A. Types of Syndromes

1. PEF1 - rare, recessive disease, usually begins in infancy
2. PEF2 - more common, polygenic disease, onset infancy through adulthood
3. PEF3 and PEF4 are likely subsets of PEF2
4. X-Linked Polyendocrinopathy - very rare, neonatal onset
5. Adrenal insufficiency is common to PEF1 and 2

1. Also called autoimmune polyendocrinopathy-candidiasis-ectodermal dysplasia (APECED)
2. Incidence is 1 per 10-25,000 persons
3. Polyendocrinopathy - one or more always present:
   1. Hypoparathyroidism
   2. Adrenal Insufficiency
4. Candidiasis - always present
5. Ectodermal Dysplasia (Keratopathy) - nearly always present
6. Common Associated Problems
   1. Chronic hepatitis
   2. Alopecia
   3. Type 1 Diabetes Mellitus
   4. Vitiligo
   5. NALP1 (Nacht leucine-rich-repeat protein 1, regulator of innate immune system) gene mutations associated with vitiligo and multiple autoimmunity [6]
7. Steatorrhea, watery diarrhea, or constipation in ~25% of patients

B. Etiology

1. Familial with autosomal recessive inheritance
2. Mutations in a gene on chromosome 21q22.3 found in affected patients
   1. This gene has been called AIRE (autoimmune regulator)
   2. Encodes zinc-finger protein with proline rich region and LXXLL motifs
   3. AIRE expressed mainly in thymic medulla and is likely a transcriptional regulator
   4. AIRE may control expression of proteins in thymus which lead to tolerance
3. Autoantigen of hypothyroidism is NALP5 (nacht leucine rich repeat protein 5) [5]
4. Patients produce antibodies against affected organs
   1. Anti-steroidal Abs against P450 scc, P450c17 and P450c21 (Adrenal Failure)
   2. Anti-L-amino-acid decarboxylase and anti-P450 1A2 in patients with hepatitis
   3. Anti-tryptophan hydroxylase Abs found in patients with gastrointestinal problems [4]
   4. These anti-tryptophan hydroxylase Abs are fairly sensitive for PEF 1 with GI symptoms and are not found in other inflammatory gastrointestinal diseases [5]

C. Polyendocrine Components

1. Usually presents in childhood
2. Hypoparathyroidism 79%
3. Adrenocortical Failure 72%
4. Gonadal Failure 60% of women, 14% of men
5. Alopecia and vitiligo also found
6. Gastric parietal cell atrophy
7. Hepatitis (autoimmune)
8. Gastrointestinal inflammation 25%
9. Dental enamal hypoplasia and keratopathy

C. Treatment

1. Replace hormones as needed
2. Search for underlying autoimmune disease
3. Attention to electrolyte levels including calcium and phosphorus
4. Treat Candidiasis - fluconazole or other agent

1. Adrenal insufficiency
2. Hypothyroidism (lymphocytic)
3. Hypoparathyroidism
4. Gonadal Failure
5. Diabetes Mellitus (common but not required)
6. Pernicious Anemia (usually develops late, if at all)

B. Characteristics

1. Multiple autoreactive antibodies
2. Usually female patients
3. HLA-B8 and Dw3 in caucasians
4. Usually adult onset

C. Treatment

1. Replace hormones as needed
2. Thyroid replacement should occur AFTER glucocorticoids and mineralocorticoids
   1. Thyroid replacement prior to glucocorticoids can precipitate an adrenal crisis
   2. Adequate adrenal replacement prior to thyroid hormones required
3. Search for underlying autoimmune disease
4. Attention to electrolyte levels including calcium and phosphorus

1. Thyroiditis - usually Hashimoto type
2. Any two additional autoimmune disease but not Addison's Disease or Type IA DM
3. Commonly includes:
   1. Pernicious Anemia
   2. Myasthenia Gravis
4. Often considered a subset of PEF II

B. PEF IV [1]

1. Two or more other organ-specific autoimmune disease
2. Often considered a subset of PEF II

References

1. Eisenbarth GTS and Gottlieb PA. 2004. NEJM. 350(20):2068
2. Arit W and Allolio B. 2003. Lancet. 361(9372):1881
3. Baker JR Jr. 1997. JAMA. 278(22):1931
4. Ekwall O, Hedstrand H, Grimelius L, et al. 1998. Lancet. 352(9124):279
5. Ekwall O, Sjoberg K, Mirakian R, et al. 1999. Lancet. 354(9178):568
6. Jin Y, Mailloux CM, Gowan K, et al. 2007. NEJM. 356(12):1216
7. Alimohammadi M, Bjorklund P, Hallgren A, et al. 2008. NEJM. 358(10):1018