Autoimmune polyglandular syndrome (APS) type 1 and candida onychomycosis

ARTICLE

Case report

History

A 21-year-old female presented at age 2 with black fragile finger- and toenails, candidiasis of the mucomembranes of the mouth and at age 3 loss of hair generalized all over the body. At the age of 6 the first generalized convulsion appeared, one year later the girl was referred to a pediatric endocrinologist who detected hypocalcaemia as the reason for seizures and hyperphosphataemia. At the age of 8 a malabsorption syndrome occurred with massive fatty stools and loss of weight. At the age of 10 the first signs of pernicious anemia occurred, furthermore adrenal insufficiency was diagnosed. Additionally the girl suffered from chronic conjunctivitis (Table I). The homozygous R-257-mutation of the AIRE-1-gene (Autoimmune Regulator Gene Responsible for APS 1) has been detected. The parents of the girl are heterozygous for this mutation.

The patient was treated with several antifungal drugs e.g. itraconazole (Sempera^®), terbinafine (Lamisil^®), fluconazole (Diflucan^®). Of these, only fluconazole (Diflucan^®) was successful, but it had to be stopped because of raised liver enzymes. In April 2000, the patient presented at the Department of Dermatology with yellow-brownish, hyperkeratotic and dystrophic finger nails (Fig. 1). Toenails, palmar and plantar skin and space between the toes and mucous membranes of the mouth were not involved. The mycological investigation of a swab from the tongue and nail scraping material revealed massive growth of Candida albicans.

Investigations

The blood sedimentation was 22/40 mm. Laboratory examinations showed low haemoglobin and calcium and raised phosphate level in serum.

Furthermore autoantibodies against several endocrine organs were detected with the following titres: adrenal gland autoantibodies 1:40, autoantibodies against Leydig cells 1:320, ovary autoantibodies 1:40, autoantibodies against Langerhans' islet cells 1:640, antimitochondrial autoantibodies 1:125.

Treatment

In the past, onychomycsosis has been treated successfully with fluconazole (Diflucan^®). But this antifungal drug had to be stopped because of raised liver enzymes.

According to MIC values of in vitro susceptibility testing: fluconazole (Diflucan^®) 0.5 mug/ml (= susceptible), itraconazole (Sempera^®) 0.125 mug/ml (= susceptible), 5-flucytosine (Ancotil^®) (= susceptible) and because of the former efficacy of fluconazole (Diflucan^® Derm) 50 mg/d, therapy was started again with the latter triazole drug. Nail lesions rapidly improved and were cleared within 3 months of treatment (Fig. 2).

The hypoparathyroidism was treated with Calcium Sandoz forte^® orally and Rocaltrol^® (Calcitriol) 0.5-1.5 mug/d. Vitamin B₁₂ intramuscular 1 mg every month and Kreon^® 10 000 2x/d were added because of the malabsorption syndrome. The adrenal insufficiency was successfully substituted with hydrocortisone (Hydrocortison^®) 25 mg/d and fludrocortisone (Fludrocortison^®) 0.1 mg/d.

Discussion

The first description of an association between hypoparathyroidism and candidiasis was published in 1929 [1]. An additional idiopathic adrenal insufficiency was reported in 1946 [2]. Autoimmune polyglandular syndrome (APS) type 1 has been described under several synonyms such as Whitaker's syndrome [3], polyglandular autoimmune diasease type 1 [4], or autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) [5].

CMC is a heterogeneous group of disorders which has been classified into several categories based on the candida infections, and associations with other disorders. A new classification is proposed by Coleman (Table II) [6].

APS type 1 is a very rare disorder. In Finland, where the highest number of patients with APS type 1 has been reported, the estimated prevalence is about 1 in 25,000 inhabitants. In the majority of the cases, the syndrome occurs in childhood. The female/male ratio varied in the different reports from 0.8-1.5 [3].

APS type 1 is a condition that may occur sporadically or among siblings [4, 7, 8]. In the early studies no association with human leucocyte antigen (HLA) class I or II antigens was found [9]. Subsequently, HLA-A28 was demonstrated to be more frequent in patients with APS type 1 than in normal controls, and HLA-A3 was more frequent in those with APS type 1 and ovarian failure than in those with APS type 1. It is the only known autoimmune disease inherited in a Mendelian fashion. The gene responsible for the syndrome was recently identified on chromosome 21 and the R-257-mutation of the AIRE-1-gene was detected in our patient [5]. This recent discovery should provide insight into the pathogenesis of APS 1 as well as autoimmune diseases in general.

An association between the clinical expression of the syndrome and a gene located in chromosome 21 has been identified [10]. In our patient homozygous R-257-X mutation on AIRE-gene was found. The parents of the girl are heterozygous for this mutation. Mutations in the gene designated as AIRE (autoimmune regulator), seem to be the cause of the disease [11]. On the other hand the most common AIRE-1 mutations R-257-X in exon 6 and a 13bp deletion in exon 8 were normally not found in patients with isolated autoimmnune disorders like type 1 diabetes mellitus, Addison's disease, Grave's disease and Hashimoto's thyroiditis [12].

The major features of APS type 1 are chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism, and autoimmune adrenal insufficiency. To define this syndrome, at least two of these disorders have to be present in one individual [8].

The spectrum of associated skin diseases include vitiligo, alopecia, and due to cellular and humoral immunological defects, condylomata accuminata and scabies crustosa. Moreover, ectodermal dystrophy has been described. Further associated autoimmune endocrinopathies and nonendocrine manifestations are shown in Table III [5, 8, 13].

We report here a patient with autoimmune skin diseases which are CMC and alopecia totalis. CMC generally presents earliest in life as in our patient and is the most frequent of the three main features of APS type 1. The nail lesions rapidly improved and healed within 3 months of treatment with fluconazole (Diflucan^® Derm) 50 mg/d and locally with ciclopirox (Batrafen^®). The patient tolerated this antifungal drug very well. During the past fluconazole (Diflucan^® Derm) also was effective, but this antifungal drug had to be stopped because of raised liver enzymes. Ketoconazole (Nizoral^®), an imidazole derivative, that is also known to inhibit the biosynthesis of cortisol and testosterone in vivo in a dose- and time-dependent fashion, should be used with caution in patients who are already at risk for adrenal insufficiency. CMC may appear as early as at the first month after birth up to 21 years of age, with a peak of occurrence in early childhood [5, 7]. In our patient the age of onset was 2 years. CMC affects the nails, the dermis, and the oral, vaginal, and esophageal mucous membranes. In the majority of cases, the infection is limited to not more than 5% of the skin surface [17]. In rare cases, this disorder can cause important complications; for example, Ahonen described 4 cases of esophagitis, with esophageal stricture in 1 patient, and 11 other cases with periodical retrosternal pain that resolved with oral antifungal therapy [5]. In our case signs of CMC involved only the fingernails. CMC is considered the clinical expression of an immunological selective T cell deficiency with an inability to respond in vivo and in vitro to candidal antigens [14-17]. However, these patients, in general, have a normal B cell response of serum antibodies to candidal antigens, which is considered important in preventing the development of systemic candidiasis [17]. For this reason, APS type 1 is also classified as an acquired immunodeficiency. At age of 2 our patient presented with complete body hair loss. Association of alopecia with APS type 1 was reported for the first time in 1946 [2]. The frequency of this disorder varies from 29-32% of all cases and involves scalp, eyelashes, eyebrows, axilla, and pubis. Alopecia appears from 3-30 years of age [5, 18].

Selective IgA deficiency and hypergammaglobulinaemia were found in a family with APS type 1 [13]. IgA deficiency in APS type 1 patients has been recently confirmed [5]. Following these immune deficiencies these patients may acquire scabies crustosa, condylomata accuminata and CMC.

In general, the first manifestation of APS usually occurs in childhood, and the complete evolution of the three main diaseases takes place in the first 20 years of life, whereas other accompanying diseases continue appearing until at least the fifth decade [5]. In a majority of cases, candidiasis is the first clinical manifestation to appear, usually before the age of 5 years, followed by hypoparathyroidism (usually before the age of 10 years), and later by Addison`s disease (usually before the age of 15 years). Overall, the three main components of APS type 1 occur in a fairly precise chronological order, but they are present together in only about one third to one half of cases [5, 7].

The clinical spectrum of APS 1 is broad. All patients need lifelong follow-up for the detection of new disease components, some of which may be life-threatening.

As CMC is most often the first manifestation of APS type 1, it can be considered a precocious marker of APS type 1. Consequently, all patients affected by isolated CMC, especially children, should be evaluated and carefully followed up by immunological, biochemical, and clinical tests to recognize signs and symptoms of imminent or ongoing endocrine glandular failure.

CONCLUSION

REFERENCES

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