Three Sisters with Addison’s Disease

Anne Grethe Myhre, Petra Björses, Are Dalen and Eystein S. Husebye

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.


    History
 Top
 History
 Discussion
 References
 
We report on a family, of mother, father, and six siblings (Table 1Go). At the age of 5 yr, sibling E was hospitalized with fever, dyspnea, and vomiting. Clinically she was dehydrated. Her blood pressure was 98/50 mm Hg; pulse, 156 min-1; and temperature, 38.9 C. Her blood hemoglobin was 152 g/L; leukocytes, 17.3 x 109 cells/L; and glucose, 1.6 mmol/L. Serum C-reactive protein was 146 mg/L; sodium, 125 mmol/L; potassium, 5.2 mmol/L; capillary blood pH, 7.15; and base excess, -22,3 mmol/L. Her condition was treated as septicemia. Psychomotoric retardation was noted, and a computer tomography revealed intracranial calcifications. On a follow-up visit, 6 weeks later, blood was drawn for serum calcium, magnesium, and PTH analysis.


View this table:
[in this window]
[in a new window]
 
Table 1. Clinical details, autoantibodies, and mutations in the APECED gene

 
Four weeks later, she contracted varicella. On admission, she was again dehydrated with hyponatremia (127 mmol/L) and hypoglycemia (2.9 mmol/L). Total serum calcium was initially 1.62 mmol/L (albumin, 47 g/L) and fell to 1.28 mmol/L, 3 days later. Treatment with calcium gluconate and 1,2-dihydroxy vitamin D3 was started. The blood test taken earlier revealed a serum calcium of 1.72 mmol/L; magnesium, 0.65 mmol/L; and undetectable levels of PTH (<0.6 pmol/L), suggesting primary hypoparathyroidism. Samples for ACTH and cortisol were drawn.

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, 85–89%; 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 10–60 pg/mL); renin activity, 65 nmol/L·h (85 ng/mL·h; normal range, 0.5–1.5 nmol/L·h); serum cortisol, 86 nmol/L (3.1 µg/dL; normal range, 250–750 nmol/L at 0800 h); and aldosterone, 256 pmol/L (9.2 ng/dL; normal range, 70–450 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{alpha}-hydroxylase (17OH), and sibling A also had antibodies against the cholesterol side-chain cleavage enzyme (SCC) (Table 1Go). 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 1Go).

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.


    Discussion
 Top
 History
 Discussion
 References
 
The three sisters’ history and findings are typical of adrenocortical insufficiency (6), i.e. hyperpigmentation, anorexia, fatigue, poor weight gain and muscle strength, hyponatremia, metabolic acidosis, and low serum cortisol with high plasma ACTH and renin activity. Siblings D and E had hypoglycemia, which is a frequent finding in children with adrenocortical insufficiency. It is a rare disease, with a prevalence of 70 per million inhabitants (7). The main cause is autoimmune destruction of the adrenal cortex, and most patients have autoantibodies against 21OH (8). The diagnosis is often delayed because it is not considered and because symptoms typically develop slowly over several months to years. Many patients are diagnosed only at an acute adrenal crisis, as was the case with both siblings D and E. This led to the diagnosis in the third sister, which illustrates the importance of considering other cases in the family, especially when adrenocortical insufficiency is diagnosed in childhood. Because sibling E also had primary hypoparathyroidism, APECED could be diagnosed on clinical criteria. It was later confirmed by autoantibody and gene analyses (see Table 1Go).

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.


    Acknowledgments
 
Ms. Wencke Trovik is thanked for expert technical assistance.

Received May 6, 1998.

Revised July 14, 1998.

Accepted August 24, 1998.


    References
 Top
 History
 Discussion
 References
 

  1. Winqvist O, Gustafsson J, Rorsman F, Karlsson FA, Kämpe O. 1993 Two different cytochrome P450 enzymes are the adrenal antigens in autoimmune polyendocrine syndrome type I and Addison’s disease. J Clin Invest. 92:2377–2385.[Medline]
  2. Peterson P, Uibo R, Peranen J, Krohn K. 1997 Immunoprecipitation of steroidogenic enzyme autoantigens with autoimmune polyglandular syndrome type I (APS I) sera; further evidence for independent humoral immunity to P450c17 and P450c21. Clin Exp Immunol. 107:335–340.[Medline]
  3. Husebye ES, Gebre-Medhin G, Tuomi T-M, et al. 1997 Autoantibodies against aromatic L-amino acid decarboxylase in autoimmune polyendocrine syndrome type I. J Clin Endocrinol Metab. 82:147–150.[Abstract/Free Full Text]
  4. The Finnish-German APECED Consortium. 1997 An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat Genet. 17:399–403.[Medline]
  5. Nagamine K, Peterson P, Scott HS, et al. 1997 Positional cloning of the APECED gene. Nat Genet. 17:393–398.[Medline]
  6. Oelkers W. 1996 Adrenal insufficiency. N Engl J Med. 335:1206–1212.[Free Full Text]
  7. Kong MF, Jeffcoate W. 1994 Eighty-six cases of Addison’s disease. Clin Endocrinol (Oxf). 41:757–761.[Medline]
  8. Winqvist O, Karlsson FA, Kämpe O. 1992 21-hydroxylase, a major autoantigen in idiopathic Addison’s disease. Lancet. 339:1559–1562.[Medline]
  9. Ahonen P, Myllärniemi S, Sipilä I, Perheentupa J. 1990 Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients. N Engl J Med. 322:1829–1836.[Abstract]
  10. Betterle C, Greggio NA, Volpato M. 1998 Autoimmune polyglandular syndrome type I. J Clin Endocrinol Metab. 83:1049–1055.[Free Full Text]
  11. Zlotogora J, Shapiro MS. 1992 Polyglandular autoimmune syndrome type I among Iranian Jews. J Med Genet. 29:824–826.[Abstract]