Progressive Impairment of Prepubertal Growth in Children With APECED.

CONTEXT: Subjects with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) have subnormal adult height. There are several potential APECED-related risk factors for suboptimal height attainment during childhood. OBJECTIVE: To determine the growth patterns in children with APECED. DESIGN: Retrospective longitudinal study. SETTING: The Finnish national APECED cohort. PATIENTS: 59 children with APECED. MAIN OUTCOME MEASURES: Length/height and weight z-scores from birth to the end of prepuberty. RESULTS: Collectively, 59 children [30 (51%) girls] were included. Their median birth weight z-score (-0.60) was below the population average; 12 (20%) patients were born small for gestational age. Height attainment progressively declined from birth until the end of prepuberty (z-score -1.95), whereas weight-for-height z-score did not (+0.26). Of the 59 patients, 38 (64%) had all height z-scores below 0 during prepuberty, and seven (12%) had z-scores below -2.0. Age at the end of prepuberty, number of APECED manifestations, duration of glucocorticoid treatment, and growth hormone deficiency correlated negatively with height z-score at the end of prepuberty (p < 0.0001; p = 0.041; p = 0.013; p = 0.034, respectively). CONCLUSIONS: Children with APECED had a progressive growth impairment from birth through prepuberty. Multiple predisposing risk factors were recognized, including disease severity and growth hormone deficiency. Timely interventions are needed to ensure optimal height attainment and new treatment options need to be developed.

Increased type 1 inflammation in gynecologic cervicovaginal samples in patients with APS-1.

BACKGROUND: Inborn errors of immunity offer important insights into mucosal immunity. In autoimmune polyendocrine syndrome type-1 (APS-1), chronic mucocutaneous candidiasis has been ascribed to neutralizing IL-17 autoantibodies. Recent evidence implicates excessive T-cell IFN-γ secretion and ensuing epithelial barrier disruption in predisposition to candidiasis, but these results remain to be replicated. Whether IL-17 paucity, increased type I inflammation, or their combination underlies susceptibility to chronic mucocutaneus candidiasis in APS-1 is debated. OBJECTIVE: Our aim was to characterize the immunologic features in the cervicovaginal mucosa of females with APS-1. METHODS: Vaginal fluid was collected with a flocked swab from 17 females with APS-1 and 18 controls, and cytokine composition was analyzed using Luminex (Luminex Corporation, Austin, Tex). Cervical cell samples were obtained with a cervix brush from 6 patients and 6 healthy controls and subjected to transcriptome analysis. RESULTS: The vaginal fluid samples from patients with APS-1 had IFN-γ concentrations comparable to those of the controls (2.6 vs 2.4 pg/mL) but high concentrations of the TH1 chemokines CXCL9 and CXCL10 (1094 vs 110 pg/mL [P < .001] and 4033 vs 273 pg/mL [P = .001], respectively), whereas the IL-17 levels in the samples from the 2 groups were comparable (28 vs 8.8 pg/mL). RNA sequencing of the cervical cells revealed upregulation of pathways related to mucosal inflammation and cell death in the patients with APS-1. CONCLUSION: Excessive TH1 cell response appears to underlie disruption of the mucosal immune responses in the genital tract of patients with APS-1 and may contribute to susceptibility to candidiasis in the genital tract as well.

Pregnancy Outcome in Women With APECED (APS-1): A Multicenter Study on 43 Females With 83 Pregnancies.

CONTEXT: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED; also known as autoimmune polyendocrine syndrome type 1) has a severe, unpredictable course. Autoimmunity and disease components may affect fertility and predispose to maternal and fetal complications, but pregnancy outcomes remain unknown. OBJECTIVE: To assess fetal and maternal outcomes and course of clinical APECED manifestations during pregnancy in women with APECED. DESIGN AND SETTING: A multicenter registry-based study including 5 national patient cohorts. PATIENTS: 321 females with APECED. MAIN OUTCOME MEASURE: Number of pregnancies, miscarriages, and deliveries. RESULTS: Forty-three patients had altogether 83 pregnancies at median age of 27 years (range, 17-39). Sixty (72%) pregnancies led to a delivery, including 2 stillbirths (2.4%) and 5 (6.0%) preterm livebirths. Miscarriages, induced abortions, and ectopic pregnancies were observed in 14 (17%), 8 (10%), and 1 (1.2%) pregnancies, respectively. Ovum donation resulted in 5 (6.0%) pregnancies. High maternal age, premature ovarian insufficiency, primary adrenal insufficiency, or hypoparathyroidism did not associate with miscarriages. Women with livebirth had, on average, 4 APECED manifestations (range 0-10); 78% had hypoparathyroidism, and 36% had primary adrenal insufficiency. APECED manifestations remained mostly stable during pregnancy, but in 1 case, development of primary adrenal insufficiency led to adrenal crisis and stillbirth. Birth weights were normal in >80% and apart from 1 neonatal death of a preterm baby, no serious perinatal complications occurred. CONCLUSIONS: Outcome of pregnancy in women with APECED was generally favorable. However, APECED warrants careful maternal multidisciplinary follow-up from preconceptual care until puerperium.

Endocrine Disorders and Genital Infections Impair Gynecological Health in APECED (APS-1).

Objective: In autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) defects in the autoimmune regulator gene lead to impaired immunotolerance. We explored the effects of immunodeficiency and endocrinopathies on gynecologic health in patients with APECED. Design: Cross-sectional cohort study combined with longitudinal follow-up data. Methods: We carried out a gynecologic evaluation, pelvic ultrasound, and laboratory and microbiologic assessment in 19 women with APECED. Retrospective data were collected from previous study visits and hospital records. Results: The study subjects' median age was 42.6 years (range, 16.7-65.5). Sixteen patients (84%) had premature ovarian insufficiency, diagnosed at the median age of 16.5 years; 75% of them used currently either combined contraception or hormonal replacement therapy. In 76% of women, the morphology and size of the uterus were determined normal for age, menopausal status, and current hormonal therapy. Fifteen patients (79%) had primary adrenal insufficiency; three of them used dehydroepiandrosterone substitution. All androgen concentrations were under the detection limit in 11 patients (58%). Genital infections were detected in nine patients (47%); most of them were asymptomatic. Gynecologic C. albicans infection was detected in four patients (21%); one of the strains was resistant to azoles. Five patients (26%) had human papillomavirus infection, three of which were high-risk subtypes. Cervical cell atypia was detected in one patient. No correlation between genital infections and anti-cytokine autoantibodies was found. Conclusions: Ovarian and adrenal insufficiencies manifested with very low androgen levels in over half of the patients. Asymptomatic genital infections, but not cervical cell atypia, were common in female patients with APECED.

Pubertal development and premature ovarian insufficiency in patients with APECED.

OBJECTIVE: To determine the natural course of pubertal development, growth during puberty, and development of POI in females with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also called autoimmune polyendocrine syndrome type I. DESIGN: Longitudinal follow-up study. METHODS: A national cohort of females with APECED aged ≥12 years were followed during 1965-2018. Attainment of adult height was defined when patients' height increased less than 1 cm per year. Diagnosis of POI was based on delayed puberty or POI symptoms with amenorrhea, and/or FSH ≥40 IU/L. RESULTS: Altogether 40 women with APECED were followed up to the average age of 37.3 (range: 14.6-61.9) years; 16 females (40%) were ≥ 40 years. Pubertal development started spontaneously in 34 patients and 29 had spontaneous menarche. POI developed in 28 patients (70%) at the median age of 16.0 years (range: 11.3-36.5), and in 20 of them (71%) before attaining adult height. In 11 cases puberty was induced or completed by hormonal therapy. Patients with POI were significantly shorter at menarche, but adult heights did not differ from non-POI females. Patients with POI had more often primary adrenocortical insufficiency (93% vs 58%, P = 0.017) and ovarian antibodies (81% vs 30%, P=0.003) compared to those with normal ovarian function (n = 12). CONCLUSIONS: POI developed in the majority of patients with APECED, often before or shortly after menarche. Timely commencement of hormonal replacement therapy is important to ensure optimal pubertal development and growth. The possibility of fertility preservation before development of POI in APECED patients should be further studied.