Department of Pediatrics (A.G.M.), Akershus Central Hospital, N-1474 Nordbyhagen, Norway; Department of Human Molecular Genetics (P.B.), National Public Health Institute, FIN-00300 Helsinki, Finland; Department of Microbiology (A.D.), University Hospital, N-7006 Trondheim and Medical Department B (E.S.H.), Haukeland University Hospital, N-5021 Bergen, Norway
Address all correspondence and requests for reprints to: Eystein S. Husebye, M.D., Ph.D., Medical Department B, Haukeland University Hospital, N-5021 Bergen, Norway.
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History |
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On the day that she was discharged, her 10-yr-old sibling D was hospitalized with fever, dyspnea, and cyanosis. On admission, her temperature was 40.1 C; blood pressure, 113/71 mm Hg; respiration, 60 per min; O2 saturation, 8589%; serum sodium, 126 mmol/L; potassium, 4.7 mmol/L; C-reactive protein, 416 mg/L; capillary blood pH, 7.22; base excess, -11.7 mmol/L; and blood glucose, 2.9 mmol/L. Her condition was treated as septicemia. Because of suboptimal response to treatment, hyponatremia, and hyperpigmented skin, adrenocortical failure was suspected. Hydrocortisone was given, and she improved dramatically. The diagnosis was confirmed by tests revealing plasma ACTH more than 1500 pg/mL (normal 1060 pg/mL); renin activity, 65 nmol/L·h (85 ng/mL·h; normal range, 0.51.5 nmol/L·h); serum cortisol, 86 nmol/L (3.1 µg/dL; normal range, 250750 nmol/L at 0800 h); and aldosterone, 256 pmol/L (9.2 ng/dL; normal range, 70450 pmol/L). Review of the history revealed episodes of nausea since the age of 6. During the last 2 yr before diagnosis, she was hospitalized twice with bacterial infections and hyponatremia. Her parathyroid function was normal.
After 1 week at home, sibling E was again admitted with fever, and hyperpigmented skin was now observed. Tests of blood drawn earlier revealed plasma ACTH of 1483 pg/mL; renin activity, 36 nmol/L·h (47 ng/mL·h); serum cortisol, 218 nmol/L (7.9 µg/dL); and aldosterone, 256 pmol/L (9.2 ng/dL). Treatment of adrenocortical failure with cortisone acetate was started, and her general condition improved. Enamel hypoplasia and oral candidiasis were observed. Review of the history revealed an extensive superficial inguinal candida infection at the age of 6 months. She had had fatigue and muscle weakness over the 8 months preceding diagnosis. Her psychomotoric development improved during treatment and was considered normal in a recent test.
The mother now reported that sibling A was hyperpigmented. She was also found to be dehydrated, with oral candidiasis, vitiligo, and nail pitting. Treatment with cortisone acetate was started, and the diagnosis (adrenocortical failure) was confirmed by tests, revealing plasma ACTH more than 1500 pg/mL; renin activity, 66.9 nmol/L·h (87 ng/mL·h); serum cortisol, 22 nmol/L (0.8 µg/dL); and aldosterone less than 77 pmol/L (<2.8 ng/mL). She had experienced insufficient weight gain, fatigue, and muscle weakness for 2 yr before diagnosis. Her parathyroid function was normal.
Adrenocortical insufficiency had now been diagnosed in three
siblings at about the same time. One of them had primary
hypoparathyroidism, suggesting autoimmune
polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also
called autoimmune polyendocrine syndrome type I. Adrenocortical
insufficiency or other components of APECED were not present in the
other siblings, parents, grandparents, uncles, aunts, or cousins. To
confirm this diagnosis, we performed analysis of autoantibodies known
to be associated with APECED (1, 2, 3). All the three affected siblings
had antibodies against 21-hydroxylase (21OH) and 17-hydroxylase
(17OH), and sibling A also had antibodies against the cholesterol
side-chain cleavage enzyme (SCC) (Table 1
). None had antibodies against
aromatic L-amino acid decarboxylase.
Recently, the APECED gene has been cloned (4, 5). It encodes a
545-amino-acid protein with two PHD-type zinc-finger domains, which
indicate involvement in transcriptional regulation. Sequence analysis
of the APECED gene revealed that the father harbored the common Finnish
mutation, a C-to-T substitution that changes Arg 257 into a stop codon
(TGA) (4, 5). The mother had a novel A insertion in codon 415,
leading to a frame shift and a truncated protein of 422 amino acids.
The affected children had inherited both mutated genes (see Table 1).
The more-or-less simultaneous presentation of adrenocortical failure in the three sisters led us to look for precipitating causes. Careful questioning revealed no exposure to chemicals or infectious agents in the months preceding their illness. Sibling A had increased levels of IgG against cytomegalovirus, suggesting previous infection. Otherwise, we found no evidence of infection by cytomegalovirus, Epstein-Barr type 1 and 2, or rubella virus, some of which are associated with autoimmune diabetes mellitus.
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Discussion |
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APECED is an autosomal recessive disease, which usually starts in childhood and often includes chronic mucocutanous candidiasis, hypoparathyroidism, and adrenocortical failure (9, 10). Two of these components have traditionally been required for the diagnosis, one when a sibling has APECED. Other potential components, in order of prevalence in Finnish patients, are: enamel hypoplasia, hypogonadism, nail pitting, keratopathy, alopecia, intestinal malabsorbtion, vitiligo, parietal cell atrophy, autoimmune hepatitis, diabetes mellitus type 1, autoimmune thyroiditis, and hypophysitis (9). Because of the diversity of components and some variation in the presentation between populations (9, 10, 11), the diagnosis can be difficult. There may not be other cases in the family, and the patient may present with a single manifestation (e.g. sibling D) and/or one of the more uncommon components. One should be alert to the possibility of APECED when two or more of the components are present and when any of the more common manifestations are present, especially in a child or adolescent. The physician should look for ectodermal components, particularly enamel hypoplasia, which is present in 77% of Finnish APECED patients (9).
When the diagnosis is suspected, measurements of autoantibodies against 21OH, 17OH, SCC, and L-amino acid decarboxylase (1, 2, 3) and, recently, analysis of the APECED gene (4, 5), provide powerful diagnostic tools, as illustrated here. It is important to diagnose APECED because cases within the family occur and because other endocrine and nonendocrine manifestations may start later on. Some of these, e.g. autoimmune hepatitis, adrenocortical failure, and hypoparathyroidism, are potentially fatal if not treated correctly.
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Acknowledgments |
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Received May 6, 1998.
Revised July 14, 1998.
Accepted August 24, 1998.
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References |
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