Polyglandular Autoimmune Syndrome Type - medIND

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JIACM 2005; 6(2): 155-7

Polyglandular Autoimmune Syndrome Type – I GQ Khan*, G Hassan**, Waseem Qureshi***, Manish Kak****, Manzoor Kadri*****, Dilshada Akhter******, Jehangir Bakshi*******

Abstract Polyglandular Autoimmune Syndrome Type – I is an autosomal recessive trait, characterised by mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency, requiring two of these three components for diagnosis. Besides, several other features are characteristic of the disorder. We report the disorder in a 23-year-old male where the diagnosis was made on the basis of mucocutaneous candidiasis, hypoparathyroidism, and hypogonadism. Bilateral subcapsular cataracts and peripheral neuropathy were noticed as additional findings. Key words: Autoimmune polyglandular syndromes, Mucocutaneous candidiasis, Adrenal insufficiency.

Introduction Polyglandular autoimmune (PGA) syndrome type-I, is an autosomal recessive disorder characterised by the triad of mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency1, 2, 3, and the accepted criteria for diagnosis is the presence of atleast two of these three major components1, 3. Other associated features include gonadal failure, hypothyroidism, type-I diabetes mellitus, hypoplasia of dental enamel, ungual dystrophy, tympanic membrane sclerosis, vitiligo, keratopathy, pernicious anaemia, malabsorption, asplenism, achalasia, cholelithiasis, chronic active hepatitis, Sjogren’s syndrome, haemolytic anaemia, vasculitis, and hypophysitis1, 2, 3. This is a rare disorder. Only 139 patients were reported till the study of 41 cases by Betterle et al in 19983. The present case is the first of its kind reported from India even though reports of this case appeared previously4, 5. Subsequently, Bhansali et al reported one case in 20036.

Case report A 23-year-old boy from non-consanguineous parents was growing normally till sixth year of age after which he started having recurrent respiratory infections, and fungal infections of nails and skin – documented as candidiasis at AIIMS, New Delhi – which proved unresponsive to the usual therapy with ketoconazole. By the eighth year of life, he developed oesophageal candidiasis which did not respond

to oral ketoconazole, but got cured with oral terbinafine. During the same year he developed chronic diarrhoea for which he was fully investigated at Sher-i-Kashmir Institute of Medical Sciences, Srinagar and was finally labelled as malabsorption syndrome without any apparent cause. At fifteenth year he was operated at the same place for bilateral undescended testes and orchipexy was done. In the same year he developed recurrent episodes of generalised tonicclonic convulsions, when computed tomography revealed no intracranial lesion. He was put on carbamazepine, while the convulsions still remained uncontrolled. At 17 years, he was not able to study because of the development of bilateral subcapsular cataracts, for which he was operated and intraocular lens implanted on both sides. Recently in 2000, he got admitted to our hospital for evaluation of recurrent haemoptysis and carpopedal spasms of recent onset. On examination, he was of normal intelligence, had alopecia with loss of eyebrows and beard, sparse scalp, axillary, and pubic hair, dystrophic nails with coarse skin on palms, malpositioned upper incisors, and no skeletal deformities. His systemic examination was normal except for loss of tendon reflexes with preserved right ankle jerk. Investigations revealed normal haemogram and other baseline investigations. Chest X-rays revealed persistent mass shadow in right hilar region. He had hypocalcaemia with serum calcium 6.0 mg/dl and normal phosphorus and

* Professor and Head, ** Registrar, Department of Medicine, *** Medical Superintendent, SMHS Hospital, **** Postgraduate Scholar, Department of Medicine, ***** Demonstrator, Department of Microbiology, ****** Lecturer, Department of Dermatology, ******* Registrar, Department of Radiology, Government Medical College and Associated Hospital, Srinagar, Kashmir - 190 010, India.

magnesium levels. Thyroid function tests were normal. Parathyroid hormone was markedly reduced to 1 pg/ml (normal, 12-72 pg/ml); testosterone level was decreased to 1.5 ng/ml (normal, 3-10 ng/ml); FSH was elevated to 35 IU/ml (normal, 2.0-6.5 IU/ml); and LH was decreased to 2.1 IU/ml (normal, 3.0-7.2 IU/ml). Serum cortisol and prolactin levels were normal. ACTH stimulation test was normal, and anti-adrenal antibodies were negative. Audiogram revealed conductive deafness of left and sensori-neural deafness of right ear. Movements of the left tympanic membrane were restricted, suggestive of tympanic sclerosis. Computed tomography (CT) of brain was normal, but that of chest revealed a soft tissue mass in the right paratracheal and hilar regions, and stereotactic biopsy done under CT guidance on two occasions was inconclusive. Bronchoscopy done on 3 occasions revealed no endobronchial lesion. Open lung biopsy done recently revealed fibrosed tissue in right upper and middle lobes and histopathologic study of the same showed lymphocytic interstitial pneumonia with nodule formation. Profile for tuberculosis was negative. Fungus study of the lung tissue was also negative. Electromyographic studies were normal, but nerve conduction studies were consistent with peripheral neuropathy (axonopathy). The patient’s carpopedal spasms are well controlled on supplemental calcium and he is under our regular follow-up.

Discussion The diagnosis of the disorder was made on the basis of mucocutaneous candidiasis and hypoparathyroidism, as mentioned in the literature 1, 2, 3 alongwith other accompanying conditions like hypogonadism, otosclerosis, and alopecia. However, the findings of cataracts and peripheral neuropathy which were seen in the present case have not been mentioned so far. Historically, candidiasis was the initial major manifestation to appear, which is true with most of the previous series2, 3 . Candidiasis is usually the first manifestation to appear13 , usually before the age of 5 years, occurring in 73-100% of all cases. The reason for marked susceptibility to mucocutaneous candidiasis without systemic involvement is unknown 2 . This is followed by hypoparathyroidism usually before 10 years and later by adrenal insufficiency before 15 years of age. Our case has

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no evidence of the latter even by 23 years of age. The three major manifestations usually occur in chronological order, but are present together in only one-third to one-half of cases3. At the outset, only one organ may be involved, but the number increases with time, so that eventually two or five components occur1. Among the various endocrinopathies, hypogonadism has been found in 17-50% of the cases, as was also true with the present one. Insulin dependent diabetes has been reported to occur in 4% of patients2; however, it was not present in our case. Malabsorption, as was found in this patient, has been found to occur in 18-22% of cases3, and the possible causes include coeliac disease, cystic fibrosis, pancreatic insufficiency, intestinal lymphangiectasia, and infections like Giardia lamblia and Candida. Chronic active hepatitis is seen in 15-18% of patients carrying significant mortality7. The disorder needs to be differentiated from Digeorge syndrome, which is a rare form of hypoparathyroidism with associated cardiovascular and developmental defects. Death in such patients occurs in early childhood due to infections, hypocalcaemia, seizures, and cardiovascular complications8. The disorder usually starts in childhood1, 2, 7 with male/ female ratio of 0.8-1.5 as per different reports3, and is inherited as an autosomal recessive trait2, 3. In the earlier studies no HLA association was found, but recently association with HLA–28 and HLA–A3 and has been found3 and has been linked to chromosome 211, 3; and recently it was found that mutation K257X is responsible for 82% of the Finnish variants of the syndrome3. In general, the patients of PGA type-I have a variety of autoantibodies directed against organ specific antigens. The antibodies recognise cytoplasmic components of various endocrine cells such as thyroid peroxidase, adrenal side chain cleavage enzyme, or pancreatic glumatic acid decarboxylase; others are directed to surface receptors, or bind to complement, impairing normal function of the organs1-3. Further studies are going on regarding the immunopathogenesis of this disorder. Treatment of the disorder involves management of each endocrine deficiency which means hormone replacement1, 2 and candidiasis is usually responsive to ketoconazole3, although our case got cured with terbinafine.

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Survival is usually limited. Betterle et al in their study of 41 cases, over around 30 years, found death occurring in 10% of cases, and cumulative survival around 75% by 48 years. In their series one patient died at the age of 36 years, of carcinoma of oral mucosa3. Our case, who is apparently stable at the age of 23, is still under our regular follow-up for future course of management.

Metab 1998; 83: 1049-55. 4.

Khan GQ, Hassan G, Kadls S et al. Polyglandular Autoimmune Syndrome Type-I. Report of First Case from India. J Assoc Physicians India 2001; 49: 140-1 (Abstract).

5.

Hassan G. Terbinafine effectiveness in ketoconazable Resistant Mucocutaneous Candidiasis in Polyglandular Autoimmune Syndrome Type-I. J Assoc Physicians India 2003; 51: 323.

6.

Bhansali A, Kotwal N, Suresh V et al. Polyglandular Autoimmune Syndrome Type-I without Chronic Mucocutaneous Candidiasis in a 16 year old male. J Pediatr Endocrinol Metab 2003; 16: 103-5.

7.

Michele TM, Fleckenstein J, Sgrignoli AR, Thuluvath PJ. Chronic active helpatitis in the type-I polyglandular autoimmune syndrome. Postgrad Med J 1994; 70: 128-31.

8.

Potts Jt, Jr. Diseases of the Parathyroid Gland and other Hyper – and hypocalcaemia disorders. In: Fauci AS, Braunwald E, Isselbacher KJ et al Eds. Harrison’s Principles of Internal Medicine. 14th Ed. New York: McGraw Hill 1998; 2227-47.

References 1.

Sherman SI, Gagel RF. Disorders Affecting Multiple Endocrine Systems. In: Fauci AS, Braunwald E, Isselbacher KJ et al. Eds. Harrison’s Principles of Internal Medicine. 14th Ed. New York: McGraw Hill 1998; 2131-8.

2.

Eisenbarth GS, Jackson RA. The immunoendocrinopathy syndromes. In: Wilson JD, Foster DW Eds. Williams Text book of Endocrinology. 8th Ed. Philadelphia: WB Sounders Company 1992; 1555-66.

3.

Betterle C, Greggio NA, Volpato M. Autoimmune Polyglandular Syndrome Type – I. J Clin Endocrinol and

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