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 Table of Contents 
Year : 2020  |  Volume : 9  |  Issue : 5  |  Page : 2496-2499  

Mixed phenotypic presentation of autoimmune polyendocrine syndrome type II in adolescent female

1 Associate Professor Pathology, Institute of Medical Science BHU, Varanasi, Uttar Pradesh, India
2 Associate Professor Pediatrics, Institute of Medical Science BHU, Varanasi, Uttar Pradesh, India
3 Resident Pediatrics, Institute of Medical Science BHU, Varanasi, Uttar Pradesh, India

Date of Submission07-Feb-2020
Date of Decision11-Mar-2020
Date of Acceptance26-Mar-2020
Date of Web Publication31-May-2020

Correspondence Address:
Dr. Sunil Kumar Rao
Associate Professor, Department of Pediatrics, Institute of Medical Science BHU, aranasi, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jfmpc.jfmpc_1237_19

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Autoimmune polyendocrine syndrome (APS) is a constellation of multiple endocrine and various autoimmune diseases. The hallmark features of APS are gradual onset, circulating autoantibodies, and tissue or organ infiltration by lymphocytes. There are genetic basis and failure of the immune system to maintain self-tolerance to a variety of molecules, which manifest as autoimmunity over a period of time. Age of onset of the syndrome may range from early infancy to adulthood, new onset of autoimmunity of the given syndrome can manifest thoughout life. We report a case of an adolescent female with endocrine and non-endocrine manifestation of APS, starting at a very young age of 7 years with nephritis and hypertension as an unusual association.

Keywords: Autoimmune disease, autoimmune polyendocrine syndrome, endocrine

How to cite this article:
Kumar S, Rao SK, Khanna P. Mixed phenotypic presentation of autoimmune polyendocrine syndrome type II in adolescent female. J Family Med Prim Care 2020;9:2496-9

How to cite this URL:
Kumar S, Rao SK, Khanna P. Mixed phenotypic presentation of autoimmune polyendocrine syndrome type II in adolescent female. J Family Med Prim Care [serial online] 2020 [cited 2021 Apr 19];9:2496-9. Available from: https://www.jfmpc.com/text.asp?2020/9/5/2496/285067

  Introduction Top

Clinical manifestation of APS is varied from latent form to clinically overt syndrome, however, latent or subtle forms are more frequent than overt manifestations.[1] Autoimmunity in APS may be a result of genetic predisposing and/or failure of self-tolerance by the immune system.[2],[3] The hallmark features of APS are gradual onset, circulating autoantibodies, and tissue or organ infiltration by lymphocytes. APS categorized into a rare monogenic (APS type 1) form and common polygenic variety[2] (APS type 2), however, Neufeld and Blizzard[4] classified APS into four main types (type 1, type 2, type 3, type 4) shown in [Table 1]. It was reported that it takes more than 2 decades between the onset of two endocrinopathic manifestations.[3] A person suffering from APS may have multiple endocrine manifestations as well as variable frequency of non-endocrine autoimmune diseases, however, limited data are available in the pediatric population.[5],[6],[7] Endocrinopathies are primary adrenal insufficiency, autoimmune thyroiditis, type 1 diabetes mellitus, and hypoparathyroidism.[5] Autoimmune conditions are associated with variable frequency, which include pernicious anemia, celiac disease, hypogonadism, vitiligo, immune gastritis, parathyroid disease, myasthenia gravis, Sjögren's syndrome, rheumatoid arthritis alopecia areata, and nephritis.[8],[9],[10],[11] We report a case of APS in an adolescent female with two endocrine and eight autoimmune manifestations of APS, clinically categorized as APS type 2 with overlapping features of type 1 and type 3.
Table 1: Biochemistry of Patient at admission and in follow up

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  Case Details Top

An adolescent female, presented with the complaints of vitiligo, starting from the face and involved the whole body for the last 7 years, progressive abdominal distension, breathlessness, and paleness of body for last 5 years, swelling of feet, New York Heart Association (NYHA) grade IV dyspnea, palpitation, and fever for 5 days. There was no history of tubercular contact, liver disease, or any skin problem in any of the family members. On physical examination, there was severe pallor, icterus, grade 3 clubbing [Figure 1], raised jugular venous pressure (JVP), pedal edema, bilateral crept, massive hepatosplenomegaly (7 cm and 16 cm, respectively), vitiligo [Figure 2], loud P2, hypertension (BP = 140/90 in the right arm, 160/100 in right leg), stunting (Ht. 138 cm vs. 159.8 cm, <-3 SD), wasting (Wt. 22 kg vs. 31, <-3 SD), and sexual maturity rating (SMR) Tanner stage 1. On laboratory evaluation, there was bicytopenia, hypoalbuminemia, iron deficiency anemia, secondary hyperparathyroidism, vitamin D deficiency, proteinurea, hematuria, and low cortisol levels, antibodies against parietal cells and anti-thyroid peroxidase (TPO) antibody and increased levels of anti-tissue transglutaminase (TTG) antibody. Biochemical findings at admission and follow-up were shown in [Table 2]. Imaging studies reveal features of portal hypertension (dilated portal vein, altered liver echotexture, increased resistive index in the hepatic artery), and fibrotic changes of liver on fibro scan. Renal color doppler showed increased resistive index in bilateral intersegment arteries, and 2-D Echo showed left ventricular (LV) dilatation and pulmonary arterial hypertension (PAH). Duodenal biopsy showed moderate villous atrophy, lymphomononuclear infiltration of lamina propria, increased intraepithelial lymphocytes, confirming celiac disease [Figure 3]. Also, antibodies were present against parietal cells and TPO. Fasting and postprandial blood glucose and thyroid profile were normal. Antinuclear antibodies (ANA), anti dsDNA, and autoimmune liver profile were normal. Out of three endocrinopathies, features of subclinical adrenal insufficiency and autoimmune thyroiditis, were present in index case with celiac disease, vitiligo, antiparietal cell antibody, a diagnosis of autoimmune polyglandular syndrome type 2 was considered.
Figure 1: Grade III, Clubbing of fingers and toes

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Figure 2: II Vitiligo

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Table 2: Classification of Autoimmune Polyendocrine Syndrome

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Figure 3: (a) Low Power. (b) High Power (H and E). The hematoxylin and eosin stained superficial duodenal biopsy is showing normal crypt and villous architecture but an increased crypt villous ratio. There are dense inflammatory cell infiltrates in the lamina propria with lymphocytes, plasma cells, occasional eosinophils, and neutrophils. There are increased intraepithelial lymphocytes (IELs). The distribution of IELs in the villi is more in the tip (Marsh type 2 lesion)

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The child was started on a gluten-free diet, calcium, iron, vitamin D supplements, hydrocortisone, and antihypertensive. In follow-up, hepatosplenomegaly regressed, anemia, and total counts improved but the child developed depression in the skull. Computed tomography (CT) scan of the head, however, was normal. Also, CT scan abdomen showed no evidence of adrenal atrophy.

  Discussion Top

We report an adolescent girl diagnosed as autoimmune polyendocrine syndrome (APS)-type-2 presented with subclinical adrenal insufficiency, autoimmune thyroiditis, hyperparathyroidism secondary to vitamin D deficiency, celiac disease, myocarditis, vitiligo, pernicious anemia, leucopenia, autoimmune hepatitis, alopecia, and unusual features of nephritis and hypertension. There are limited data available on APS in the pediatric population,[12],[13],[14] Kirmizibekmez et al.[15] report a case of adolescent boy presenting as APS-2 with features of Addison disease, Hashimoto thyroiditis, celiac disease, and autoimmunity for type-1 diabetes mellitus. Whereas Smith et al.[16] reported a case of APS-2 presented with persistent fatigue and skin color changes after viral prodrome. The present case has subclinical adrenal insufficiency, autoimmunity against thyroid gland, liver, gastric cells, established celiac disease. There are four types of presentation of APS, the present case resembles type 2 APS, but there are certain associations in index cases found in other types of APS. Clinical presentation of type-1 APS has shown in [Table 1], however, it may be associated with vitiligo, pernicious anemia, and nephritis,[2] our case was initially presented with vitiligo, anemia, cardiac failure, nephritis, hypertension, and laboratory evidence of subclinical adrenal insufficiency. This observation showed that APS clinically presents with features of non-endocrine autoimmune diseases and later endocrine features, which ultimately depend upon interaction between genetic and environmental factors. Therefore, there is overlapping features co-exist between different types of APS.[17] The present case has established features of celiac disease (histological proven), as we started gluten-free diet, adolescents showed a response and there is a regression of organomegaly, improvement in anemia and leucocyte count. A study by Valenzise et al.[5] showed that 28.9% of children with Hashimoto thyroiditis have associated with one autoimmune disease (AD) and 0.9% were associated with two AD, the common ADs were celiac disease and type 1 diabetes. Our case has two endocrinopathy and eight ADs. Currently, management of these diseases is restricted to the pharmacological replacement therapy, i.e. hormones, however before starting the therapy subclinical adrenal insufficiency should be ruled out as a treatment of an endocrine disease may also trigger the onset of another endocrine disease.[18] The highlight of the present case was that an adolescent presented with a mixed phenotypic presentation of APS at the time of diagnosis with overlapping features of type 1, 2, and type 3.

  Conclusion Top

We report a rare condition in childhood with a mixed phenotypic presentation of APS. In the case of monoglandular autoimmune endocrinopathy, latent manifestation of endocrine and non-endocrine autoimmune diseases can be rule out by organ-specific screening of autoantibodies.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Betterle C, Lazzarotto F, Presotto F. Autoimmune polyglandular syndrome Type 2: The tip of an iceberg? Clin Exp Immunol 2004;137:225-33.  Back to cited text no. 1
Husebye ES, Anderson MS, Kämpe O. Autoimmune polyendocrine syndromes. N Engl J Med 2018;22:378:1132-41.  Back to cited text no. 2
Eisenbarth GS, Gottlieb PA. Autoimmune polyglandular syndromes. N Engl J Med 2004;350:2068-80.  Back to cited text no. 3
Neufeld MN, Blizzard RM. Autoimmune polyglandular syndromes. Pediatr Ann 1980;9:154-62.  Back to cited text no. 4
Valenzise M, Aversa T, Saccomanno A, De Luca F, Salzano G. Epidemiological and clinical peculiarities of polyglandular syndrome type 3 in pediatric age. Ital J Pediatr 2017;43:69.  Back to cited text no. 5
Passanisi S, Timpanaro T, Lo Presti D, Caruso-Nicoletti M. Recurrent hypoglycaemia in type-1 diabetes mellitus may unravel the association with Addison's disease: A case report. BMC Res Notes 2014;7:634.  Back to cited text no. 6
Kahaly GJ. Polyglandular autoimmune syndromes. Eur J Endocrinol 2009;161:11-20.  Back to cited text no. 7
Valenzise M, Alessi L, Bruno E, Cama V, Costanzo D, Genovese C, et al. APECED syndrome in childhood, clinical spectrum is enlarging. Minerva Pediatr 2016;68:226-9.  Back to cited text no. 8
Valenzise M, Aversa T, Salzano G, Zirilli G, De Luca F, Su M. Novel insight into chronic inflammatory demyelinating polineuropathy in APECED syndrome, molecular mechanisms and clinical implications in children. Ital J Pediatr 2017;43:11.  Back to cited text no. 9
Michels A, Gottlieb P. Autoimmune polyglandular syndromes. Nat Rev Endocrinol 2010;6:270-7.  Back to cited text no. 10
Dittmar M, Kahaly GJ. Polyglandular autoimmune syndromes, immunogenetics and long-term follow-up. J Clin Endocrinol Metab 2003;88:2983-92.  Back to cited text no. 11
Miconi F, Savarese E, Miconi G, Cabiati G, Rapaccini V, Principi N, et al. Unusual onset of celiac disease and Addison's disease in a 12-yearold boy. Int J Environ Res Public Health 2017;14:E855.  Back to cited text no. 12
Lakhotia M, Pahadia HR, Kumar H, Singh J, Tak S. A case of Autoimmune polyglandular syndrome (APS) type II with hypothyroidism, hypoadrenalism, and celiac disease—a rare combination. J Clin Diagn Res 2015;9:OD01-3.  Back to cited text no. 13
Correia F, Fernandes A, Mota TC, Garcia M, Castro-Correia C, Fontoura M, et al. Hyponatremia in a teenager: A rare diagnosis. Pediatr Emerg Care 2015;31:860-3.  Back to cited text no. 14
Kırmızıbekmez H, Mutlu RGY, Urganc ND, Öner A. Autoimmune polyglandular syndrome type 2: A rare condition in childhood. J Clin Res Pediatr Endocrinol 2015;7:80-2.  Back to cited text no. 15
Smith RK, Gerrits PM. A rare case of autoimmune polyglandular syndrome type 2 in child with persistent fatigue. Global Pediatric Health 2019;:1-5.  Back to cited text no. 16
Betterle C, Garelli S, Coco G, Burra P. A rare combination of type 3 autoimmune polyendocrine syndrome or multiple autoimmune syndrome. Autoimmun Highlights 2014;5:27-31.  Back to cited text no. 17
Majeroni BA, Patel P. Autoimmune polyglandular syndrome, type II. Am Fam Physician 2007;75:667-70.  Back to cited text no. 18


  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2]


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