Case report doi: 10.4183/aeb.2015.103

An adolescent suspected by IPEX syndrome: , Polyendocrinopathy, X-Linked

O. Belei*, G.F. Brad, O. Marginean

“Victor Babes” University of Medicine and Pharmacy - First Pediatric Clinic, Timisoara, Romania Abstract Introduction Introduction. Immune Dysregulation, Polyendo- crinopathy, Enteropathy X-Linked (IPEX) Syndrome represents Autoimmune Polyendocrine Syndromes a rare X linked disorder, characterised by development of are characterized by specific endocrine immune systemic from the first year of life. IPEX is due self-destruction of a glandular organ (with internal to in the FOXP3 gene located on the X-chromosome. There are no specific laboratory tests to confirm the diagnosis. secretion), which induces the alteration of other Molecular analysis of the FOXP3 gene(Xp11.2-q13.3) is autoimmune response after a certain period. Immune required for the diagnosis. Chronic immunosuppression and Dysregulation, Polyendocrinopathy, Enteropathy hematopoietic stem cell transplantation represent the two main X-Linked (IPEX) Syndrome represents a rare X linked therapeutic interventions for this immune dysfunction, the last disorder, characterised by the development of systemic one being the only curative treatment. autoimmunity from the first year of life. Case presentation. The authors present the case of IPEX phenotype is similar with the clinical a male patient aged 14 years old, who was admitted for keto- features of Autoimmune Polyendocrine Syndromes. Type acidotic diabetes onset. He was diagnosed with polyendocrine 1 Diabetes Mellitus (DM) is a common manifestation autoimmune association (diabetes mellitus type 1, autoimmune of IPEX syndrome. Other symptoms due to profound thyroiditis and hypo-gonadotrophic hypogonadism). This patient associated celiac disease, sustained on clinical, immune dysregulation that can be seen in males with immunological and histological changes:recurrent diarrhea, IPEX syndrome include enteropathy, , failure positive IgA anti-tissue transglutaminase antibodies and total to thrive, thyroiditis and recurrent infections. Many other villous atrophy on intestinal biopsy sample. He also presented autoimmune conditions like nephritis, pneumonitis, recurrent eczematous dermatitis associated to elevated serum hepatitis, vasculitis, arthritis, myositis, alopecia and concentration of immunoglobulin E. The authors sustained autoimmune cytopenias can be present. the diagnosis of IPEX syndrome in this case based on family If a patient has hyper-IgE syndrome and one or history of unexplained early deaths of the patient´s uncles from more features of the classical triad of watery diarrhea, the motherside, along with clinical and laboratory aspects. Drug dermatitis and type 1 DM or autoimmune thyroiditis, treatment included nutritional support, immunosuppressant pediatricians should consider several immune disorders therapy and hormone replacement. Conclusions. The most important aspect in this with hyper-IgE syndrome: Job syndrome, Wiskott- case was considering IPEX syndrome after integration of all Aldrich syndrome, Omenn syndrome, atypical complete clinical and paraclinical data but without molecular analysis DiGeorge syndrome or IPEX syndrome. of the FOX P3 gene. The presumption of IPEX syndrome IPEX syndrome is an X-linked recessive reconsidered in this case the treatment and the prognosis. Life disorder with exclusive expression in males. It is expectancy is reduced in this condition that usually occurs in due to gene responsible for FOXP3 the first months of life. The particularity of this case was the synthesis, which by differentiation and activation of late onset of IPEX syndrome, presenting a severe phenotype regular T-lymphocytic CD4+CD25+ has the key role with aggressive autoimmune associations that led finally to the in the induction and maintenance of the peripheral self patient’s death. tolerance (1). The identification of mutations in the forkhead box protein 3 (FOXP3) gene associated with Key words: IPEX syndrome, diabetes mellitus type 1, autoimmune thyroiditis, celiac disease. IPEX syndrome and a murine model has generated a considerable amount of interest and research. The critical functions of FOXP3 Treg cells in immune homeostasis

*Correspondence to: Oana Belei MD, “Victor Babes” University of Medicine and Pharmacy, First Pediatric Clinic, No 2, Iosif Nemoianu street Timisoara, 300011, Romania, E-mail: [email protected] Acta Endocrinologica (Buc), vol. XI, no. 1, p. 103-108, 2015 103 O. Belei et al. have been amply demonstrated in several mouse models The Kussmaul respiration was associated with productive where abrogation of the development, homeostasis or cough and crackles were found at the base of both lungs. function of FOXP3 Treg cells simultaneously triggers He presented tachycardia and low blood pressure (HR = multi-organ autoimmunity and provokes immunity to 185 bpm, BP = 100/65 mm Hg). He had a pale face with tumours, transplants, infectious and commensal microbes thin lips and psoriasiform dermatitis. and allergens (2). Biological investigations were carried out in Most affected children die within the first 2 years order to stabilize the patient and to find other associated of life. Late onset cases can be identified in patients with conditions. We found an increased number of red blood less severe symptoms. Several cases associated with cells secondary to hemoconcentration, leukocytosis late onset were described, with mild phenotype, that and positive inflammatory tests. The increased value reached the second decade of life (3). There is an interest of glycated hemoglobin (HbA1c = 10%) showed the allocated by researchers to study the correlation between presence of a long-lasting hyperglycemia. In addition, the genotype and the phenotype of IPEX patients and uncompensated respiratory and metabolic acidosis was this could help understanding the effects of different observed. Central and peripheral cultures excluded the mutations on the disease severity. possible association of a bacterial infection. Based on molecular genetic tests, it is important The treatment during hospital admission to diferentiate between autoimmune polyendocrine consisted in fluid and electrolytes replacement, insulin syndromes (diabetes mellitus type I, thyroiditis, therapy and treatment of acute viral pneumonia which , Addison’s disease, vitiligo, was a precipitant factor for the onset of DM. The lupus, myasthenia gravis, etc.) and IPEX syndrome, the evolution was favorable, coma was resolved within last one having a more severe prognosis. 12 hours, consciousness was restored and electrolyte imbalances were corrected. CASE REPORT After patient was stabilized, clinical reexamination revealed other associated comorbidities, Patient M. G, 14 years old, from a rural such as protruding eyes and stage I goiter. The patient environment was admitted to a territorial hospital presented trophic skin alterations such as palmar and reporting malaise, dizziness, polyuria/polydipsia and plantar desquamation. Eczematous dermatitis with vomiting. The laboratory data showed the presence pruritus appeared on the 4th day of hospitalization. of hyperglycemia (324 mg%), glycosuria and urinary The patient had also recurrent diarrhea. Although both ketones bodies. After fluid replacement therapy, the testicles were found in the scrotum, they were under- patient was transferred to our University Emergency developed, he presented micropenia and puberty stage I Pediatric Hospital with the diagnosis of type 1 DM at according to Tanner stages. onset with keto-acidosis. All photographs were taken after obtaining the The family history revealed two death of written consent of the patient and his parents. unknown cause at early age in two uncles (mother’s Further laboratory investigations and brothers). The patient was born in a family with poor interdisciplinary consults were done in order to find other socio-economic conditions, from rural area. He was the conditions associated with DM type 1. Thyroid function fifth born (single boy among 4 girls) from twenty-three assessment showed the presence of hyperthyroidism pregnancies (eighteen spontaneous abortions). His weight suggested by decreased value of TSH, increased titer of at birth was 3300 g and his height at birth was 50 cm. The FT3, FT4 and increased thyroid peroxidase antibodies personal medical history showed previous admission in (TPO) level. Thyroid stimulatory immunoglobulin (TSI) hospital for chronic diarrhea associated with interstitial levels were within normal ranges. Thyroid ultrasound pneumonia and moderate mental retardation (IQ = 35) at showed an increased size of the thyroid gland with 11 years old. heterogeneous structure. Chronic diarrhea in the medical Clinical examination upon admission to our history of this patient and the possible association of type Pediatric Clinic reported a patient with severe influenced 1 DM with celiac disease imposed the determination of general status, non-reactive to pain, verbal or tactile IgA antiendomysial antibodies (EMAs) and IgA/IgG stimulus. The patient’s weight upon admission was 27 antibodies against tissue transglutaminase (tTG). All kg and his height was 151 cm, with a body mass index serological tests were positive. Upper gastrointestinal of 11.84 kg/m2 (under the 3rd percentile for age). He endoscopy with duodenum biopsies were performed. presented fever (39°C), tachypnea and ketonic halitosis. Histological examination of the biopsies classified

104 Adolescent suspected by IPEX syndrome

Figure 2. The appearance of skin rash.

Figure 1. The general appearance of the patient. the lesions as type Marsh IIIc: increased lymphocytes infiltrated in the lamina propria, hyperplasic crypts and total villous atrophy. Dermatological examination showed pityriasis rosea Gilbert. Total IgE serum titer was above the normal value (total IgE = 6465 IU /mL) and the majority of specific IgE antibodies tested (against Figure 3. The aspect of plantar desquamation. food and respiratory allergens: peanut, milk’s , codfish, soya, wheat flour, birch pollen, mugwort pollen, The following diagnoses were established D. pteronyssinus, D. farinae, dog epithelia, cat epithelia, based on the clinical examination, laboratory data and Asp. fumigatus) were at high levels. Retardation of interdisciplinary consults: puberty proved by hormonal determinations showed Autoimmune Polyendocrine Syndrome (type 1 a low value of LH, while the testosterone value was at DM, Autoimmune Thyroiditis and Hypogonadotrophic the lower limit of the normal value. The diagnosis of Hypogonadism); hypogonadotrophic hypogonadism was based on the Celiac Disease; abnormal hormone level. The authors presumed that Mixed food allergy; the cause of hypogonadotropic hypogonadism was an Pityriasis rosea Gilbert; autoimmune process. But, due to the fact that the patient Moderate mental retardation (IQ = 34); was only 14 years old and he was cashectic, a delayed Depression. puberty could also have contributed to the development Correlating the conditions diagnosed in this case of hypogonadotropic hypogonadism. (type1 DM, autoimmune thyroiditis, hypogonadotrophic Depressive status and mental retardation hypogonadism, chronic enteropathy - celiac disease was suggested by the neuropsychiatric consult and and eczematous dermatitis) with abnormal laboratory psychological examination (IQ = 34). tests (Hyper IgE), the authors took into consideration

105 O. Belei et al. the diagnosis of IPEX syndrome. In order to confirm The above classification is based on the clinical this diagnosis, DNA sequencing of the FOXP3gene and manifestations presented at the onset of these conditions. mutation analysis are mandatory. Unfortunately, the As we can see from this classification, not all of these genetic test could not be performed in this case, but the syndromes are associated with type 1 DM. presumption of IPEX syndrome was strongly sustained by The following informations are necessary in order the phenotype of the patient integrating the autoimmune to understand the clinical manifestations and evolution of disorders with the abnormal laboratory tests and with type III Autoimmune Polyendocrine Syndrome. family antecedents of this patient. The lab tests that Type 1 DM may precede or may be consecutive indicated disturbances in immunity in this case were high to thyroiditis. DM influences the synthesis of thyroid IgE serum level, increased thyroid peroxidase antibodies hormone, while thyroid hormones have an effect on level and positive anti tissue transglutaminase antibodies. (5). FOXP3 mutation was suspected in both brothers of the Dorchy and collaborators have shown in 1985 mother who died at a young age. that the thyroid hormonal changes attributed to inadequate In this case, the diet respected the nutritional blood glucose control hampers the transformation of T4 principles characteristic to type 1 DM, associating the into T3. Subsequently, they noted the existence of a exclusion of gluten and potentially food allergens. Insulin subclinical hypothyroidism with increased TSH value substitution and the medical treatment of associated and normal or low T3 and T4 levels. Medical literature diseases were done, too. Also, considering the diagnosis underlined the important role of TSH as reliable marker of IPEX syndrome, immunosuppressant therapy was of thyroid dysfunction associated with type 1 DM (6). initiated with short term oral steroids (1 mg/kg/day) More recently, there was a great interest followed by azathioprine (2 mg/kg/day) as maintenance in studying the association between autoimmune therapy. thyroiditis, type 1 DM and other autoimmune disorders. Evolution was slowly favorable during A recent work of a Polish author assessed the prevalence hospitalization (3 weeks) with moderate weight gain. of Type III Polyglandular Autoimmune Syndromes in HbA1c decreased from 10% to 8.2%, while the dose children with type 1 DM. He found among 461children of insulin was reduced from 1IU/kg to 0.6 IU/kg. with type 1 DM a percent of 11.1 % cases that associated After hospital discharge, the patient’s compliance to autoimmune thyroiditis and they were considered as recommended diet and medical treatment was poor. Two Polyglandular Autoimmune Syndromes type IIIA. In months after discharge from our Pediatric University 3.5% of cases the author found type 1 DM associated Hospital, the patient died in a territorial hospital, due to with other autoimmune disorders such as celiac disease, sepsis and tachyarrhythmia episode. juvenile arthritis, and vitiligo. These cases were considered Polyglandular Autoimmune Syndromes DISCUSSION type IIIB (7). The results of this study showed a high prevalence of autoimmune thyroiditis in the diabetic Currently, there are 4 main classes of pediatric population which indicates that screening for Autoimmune Polyendocrine Syndrome (4): thyroid disease among children with diabetes should be Type I - Blizzard syndrome: muco-cutaneous routinely performed. candidiasis, chronic idiopathic hypoparathyroidism, Hyperthyroidism with goiter found in our patient Addison’s disease; has been described as an autoimmune manifestation Type II - Schmidt syndrome: Addison’s disease associated to type 1 DM in context of type III Autoimmune associated with autoimmune thyroiditis; Carpenter Polyendocrine Syndromes. Both Graves disease or syndrome: Addison’s disease associated with type 1 DM; Hashimoto autoimmune thyroiditis can be responsible Type III - Autoimmune thyroiditis with other for the etiology of hyperthyroidism. Increased FT3 and autoimmune diseases (excluding Addison’s disease and FT4, decreased TSH and positive thyroid thyroglobulin hypoparathyroidism): type 1 DM, atrophic gastritis antibodies and TPO levels are found in both conditions. (+ / - pernicious anemia), vitiligo and/or alopecia and Thyroid stimulatory immunoglobulins (TSI) which are myasthenia gravis, hypogonadotrophic hypogonadism, specific for Graves disease, can make the difference. non-organ-specific autoimmune diseases (lupus, However, when TSI assessment is not available, rheumatoid arthritis, Sjögren’s syndrome); evolution in time is the only way to differentiate Type IV - other associations: alopecia and/or between the two conditions. The clinical manifestation vitiligo and type 1 MD, myasthenia gravis and diabetes. of untreated Graves disease evolves to hyperthyroidism,

106 Adolescent suspected by IPEX syndrome while untreated Hashimoto thyroiditis gradually progress In conclusion, the mixed endocrine pathology to thyroid hypofunction (8). Due to the fact that TSI level described in this case (type 1 DM, autoimmune thyroiditis, was within normal ranges in our patient, associated to hypogonadism) detected by the onset of diabetes, has decreased value of TSH, increased titer of FT3, FT4 and initially orientated the diagnosis to type III Autoimmune increased TPO level, we considered the autoimmune Polyendocrine Syndrome. Celiac disease was considered thyroid disorder as Hashimoto thyroiditis in this case. as an associated condition. Retardation of puberty was suggested by The genetic molecular analysis for FOXP3 the hypogonadotrophic hypogonadism caused by mutations could have marked the difference between type hypothalamic-pituitary function (possibly autoimmune). III Autoimmune Polyendocrine Syndrome associated Diabetes can also be the cause of hypogonadism when with celiac disease and IPEX syndrome. The presumption the onset occurs long time before puberty (9). of IPEX syndrome reconsidered in this case the treatment The association of celiac disease with type 1 and the prognosis. DM was the subject of several researches. Recent studies Although the life expectancy of patients with have shown a low prevalence of symptomatic (typical) IPEX syndrome does not exceed 1-2 years, this condition celiac disease upon the onset of diabetes (0,7%). There should be taken into consideration in every male patient is an increasing prevalence of celiac disease up to 10% with associated autoimmune endocrinopathies and in diabetic patients during the first 2 years after diagnosis chronic regardless the age of the patient. (10). Most forms of celiac disease associated with type 1 Limitation of this Case report: The molecular DM are sub-clinical, silent, latent. Screening for celiac genetic exploration is compulsory for the diagnosis of disease is recommended at onset and during the first 2 IPEX syndrome, but it could not be performed in this years after type 1 DM diagnosis. The prevalence of celiac case. disease among diabetic patients is 10 times higher than the prevalence in the general population (7-10%) (11). Conflict of interest The most important aspect in this case was The authors declare that they have no conflict of considering IPEX syndrome after integration of all interest concerning this article. clinical and paraclinical data. Immune dysregulation, polyendocrinopathy, enteropathy X-linked syndrome is characterized by the development of systemic References autoimmunity in the first year of life. It consists in the following association: enteropathy (watery diarrhea, 1. Schneller C, Finkel L, Wise M, Wise M, Hageman JR, Littlejohn E. Autoimmune polyendocrine syndrome: a case-based review, Pediatr villous atrophy and mononuclear infiltrates in lamina Ann. 2013;42(5):203-208. propria), dermatitis eczema and endocrine pathology - 2. Passerini L, Mel ER, Sartirana C, Fousteri G, Bondanza A, Naldini especially type 1 DM (12, 13). Most cases are associated L, Roncarolo MG, Bacchetta R. CD4+ T cells from IPEX patients convert into functional and stable regulatory T cells by FOXP3 gene with other autoimmune diseases - autoimmune hemolytic transfer, Sci Transl Med. 2013; 11(5):215-220. anemia, neutropenia and/or tubular nephropathy (14). 3. Bae KW, Kim BE, Choi JH, Lee JH, Park YS, Kim GH, Yoo HW, Although life expectancy is reduced, few cases have Seo JJ. A novel mutation and unusual clinical features in a patient with immune dysregulation, polyendocrinopathy, enteropathy, X-linked been described that reached the second or third decade (IPEX) syndrome, Eur J Pediatr. 2011;170(12):1611-1623. of life (3). There are no specific tests for the IPEX 4. Cutolo M, Autoimmune polyendocrine syndromes, Autoimmun diagnosis. Disturbances in immunity may consist in Rev. 2014 ;13(2):85-87. 5. Korzeniowska K, Jarosz-Chobot P, Szypowska A, Ramotowska A, increased levels of IgE, and transient Fendler W, Kalina-Faska B, Szadkowska A, Mlynarski W, Mysliwiec circulating autoantibodies such as anti pancreatic island M. L-thyroxine Stabilizes Autoimmune Inflammatory Process in cells, anti-platelet, anti-thyroid antibodies, anti tissue Euthyroid Nongoitrous Children with Hashimoto’s Thyroiditis and Mellitus, J Clin Res Pediatr Endocrinol. transglutaminase antibodies and decreased number of 2013;15(4):240-244. peripheral T cells expressing FOXP3 on their surface 6. Dorchy H, Bourdoux P, Lemiere B. Subclinical thyroid hormone (determined by flowcytometry). (15) The genetic test abnormalities in type I diabetic children and adolescents. Relationship to metabolic control, Acta Paediatr Scand. 1985;74(3):386-389. certifies the diagnostics - sequential analysis for gene 7. Ben-Skowronek I, Michalczyk A, Piekarski R, Wysocka-Lukasik mutations in FOXP3 (mutant gene locus Xp11.2-q13.3). B, Banecka B. Type III Polyglandular Autoimmune Syndromes Chronic immunosuppression and hematopoietic stem cell in children with type 1 diabetes mellitus, Ann Agric Environ Med. transplantation are the two main therapeutic alternatives, 2013;20(6):140-146. 8. Balázs C, The role of hereditary and environmental factors in the last one being the only curative for IPEX syndrome autoimmune thyroid diseases, Orv Hetil. 2012 ;153(9):1013-1022. (16).

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