Autoimmune polyendocrine syndrome type 1 in an Indian cohort: a longitudinal study

Abstract

Objective: Autoimmune polyendocrine syndrome type 1 (APS1) is a rare autosomal recessive disorder characterized by progressive organ-specific autoimmunity. There is scant information on APS1 in ethnic groups other than European Caucasians. We studied clinical aspects and autoimmune regulator (AIRE) gene mutations in a cohort of Indian APS1 patients.

Design: Twenty-three patients (19 families) from six referral centres in India, diagnosed between 1996 and 2016, were followed for [median (range)] 4 (0.2-19) years.

Methods: Clinical features, mortality, organ-specific autoantibodies and AIRE gene mutations were studied.

Results: Patients varied widely in their age of presentation [3.5 (0.1-17) years] and number of clinical manifestations [5 (2-11)]. Despite genetic heterogeneity, the frequencies of the major APS1 components (mucocutaneous candidiasis: 96%; hypoparathyroidism: 91%; primary adrenal insufficiency: 55%) were similar to reports in European series. In contrast, primary hypothyroidism (23%) occurred more frequently and at an early age, while kerato-conjunctivitis, urticarial rash and autoimmune hepatitis were uncommon (9% each). Six (26%) patients died at a young age [5.8 (3-23) years] due to septicaemia, hepatic failure and adrenal/hypocalcaemic crisis from non-compliance/unexplained cause. Interferon-α and/or interleukin-22 antibodies were elevated in all 19 patients tested, including an asymptomatic infant. Eleven AIRE mutations were detected, the most common being p.C322fsX372 (haplotype frequency 37%). Four mutations were novel, while six others were previously described in European Caucasians.

Conclusions: Indian APS1 patients exhibited considerable genetic heterogeneity and had highly variable clinical features. While the frequency of major manifestations was similar to that of European Caucasians, other features showed significant differences. A high mortality at a young age was observed.

Keywords: APECED syndrome; India; autoimmune polyendocrine syndrome 1; autoimmune regulator gene.

Figure 1

Kaplan Meier analysis of cumulative survival frequency of three major manifestations. Cumulative frequency of mucocutaneous candidiasis, hypoparathyroidism and primary adrenal insufficiency at different ages in 22 patients with APS1. MCC: mucocutaneous candidiasis; HP: hypoparathyroidism; PAI: primary adrenal insufficiency.

Figure 2

Location of AIRE mutations detected in Indian APS1 probands. The location of mutations observed in 19 probands is shown in relation to the functional domains of the AIRE protein. All mutations were homozygous except for compound heterozygous mutation (p.M1V/p. R92W) in 3 members of one family. The mutation p.C322fs372X (7 probands) was the most frequent, followed by p.V80G (3 probands) and p.M1V (2 probands). All other mutations were identified in only a single proband. CARD: caspase activation and recruitment domain; NLS: nuclear localization signal; SAND: Sp100, AIRE, NucP41/75, DEAF-1 DNA-binding domain; PHD: plant homeodomain zinc finger; L: LXXLL nuclear receptor interaction motif.