A Longitudinal Follow-up of Autoimmune Polyendocrine Syndrome Type 1

Abstract

Context: Autoimmune polyendocrine syndrome type 1 (APS1) is a childhood-onset monogenic disease defined by the presence of two of the three major components: hypoparathyroidism, primary adrenocortical insufficiency, and chronic mucocutaneous candidiasis (CMC). Information on longitudinal follow-up of APS1 is sparse.

Objective: To describe the phenotypes of APS1 and correlate the clinical features with autoantibody profiles and autoimmune regulator (AIRE) mutations during extended follow-up (1996-2016).

Patients: All known Norwegian patients with APS1.

Results: Fifty-two patients from 34 families were identified. The majority presented with one of the major disease components during childhood. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. With age, most patients presented three to five disease manifestations, although some had milder phenotypes diagnosed in adulthood. Fifteen of the patients died during follow-up (median age at death, 34 years) or were deceased siblings with a high probability of undisclosed APS1. All except three had interferon-ω) autoantibodies, and all had organ-specific autoantibodies. The most common AIRE mutation was c.967_979del13, found in homozygosity in 15 patients. A mild phenotype was associated with the splice mutation c.879+1G>A. Primary adrenocortical insufficiency and type 1 diabetes were associated with protective human leucocyte antigen genotypes.

Conclusions: Multiple presumable autoimmune manifestations, in particular hypoparathyroidism, CMC, and enamel hypoplasia, should prompt further diagnostic workup using autoantibody analyses (eg, interferon-ω) and AIRE sequencing to reveal APS1, even in adults. Treatment is complicated, and mortality is high. Structured follow-up should be performed in a specialized center.

Figure 1.

Disease histories of Norwegian APS1 patients. The lines start at birth and end at death (bracket) or at current age (>). Age at appearance of disease component is indicated by a symbol of the disease. Disease components of uncertain time of onset are listed at the end of the line. The major disease components CMC, HP, and PAI are marked in red, blue, and green, respectively. Al, alopecia; AS, asplenia; AT, hypothyroidism; Ca, cancer; DM, diabetes mellitus; E, enamel hypoplasia/defects; G, hypogonadism; H, hepatitis; HP, hypoparathyroidism; K, keratoconjunctivitis; M, malabsorption; N, nail dystrophy; P, pancreas failure exocrine; PA, pernicious anemia; PS, psoriasis; TIN, tubule interstinal nephritis; V, vitiligo.

Figure 2.

Typical enamel hypoplasia in APS1. A, Hypomineralization (white areas on front teeth) and enamel hypoplasia revealed by horizontal hypoplastic bands. B, Severe enamel hypoplasia with loss of normal enamel structure. C, Enamel hypoplasia varying in size and location, affecting both front teeth and molars.

Figure 3.

AIRE mutations in Norwegian APS1 patients. A, Overview of the identified mutations and their frequencies. B, Location of AIRE mutations in Norwegian APS1 patients together with a schematic representation of the AIRE protein and its functional domains. Boxes 1–14 represent the exons, and the different mutations are given in the text boxes above. CARD/HSR, Caspase recruitment domain/homodimerization domain (amino acids 1–105); NLS, nuclear localization signal (amino acids 100–189); SAND, Sp100, AIRE-1, NucP41/75 (181–280), DEAF-1; L (LXXLL), nuclear receptor-binding motifs (amino acids 7–11, 63–67, 414–418, 516–520); PHD, plant homeodomain type zinc fingers (amino acids 296–343 and 434–475); PRR, proline-rich region (amino acids 350–430).

Figure 4.

Heat map of clinical manifestations and autoantibodies in Norwegian APS1 patients. Family number and patient number are given in the first two rows. A black square represents a disease manifestation, and a gray square represents positive autoantibodies. If the square is dotted, the examination/analyses are not performed; a white square represents negative disease component/AIRE mutation/autoantibodies that are tested for.