Original Article
Clinical Variation of Autoimmune Polyendocrinopathy–Candidiasis–Ectodermal Dystrophy (APECED) in a Series of 68 Patients
N Engl J Med 1990; 322:1829-1836June 28, 1990
- Abstract
- Abstract
To define the clinical picture and course of the autosomal recessive disease called autoimmune polyendocrinopathy—candidiasis—ectodermal dystrophy (APECED), we report data from our 10-month to 31-year follow-up of 68 patients from 54 families, now 10 months to 53 years of age.
The clinical manifestations varied greatly and included from one to eight disease components, 63 percent of the patients having three to five of them. The initial manifestation was oral candidiasis in 41 patients (60 percent), intestinal malabsorption in 6 (9 percent), and keratopathy in 2 (3 percent). All the patients had candidiasis at some time. The earliest endocrine component appeared at 19 months to 35 years of age. Hypoparathyroidism was present in 54 patients (79 percent), adrenocortical failure in 49 (72 percent), and gonadal failure in 15 (60 percent) of the female patients ≥ years of age and 4 (14 percent) of the male patients ≥16 years of age. There were multiple endocrine deficiencies in half the patients.
From 4 to 29 percent of the patients had periodic malabsorption, gastric parietal-cell atrophy, hepatitis, alopecia, vitiligo, or a combination of these conditions. Dental-enamel hypoplasia and keratopathy were also frequent but were not attributable to hypoparathyroidism. In the patients whose initial manifestation (other than candidiasis) was adrenal failure, the other components developed less often than in the remaining patients.
We conclude that the clinical spectrum in patients with APECED is broad. The majority of patients have three to five manifestations, some of which may not appear until the fifth decade. Therefore, all patients need lifelong follow-up for the detection of new components of the disease. (N Engl J Med 1990; 322:1829–36.)
Media in This Article
Figure 1
Distribution of Numbers of Disease Components among 68 Patients with APECED.Figure 2
Incidence Rates of the Three Most Common Components of APECED in 68 Patients, According to Age.Article Activity
- Article
AUTOIMMUNE polyendocrinopathy—candidiasis—ectodermal dystrophy (APECED) is an autosomal recessive disease characterized by a variable combination of (1) failure of the parathyroid glands, adrenal cortex, gonads, pancreatic beta cells, gastric parietal cells, and thyroid gland, and hepatitis; (2) chronic mucocutaneous candidiasis; and (3) dystrophy of dental enamel and nails, alopecia, vitiligo, and keratopathy.1 2 3 4 5 This disease has many names, one being autoimmune polyglandular disease Type I.4 We prefer the name APECED, because it emphasizes the three groups of disease components.2 , 3 There are numerous reports describing single patients or a few patients with APECED. These have been reviewed extensively,4 5 6 7 8 9 10 but the reviews have given undue emphasis to the more severe or unusual manifestations of the disease. Consequently, patients with milder forms of the disease may remain unidentified. Apart from earlier studies in Finnish patients,2 , 3 , 11 12 13 14 the largest number of patients examined by any author was nine.15
In this study we define the range of clinical presentation and development of APECED in a population-based study.
Methods
Patients
This series, comprising 68 patients, 10 months to 60 years of age, from 54 families, consists of all the patients documented to have had APECED in Finland between 1910 and 1988. The members of the series were identified in three ways. First, because ours is a national center for pediatric endocrinology, patients are referred to us from all parts of Finland (population, 4.9 million). Second, we sought information from all hospital departments of pediatrics and internal medicine and all clinical endocrinologists and dermatologists about patients with any of the three most common components of APECED (hypoparathyroidism, chronic mucocutaneous candidiasis, and adrenocortical failure).2 3 4 5 , 10 Third, we searched the Finnish medical literature for published cases.16 Fifty patients were identified through the referrals, nine through the inquiries, two from the literature, six among the siblings or close relatives of the referred patients, and one in general practice by one of us.
The criteria for inclusion were the unequivocal presence of at least two of the following: hypoparathyroidism,2 adrenocortical failure,12 , 13 and chronic mucocutaneous candidiasis. One disease component was sufficient for inclusion if a sibling had two or more components.2 , 3
In 52 of the 54 families, we interviewed the patients, the parents, most of the siblings, and other close relatives about the sequence and timing of the appearance of symptoms and signs of APECED in the patients. In the two remaining families, our sources of information were a case report,17 medical records, and interviews with the patients' physicians.
A genetic analysis establishing autosomal recessive inheritance has been published,2 as have some of the dental findings,11 staging of the adrenal failure,12 a study of the autoantibodies whose presence predicts adrenal failure,13 and a study of the associations of the disease and its components with HLA antigens.14
Clinical Data
We review here the case records for all 68 patients. We examined 61 patients, and followed 60 patients regularly for 10 months to 20 years (mean, 11.2 years). The longest follow-up at this hospital was 31 years. Patients who did not have the clinical features of adrenal failure had ACTH stimulation tests at least annually.12 , 13 Blood samples were studied repeatedly for the presence of antibodies to thyroid microsomes, thyroglobulin, pancreatic islet cells, gastric parietal cells, adrenal cells, and steroidal cells. Patients ≥12 years of age who did not have gonadal failure had repeated gonadotropin-releasing hormone stimulation tests.13 Fifty-nine living siblings and 83 parents of the patients were also examined. Their plasma concentrations of calcium, inorganic phosphate, sodium, and potassium were measured, and they were tested for the presence of organ-specific autoantibodies. The siblings also had ACTH stimulation tests.12 , 13 Fifty-six patients had dental examinations, and their ages at the time of the development of hypoplastic dental enamel were determined.11 , 18 Fifty-four patients had ophthalmologic examinations.7 , 19
The diagnosis of hypoparathyroidism was based on findings of subnormal plasma calcium and supranormal plasma phosphate concentrations and normal renal function.2 , 20 The diagnosis of primary cortisol deficiency was based on findings of repeatedly subnormal maximal plasma cortisol concentrations or subnormal maximal 24-hour urinary excretion of 17-ketogenic steroids in response to stimulation by ACTH.12 , 13 The diagnosis of primary aldosterone deficiency was based on findings of inability to retain sodium when the sodium intake was under 10 mmol per 24 hours or grossly elevated plasma renin activity.12 , 13 The diagnosis of ovarian failure was based on findings of supranormal plasma concentrations of follicle-stimulating hormone or luteinizing hormone at base line or after stimulation with gonadotropin-releasing hormone, amenorrhea, and inappropriately absent, slow, or regressing pubertal development.13 In the patients with primary amenorrhea, we used 13.3 years, the mean menarcheal age of women in Finland,21 to represent the age at onset of ovarian failure, and in the patients with secondary amenorrhea we used the age at the time of the patient's last menstruation. The diagnosis of testicular failure was based on findings of supranormal plasma concentrations of luteinizing hormone or follicle-stimulating hormone at base line or after stimulation with gonadotropin-releasing hormone, and a subnormal testosterone concentration22; that of hypothyroidism on subnormal plasma thyroxine concentrations and supranormal concentrations of thyroid-stimulating hormone23; and that of gastric parietal-cell failure on subnormal plasma concentrations of vitamin B12 (or megaloblastic anemia) and a positive Schilling test (often with circulating antibodies to parietal cells or intrinsic factor).24 25 26 Patients with insulin-dependent diabetes mellitus had severe hyperglycemia and, in all but one, ketoacidosis at the time of diagnosis.27 Periodic intestinal malabsorption was defined on the basis of episodes of floating stools, as reported by the patient or the parents, and increased fecal fat excretion, as determined from pooled four-day fecal collections. The diagnosis of chronic mucocutaneous candidiasis (hereafter, candidiasis) was made if the patient had had candidiasis of the oral mucosa or nails for three months or longer. The age at the onset of candidiasis (at each site) was reported by the patient or the parents. Oral specimens were obtained for culture by rinsing the mouth with 0.9 percent saline and scraping the oral mucosa with a cotton swab; ungual and dermal specimens were obtained by scraping, and additional ungual specimens by cutting off small pieces of the nails with a scalpel. Vaginal specimens were obtained with a cotton swab. The specimens were cultured for Candida albicans and other fungi,28 and the nail specimens were examined microscopically.29 The diagnosis of keratopathy was based on findings of irregular, initially slightly raised, confluent, and grayish corneal opacities, mild bulbar injection of the conjunctiva, and subsequent superficial corneal neo-vascularization of the hazy areas.7 , 19 If severe photophobia and blepharospasm had appeared six months or more before an ophthalmologist's diagnosis, we used the patient's age at the onset of these conditions in the analysis. The presence of organ-specific autoantibodies was determined by the indirect immunofluorescence technique.13
For the seven patients whom we did not investigate personally, we reevaluated the diagnoses of the various disease components in the medical records and determined their sequence and timing, beginning with the age at diagnosis or the unequivocal appearance of pathognomonic manifestations.
Statistical Analysis
The data were analyzed by BMDP programs (BMDP Statistical Software, Los Angeles) with the t-test (Student's or Welch's, as appropriate), an analysis of variance, the chi-square test, and Fisher's exact-probability test. The occurrence of new disease components was studied by comparing the distributions of time to response among groups of patients in a survival analysis (BMDP 1L).
Results
Frequency of Disease Components
The number of components of APECED present in each of the 68 patients varied from one to eight, the most frequent number being four (Fig. 1Figure 1
Distribution of Numbers of Disease Components among 68 Patients with APECED.). The most common form of endocrinopathy was hypoparathyroidism, which was present in 54 patients (79 percent; Table 1Table 1
Characteristics of 68 Patients with APECED and Prevalence of Components of the Disease during Follow-up, According to Age.*). It was diagnosed at ages ranging from 19 months to 44 years. Adrenocortical failure was present in 49 patients (72 percent); it was diagnosed at ages ranging from 4.2 to 41 years. Cortisol and aldosterone deficiencies occurred simultaneously in 38 patients, but their times of onset differed by six months to 5.8 years in the other 11 patients, Cortisol deficiency appearing first in 6 and aldosterone deficiency appearing first in 5. Gonadal failure was present in 15 of the 25 female patients ≥13 years old (60 percent) and in 4 of the 28 male patients ≥16 years old (14 percent); it occurred in all patients by the age of 30. In one man the hypogonadism was hypothalamic in origin rather than primary. Eight patients (12 percent) had insulin-dependent diabetes mellitus, with the age at onset ranging from 4.1 to 37 years. Nine patients (13 percent) had vitamin B12 deficiencies that began at the ages of 6.1 to 47. Two female patients had nongoitrous hypothyroidism; no other patient had any thyroid autoimmune disease.All 68 patients had oral candidiasis at least periodically; this condition first appeared at ages ranging from one month to 21 years. In six patients the candidiasis was very mild and disappeared spontaneously for as long as several years, but it always recurred. Other patients had chronic hypertrophic lesions, atrophic lesions, or both. Ungual candidiasis was present in 48 patients (71 percent), and dermal candidiasis in 6 (9 percent). The lesions were usually located on the hands and face. No patient had cutaneous lesions that covered more than 5 percent of the skin surface or that were granulomatous.29 Four patients had esophagitis that was diagnosed by endoscopy, with stricture in one. Eleven other patients reported periods of retrosternal pain that resolved within days after the initiation of oral antifungal therapy.
Twelve patients (18 percent) had periodic malabsorption, which first appeared at the ages of four months to 21 years. Twenty patients (29 percent) had alopecia beginning at the ages of 5 to 30 years, and vitiligo had developed in nine patients (13 percent) by one month to 15 years of age. Keratopathy was present in 24 patients (35 percent); it first developed when they were 1 to 15 years old (Table 1). Two patients had episodes of cutaneous vasculitis.
Associations of Components
The triad of candidiasis, hypoparathyroidism, and adrenal failure — with or without other disease components — was present in 35 patients, beginning at the ages of 4.5 to 44 years (mean, 14).
Thirty-three of the 43 patients who could be evaluated (77 percent) had hypoplasia of the dental enamel that had begun at birth or during the first seven years. The deciduous teeth were never affected. The occurrence of enamel hypoplasia was not associated with hypoparathyroidism: 28 of the 33 patients with enamel hypoplasia had hypoparathyroidism, as did 8 of the 10 patients who did not have enamel hypoplasia (P = 0.90, chi-square test). In five patients, enamel hypoplasia had developed substantially earlier than hypoparathyroidism (by 8 to 12 years), and two of the five had normal plasma calcium levels during that period. In addition, three patients have lived for 20 to 37 years after the development of enamel hypoplasia without having hypoparathyroidism.
Keratopathy was present in 24 patients. Its occurrence was likewise not associated with hypoparathyroidism: 22 of the patients with keratopathy had hypoparathyroidism, as did 32 of the 44 patients who did not have keratopathy (P = 0.13). In six patients keratopathy developed substantially earlier than hypoparathyroidism (1 to 34 years); of these, three had normal plasma levels of calcium during this interval. Adrenal failure was more frequent in the patients with keratopathy (21 of 24) than in those without it (28 of 44; P = 0.048).
Hypoparathyroidism was present in all but one of the patients with intestinal malabsorption. This was a 12-year-old boy who had steatorrhea for 10 years, with consistently normal plasma calcium levels. In most patients who had steatorrhea, it appeared as the initial manifestation. It tends to recur whenever the patients become hypocalcemic, whereas in other patients with a comparable degree of hypocalcemia normal stool quality is maintained.
Calcified plaques were observed in 24 of the 84 tympanic membranes studied — that is, in 14 of 42 patients. Plaques were usually located in the posterior part of the membrane. No patient had a history of tympanostomy-tube placement or repeated ear infection. One patient had a history of ear discharge. Initially, most patients were thought to have tympanic-membrane atrophy, but clear differentiation between normal and atrophic membranes appears impossible (Grahne B, Rinne J, Ahonen P, Perheentupa J: unpublished data).
Twenty-six of the 50 patients who could be evaluated (52 percent) had pitted dystrophy of the nails. In 33 of these 50, ungual candidiasis was or had been present or was suspected. Of the 17 patients who did not have candidiasis, 11 had pitted dystrophy (65 percent). The pits were 0.5 to 1 mm in diameter and affected several nails. These lesions were not as extensive as the "sandpaper nails" described in some patients with alopecia,30 , 31 because the surface of the nail appeared otherwise smooth. Also, the lesions were never observed in all 20 nails of any patient.30 , 31 Repeated tests of specimens from such pitted nails for fungal cultures and repeated staining were negative. Some patients had typical candidal lesions in some nails, confirmed by culture, and pitted dystrophy in others. The pitted dystrophy sometimes resolved spontaneously and then reappeared unassociated with any other disease component.
Course of the Disease
Of the 68 patients, 53 (78 percent) had nonendocrine manifestations of APECED before the first endocrinopathy. The initial nonendocrine manifestation was oral candidiasis alone in 41 (60 percent), intestinal malabsorption in 6 (9 percent), keratopathy in 3 (4 percent), and vitiligo, alopecia, and hepatitis in 1 each. Two of the patients with malabsorption, one patient with keratopathy, and the patient with alopecia had a simultaneous diagnosis of oral candidiasis. Among the other 15 patients, the initial manifestation was hypoparathyroidism in 13 (with a simultaneous diagnosis of oral candidiasis in 7) and either hypoparathyroidism or oral candidiasis in 2, the sequence being uncertain. Thus, oral candidiasis was the initial component (often appearing simultaneously with another component) in at least 52 patients (76 percent). The disease developed in infancy in some patients, and the majority were symptomatic by the age of five years (Table 1).
The three most common components, candidiasis, hypoparathyroidism, and adrenal failure, tended to appear early (Fig. 2Figure 2
Incidence Rates of the Three Most Common Components of APECED in 68 Patients, According to Age.). The incidence rate for candidiasis was highest in infancy and declined gradually thereafter. For hypoparathyroidism, an initially low incidence rate rose sharply to a peak in years three to five. For adrenal failure, the incidence rate rose later and less steeply to a peak in years 11 to 15 and then declined, paralleling the rate for hypoparathyroidism. Hypogonadism was usually diagnosed during the second decade; we did not, however, test for it before pubertal age. In patients with insulin-dependent diabetes mellitus, gastric parietal-cell failure, and hypothyroidism, the age at onset was more evenly distributed. The earliest endocrine component appeared between the ages of 19 months and 35 years (mean, 8.7 years), the second component between 4.1 and 44 years (mean, 13), and the third between 5.5 and 26 years (mean, 16). New components continued to appear until at least the fifth decade. Thus, in a man who had had keratopathy since the age of 10, alopecia and candidiasis since the age of 30, and adrenal failure since the age of 35, hypoparathyroidism developed at the age of 44. In a woman who had had malabsorption since the age of 4, hypoparathyroidism since the age of 6, alopecia since the age of 10, candidiasis since the age of 20, and pernicious anemia since the age of 32, insulin-dependent diabetes mellitus developed at the age of 37. Among the few patients 40 years of age or older, the frequency of adrenal failure was lower and that of insulin-dependent diabetes mellitus and gastric parietal-cell failure higher than in the others (Table 1).The mean age at the appearance of the first component of disease other than candidiasis was 6.6 years (range, 0.1 to 21). The mean age at the appearance of the first such component was 11 years in the 13 patients with one or two components, 7.5 years in the 31 patients with three or four components, 4.2 years in the 20 patients with five or six components, and 2.7 years in the 4 patients with seven or eight components (P = 0.0008).
We then analyzed the course of the disease in terms of the appearance of its components other than candidiasis. When the patients were grouped according to the first such component, there were six groups. Hypoparathyroidism occurred as the first component in 40 patients, adrenal failure in 8, intestinal malabsorption in 7, keratopathy in 6, and alopecia in 3 (Fig. 3Figure 3
Sequence in Which Disease Components Other than Candidiasis Appeared in 66 Patients with APECED, Grouped According to the First Such Component to Appear.). There were clear differences among these five groups in the frequency of the third and subsequent components. In the patients in whom adrenal failure was the first component other than candidiasis, other components developed less often than they did in the patients in the remaining groups (P = 0.006 by the chi-square test for a difference among the five groups in the presence of a third component). The frequency of appearance of five components, again excluding candidiasis, was highest among the patients in whom the initial manifestation was intestinal malabsorption or keratopathy (P = 0.005). The mean ages of the patients in each of these five groups were similar, ranging from 24 to 35 years. However, survival analysis revealed clear differences between the groups with regard to the appearance of the first component other than candidiasis. Initial malabsorption or keratopathy appeared relatively early, initial alopecia or hypoparathyroidism appeared at an intermediate time, and initial adrenal failure appeared latest (P<0.0001 by the Mantel–Cox test). The groups differed similarly with respect to the appearance of the second component, again when candidiasis was excluded. The second component appeared earlier when malabsorption or keratopathy appeared first (P = 0.04 by the Mantel–Cox test).Four patients were not included in these five groups. At the ages of 22 and 25, two of them had no other disease manifestation than candidiasis (present since the ages of 5 and 6, respectively). One 10-month-old patient had candidiasis, hepatitis, and vasculitis, which had all appeared at the age of 8 months. Vitiligo had developed in another patient at the age of two months, followed by candidiasis and alopecia at the age of 7 years, and hypoparathyroidism and adrenal failure at 23 years.
Survival and Quality of Life
The patients were born during a period spanning more than 70 years. Ten patients were born between 1910 and 1949, of whom four had died. Fourteen patients were born in the 1950s, of whom 2 had died; 29 in the 1960s, of whom 3 had died; and 15 after 1969, of whom none had died.
Of the 68 patients, 59 were alive at the writing of this report. The causes of death in the other nine were adrenal crisis with hypoparathyroidism (one patient) or diabetic ketoacidosis (one), fulminant hepatic failure (two), metastatic squamous-cell carcinoma of the oral mucosa (one), accident (one), septicemia after prosthetic surgery for severe rheumatoid arthritis of both hips (one), sudden death possibly related to hypoparathyroidism (one), and unknown (one). Pulmonary tuberculosis was diagnosed and treated successfully in one male patient.
Of the 38 living patients more than 18 years of age, 35 were working or studying at this writing, and 3 had retired prematurely. Of the 35, 3 were professional or managerial workers, 13 were clerical workers, 12 were manual workers, and 7 were students. Six had received special vocational training for the handicapped. Two women had given birth, and three men reported having fathered healthy children. Eleven patients were married or lived in stable relationships, but infertility was frequently a problem. The adolescent patients with multiple endocrinopathies or severe keratopathy often had difficulty in adapting to their disease and often did not comply with the therapeutic regimen.
Discussion
The patients we studied had a wide range of clinical manifestations of APECED. Many patients had failure of several endocrine glands and other troublesome or disfiguring manifestations of disease. At the other end of the spectrum were two patients with long-standing cases of candidiasis alone. This mild phenotype appears to be rare, however, and most patients have two to four components of the disease. Patients with the classic triad (hypoparathyroidism, adrenal failure, and candidiasis) made up only half the series. In accordance with previous findings, hypogonadism among women was frequent,4 , 5 and some men had hypogonadism as well.32 , 33
All patients had candidiasis at some time, always before the age of 30 years. However, candidiasis is not a reliable hallmark of APECED, because it appeared much later than the endocrine components in several patients. Furthermore, it was often mild and remittent. The nails were affected in two thirds of the patients, but the skin in only 10 percent, and the cutaneous lesions were never severe, in contrast with the extensive lesions in patients with other forms of chronic mucocutaneous candidiasis.29 , 34
There are probably other patients with APECED who have only candidiasis, but they cannot be ascertained in the absence of siblings who are more clearly affected, and even in affected families some persons may have had mild, transient candidiasis that was not recognized. In a similar way, it may be difficult to differentiate APECED that appears in the form of an isolated disease component from the same condition appearing independently — for example, as idiopathic adrenal failure or hypoparathyroidism. Patients with dental-enamel hypoplasia, nail dystrophy, keratopathy, intestinal malabsorption, or hepatitis should be carefully examined, since these conditions point to the diagnosis of APECED. The same is true for vitiligo or alopecia in patients with hypoparathyroidism. Other variant manifestations of APECED may remain unrecognized until severe endocrine failure develops.
Hypothyroidism, alopecia, nail and enamel dystrophy, vitiligo, premature ovarian failure, testicular failure, gastric parietal-cell failure, chronic active hepatitis, and insulin-dependent diabetes mellitus most often occur independently of APECED. In Finland, this cannot be said of truly isolated idiopathic hypoparathyroidism. However, further disease components do not develop in many patients with idiopathic hypoparathyroidism or idiopathic adrenal failure.20 , 35 , 36 Likewise, an unknown proportion of patients with candidiasis are not at risk of endocrinopathies.27 , 33 Hypoplasia of the dental enamel has many causes, and mild lesions are common.37 , 38 However, in patients with APECED the lesions are severe.
Pitted-nail dystrophy is readily overlooked, although it is easily detected. In patients with endocrinopathies it is suggestive of APECED, but not in patients with isolated alopecia.30 , 31 In APECED it may be a component of the ectodermal dystrophy that includes enamel hypoplasia and dystrophy of the tympanic membranes, although we cannot exclude the possibility that it is a mild manifestation of nail candidiasis. The calcifications in the tympanic membranes were similar to those seen in patients who have had a tympanostomy and in patients with frequent middle-ear infections,39 but our patients had no history of ear infections.
Although most patients with APECED became symptomatic in the first decade of life, a large minority did so only later. Thus, APECED should not be regarded exclusively as a disease with an onset in childhood or youth. Clearly, the autoimmune process may continue, because new components of disease developed in several patients at least into their 40s. The components of APECED found most frequently are those that appear earliest. Furthermore, the earlier the first component appears, the more likely it is that multiple components will develop. Conversely, patients who have late manifestations of disease are likely to have fewer components. Consequently, the correct diagnosis of their disease is less likely.
One subgroup with milder disease activity emerged: it consisted of the eight patients, seven of them male, whose initial component other than candidiasis was adrenal failure. These patients had few other disease components. Their mild disease may have been due to genetic or environmental factors that affect the expression of APECED or to allelic polymorphism of the APECED gene — a possibility that seems unlikely for an enriched gene in an isolated population, but one that has been demonstrated for another "Finnish" gene.40 Since the patients all had candidiasis and since hypoparathyroidism developed in one, misdiagnosis appears very unlikely. It is possible that autoimmunity initiated against the adrenal cortex results in a down-regulation of the autoimmune process. An unlikely alternative is slight oversubstitution with glucocorticoid; in the other groups, the patients continued to have further disease components during cortisol-replacement therapy.
There was a bell-shaped distribution for the year of birth among our 68 patients, with a peak in the 1960s. It is remarkable that we found so few patients born before 1940. If we assume a constant rate of appearance for APECED between 1910 and 1969 and a complete ascertainment of patients born during the 1960s, this series includes only 43 percent of the Finnish patients with APECED. Presumably, most patients born earlier died from their endocrinopathies without a correct diagnosis, or perhaps from tuberculosis,3 and so their disease escaped detection. We did not search death registers for additional cases. The true incidence of disease has probably decreased with time, as isolated subpopulations with high frequencies of gene carriers have diminished because of migration, especially during the past few decades. The ostensible increase in incidence must be due to improved survival and methods of detection. The frequency of adrenal failure was lowest among the older (surviving) patients, suggesting that this endocrinopathy was a major cause of the excess mortality.
Only a minority of the known deaths were directly attributable to a lack of adequate therapy for the endocrinopathies. Fulminant hepatic failure accounted for 25 percent of the deaths. Whether it represents a subtype of chronic active hepatitis that appears in APECED9 , 10 , 41 is not clear, but in both patients who died of fulminant hepatic failure, the plasma aminotransferase activities had been normal before the short fatal episode. One patient who died had carcinoma of the oral mucosa,28 and other cases have been reported,42 , 43 suggesting that long-lasting candidiasis is carcinogenic. Presumably, adequate hormone-replacement therapy has eliminated the cause of most premature deaths, but fulminant hepatic failure remains a danger.
We conclude that the majority of patients with APECED have multiple components of the disorder. The first component — usually candidiasis — develops in most patients in childhood, but other components may develop as late as the fifth decade. Thus, all patients need lifelong follow-up and counseling to facilitate the early detection of new components.
Supported by the Foundation for Pediatric Research, the Paulo Foundation, the Finnish Cultural Foundation, and the National Medical Research Council of the Academy of Finland, Helsinki, Finland.
Source Information
From the Children's Hospital, University of Helsinki, Finland. Address reprint requests to Dr. Perheentupa at the Children's Hospital, SF-00290 Helsinki, Finland.
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