of celiac disease. Many patients have asymptomatic celiac disease that is nevertheless associated with osteopenia and impaired growth. If left untreated, symptomatic celiac disease has been reported to be associated with an increased risk of gastrointestinal malignancy, especially lymphoma, and osteoporosis later in life. Screening of 21-hydroxylase antibody–positive patients can be performed measuring morning ACTH and cortisol on a yearly basis. Rising ACTH values over time or low morning cortisol in association with signs or symptoms of adrenal insufficiency should prompt testing via the cosyntropin stimulation test (Chap. 398). T1D can be screened for by measuring autoantibodies directed against insulin, GAD65, IA-2, and ZnT8. Risk for progression to disease is based on the number of antibodies (≥2 islet autoantibodies with normal glucose tolerance is now defined as stage 1 of T1D as the lifetime risk for developing clinical symptoms is nearly 100%) and metabolic factors (impaired oral glucose tolerance test). Many efforts are ongoing and underway to screen relatives of T1D patients and those in the general population for islet autoantibodies to identify individuals with preclinical disease who may elect to have treatment with teplizumab, to delay the clinical onset of diabetes. Screening tests for thyroid disease can include anti–thyroid peroxidase (TPO) or anti-thyroglobulin autoantibodies or anti-TSH receptor antibodies for Graves' disease. Yearly measurements of TSH can then be used to follow these individuals.

10. KEY PEARLS & CLINICAL TRAPS

Adrenal insufficiency can be masked by primary hypothyroidism by prolonging the half-life of cortisol. The caveat therefore is that replacement therapy with thyroid hormone can precipitate an adrenal crisis in an undiagnosed individual. Hence, all patients with hypothyroidism and the possibility of APS should be screened for adrenal insufficiency to allow treatment with glucocorticoids prior to the initiation of thyroid hormone replacement. Mucocutaneous candidiasis may be difficult to eradicate entirely. Severe cases of disease involvement may require systemic immunomodulatory therapy, but this is not commonly needed. Hypocalcemia in APS-2 patients is more likely due to malabsorption, potentially from undiagnosed celiac disease, than hypoparathyroidism. ICI-induced T1D has a very rapid onset, presents with diabetic ketoacidosis, is permanent, and requires lifelong exogenous insulin therapy for treatment. There is a strong genetic association, with HLA-DR4 being present in ~70% of patients, and islet autoantibodies may be present at diagnosis. The pathogenesis is immune mediated as T lymphocyte infiltration has been documented in the pancreatic islets of an ICI-T1D patient. Determining the mechanisms of autoimmune disease development following ICI therapies and developing biomarkers to stratify risk for autoimmune side effects prior to therapy are active areas of research. Notably, the anti-CD3 monoclonal antibody (teplizumab) does delay the onset of clinical diabetes by an average of 3 years when administered to individuals with stage 2 T1D (e.g., those with autoantibodies and impaired glucose tolerance) and is now approved for clinical use in the United States. Active basic and clinical research using novel therapies and combinations may change the treatment landscape of this disease and other autoimmune conditions that share similar pathways. The presence of two or more of the following endocrine deficiencies in the same patient defines the presence of APS-2. Diagnosis of APS-1 is usually made clinically when autoantibodies to two of the three major component disorders are found in an individual patient. Siblings of individuals with APS-1 should be considered affected even if only one component disorder has been detected due to the known inheritance of the syndrome. Genetic analysis of the AIRE gene should be undertaken to identify mutations. Detection of anti–interferon α and anti–interferon ω antibodies can identify nearly 100% of cases with APS-1. The autoantibody arises independent of the type of AIRE gene mutation and is not found in other autoimmune disorders. The presence of anti-21-hydroxylase antibody or anti-17-hydroxylase antibody (which may be found more commonly in adrenal insufficiency associated with APS-1) would confirm the presence or risk for Addison's disease. Other autoantibodies found in type 1 diabetes (e.g., anti-GAD65), pernicious anemia, and other component conditions should be screened for on a regular basis (6- to 12-month intervals depending on the age of the subject).

10.1 Diagnostic Clues

Chronic mucocutaneous candidiasis without signs of systemic disease is often the first manifestation. It affects the mouth and nails more frequently than the skin and esophagus. Chronic oral candidiasis can result in atrophic areas suggestive of leukoplakia, which can pose a risk for future carcinoma. The etiology is associated with anticytokine autoantibodies (anti-interleukin [IL] 17A, IL-17F, and IL-22) related to T helper (Th) 17 T cells and depressed production of these cytokines by peripheral blood mononuclear cells. Hypoparathyroidism usually develops next, followed by adrenal insufficiency. The time from development of one component of the disorder to the next can be many years, and the order of disease appearance is variable. Specific physical examination findings of hyperpigmentation, vitiligo, alopecia, tetany, and signs of hyper- or hypothyroidism should be considered as signs of development of component disorders. The development of disease-specific autoantibody assays can help confirm disease and also detect risk for future disease. For example, where possible, detection of anticytokine antibodies to IL-17 and IL-22 would confirm the diagnosis of mucocutaneous candidiasis due to APS-1. The presence of anti-21-hydroxylase antibody or anti-17-hydroxylase antibody (which may be found more commonly in adrenal insufficiency associated with APS-1) would confirm the presence or risk for Addison's disease. Other autoantibodies found in type 1 diabetes (e.g., anti-GAD65), pernicious anemia, and other component conditions should be screened for on a regular basis (6- to 12-month intervals depending on the age of the subject). Myocarditis, Serositis, Stiff man syndrome, Idiopathic heart block, Myasthenia gravis, Cerebellar ataxia, Chronic inflammatory demyelinating polyneuropathy, Hypophysitis, IgA deficiency, Vitiligo, Alopecia, Parkinson's disease, Asplenism, Malabsorption syndromes, Pernicious anemia, Splenic atrophy, Type 1 diabetes, Ovarian failure, Obstipation, Hypothyroidism/Graves' disease, Hepatitis, Hypoparathyroidism, Ectodermal dysplasia, Diarrhea, Addison's disease are all potential features.

10.2 Clinical Pearls

Adrenal insufficiency can be masked by primary hypothyroidism by prolonging the half-life of cortisol. The caveat therefore is that replacement therapy with thyroid hormone can precipitate an adrenal crisis in an undiagnosed individual. Hence, all patients with hypothyroidism and the possibility of APS should be screened for adrenal insufficiency to allow treatment with glucocorticoids prior to the initiation of thyroid hormone replacement. Mucocutaneous candidiasis may be difficult to eradicate entirely. Severe cases of disease involvement may require systemic immunomodulatory therapy, but this is not commonly needed. Hypocalcemia in APS-2 patients is more likely due to malabsorption, potentially from undiagnosed celiac disease, than hypoparathyroidism. ICI-induced T1D has a very rapid onset, presents with diabetic ketoacidosis, is permanent, and requires lifelong exogenous insulin therapy for treatment. There is a strong genetic association, with HLA-DR4 being present in ~70% of patients, and islet autoantibodies may be present at diagnosis. The pathogenesis is immune mediated as T lymphocyte infiltration has been documented in the pancreatic islets of an ICI-T1D patient. Determining the mechanisms of autoimmune disease development following ICI therapies and developing biomarkers to stratify risk for autoimmune side effects prior to therapy are active areas of research. Notably, the anti-CD3 monoclonal antibody (teplizumab) does delay the onset of clinical diabetes by an average of 3 years when administered to individuals with stage 2 T1D (e.g., those with autoantibodies and impaired glucose tolerance) and is now approved for clinical use in the United States. Active basic and clinical research using novel therapies and combinations may change the treatment landscape of this disease and other autoimmune conditions that share similar pathways. The presence of two or more of the following endocrine deficiencies in the same patient defines the presence of APS-2. Diagnosis of APS-1 is usually made clinically when autoantibodies to two of the three major component disorders are found in an individual patient. Siblings of individuals with APS-1 should be considered affected even if only one component disorder has been detected due to the known inheritance of the syndrome. Genetic analysis of the AIRE gene should be undertaken to identify mutations. Detection of anti–interferon α and anti–interferon ω antibodies can identify nearly 100% of cases with APS-1. The autoantibody arises independent of the type of AIRE gene mutation and is not found in other autoimmune disorders. The presence of anti-21-hydroxylase antibody or anti-17-hydroxylase antibody (which may be found more commonly in adrenal insufficiency associated with APS-1) would confirm the presence or risk for Addison's disease. Other autoantibodies found in type 1 diabetes (e.g., anti-GAD65), pernicious anemia, and other component conditions should be screened for on a regular basis (6- to 12-month intervals depending on the age of the subject).

Generated from Harrison's Principles of Internal Medicine, 22nd Edition.