1. Immune Conference By NTUH Ped.R2 鄭嘉琪 /VS. 楊曜旭 /P 江伯倫, 周正成

2. C.C Abnormal liver function for 2+ years

3. Brief Hx 1. Birth history: G1P1, GA: 42wks, NSD, BW: 3780gm, PROM (-), DOIC (-), perinatal insult (-), neonatal hyperbilirubinemia (-) 2. Vaccination: As scheduled, Hibx3. 3. G & D: BW: 43kg ( 25-50 th percentile) BH: 144cm ( 3-10 th percentile) DMS: WNL 4. Maternal history: n.p 5. Previous history: n.p 6. Family history: no contributory

4. P.I. 1993 (4y/o) in 高醫 hospital ‧ Several episodes of GTC ‧ Hypocalcemia Hypoparathyroidism(PTH<8pg/ml) -Ca. carbonate 5# qd and calcitriol 5# qd 1997 (8y/o) ‧ Frequent infections (HSV, oral thrush, submandibular cellulitis); pneumonia r/o sepsis -> admitted 高醫 hospital T-cell immune deficiency was found

5. P.I. 2000 ( 11 Y/O) -> Admitted to 高醫 hospital Hypoparathyroidism & hypocalcemia T3,T4, TSH, ACTH and cortisol: WNL T cell & B cell number: WNL T cell & B cell function: WNL Total T cell:74.2; Active T cell:27.29 Total B cell: 20.42 CD4 36.13; CD8:28.79

6. P.I. 2000 ( 11 Y/O) Impaired liver function GOT/GPT: 97/104; Bil(T/D): 1.53/0.49 ‧ Gallstone and medullary nephrocalcinosis Anemia: IDA or chronic dx related 2002.4(13y/o) -> 小港 hospital Abnormal liver function Amnonia:195;GOT/GPT:403/411; Bil(T/D):6.79/5.63; ALP:1464; γ-GT:67

7. Nail onychomycosis Nail dystrophy

8. Brief hx Summary 13 y/o 7 m/o boy : (1) GTC-> Hypocalcemia-Hypoparathyroidism since 4 y/o,1993, s/p Ca and Vit D3 supplement (2) Chronic mucocutaneous candidiasis (oral thrush, onychomycosis), viral infection (3) Vitiligo, enamel hypoplasia, nail dystrophy (4) Anemia, cause to be determined since 8y/o, 1997 (5) Impaired liver function since 11y/o, 2000 (6) Gallstones and nephrocalcinosis since 11y/o, 2000

9. Our Work Up

10. Hypocalcemia 24hr Ca2+ excretion: 1.75mg/kg/day 24hr CCR: 145.2 cc/min/1.73m2 Urinary Ca/Cr ratio: 0.09 24hr Mg2+excretion: 0.05mmol/kg/day % TRP: 98.2% iPTH < 1 pg/ml 2002.7.2CaPMgCre Serum1.549.50.730.5 Urine3.5951.64.14152.2

11. D/D of Hypocalcemia Parathyroid hormone (PTH) deficiency PTH receptor defects (pseudohypoparathyroidism) Ca 2+ -sensing receptor activating mutation Magnesium deficiency Exogenous inorganic phosphate excess Vitamin D deficiency

12. D/D of PTH deficiency * Aplasia or hypoplasia of parathyroids & DiGeorge syndrome ; Velocardiofacial syndrome * Surgery * Autoimmune parathyroiditis & Autoimmune Polyendocrinopathy-Candidiasis- Ectodermal Dystrophy (APECED)(APS type I) & Wilson disease * Idiopathic hypoparathyroidism

13. R/O DiGeorge syndrome Parathyroid glands aplasia/ hypoplasia → hypoparathyroidism (+) Thymus aplasia/ hypoplasia (?) → T-cell immunity deficiency (+) ‧ Congenital heart disease (atrial and ventricular septal defects) (-) ‧ Anomalies of the great vessels (-) ‧ Facial anomalies: (-) ‧ Chromosome: normal

14. Autoimmune Polyendocrinopathy-Candidiasis- Ectodermal Dystrophy (APECED)(APS type I) Chronic mucocutaneous candidiasis (CMC) Hypoparathyroidism Addison’s disease Other associated disorders

15. CMC- Immunodeficiency ? T.B cell amount( 07/05 ): WNL IgG, IgA, IgM: WNL T cell: 82; B cell: 9, NK cell:7; CD8:32, CD4:44; Native23; Memory:21. Mitogen stimulation test (proliferation ): normal Candida delayed skin test: (-) Induration< 1 cm at 48 hour & 72 hour T cell function to candida: decreased B-cell function: blood type: O ; Anti-A Titer, Anti-B Titer: WNL

16. APECED Other associated disorders Endocrine components Prevalence % Non-endocrine components Prevalence % Ovarian failure60Enamel hypoplasia77 IDDM18Nail dystrophy52 Testicular atrophy14T.M calcification33 Parietal cell atrophy13Alopecia27 Hypothyroidism6Keratopathy22 Non- endocrineVitiligo13 CholelithiasisrareAutoimmune Hepatitis 13 AsplenismrareIntestinal malabsorption 10

17. APECED- Other Endocrinopathy w/u Cortisol, ACTH: WNL Anti-microsomal Ab, thyroglobulin Ab: (-) T3, T4, free T4, hs TSH:WNL FSH, LH, and testosterone: WNL HbA1C, AC sugar: WNL Gastric parietal cell Ab (-) Anti-parathyroid Ab: (-)

18. D/D of chronic hepatitis Chronic viral hepatitis HAV, HBV, HCV, EBV, CMV infection evidence Drug induced hepatitis Metabolic disorder associated with chronic liver dx Autoimmune hepatitis elevated liver enzyme, ANA(+), biopsy: chronic hepatitis, negative viral infection

19. Chronic Hepatitis w/u Liver span: 2fb below RCM Anti-HAV; HbsAg, AntiHbs-Ag;Anti- HCV(-) EBV: no recent infection CMV IgM, IgG: (-) Ceruloplasmin : WNL Elevated liver enzyme Autoimmune hepatitis: anti-smooth muscle Ab(-) and ANA (+) Liver echo: increased echogenicity, gallstone.

20. Chronic hepatitis Piece-meal necrosis Limiting plate disruption Enlarged portal area

21. Work up Summary at NTUH Definite diagnosis * Hypoparathyroidism * Nephrocalcinosis * Chronic mucocutaneous candidiasis (CMC) * T cell immunodeficiency * Ectodermal dystrophy: vitiligo, enamel hypoplasia, nail dystrophy * Chronic hepatitis (autoimmune hepatitis) * Anemia Combined hypoparathyroidism,CMC,and chronic hepatitis in OMIM -> Tentative Dx: APECED

22. Discussion

23. Autoimmune Polyendocrinopathy-Candidiasis- Ectodermal Dystrophy (APECED)(APS type I) Chronic mucocutaneous candidiasis (70%, <5 y/o) Hypoparathyroidism (90%, >3 y/o) Addison’s disease (90%, > 6 y/o) Other associated disorders AIRE(autoimmune regulator) gene mutation

24. Chronic mucocutaneous candidiasis Oral thrush, onychomycosis without disseminated candidiasis (cause ?)

25. In our patient Autoimmune hepatitis: Steroid full dose for autoimmune process -> f/u liver function and immune profile at OPD CMC: Give topical anti-candida drug Hypoparathyroidism: Keep Ca and vit D3, nutrition education of Ca & P balance for prevention of nephrocalcinosis progression -> check level and f/u renal echo per year Educate the patient about possible disorders in the future, like Addison’s disease and adequate mx

26. OPD f/u GOTGPTALPLDHCaPAm- monia ANAmedication 7/2896413975991.549.5861:640nil 7/15182916575531.634.8671:40-Predonine Sandimmun Oral thrush 7/22888917385811.380.4Predonine, Sandimmun, Imuran 8/124291.426.8 8/330328621.0110. 8/5323510736141.387.5Imuran, Predonine

27. Reference Behrman: Nelson Textbook of Pediatrics, 16th ed Goldman: Cecil Textbook of Medicine, 21st ed. Wilson: Williams Textbook of Endocrinology, 9th ed. The Pediatric Infectious Dis. J. 2001;20;197-206 Current Opinion in Infectious Dis. 2002,15:143-147 The Journal of Clinical Endocrinology & Metabolism 87(6):2568-2574 Human Molecular Genetics Pages 1547-1553

28. Thank for Your Attention!