Table 1 Summary of renal disorders in patients with APECED

*

19 patients (out of 27) with nephrocalcinosis (Rows 1–19)

92% of the adults and 54% of children in the cohort had evidence of nephrocalcinosis.

An average rhPTH1-34 dose of 9.6 ± 1.4 µg was administered by subcutaneous injection

Mean calcium levels remained stable and ranged from 2.06 to 2.17 mmol/L with minimal fluctuation.

1

USA

-

F

4

2

-

HP

-

2

USA

-

M

17

8

17

HP

-

3

USA

-

F

9

3

-

HP

-

4

USA

-

F

15

9

10

HP

-

5

USA

-

M

16

13

14

HP

-

6

USA

-

F

17

4

10

HP

-

7

USA

-

M

16

6

15

HP

-

8

USA

-

M

41

9

9

HP

-

9

USA

-

F

37

5

15

HP

-

10

USA

-

F

35

4

-

HP

-

11

USA

-

F

35

1

10

HP

-

12

USA

-

F

28

9

9

HP

-

13

USA

-

F

42

11

18

HP

-

14

USA

-

F

42

7

-

HP

-

15

USA

-

F

21

3

11

HP

-

16

USA

-

F

35

4

4

HP

-

17

USA

-

F

55

3

13

HP

-

18

USA

-

F

54

0.5

10

HP

-

19

USA

-

M

53

6

14

HP

-

20

Turkey

AIRE:

a homozygous frameshift mutation (p.Asp70fs, c.208_209insCAGG) in exon 2, in AIRE gene

M

13

5

10

Autoimmune Diabetes,

PAI

No

21

Portugal

Hemozygosity for the pathogenic variant c.1103dup p. (Leu370Alafs*2), a frameshift mutation resulting in the introduction of a premature stop codon

M

50

-

7

HP, PAI

Bilateral cataracts and recurrent keratitis,

transient alopecia,

onychomycosis,

22

North or

south

America

c.967_979del13 mutation in homozygosity

2 patients

Gender not available

-

-

12.1

HP

Enamel hypoplasia

23

Austria

com-

pound heterozygous mutations in the AIRE-gene, c.931del and

c.967_979de

F

5

-

-

HP

No

24

Ethnicity:

Caucasian

Country:

USA

Allele 1: c.967_979del13

Allele 2: c.1249_1250insC

F

19

11

-

HP, PAI

ENAMEL HYPOPLASIA,

25

Ethnicity:

Caucasian

Country:

USA

Allele 1: c.967_979del13

Allele 2: c.769 C > T

F

10

-

-

HP, PAI

ENAMEL HYPOPLASIA,

26

Italy

a heterozygous R203X mutation, in exon 5 in the SAND domain (amino acid 181–280)

F

7

-

-

chronic thyroiditis,

subclinical hypothyroidism

Alopecia

27

Finland

R257X/R257X

1

-

2

-

Autoimmune thyroiditis, PAI, HP, hypogonadism

Enamel hypoplasia, alopecia

28

Brazil

-

1

28

-

-

HP

Dental enamel and nail dysplasia, corneal keratopathy

29

Ireland

c.967-979del at exon 8

p.L323_L327 > SfsX51

1

12

-

-

HP, PAI

Superior Corneal Vascularization, Reduced Tears

30

Brazil

c.[560 C > G]; [560 C > G]

p.[(Ser187*)]; [(Ser187*)]

1

-

-

-

HP, PAI, hypogonadism

Dental enamel hypoplasia, nail dystrophy, keratopathy

31

Italy

P539L

1

7

-

-

HP, PAI

Enamel hypoplasia l

32

Italy

1058delT and 1058delT

0

23

-

-

HP

Alopecia, Enamel hypoplasia

33

Italy

W78R and W78R

0

42

-

-

PAI, HP

Alopecia, Enamel hypoplasia

34

Italy

W78R and W78R

1

37

-

-

HP, hypogonadism

Alopecia, Enamel hypoplasia

35

Lebanon

c. (132 + 1 133-1) (463 + 1_464-1) del

p. Glu45Alafs*3

0

15

-

-

HP

Nail Dystrophy, Cataract

36

Italy

R203X

1

28

-

-

HP, PAI, POF

-

37

Canada

-

1

29

-

13

Thyroiditis, hypothyroidism, hypogonadism

-

38

Iran

-

1

12

-

-

HP, IDDM

Alopecia universalis

39

Iran

-

0

15

-

-

Thyroiditis, HP, hypothyroidism

Alopecia universalis

40

Iran

c.1236 1237insGCCG

p.Leu414GlyfsX12

1

17

-

-

PAI, HP, POI

No

41

Iran

c.93 94insT

p.Leu32SerfsX3

1

12

-

-

Thyroiditis, PAI, HP, hypothyroidism

Alopecia universalis

42

Iran

c.205 208dupCAGG

p.Asp70AlafsX148

0

35

-

-

PAI, HP

No

43

Turkey

-

1

36

-

-

PAI, HP, ovarian failure

No

44

Finland

-

1

41

-

-

PAI, HP, Ovarian Atrophy

Alopecia Universalis

45

Japan

-

-

-

-

-

Autoimmune thyroiditis, IDDM

-

46

Iran

large homozygous deletion encompassing exons 2– 4 (g.424_2157del1734) in the AIRE gene

1

23

-

-

Thyroiditis, HP, PAI, hypothyroidism

Alopecia, keratitis punctata

47

Netherlands

c.967_979del13+ [(?_68)_(1567-14_? )del]

p.[Cys322fs]+(0?)

0

15

-

-

PAI

No

48

Saudi Arabia

c.845 846insC/ 4q 33 deletion

p.Leu283SerfsX6

0

-

-

-

PAI, HP

Nail dystrophy

49

China

c.206 A > C

p.Q69P

0

21

-

-

PAI, HP

Enamel dysplasia

*

Kidney Transplantations And Clinical Characteristics In Patients With TIN Due To APECED

(Aoos Are The Ages At Kidney Transplantation)

6 Rows Below:

50

Finland

c.769 C > T/ c.769 C > T

F

-

15–20

-

POI,

HP,

PAI

Iridocyclitis

51

Finland

c.967–979del13bp/x

M

-

10–15

-

Hypothyroidism, PAI,

growth hormone deficiency

-

52

Finland

c.769 C > T/c.769 C > T

F

-

20–25

-

Hypothyroidism,

HP,

PAI,

POI

Alopecia

53

Finland

c.769 C > T/c.769 C > T

F

-

25–30

-

PAI,

Hypothyroidism,

HP,

POI

Glaucoma

54

Finland

c.769 C > T/c.769 C > T

F

-

First KT:220–25

Second KT:

50–55

-

PAI,

HP

Alopecia

55

Finland

c.769 C > T/c.769 C > T

F

-

First KT: 45–50

Second KT:

50–55

-

HP, PAI, POI, DM

-

*

N = 30 Patients with Confirmed APECED Syndrome (Percentages Belong to All 30 Patients)

N = 14 Patients with Confirmed APECED Syndrome Who Had Experienced At Least One Kidney/Urinary Tract-Related Symptom During Lifetime (Row 56)

Among The Five Patients with Diminished GFR, Three Women(N = 3) (3/30, 10%) Had A Chronic Renal Failure Related To TIN, Confirmed by A Kidney Biopsy (Rows 57–59)

56

Finland

-

Male :10 Female :20(of all APECED patients available)

Mean (± SD):

40 ± 15.5

Range:

7–68

Mean:

4 ± 3.6

Mean:

8 ± 4.8

HP (83%),

PAI (76%),

Hypogonadism (48%),

Hypothyroidism (33%),

DM-1(16%),

Growth hormone deficiency (6%),

Alopecia areata/hair loss (50%),

Keratitis (23%)

57

Finland

the

Finn major AIRE mutation (R257X×2)

F

48

-

20

-

-

58

Finland

the

Finn major AIRE mutation (R257X×2)

F

27

-

16

-

-

59

Finland

the

Finn major AIRE mutation (R257X×2)

F

12

-

9

-

-

60

Ethnicity:

Caucasian

Country:

Poland

-

F

14

9

-

HP,

subclinical Hashimoto’s disease

Dental enamel hypoplasia

*

19 patients (out of 27) with nephrocalcinosis (Rows 1-19)

92% of the adults and 54% of children in the cohort had evidence of nephrocalcinosis.

An average rhPTH1-34 dose of 9.6 ± 1.4 µg was administered by subcutaneous injection

Mean calcium levels remained stable and ranged from 2.06 to 2.17 mmol/L with minimal fluctuation.

[10]

1

-

-

Nephrocalcinosis

25-OH-Vit D, rhPTH 1-34

-

-

[10]

2

-

-

Nephrocalcinosis

25-OH-Vit D, rhPTH 1-34

-

-

[10]

3

-

-

Nephrocalcinosis

25-OH-Vit D, rhPTH 1-34

-

-

[10]

4

-

-

Nephrocalcinosis

25-OH-Vit D, rhPTH 1-34

-

-

[10]

5

-

-

Nephrocalcinosis

25-OH-Vit D, rhPTH 1-34

-

-

[10]

6

-

-

Severe Nephrocalcinosis

25-OH-Vit D, rhPTH 1-34

-

-

[10]

7

-

-

Nephrocalcinosis

25-OH-Vit D, rhPTH 1-34

-

-

[10]

8

-

-

Nephrocalcinosis

25-OH-Vit D, rhPTH 1-34

-

-

[10]

9

-

-

Nephrocalcinosis

25-OH-Vit D, rhPTH 1-34

-

-

[10]

10

-

-

Severe Nephrocalcinosis

25-OH-Vit D, rhPTH 1-34

-

-

[10]

11

-

-

Severe Nephrocalcinosis

25-OH-Vit D, rhPTH 1-34

-

-

[10]

12

-

-

Nephrocalcinosis

25-OH-Vit D, rhPTH 1-34

-

-

[10]

13

-

-

Nephrocalcinosis

25-OH-Vit D, rhPTH 1-34

-

-

[10]

14

-

-

Nephrocalcinosis

25-OH-Vit D, rhPTH 1-34

-

-

[10]

15

-

-

Severe Nephrocalcinosis

25-OH-Vit D, rhPTH 1-34

-

-

[10]

16

-

-

Moderate Nephrocalcinosis

25-OH-Vit D, rhPTH 1-34

-

-

[10]

17

-

-

Moderate Nephrocalcinosis

25-OH-Vit D, rhPTH 1-34

-

-

[10]

18

-

-

Moderate Nephrocalcinosis

25-OH-Vit D, rhPTH 1-34

-

-

[10]

19

-

-

Severe Nephrocalcinosis

25-OH-Vit D, rhPTH 1-34

-

-

[10]

20

Yes

JIA, recurrent oral candidiasis, chronic diarrhea,

Generalized hyperpigmentation,

necrotizing pneumonia and lung abscess,

functional hyposplenism,

Eosinophilic ileitis and focal active colitis,

Autoimmune enteropathy

TIN

-

Steroids,

Antibacterial therapy and prophylaxis, antifungal,

IVIG, insulin, sodium bicarbonate therapy,

azathioprine, and sirolimus

Alive

[11]

21

Yes

generalized tonic-clonic seizures,

ocular disorders, chronic, gastritis, extraskeletal calcifications,

cholelithiasis,

weakness, musculoskeletal pain, fatigue, nausea, anorexia,

weight loss, dyspepsia, dysphagia (even under esomeprazole), constipation,

flatulence, occasional paresthesia in the extremities, mucocutaneous hyperpigmentation,

a Bethesda IV thyroid nodule

Nephrolithiasis

elemental calcium (calcium lactate gluconate and calcium carbonate), calcitriol

selective laser trabeculoplasty,

topical minoxidil,

hemithyroidectomy,

cholecystectomy,

Antifungal therapy,

 hormonal replacement:

hydrocortisone,

mineralocorticoid replacement,

oral fluconazole

topical treatment with ciclopirox olamine for onychomycosis,

levothyroxine, esomeprazole

Alive

[12]

22

yes

unattributable

Tubulointerstitial Nephritis

-

-

-

[13]

23

No

mild chronic diarrhea since infancy, generalized tonic-clonic seizures

Mild Hypercalciuria

(To Date, Not Seen AnySigns of Nephrocalcinosis or Nephrolithiasis)

high-dose therapy with oral calcium,alfacalcidol , recombi-nant rhPTH

-

Alive

[14]

24

No

chronic colitis, Ovarian failure, pneumonitis, hypertension

Tubulointerstitial Nephritis

-

Azathioprine,

MPS

-

[15]

25

Yes

gastritis, pneumonitis,alopecia, hypothyroidism, Sjogren’s-like syndrome

Tubulointerstitial Nephritis

-

MMF, Azathioprine

-

[15]

26

-

episodic weakness, chronic vaginal mycosis, stomach pains

LKM Ab Positive with No Other Renal Dysfunction.

-

-

-

[16]

27

Yes

tongue SCC in situ

Tubulointerstitial Nephritis

-

SCC radical resection, Photodynamic therapy

-

[17]

28

Yes

malabsorption, bronchiectasis, pernicious anemia, autoimmune thrombopenia, autoimmune gastrointestinal disease)

Tubulointerstitial Nephritis

-

-

-

[18]

29

Yes

Epilepsy

Recurrent UTI

-

-

-

[19]

30

Yes

pernicious anemia, autoimmune thrombopenia, intestinal dysfunction

Nephropathy (no further details)

-

-

-

[20]

31

Yes

-

Nephrocalcinosis, Multicystic Left Kidney

-

-

-

[21]

32

Yes

malabsorption

Nephrocalcinosis

-

-

-

[21]

33

Yes

Tympanic calcifications, Nephrocalcinosis, esophageal carcinoma, optic nerve atrophy, Atrophic gastritis, Cataract, chorioretinitis

Nephrocalcinosis

-

-

-

[21]

34

Yes

Sjogren's syndrome

Atrophic gastritis, Cataract

Nephrocalcinosis

-

-

-

[21]

35

Yes

Hepatitis

autoimmune hepatitis

Nephrocalcinosis

-

Azathioprine

-

[22]

36

No

Epilepsy

Nephrocalcinosis

-

-

-

[23]

37

-

arthritis

Nephrocalcinosis

-

-

-

[24]

38

Yes

vit B12 deficiency

Nephrocalcinosis

-

-

-

[25]

39

Yes

celiac disease,

iridiocyclitis

Nephrocalcinosis

-

-

-

[25]

40

Yes

-

Nephrocalcinosis

-

-

-

[25]

41

Yes

-

Nephrocalcinosis

-

-

-

[25]

42

Yes

-

Nephrocalcinosis

-

-

-

[25]

43

No

Asplenism, pernicious anemia, autoimmune thrombopenia, corneal vascularization,corneal scarring

Nephrolithiasis

-

prednisone, prednisolone acetate

-

[26]

44

Yes

SCC,

TIN

-

-

-

[27]

45

-

Intestinal dysfunction, autoimmune hepatitis

Glomerulonephritis

-

-

-

[28]

46

Yes

generalized seizures, severe cerebral atrophy and an arachnoid cyst of the posterior fossa, myocardiopathy, pernicious anemia, autoimmune thrombopenia, sicca syndrome, chronic diarrhea, exocrine pancreatic insufficiency,

ESRD, TIN

-

-

-

[29]

47

Yes

chronic/tension headache

Tubulointerstitial Nephritis

-

-

-

[30]

48

Yes

craniofacial features, FTT, Diffuse cerebellar atrophy, profound psychomotor retardation, recurrent vomiting

Glomerulonephritis

-

-

-

[31]

49

Yes

fatigue and hypercalcemic tetany, vertigo, chronic intestinal dysfunction, binocular cataract

Glomerulonephritis

-

Steroid therapy

-

[32]

*

Kidney Transplantations And Clinical Characteristics In Patients With Tubulointerstitial Nephritis Due To APECED

 (Aoos Are The Ages At Kidney Transplantation)

 6 Rows Below:

50

Yes

rash with fever

Infections requiring hospitalization:

Mastoiditis; Pyelonephritis Proteus mirabilis

Tubulointerstitial Nephritis

-

immunosuppressive treatment:

Basiliximab + CsA + MMF + steroids

anti-CD20 therapy

At the age of 19 y alive with functioning graft (mGFR, 39 mL/min)

[33]

51

Yes

rash with fever,

AIHA,

Hepatitis,

exocrine pancreas insufficiency

Tubulointerstitial Nephritis

-

immunosuppressive treatment:

CsA+ Aza+ steroids

Deceased at 19 y with a functioning graft

[33]

52

Yes

Hyposplenia

Epithelial carcinoma of tongue, Infections requiring hospitalization:

Pneumocystis carinii, campylobacter jejuni

Tubulointerstitial Nephritis

-

immunosuppressive treatment:

CsA + Aza+ steroids

At the age of 54 y alive with functioning graft (eGFR, 71 mL/min)

[33]

53

Infections requiring hospitalization:

; Escherichia coli pyelonephritis; Cholecystitis, peritonitis and E coli septicemia.

Tubulointerstitial Nephritis

-

immunosuppressive treatment:

CsA+ MMF + steroids

At the age of 33 y alive with functioning graft (eGFR, 36 mL/min)

[33]

54

Yes

atrophic gastritis

Infections requiring hospitalization:

Enterococcus faecalis pyelonephritis; Staphylococcus aureus septicemia

Tubulointerstitial Nephritis

-

immunosuppressive treatment:

CsA + Aza+ steroids

After second KT:

Tac + MMF + steroids

Return to dialysis in 2013

Deceased at 58 y with a functioning graft (eGFR, 25 mL/min)

[33]

55

Yes

-

Tubulointerstitial Nephritis

-

immunosuppressive treatment:

CsA + MMF + steroids

After second KT:

Basiliximab + Tac + MMF + steroids

Graft removed 1 y post-KT

Deceased at 56 y with a functioning graft (eGFR, 70 mL/min)

[33]

*

N=30 Patients with Confirmed APECED Syndrome (Percentages Belong to All 30 Patients)

N=14 Patients with Confirmed APECED Syndrome Who Had Experienced At Least One Kidney/Urinary Tract-Related Symptom During Lifetime (Row 58)

Among The Five Patients with Diminished GFR, Three Women(N=3) (3/30, 10%) Had A Chronic Renal Failure Related To TIN, Confirmed by A Kidney Biopsy (Rows 59-61)

56

Yes,

96%

11 patients with HTN,

Asplenia (30%),

Vitiligo (23%),

Pernicious anemia (6%),

Autoimmune hepatitis (6%),

14 UTI,

2 Nephrolithiasis,

2 Nephrocalcinosis,

2 RTA,

3 TIN,

2 Diabetic Nephropathy

-

-

-

[8]

57

-

-

A Chronic Renal Failure Related To TIN

(A Renal Transplantation (33 Y/O))

-

cyclosporine

Alive

[8]

58

-

HTN

TIN With Nephrocalcinosis

-

-

Alive,

currently on hemodialysis

[8]

59

-

-

TIN,

RTAType 1

-

Supportive treatment by sodium bicarbonate,

Mycophenolatemofetil (MMF),

rituximab

Alive,

progressiveworsening of kidney function

[8]

60

Yes,

Oral candidiasis

syncope andseizure,

Nephrocalcinosis

calcium supplementation and 1-α-hydroxycholecalciferol administration

-

-

[34, 35]