Open Access

Late-onset of immunodysregulation, polyendocrinopathy, enteropathy, x-linked syndrome (IPEX) with intractable diarrhea

  • Daniele Zama1Email author,
  • Ilaria Cocchi1,
  • Riccardo Masetti1,
  • Fernando Specchia1,
  • Patrizia Alvisi2,
  • Eleonora Gambineri3, 4,
  • Mario Lima5 and
  • Andrea Pession1
Italian Journal of Pediatrics201440:68

DOI: 10.1186/s13052-014-0068-4

Received: 17 April 2014

Accepted: 7 July 2014

Published: 18 October 2014

Abstract

The syndrome of immune dysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) is a rare disorder caused by mutations in the FOXP3 gene. Diarrhea, diabetes and dermatitis are the hallmark of the disease, with a typical onset within the first months of life. We describe the case of a twelve-year old male affected by a very late-onset IPEX with intractable enteropathy, which markedly improved after starting Sirolimus as second-line treatment. This case suggests that IPEX should always be considered in the differential diagnosis of watery intractable diarrhea, despite its unusual onset.

Keywords

Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) Sirolimus Forkhead box P3 (FOXP3)

Correspondence

The syndrome of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) is a rare disorder, characterized by diarrhea, type-1 diabetes mellitus (T1DM) and dermatitis with onset within the first months of life [1],[2]. Diarrhea is intractable and persists despite dietary exclusions and bowel rest, resulting in malabsorption and failure to thrive [3]; T1DM can precede or follow enteritis [4]-[6]; dermatitis is severe with eczematiform, ichthyosiform or psoriasiform aspects [7]-[10], other autoimmune diseases are often associated [11].

IPEX is caused by germ-line mutations in the FOXP3 gene, a key regulator of immune tolerance, located in the X-chromosome at Xp11.23-Xq13.3 [12]-[17]. It is critical for the function of CD4+CD25+ regulatory T-cells (TREG) and for the maintenance of peripheral immunologic tolerance [17],[18].

Findings

We describe a 12-year-old boy born at term from natural birth after an uncomplicated pregnancy from unrelated parents, referred to our hospital for severe enteritis started one month before with liquid mucus-haematic diarrhoea (height: 50th centile, weight: 10th centile, regularly vaccinated). No potentially triggering events have been reported, such as vaccinations, viral infections or changes in nutrition. In his past history he had recurring episodes of mild atopic dermatitis since the first year of life, a high level of total IgE (400 UI/L), and a constipated bowel (once every two/three days).

On admission, he was dehydrated (7% of weight loss). Blood tests revealed hypoproteinaemia and hypogammaglobulinemia (Table 1), so albumin was replaced.
Table 1

The molecular and clinical features of the patient with IPEX who received sirolimus have been reported

Patient

Mutation

Clinical features

Histology

Management

Outcome

Ref.

 

Age at onset age at dg

Nucleotide change

AA change

FOXP3

Molecular defect

Previous therapy

SIR

HSCT

1

7 y 10 y

c.968-20A>C

NA

NA

NA

Dermatitis, enteropathy

Lymphoplasmocellular eosinophilic infiltrate. Villous atrophy.

Steroids, AZA, CsA, FK, MTX. TPN, Total colectomy at 10 y

Y

N

Stable at 16 yr on SIR+MTX.

[19]

2*

2 m NA

NA

Enteropathy, erythematous eczema-like dermatitis

Lymphoplasmocellular infiltrate with marked eosinophilia. High rate of enterocyte apoptosis. Subtotal villous atrophy.

Steroids, FK, AZA

Y

N

Stable for 1.5 yr on SIR+AZA

[19]

3*

2 m NA

NA

Enteropathy, erythematous eczema-like dermatitis

Similar findings with that of his brother (pt.4)

Steroids, FK; AZA

Y

N

Stable for 6 m on SIR+AZA

[19]

4

2 y 4 y

1061 delC

Frameshift P354Q

NA

Premature stop codon. Truncated FKH domain

Enteropathy, nonspecific dermatitis

Mild villous blunting

Metronidazole, steroids, mesalamine, IFX, AZA, 6-MP

Y

N

Stable at 7 yr

[20]

5

1 w 7 y

200G>T

Q70H

NA

Predicted abnormal reading frame

Eczema, enteropathy, AHA, ITP, arthritis

Inflammation with villous atrophy

IVIG, steroids, TPN, antibiotics

Y

N

Stable at 8 yr

[20],[21]

6*

3 w NA

g.-6247-4859del

NA

Accumulation of unspliced mRNA

Skin/food allergies, Enteropathy, erythematous- eczematous skin rash

Lymphoplasmocellular infiltrate with marked eosinophilia. High rate of enterocytes apoptosis. Severe to total villous atrophy

Steroids, FK, AZA TPN

Y

N

Stable for 6 yr on SIR+AZA

[22]

7*

2 m NA

g.-6247-4859del

NA

Accumulation of unspliced mRNA

Skin/food allergies, Eczema, Enteropathy

NA

Steroids, FK, AZA TPN

Y

N

Stable for 4 yr on SIR+AZA

[22]

8

5 w NA

g.-6247-4859del

NA

Accumulation of unspliced mRNA

Enteropathy, Eczema, Allergy

NA

Steroids, FK, AZA

Y

N

Stable at 9 yr on SIR+AZA

[23]

9

3 w NA

g.-6247-4859del

NA

Accumulation of unspliced mRNA

Enteropathy, Eczema, HP gastritis, Allergy

NA

Steroids, FK AZA

Y

N

Stable at 6 yr on SIR+AZA

[23]

10

Birth NA

g.-1121 T>G

F374C

Full length FOXP3 with abnormal FKH domain

T1DM, HTH, Enteropathy, Eczema, AHA, ITP, Allergy.

NA

Steroids, FK506

Y

N

Died at 14 m during HSCT induction

[23]

11

6 w NA

751-753 del GAG

E251del

Disrupts FOXP3 oligomerisation

Enteropathy, Eczema, HTH, Interstitial Nephritis, AHA, Allergy.

NA

FK506

Y

Y

Died at 10 yr after HSCT

[23]

12

1 m 6 y

1150G>A

A384T

Full length FOXP3 with abnormal FKH domain

Enteropathy, Eczema, FTT, T1DM, AHA, Interstitial Pneumonia, Alopecia, Thyroiditis.

Eosinophil infiltration without villous atrophy

IVIG, CsA, steroids, TPN, fludarabine-autologous lymphocytes, FK, MTX, Rituximab, cyclophosphamide.

Y

N

Stable at 16 yr on others drugs

[4],[24],[25]

13

Birth 7 w

1150G>A

A384T

Full length FOXP3 with abnormal FKH domain

Enteropathy, T1DM, Exfoliative Dermatitis, HTH, Pancytopenia

NA

TPN

Y

N

Died at 7 w

[26]

14

Birth 4½ y

AAUAAA/AAUAAG

NA

Polyadenylation defect resulting in unstable FOXP3 mRNA

Enteropathy, Dermatitis, FTT, T1D.

NA

MTX, steroids, TPN.

Y

Y

Stable at 1 yr

[27]

15

1 w

1015C>G

P339A

Missense mutation. Predicted to yield full length FOXP3

Enteropathy, Eczema, T1DM, FTT, Euthyroid Thyroiditis, AIH, AHA

Villous atrophy

Steroids, FK; AZA

Y

N

Died at 5.5 m before HSCT

[28]

16

3 m 1y

Exon 10

NA

NA

NA

FTT, Enteropathy, Eczematous Dermatitis, ITP stomatitis

NA

Cyclophosphamide, VCR, TPN

Y

N

Stable 2½ yr on other drugs

[29]

*Brothers; 6-MP 6-Mercaptopurina; AHA autoimmune haemolytic anaemia; AIH Autoimmune hepatits; AZA Azathioprine; CsA Cyclosposporine; FTT: failure to thrive; FK: tacrolimus; HSCT hematopoietic stem cell transplantation; HTH Hypothyroidism; IFX Infliximab; ITP immune thrombocytopenic purpura; IVIG Intravenous Immunoglobulin; Y: Yes; yr: years; m: months; MTX Methotrexate; NA Not Available; N: No; Ref. References; SIR Sirolimus; T1DM Type 1 Diabetes mellitus; TPN Total Parenteral Nutrition; VCR Vincristine; w: weeks; ↓: reduction of expression.

Abdominal ultrasound highlighted wall thickening of the bowel loops. Esophagogastroduodenoscopy (EGDS) and colonoscopy revealed ulcerative lesions at the stomach, duodenum, terminal ileum and colon, giving rise to a suspect of inflammatory bowel disease. Biopsies revealed villous blunting and inflammatory infiltration of the mucosa. After starting intravenous methylprednisolone, metronidazole and parenteral nutrition a partial remission was observed.

Ten days later, for a worsening of symptoms, EGDS and colonoscopy were repeated, with a superimposable picture. Particularly, the biopsies of the colon showed lympho-granulocytic acute inflammation with Graft versus Host Disease-like aspect, a lesion typically reported in IPEX (Figure 1) [30]. Due to the inability to control the symptoms the patient underwent ileostomy.
https://static-content.springer.com/image/art%3A10.1186%2Fs13052-014-0068-4/MediaObjects/13052_2014_Article_68_Fig1_HTML.jpg
Figure 1

Biopsy of the colon mucosa highlights a marked inflammatory infiltrate. (A: H&E 5x) with a GVHD-like aspect characterized by a prevalence of lymphocytes CD8+ (red; B) than lymphocytes CD4+ (red; C). Rare lymphocytes expressing FOXP3 were found (red; D).

Despite the age of the patient was atypical for the onset of IPEX, we evaluated the presence of autoantibodies to harmonin, which resulted positive (>100 U.A.). Then, diagnosis was confirmed by the genetic examination of FOXP3 gene, revealing a mutation in the exon 9 (1040G > A), with substitution of Arginine to Histidine (R347H). The mother resulted negative. The total number of lymphocyte and lymphocyte subpopulations was normal, particularly TREG were 5% of the total number.

Intravenous cyclosporine (range: 200-350 mg/dl) and methylprednisolone (2 mg/kg) were started, which reduced diarrhea and abdominal pain. After sixty days of parenteral nutrition the patient returned to oral feeding with the normalization of albumin levels (Table 1). Because of the onset of post-prandial hyperglycaemias, we excluded T1DM (Table 1) and glycaemia normalized after tapering steroid therapy. For a new worsening of the disease we introduced sirolimus (0.15 mg/kg/day; range: 8-12 mg/dl). The patient improved with a progressive reduction of intensity and frequency of abdominal pain and mucus emission. A new colonoscopy highlighted a marked decrease of the inflammation. After thirty-four days since the beginning of sirolimus, cyclosporine was suspended. After twelve months the patient is well, without recurrence of the disease.

Conclusions

This case indicates that IPEX can have an atypical age of presentation. Thus, it should always be considered in the differential diagnosis of intractable diarrhea.

Four patients have been previously reported with IPEX with the same amino-acid substitution (R347H) found in our patient. The age of onset for all these subjects was within the first year of life and the first symptoms were recurrent ear infection, high IgE levels, T1DM, and gastritis. All had gastrointestinal symptoms with failure to thrive: two intractable diarrhea, two severe gastritis with mucosal atrophy or eosinophilic infiltration. Other symptoms were: coombs-negative haemolytic anaemia, food allergy, pancreatic exocrine failure, intractable hypertension, intestinal metaplasia, steatorrhea, and hypogammaglobulinemia. Patients received corticosteroid and calcineurin inhibitors. One patient died after allogeneic hematopoietic stem cell transplantation (HSCT) due to an infection.

Recently, evidence that patients with a severe form of IPEX may have circulating FOXP3+ T cells, as it is the case of our patient, which suggests that the cellular basis for the disease may be a result of a functional defect of Treg cells [1],[26]. Mainly, R347H mutated-FOXP3 has been demonstrated as effective as wild-type-FOXP3 in converting normal T cell into Treg in vitro [31] and in maintaining the ability to suppress the production of cytokines, hallmark of Treg cells, conferring suppressive capacity on CD4+ T cells.

In 2005, three patients were successfully treated with sirolimus [19]. Since then, 16 patients received sirolimus and nine are in complete or partial remission (Table 2). Considering that sirolimus seems to be as effective as the calcineurin inhibitors, with less toxic effects, it can be considered as a valid therapeutic option for bringing these patients to HSCT in their best clinical condition.
Table 2

Variables of our patient at the time of admission to our hospital, when he started the second line therapy with Sirolimus and after three months since the begging of this therapy

Variables

Reference range, age and sex-adjusted

Admission

Start SIROLIMUS

3 months after SIROLIMUS

White-cell count — per mm 3

4.5 - 13.5

15.01

4.04

5.01

Hemoglobin — g/dl

11.5 - 14.5

16.3

11.7

11.5

Hematocrit —%

35 - 42

46.0

34.4

35.7

Differential count —%

    

Neutrophils

40.0 - 74.0

89.6

51.2

48.0

Lymphocytes

19.0 - 48.0

6.6

30.3

38.0

Monocytes

3.0 - 9.0

2.4

13.5

7.6

Eosinophils

0.0 - 6.0

0.4

1.7

4.4

Basophils

0.0 - 1.5

0.3

1.1

0.7

Platelet count — per mm 3

250 - 550

522

247

273

Glucose — mg/dl

60 - 100

125

107

77

Insulinemia — microU/mL

7 - 24

 

6.8

 

C-peptide — ng/mL

1.1 - 4.4

2.7

 

Islet cell autoantibodies

Neg

Neg

Neg

Glutamic acid decarboxylase— UI/ml

<10 Neg

Neg

Neg

 

>10 Pos

   

UREA — mg/dl

15 - 50

72

40

18

Creatinine — mg/dl

0.5 - 1

0.91

0.54

0.35

Uric Ac. — mg/dl

2.2 - 6.6

8.6

5.2

3.4

Total Colesterol — mg/dl

130 - 204

 

121

 

TG — mg/dl

31 - 108

40

HDL — mg/dl

> 35

62

LDL — mg/dl

< 170

50

Electrolytes — mmol/L

    

Sodium

136 - 146

128

139

142

Potassium

3.5 - 5.3

5.5

4.3

4.3

Chlorine

98 - 106

85

103

105

Calcium

8.8 - 10.8

9.6

9.3

9.2

Phosphorus — mg/dl

2.9 - 5.4

7.6

5

4.4

Magnesium — mg/dl

1.6 - 2.6

2.2

1.6

2.1

Plasma Osmolarity — mOsm/L

278 - 305

266

  

Protein — g/dl

    

Total

6,4 - 8.1

4.1

6.2

6.7

Albumin

3.5 - 5

2.4

4.2

4.3

γ–Globulin —%

11.1 - 18.8

10.5

11.4

13.4

Bilirubin — mg/dl

    

Total

0.20 - 1.10

1.54

0.44

0.3

Direct/Indirect

0.00-0.30/< 0.80

0.48/1.06

0.21/0.23

0.1/0.2

AST/ALT — U/L

< 38/< 41

44/34

16/10

22/17

Total Amylase — U/L

30 - 100

50

60

 

Iron — μg/dl

53 - 119

 

47

52

U.I.B.C./T.I.B.C. — μg/dl

110-330/250-400

300/347

273/325

Ferritin — ng/mL

7 - 140

22

16

TSH — microU/mL

0.6 - 6.3

 

1.93

1.02

FT3 — pg/mL

2.5 - 5.5

3.6

4.1

FT4 — pg/mL

9.0 - 17.0

20.7

12.9

ATA — UI/mL

< 115

23

16

Anti TPO Ab — UI/mL

< 34

12

13

ESR — mm

< 15

6

15

9

CRP — mg/dl

< 0.5

0.05

2.05

0.09

Ab anti harmonine IgG — U.A.

< 3.0 absent

 

>100

 

> 0.3 present

ANA

< 1:80

 

< 1:80

 

AMA

< 1:40

 

< 1:40

ENA

< 0,7 Neg

 

Neg

 

0.7 - 1-0 Bl

  
 

> 1.0 Pos

  

ALT Alanine aminotransferase, AMA Anti-mitochondrial antibodies, ANA Antinuclear antibodies, anti-TPO Ab Anti-ThyroidPeroxidase Antibodies, AST aspartate aminotransferase, ATA Anti-Thyroglobulin Antibodies, Bl Borderline, CRP C-reactive protein, ENA Extractable Nuclear Antigens, ESR erythrocyte sedimentation rate, FT3 Free Triiodothyronine, FT4 Free Thyroxine, HDL High-Density Lipoprotein, LDL Low-Density Lipoprotein, Neg Negative, Pos Positive, T.I.B.C. Total iron-binding capacity, TG triglycerides, TSH Thyroid-Stimulating Hormone, U.I.B.C. Unsaturated Iron Binding Capacity.

Consent

Written informed consent was obtained from the parents of the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Ethical approval

Internal ethical committee of Sant-Orsola approved the study.

Authors’ contributions

ZD and IC reviewed relevant articles on the literature, collected all the patient’s data and drew the manuscript. FS and PA contributed to the diagnosis and provided clinical assistance. RM, ML and AP contributed to the conception and design, and revisited critically the manuscript. EG carried out the molecular genetic studies and drafted the manuscript. All authors read and approved the final manuscript.

Abbreviations

IPEX: 

Syndrome of immune dysregulation, polyendocrinopathy, enteropathy, X linked

T1DM: 

Type-1 diabetes mellitus

EGDS: 

Esophagogastroduodenoscopy

FKH: 

Forkhead/winged helix domain

mTOR: 

Mammalian target of rapamycin

HSCT: 

Hematopoietic stem cell transplantation

Declarations

Authors’ Affiliations

(1)
Pediatric Oncology and Haematology Unit “Lalla Seràgnoli”, Department of Pediatrics, University of Bologna Sant’Orsola-Malpighi Hospital
(2)
Pediatric Department, Maggiore Hospital
(3)
Department of `NEUROFARBA’, Section of Child’s Health, University of Florence
(4)
BMT Unit, Department of Hematology-Oncology, Anna Meyer Children’s Hospital
(5)
Department of Pediatric Surgery, University of Bologna

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© Zama et al.; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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