Logo American Journal of Case Reports

Call: 1.631.629.4328
Mon-Fri 10 am - 2 pm EST

Contact Us

Logo American Journal of Case Reports Logo American Journal of Case Reports Logo American Journal of Case Reports

17 October 2020: Articles  Jordan

A Case of Critical Lower-Limb Ischemia in a 29-Year-Old Man with Autoimmune Polyglandular Syndrome Type 1 (APS-1)

Rare disease

Raed M. Ennab1ABDEFG*, Nesreen A. Saadeh2ABDEF

DOI: 10.12659/AJCR.924705

Am J Case Rep 2020; 21:e924705

0 Comments

Abstract

BACKGROUND: Autoimmune polyglandular syndrome type 1 (APS-1) is an extremely rare autoimmune disorder with an autosomal recessive inheritance pattern. Its manifestations present in chronological sequence of the components mucocutaneous candidiasis, Addison disease, and hypoparathyroidism. Vascular calcification is a very rare manifestation of the disease, and it may be severe, causing critical lower-limb ischemia and significant morbidity. To the best of our knowledge, this is the first such case to be reported in Jordan and the Arab region.

CASE REPORT: We present the case of a 29-year-old patient diagnosed with autoimmune polyglandular syndrome type 1 (APS-1). He has Addison disease, hypoparathyroidism, and mucocutaneous candidiasis. He presented with features of critical lower-limb ischemia and bacterial infection of the left foot. The patient underwent a successful angioplasty, and received management of his bacterial and fungal infections and the chronic endocrinopathies.

CONCLUSIONS: Autoimmune polyglandular syndrome type 1 (APS-1) is a very rare disorder. Recognizing its syndromic nature will facilitate an active search for the component diseases and the possible complications, which would allow early diagnosis and management. This applies to the rare vascular complications, which can lead to significant morbidity.

Keywords: Addison Disease, Angioplasty, Candidiasis, Chronic Mucocutaneous, hypoparathyroidism, peripheral arterial disease, Polyendocrinopathies, Autoimmune, Candidiasis, Ischemia, Jordan

Background

Autoimmune polyglandular syndromes (APS) are rare syndromes diagnosed by the coexistence of at least 2 autoimmune endocrinopathies. In addition, nonendocrine autoimmune manifestations may be present [1]. Autoimmune polyglandular syndrome type 1 (APS-1) is defined by the coexistence of at least 2 of 3 major component diseases: chronic mucocutaneous candidiasis, autoimmune adrenal insufficiency, and primary hypoparathyroidism, or only 1 if a sibling has the disease [1–3]. The syndrome is a rare disorder with an autosomal recessive inheritance pattern [1,2,4,5]. Vascular calcification is a rare manifestation of the syndrome [6], and it can be severe, causing significant lesions and ischemia [7]. We present the case of a young patient with mucocutaneous candidiasis and multiple endocrinopathies who presented with features of critical lower-limb ischemia.

Case Report

A 29-year-old male patient presented with acute left-foot redness, swelling (Figure 1B), and chronic dystrophic nails of hands and feet with discoloration (Figures 1, 2). The distal pulses were diminished, with monophasic signals on Doppler examination, and he previously had amputation of left fourth toe due to gangrene. He was a known case of adrenal insufficiency and hypoparathyroidism, taking hydrocortisone, fludrocortisone, and calcium supplements and alphacalcidol. The patient had no intermittent claudication or resting pain, he was not diabetic, and he was a non-smoker. Treatment was started with an intravenous antibiotic (Piperacillin/Tazobactam) and antifungal medications (intravenous Fluconazole and Miconazole ointment). Bacterial and fungal cultures showed Morganella morganii and Candida albicans sensitive to the given medications. Lab investigations showed elevated WBC count 21.3/mm3, elevated ESR and CRP, low parathyroid hormone 1.2 ng/l (N 13–54), hypocalcemia Ca 1.7 mmol/l (N 2.1–2.6), and hyperphosphatemia P 1.69 mmol/l (N 0.8–1.6). Otherwise, he had normal kidney, liver, and thyroid function tests, and normal adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), prolactin, and testosterone levels.

A CT angio showed diffuse calcified atherosclerotic changes of the abdominal aorta and lower-limb arteries, with significant stenosis of the left popliteal artery and poor bilateral distal run off (Figure 3). He underwent an angioplasty with drug-eluting balloons for the left popliteal and tibial vessels. He lab test results and clinical condition improved, and he was discharged after a hospital stay of 2 weeks, with prescription of oral medications (prednisolone, fludrocortisone, calcium supplements, alphacalcidol, and voriconazole) in addition to miconazole ointment. On follow-up, he had improvement of lower-limb vascularity and the bacterial and fungal infections were cured.

Discussion

Polyglandular autoimmune syndromes are a rare heterogeneous group of genetic diseases of the immune system leading to multiple endocrinopathies. Three types are described in the literature: type 1 (juvenile type), type 2 (adult type), and type 3 (the rarest). APS-1 is also known as Whitaker syndrome and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) [2]. It is a very rare disorder inherited in a sporadic autosomal recessive pattern and caused by genetic mutations affecting the autoimmune regulator (AIRE) gene on chromosome 21 [2,5,8]. Studies have demonstrated the presence of various circulating tissue-specific autoantibodies that cause dysfunction of the target endocrine glands [4,9]. Also, the mutations lead to defective T cells and neutralizing auto-antibodies against IL-22, IL-17A, and/or IL-17F, leading to the immunodeficiency underlying candidiasis [4,9–11].

The syndrome clusters in certain ethnic populations, including Iranian Jews, Sardinians, and Finns [8]. The highest prevalence was reported in Iranian Jews with 1 case per 9000, Sardinians with 1 case per 14 400, and Finns with 1 case per 25 000 [8,12–14]. Low incidences (1: 90 000 to 1: 200 000) had been reported in Norway, Sweden, Poland, Slovenia, Slovakia, Russia, Great Britain, Ireland, and Italy [8,15,16,17,18,19]. To the best of our knowledge, the present case is the first to be reported in Jordan and the Arab region. It is suspected that this disorder is underdiagnosed because of a lack of knowledge of the condition, the long intervals between the development of manifestations, the variability of disease severity, and the wide spectrum of clinical presentation [5].

In APS-1, which is the focus of the present report, 2 out of 3 main components are sufficient for diagnosis, or only 1 if a sibling has the disease [2,3]. In our patient, all 3 components were present: chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency or Addison disease. Classically, these components occur in chronological order, with mucocutaneous candidiasis usually occurring earliest, followed by hypoparathyroidism, then adrenocortical failure [2]. Additional endocrine and nonendocrine manifestations may be present, including diabetes type 1, hypothyroidism, gonadal failure, alopecia, vitiligo, nail dystrophy, enamel hypoplasia, pure red cell aplasia. pernicious anemia, asplenia, malabsorption, and autoimmune hepatitis [3,5,8,20].

Vascular calcification is an extremely rare manifestation of the syndrome. Our patient presented with critical lower-limb ischemia due to significant stenosis of popliteal and tibial vessels and diffuse calcifications of the abdominal aorta and lower-limb vasculature. Vascular calcification in general is an active cellular process that occurs in response to metabolic insults causing disturbance in the balance between inhibiting and promoting factors of vascular calcification [21,22]. It is suggested that certain cells in the vessel wall can be triggered to differentiate into osteoblast-like cells, including vascular smooth muscle cells, stem cells, and pericytes [21,23]. Proposed triggers include oxidative stress, hyperphosphatemia, bone morpho-genetic protein, vitamin D, and parathyroid hormone [21,23]. Proposed inhibitors include fetuin, osteotegrin, osteopontin, and pyrophosphate [21,23].

Vascular calcification is usually associated with aging, atherosclerosis, diabetes mellitus, and chronic kidney disease [21,24–26]. One study found coronary artery calcification in 3 out of 30 cases of sporadic idiopathic hypoparathyroidism [27]. There are few reported cases in the literature of aortic and/or lower-limb arterial calcification associated with APS-1 [6,7,21,28], and only 2 of them had critical lower-limb ischemia [7,21]. Shikata et al. [6] proposed the progressive vascular calcification as a peculiar non-random part of APS-1. Also, Ohga et al. [7] proposed that progressive vascular calcification will eventually be recognized as a rare, unexplained, but grave component of APS-1.

The management of our patient included a revascularization procedure for limb salvage, and correction of serum calcium and phosphate disturbances. In APS-1, hypocalcemia is due to hypoparathyroidism and the gastrointestinal manifestations of the syndrome, including intestinal malabsorption, pancreatic exocrine failure, celiac disease, and intestinal lymphangiectasia. Calcium levels should be monitored on follow-up and maintained in the low-normal range [20,21].

Conclusions

Autoimmune polyglandular syndrome type 1 (APS-1) is a very rare disorder. Recognizing its syndromic nature will facilitate an active search for the component diseases and possible complications, which would allow early diagnosis and management. This applies to the rare vascular complications, which can lead to significant morbidity.

References:

1.. Dittmar M, Kahaly GJ, Polyglandular autoimmune syndromes: Immunogenetics and long-term follow-up: J Clin Endocrinol Metab, 2003; 88; 2983-92

2.. Humbert L, Cornu M, Proust-Lemoine E, Chronic mucocutaneous candidiasis in autoimmune polyendocrine syndrome type 1: Front Immunol, 2018; 9; 2570

3.. Bruserud Ø, Oftedal BE, Landegren N, A longitudinal follow-up of autoimmune polyendocrine syndrome type 1: J Clin Endocrinol Metab, 2016; 101; 2975-83

4.. Constantine GM, Lionakis MS, Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy-candidiasisectodermal dystrophy: Immunol Rev, 2019; 287; 103-20

5.. Sanford E, Watkins K, Nahas S, Rapid whole-genome sequencing identifies a novel AIRE variant associated with autoimmune polyendocrine syndrome type 1: Cold Spring Harb Mol Case Stud, 2018; 4; a002485

6.. Shikata A, Sugimoto T, Kosaka K, Thoracic aortic calcification in 3 children with candidiasis-endocrinopa – thy syndrome: Pediatr Radiol, 1993; 23; 100-3

7.. Ohga S, Matsumoto N, Takada H, Progressive vascular calcification in autoimmune polyglandular syndrome type I: Pediatr Radiol, 2001; 31(3); 213-14

8.. Ferre EMN, Rose SR, Rosenzweig SD, Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy: JCI Insight, 2016; 1(13); e88782

9.. Hetemäki I, Jarva H, Kluger N, Anticommensal responses are associated with regulatory T cell defect in autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy patients: J Immunol, 2016; 196; 2955-64

10.. Okada S, Puel A, Casanova J-L, Kobayashi M, Chronic mucocutaneous candidiasis disease associated with inborn errors of IL-17 immunity: Clin Transl Immunology, 2016; 5; e114

11.. Puel A, Döffinger R, Natividad A, Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I: J Exp Med, 2010; 207; 291-97

12.. Rosatelli MC, Meloni A, Meloni A, A common mutation in Sardinian autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients: Hum Genet, 1998; 103; 428-34

13.. Zlotogora J, Shapiro MS, Polyglandular autoimmune syndrome type I among Iranian Jews: J Med Genet, 1992; 29; 824-26

14.. Meloni A, Willcox N, Meager A, Autoimmune polyendocrine syndrome type 1: An extensive longitudinal study in Sardinian patients: J Clin Endocrinol Metab, 2012; 97; 1114-24

15.. Wolff AS, Erichsen MM, Meager A, Autoimmune polyendocrine syndrome type 1 in Norway: Phenotypic variation, autoantibodies, and novel mutations in the autoimmune regulator gene: J Clin Endocrinol Metab, 2007; 92; 595-603

16.. Dominguez M, Crushell E, Ilmarinen T, Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in the Irish population: J Pediatr Endocrinol Metab, 2006; 19; 1343-52

17.. Magitta N, Pura M, Wolff A, Autoimmune polyendocrine syndrome type I in Slovakia: Relevance of screening patients with autoimmune Addison’s disease: Eur J Endocrinol, 2008; 158; 705-9

18.. Orlova EM, Bukina AM, Kuznetsova ES, Autoimmune polyglandular syndrome type 1 in Russian patients: Clinical variants and autoimmune regulator mutations: Horm Res Paediatr, 2010; 73; 449-57

19.. Stolarski B, Pronicka E, Korniszewski L, Molecular background of polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome in a Polish population: Novel AIRE mutations and an estimate of disease prevalence: Clin Genet, 2006; 70; 348-54

20.. Perheentupa J, APS-I/APECED: The clinical disease and therapy: Endocrinol Metab Clin North Am, 2002; 31; 295-320

21.. Wallace IR, McConnell V, Bell PM, Lindsay JR, Challenges in management of primary hypoparathyroidism associated with autoimmune polyglandular syndrome type 1: Case Rep Endocrinol, 2011; 2011; 281758

22.. Vattikuti R, Towler DA, Osteogenic regulation of vascular calcification: An early perspective: Am J Physiol Endocrinol Metab, 2004; 286; E686-96

23.. Johnson R, Leopold J, Loscalzo J, Vascular calcification pathobiological mechanisms and clinical implications: Circ Res, 2006; 99; 1044-59

24.. Leem J, Lee IK, Mechanisms of vascular calcification: The pivotal role of pyruvate dehydrogenase kinase 4: Endocrinol Metab (Seoul), 2016; 31; 52-61

25.. Rocha-Singh KJ, Zeller T, Jaff MR, Peripheral arterial calcification: Prevalence, mechanism, detection, and clinical implications: Catheter Cardiovasc Interv, 2014; 83; E212-E20

26.. Demer LL, Tintut Y, Inflammatory, metabolic, and genetic mechanisms of vascular calcification: Arterioscler Thromb Vasc Biol, 2014; 34; 715-23

27.. Agarwal P, Prakash M, Singhal M, To assess vascular calcification in the patients of hypoparathyroidism using multidetector computed tomography scan: Indian J Endocrinol Metab, 2015; 19; 785-90

28.. Rangaswami N, Chaudhary S, Flinn G, Sanyal SK, Idiopathic linear calcification of the ascending aorta in an adolescent: Am J Dis Child, 1979; 133; 860-61

In Press

12 Feb 2024 : Case report  Germany

Diagnostic Challenges and Imaging Considerations for Intraparotid Facial Nerve Schwannoma: A Case Report an...

Am J Case Rep In Press; DOI: 10.12659/AJCR.942870  

0:00

12 Feb 2024 : Case report  USA

Erdheim-Chester Disease Occult on Radiographs and CT but Visible on MRI and PET

Am J Case Rep In Press; DOI: 10.12659/AJCR.941169  

0:00

12 Feb 2024 : Case report  USA

Surgical Treatment of Spontaneous Superficial Temporal Artery Arteriovenous Malformation: A Case Report

Am J Case Rep In Press; DOI: 10.12659/AJCR.942839  

13 Feb 2024 : Case report  Bahrain

Warfarin Woes: A Rare Case of Hemoperitoneum with Intramural Small Bowel Hematoma

Am J Case Rep In Press; DOI: 10.12659/AJCR.943519  

Most Viewed Current Articles

10 Jan 2022 : Case report  Germany

A Report on the First 7 Sequential Patients Treated Within the C-Reactive Protein Apheresis in COVID (CACOV...

DOI :10.12659/AJCR.935263

Am J Case Rep 2022; 23:e935263

19 Jul 2022 : Case report  Saudi Arabia

Atlantoaxial Subluxation Secondary to SARS-CoV-2 Infection: A Rare Orthopedic Complication from COVID-19

DOI :10.12659/AJCR.936128

Am J Case Rep 2022; 23:e936128

05 Mar 2022 : Case report  Brazil

Acute Limb Ischemia After Self-Injection of Crushed Morphine Tablets into the Radial Artery: Role of Infrar...

DOI :10.12659/AJCR.935336

Am J Case Rep 2022; 23:e935336

02 Apr 2022 : Case report  Saudi Arabia

Infective Endocarditis Caused by Pseudomonas luteola in a Pediatric Patient. A Case Report and Review of Li...

DOI :10.12659/AJCR.935743

Am J Case Rep 2022; 23:e935743

Your Privacy

We use cookies to ensure the functionality of our website, to personalize content and advertising, to provide social media features, and to analyze our traffic. If you allow us to do so, we also inform our social media, advertising and analysis partners about your use of our website, You can decise for yourself which categories you you want to deny or allow. Please note that based on your settings not all functionalities of the site are available. View our privacy policy.

American Journal of Case Reports eISSN: 1941-5923
American Journal of Case Reports eISSN: 1941-5923