Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dysplasia

Autoimmune Polyendocrinopathy-Candidiasis–Ectodermal Dysplasia

Yoavanit Srivaro M.D.

Outlines

•Introduction

•Epidemiology

•Pathogenesis

•Clinical Manifestations

•Laboratory Evaluation

•Diagnosis

•Management

•Prognosis

Introduction

1st mentionedliterature by

Thorpe and Handley in 1929

CMC & HP

1929 1946

Clinical triad of 1.Chronic mucocutaneouscandidiasis 2.Hypoparathyroidism 3.Adrenal insufficiency

was reported

1956

Recognized as “Whitaker’s syndrome”

1980

Recognized as“APS-1”

Peltonen-Palotie L, Halonen M, Perheentupa J. Autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy. In: Ochs HD, Smith CI, Puck JM, editors. Primary immunodeficiency diseases: a molecular and genetic approach. 2nd ed. New York: Oxford University Press; 2007. p. 342-53.

Eisenbarth GS, Gottlieb PA. Autoimmune polyendocrine syndromes. N Engl J Med. 2004;350:2068-79.

1st mentionedliterature by

Thorpe and Handley in 1929

CMC & HP

1929 1946

Clinical triad of 1.Chronic mucocutaneouscandidiasis 2.Hypoparathyroidism 3.Adrenal insufficiency

was reported

1956

Recognized as “Whitaker’s syndrome”

1980

Recognized as“APS-1”

1990

Acronym “APECED”was introduced by Finnish pediatrician Professor JaakkoPerheentupa


1994 1997 2002

Analysis 1st knockout mouse models: A role for AIRE in the development of both central& peripheral tolerance.


APECED locus was mapped in the Finnish families to 21q22.3

A novel gene, AIRE was positionallycloned.

APECED

•Monogenic autosomal recessive disease

•Characterized by

1. Chronic candidiasis

2. Multiple autoimmune diseases

• Loss-of-function mutations in the autoimmune

regulator (AIRE) gene

Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. J Clin Immunol. 2015;35:463-78.

Burmester, Color Atlas of Immunology © 2003

Epidemiology

Country Prevalence

Iranian Jews 1: 9,000

Sardinians 1:14,000

Finns 1:2,5000

Slovenia 1:43,000

Norway 1:80,000

Poland 1:129,000


Pathogenesis



Abbas AK, Lichtman AH, Pillai S. Cellular and molecular immunology. 8th ed.Philadelphia, W.B. Saunders Company.2015

FIGURE 2-10 Morphology of the thymus.

FIGURE 8-18 Maturation of T cells in the thymus.

Abbas AK, Lichtman AH, Pillai S. Cellular and molecular immunology. 8th ed.Philadelphia, W.B. Saunders Company.2015

Abbas AK, Lichtman AH, Pillai Shiv. Cellular and molecular immunology. 8th ed.Philadelphia, W.B. Saunders Company.2015.

FIGURE 15-2 Central T cell tolerance.

FIGURE2Thymocyte-intrinsic pathways required for negative selection.

Siggs OM, Makaroff LE, Liston A. The why and how of thymocyte negative selection. Curr Opin Immunol. 2006;18:175-83.


FIGURE 15-2 Central T cell tolerance.


FIGURE 15-3 The function of AIRE in deletion of T cells in the thymus.


FIGURE 15-3 The function of AIRE in deletion of T cells in the thymus.

Eisenbarth GS, Gottlieb PA. Autoimmune polyendocrine syndromes. N Engl J Med. 2004;350:2068-79.


The AIRE gene is located in chromosome 21 region q22.3


Peterson P, Org T, Rebane A. Transcriptional regulation by AIRE: molecular mechanisms of central tolerance. Nat Rev Immunol. 2008;8:948-57.

AIRE protein: 545–amino acid protein, molecular weight of 57.5 kDa

Figure 1 AIRE gene and AIRE 1 protein

Proust-Lemoine E, Saugier-Veber P, Wemeau JL. Polyglandular autoimmune syndrome type I. Presse Med. 2012;41:e651-62.

Figure 1 AIRE gene and AIRE 1 protein



HSR

NLS

SAND

PHD1

PRR

PHD2

Homogeneously Staining Region

Nuclear Localisation Signal

DNA liaison domain

Plant HomeoDomain

ProlineRich Region

Plant HomeoDomain

LXXLL motifs: motifs of nuclear receptor liaison


Fig. 1 In the medullary thymic epithelial cells (mTEC) AIRE promotesthe expression of tissue specific antigens by interacting with largechromatin-associated complex.

AIRE Protein

•Restricted expression pattern

1. Mainly present in

:Medullary thymic epithelial cells (mTECs)

2. Rare present in

:Dendritic-like cells in the lymph nodes & tonsils

Heino M, Peterson P, Kudoh J, Nagamine K, Lagerstedt A, Ovod V, et al. Autoimmune regulator is expressed in the cells regulating immune tolerance in thymus medulla. Biochem Biophys Res Commun. 1999;257:821–5.

Poliani PL, Kisand K, Marrella V, Ravanini M, Notarangelo LD, Villa A, et al. Human peripheral lymphoid tissues contain autoimmune regulator-expressing dendritic cells. Am J Pathol. 2010;176: 1104–12.



FIG. 1. Expression of AIRE in thymus medulla

Heino M, Peterson P, Kudoh J, Nagamine K, Lagerstedt A, Ovod V, et al. Autoimmune regulator is expressed in the cells regulating immune tolerance in thymus medulla. Biochem Biophys Res Commun. 1999;257:821-5.

FIG. 2. Intracellular expression of AIRE in vivo and in vitro.

Heino M, Peterson P, Kudoh J, Nagamine K, Lagerstedt A, Ovod V, et al. Autoimmune regulator is expressed in the cells regulating immune tolerance in thymus medulla. Biochem Biophys Res Commun. 1999;257:821-5.

AIRE Gene Mutation

•More than 50 mutations

: Deletions

: Insertions

: Missense point mutations

: Nonsense point mutations


Finnish mutation

English mutation

Sardinainmutation

Anderson MS, Casanova JL. More than Meets the Eye: Monogenic Autoimmunity Strikes Again. Immunity. 2015;42:986-8.

Husebye ES, Perheentupa J, Rautemaa R, Kampe O. Clinical manifestations and management of patients with autoimmune polyendocrinesyndrome type I. J Intern Med. 2009;265:514–29

Clinical Manifestations

Husebye ES, Perheentupa J, Rautemaa R, Kampe O. Clinical manifestations and management of patients with autoimmunepolyendocrine syndrome type I. J Intern Med. 2009;265:514–29

• Chronic Mucocutaneous Candidiasis

• Endocrine Manifestations

• Gastrointestinal Manifestations

• Ectodermal Manifestations

• Tubulo-Interstitial Nephritis

• Interstitial Lung Disease

• Other Manifestations








Chronic Mucocutaneous Candidiasis

• Heterogeneous group of syndromes

1. Common features

: Chronic noninvasive Candida infections of the

skin,nails, and mucous membranes

2. Associated autoimmune manifestations


Finn Sardinian2006 201291 (%) 22 (%)

88 69

84 77

100 97

33 5

31

18 27

39

31

22

Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab. 2006;91:2843-50.


Collins SM, Dominguez M, Ilmarinen T, Costigan C, Irvine AD. Dermatological manifestations of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome. Br J Dermatol. 2006;154:1088-93.


• Less than 10% of cases : limited to the skin & often localized. • Up to 100% of cases :mainly affects the oral mucous membranes.• 2/3 of cases : mainly affects the nails.


• More rarely : Genitals candidiasis• 15 to 22% of cases:Oeosophageal candidiasis


Milner JD, Holland SM. The cup runneth over: lessons from the ever-expanding pool of primary immunodeficiency diseases. Nat Rev Immunol. 2013;13:635-48.

FIGURE 4 Defects in immunity to Candida albicans.

Milner JD, Holland SM. The cup runneth over: lessons from the ever-expanding pool of primary immunodeficiency diseases. Nat Rev Immunol. 2013;13:635-48.

FIGURE 4 Defects in immunity to Candida albicans.

Puel A, Doffinger R, Natividad A, Chrabieh M, Barcenas-Morales G, Picard C, et al. Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J Exp Med. 2010;207:291-7.

Gouda MR, Al-Amin A, Grabsch H, Donnellan C. A multidisciplinary approach to management of autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED). BMJ Case Rep. 2013;2013.

Sivabalan S, Mahadevan S, Srinath MV. Recurrent oral thrush. Indian J Pediatr. 2014;81:394-6.









Endocrine Manifestations

•Hypoparathyroidism

•Adrenocortical failure

•Hypergonadotropic hypogonadism

•Type 1 diabetes

•Autoimmune thyroiditis

•Pituitary failure and growth hormone deficiency




Finn Sardinian2006 201291 (%) 22 (%)

88 69

84 77

100 97

33 5

31

18 27

39

31

22



Hypoparathyroidism

•Symptoms are related to hypocalcemia

: Muscle cramps, mild paresthesia and clumsiness






•Type 1 diabetes






Finn Sardinian2006 201291 (%) 22 (%)

84 69

88 77

100 97

33 5

31

18 27

39

31

22



Addison’s disease

•Mediated by autoreactive cytotoxic T-cells

•Adrenal hormone deficiencies do not manifest

clinically until at least 90 % of the functional

adrenocortical cells have been destroyed


Addison’s disease

•Characteristic symptoms include

:Fatigue, salt craving, hypotension, weight loss and

an increased pigmentation of the skin and mucous

membranes






•Type 1 diabetes





Hypergonadotropic hypogonadism

•Ovarian insufficiency

•Testicular insufficiency


Ovarian insufficiency

•Start early with arrested pubertal development

•Manifest as premature menopause


Testicular insufficiency

• Less frequent

•Affects approximately 10 % of male patients

•Usually develops during adulthood






•Type 1 diabetes





Finn Sardinian2006 201291 (%) 22 (%)

80 69

87 77

100 97

33 5

31

22

39

18 27

31







•Type 1 diabetes




Autoimmune thyroiditis

•Hypothyroidism also develops during adulthood

:Dx in one-fourth of patients

•Hyperthyroidism is very rare and transient






•Type 1 diabetes




Pituitary failure and Growth hormone deficiency

•Rare manifestations

•Higher prevalence in certain populations

Meloni A, Willcox N, Meager A, Atzeni M, Wolff AS, Husebye ES, et al. Autoimmune polyendocrine syndrome type 1: an extensive longitudinal study in Sardinian patients. J Clin Endocrinol Metab. 2012;97:1114–24.

Meloni A, Willcox N, Meager A, Atzeni M, Wolff AS, Husebye ES, et al. Autoimmune polyendocrine syndrome type 1: an extensive longitudinal study in Sardinian patients. J Clin Endocrinol Metab. 2012;97:1114-24.

Sardinians 25 %








Gastrointestinal Manifestations



Finn Sardinian2006 201291 (%) 22 (%)

80 69

87 77

100 97

33 5

31

18 27

39

31

22




Finn Sardinian2006 201291 (%) 22 (%)

80 69

87 77

100 97

33 5

31

18 27

39

31

22













Ectodermal Manifestations



Finn Sardinian2006 201291 (%) 22 (%)

80 69

87 77

100 97

33 5

31

18 27

39

31

22

FIGURE. 6-13 Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome.

A.Erythematous candidiasis diffusely involving the dorsal tongue of a 32-year-old man.

B.Same patient showing nail dystrophy.

C.Corneal keratopathy

http://pocketdentistry.com/6-fungal-and-protozoal-diseases




FIGURE 2 Dental Enamel hypoplasia

Winer KK, Merke DP. Picture of the month. Autoimmune polyglandular syndrome type 1. Arch Pediatr Adolesc Med. 2000;154:745-6.




Finn Sardinian2006 201291 (%) 22 (%)

80 69

87 77

100 97

33 5

31

18 27

39

31

22

Fig 3a: hyperpigmentation and periorificial vitiligo in a 23 year-old female patient


FIGURE 1 Depigmented patchs around both eyes were noted


FIGURE 1 Dermatological manifestations of autoimmune polyendocrinopathy–candidiasis– ectodermal dystrophy syndrome

Oral candidiasis

Halo naevi

Candidalonychomycosis & paronychia

Poliosis


FIGURE 1 Dermatological manifestations of autoimmune polyendocrinopathy–candidiasis– ectodermal dystrophy syndrome

Oral candidiasis

Halo naevi

Candidalonychomycosis & paronychia

Poliosis





Finn Sardinian2006 201291 (%) 22 (%)

80 69

87 77

100 97

33 5

31

18 27

39

31

22

Fig 3 b: alopecia of the scalp (note the absence of eyelashes and eyebrows) in a 34 year-old subject





FIGURE 3 Nail pitting









Tubulo-Interstitial Nephritis

•Serious but rare manifestation

•Affecting up to 10 % of patients

• Serum Cr , ESR, Abn UA , Proteinuria & Glycosuria

•Permanent renal dysfunction, H/D, KT

•Biopsy T cell infiltration & antiproximal tubular autoab.









Interstitial Lung Disease

•Rare ,Affecting less than 5%of patients

• It can lead to chronic respiratory failure

•Chronic cough, dyspnea, thoracic pain & recurrent

LRTI

• Lung bx severe peribronchiolar lymphoid infiltrate

•Two autoantibodies :KCNRG, BPIFB1









Other Manifestations

•Asplenia

•Chronic inflammatory demyelinating polyneuropathy

•Sjögren’s syndrome

•Rheumatoid arthritis

•Cutaneous vasculitis


Other Manifestations

•Scleroderma

•Metaphyseal osteodysplasia

•Amyotrophic lateral sclerosis

•Retinal pigment degeneration

•Celiac disease


Asplenia

•Presenting in up to 20 % of adult patients

• Impaired immune responses to encapsulated

bacteria

•Pathogenesis of asplenia remains unknown


Rash with fever

•One of the first signs of APECED

• It usually develops before the age of 5 years

•Skin bx : Presence of vasculitis







• 22 patients from 17 Sardinian families with APS1

• Female/male :13/9

• Median current age : 30.7yr (1.8–46yr)

• Median early disease onset : 3.5 yr (0.3–10 yr)



• Classic triad : 58%

• First sign with CMC : 18 patients

• First sign with HP : 3 patients

• CMC : 95%

• HP :77%

• AD :68%


• Major nonsense mutation, R139X :93%

• Died during follow-up : 3 patients

:Hyperacute AIH (aged 5–12 yr) : 2 patients

:Unrelated HIV infection: 1 patients

Laboratory Evaluation

• Immunologic Evaluation

• Endocrine Work Up

• Gastrointestinal Work Up

• Serum autoantibody Work Up




• Serum autoantibodies Work Up

Picard C, Al-Herz W, Bousfiha A, Casanova JL, Chatila T, Conley ME, et al. Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015. J Clin Immunol. 2015.





Endocrine Work Up





Gastrointestinal Work Up






Husebye ES, Perheentupa J, Rautemaa R, Kampe O. Clinical manifestations and management of patients with autoimmune polyendocrinesyndrome type I. J Intern Med. 2009;265:514–29




Diagnosis


Management

Treatment

•Require continuous hormone replacement therapy

•Calcium and vitamin D supplements

•Systemic antibiotics for candidal infections

• Immunosuppressive therapy


Hormone replacement therapy

•Hydrocortisone 20 mg /day (divided in three dose)

•Cortisone acetate 25 mg /day (divided in three dose)


Calcium and vitamin D supplements

•Elementary Ca 100–500 mg 2–3 daily doses

•Ca-citrate is preferable


Calcium and vitamin D supplements

•Dihydrotachysterol (T½ 7 days)

•Alphacalcidol (T½ 2 days)

•Calcitriol (T½ 1 day)


Antibiotics for candidal infections

•Oral mucositis

: First, 1–2 mL of nystatin suspension oral 4 times daily

: Then, Amphotericin B lozenge oral 4 times daily

for 4 to 6 weeks or for at least 1 week after the

resolution of symptoms



•Recurrent candidosis

: Pulse prophylaxis

: 1-week course of either of the polyenes q 3 week.

: 3 mL of nystatin suspension oral 3 times daily

: Chlorhexidine mouth rinse 2 times daily



• Infected corners of the mouth

: Natamycin

: Amorolphine hydrochloride cream

: Nonalcoholic chlorhexidine gel

: Miconazole gel

several times daily continuing for 4–5 days after the

corners have healed.



•Failure of the topical therapy & Severe oral mucositis

:Fluconazole adults 200–300 mg once daily

for 1-week course of high dose



•Fingernail candidosis

:Amorolphine nail lacquer 40%

:Urea paste with the help of a podiatrist.

:Itraconazole continued for up to 6 weeks.


Immunosuppressive treatments

•Hepatic involvement

•Severe malabsorption




Immunization

• Live virus vaccines must be avoided


General considerations on follow-up

•Regular follow-up serum alanine aminotransferase

(ALT) activity to monitor liver function


General considerations on follow-up

• F/U with endocrinologist and an oral specialist at

least once annually

•An SOS Emergency Bracelet

•Need professional support to avoid depression,

social isolation and alcoholism.


Prognosis




Take Home Message

•Rare autosomal recessive disease

•Autoimmune Regulator (AIRE) gene mutations

Take Home Message

•Diagnosis :based on presence of at least two

out of three ‘‘majors’’ criterions

1. Candidiasis

2. Autoimmune hypoparathyroidism

3. Adrenal insufficiency

Take Home Message

•Hormone replacement therapy

•Candidiasis and other infections should be

carefully screened and treated

Take Home Message

•Potentially letal components :treated by

immunosuppressors

:Hepatitis

:Intestinal malabsorption

Thank You

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Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dysplasia

Health & Medicine