Lessons from prospective longitudinal follow-up of a French APECED cohort.

BACKGROUND: APECED syndrome is a rare disease caused by biallelic mutations of the AIRE gene, usually presenting with the triad "hypoparathyroidism-adrenal failure-chronic mucocutaneous candidiasis (CMC)" and non-endocrine manifestations. The aim of this study was to determine the molecular profile of the AIRE gene, the prevalence of rare manifestations and to characterize immunological disturbances in a French cohort. PATIENTS AND METHODS: A national, multicenter prospective observational study to collect genetic, clinical, biological and immunological data (NCT03751683). RESULTS: 25 patients (23 families) were enrolled. Eleven distinct AIRE variants were identified, two of which were not previously reported: an intronic variant, c.653-70G > A, and a c.1066del (p.Arg356GlyfsX22) variant (exon 9). The most common was the Finnish variant c.769C > T (16 alleles), followed by the variant c.967_979del13 (15 alleles), which seemed associated with a less severe phenotype. 17/25 patients were homozygote. The median number of clinical manifestations was seven; 19/25 patients presented with the hypoparathyroidism-adrenal failure-CMC triad, 8/13 showed pulmonary involvement, 20/25 had ectodermal dystrophy, 8/25 had malabsorption, and 6/23 had asplenia. Fifteen out of 19 patients had NK cell lymphopenia with an increase in CD4+ and CD8+ T lymphocytes and an age-dependent alteration of B lymphocyte homeostasis compared with matched controls (p < 0.001), related to the severity of the disease. All tested sera (n = 18) were positive for anti-interferon-α, 15/18 for anti-interleukin-22 antibodies, and 13/18 for anti-interleukin-17F antibodies, without clear phenotypic correlation other than with CMC. CONCLUSION: This first prospective cohort showed a high AIRE genotype variability, with two new gene variants. The prevalence of potentially life-threatening non-endocrine manifestations, was higher with systematic screening. These manifestations could, along with age-dependent B-cell lymphopenia, contribute to disease severity. Systematic screening for all the manifestations of the syndrome would allow earlier diagnosis, supporting vaccination, and targeted therapeutic approaches.

[Autoimmune polyendocrine syndrome type 1: clinical features and course in France]. / Polyendocrinopathies auto-immunes de type 1: caractéristiques cliniques et évolutives sur la base d'une enquête interrégionale et nationale.

Nineteen patients with autoimmune polyendocrine syndrome type 1 were identified in a longitudinal study conducted in northern France (Nord-Picardie-Normandie region, 9 million inhabitants), giving a prevalence of 1/500 000 inhabitants. This survey confirmed the usual onset in childhood, and the high frequency of candidiasis, adrenal insufficiency, alopecia and hypoparathyroidism. Broad phenotypic variability was observed, even within a given family. The AIRE gene mutations identified in these patients were closer to those observed in the United Kingdom than in Finland. Preliminary results of an ongoing nationwide survey suggest that the prevalence tends to be higher in the north.

Chronic Mucocutaneous Candidiasis in Autoimmune Polyendocrine Syndrome Type 1.

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is an autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene, characterized by the clinical triad of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and adrenal insufficiency. CMC can be complicated by systemic candidiasis or oral squamous cell carcinoma (SCC), and may lead to death. The role of chronic Candida infection in the etiopathogenesis of oral SCC is unclear. Long-term use of fluconazole has led to the emergence of Candida albicans strains with decreased susceptibility to azoles. CMC is associated with an impaired Th17 cell response; however, it remains unclear whether decreased serum IL-17 and IL-22 levels are related to a defect in cytokine production or to neutralizing autoantibodies resulting from mutations in the AIRE gene.

SFE/SFEDP adrenal insufficiency French consensus: Introduction and handbook.

The French endocrinology society (SFE) and the French pediatric endocrinology society (DFSDP) have drawn up recommendations for the management of primary and secondary adrenal insufficiency in the adult and child, based on an analysis of the literature by 19 experts in 6 work-groups. A diagnosis of adrenal insufficiency should be suspected in the presence of a number of non-specific symptoms except hyperpigmentation which is observed in primary adrenal insufficiency. Diagnosis rely on plasma cortisol and ACTH measurement at 8am and/or the cortisol increase after synacthen administration. When there is a persistant doubt of secondary adrenal insufficiency, insulin hypoglycemia test should be carried out in adults, adolescents and children older than 2 years. For determining the cause of primary adrenal insufficiency, measurement of anti-21-hydroxylase antibodies is the initial testing. An adrenal CT scan should be performed if auto-antibody tests are negative, then assay for very long chain fatty acids is recommended in young males. In children, a genetic anomaly is generally found, most often congenital adrenal hyperplasia. In the case of isolated corticotropin (ACTH) insufficiency, it is recommended to first eliminate corticosteroid-induced adrenal insufficiency, then perform an hypothalamic-pituitary MRI. Acute adrenal insufficiency is a serious condition, a gastrointestinal infection being the most frequently reported initiating factor. After blood sampling for cortisol and ACTH assay, treatment should be commenced by parenteral hydrocortisone hemisuccinate together with the correction of hypoglycemia and hypovolemia. Prevention of acute adrenal crisis requires an education of the patient and/or parent in the case of pediatric patients and the development of educational programs. Treatment of adrenal insufficiency is based on the use of hydrocortisone given at the lowest possible dose, administered several times per day. Mineralocorticoid replacement is often necessary for primary adrenal insufficiency but not for corticotroph deficiency. Androgen replacement by DHEA may be offered in certain conditions. Monitoring is based on the detection of signs of under- and over-dosage and on the diagnosis of associated auto-immune disorders.

[Oral diseases in auto-immune polyendocrine syndrome type 1]. / Polyendocrinopathies auto-immunes de type 1 et pathologies buccales.

Auto-immune polyendocrine syndrome type 1 (APS1) also called Auto-immune Polyendocrinopathy Candidiasis Ectodermal Dystrophy (APECED) is a rare monogenic childhood-onset auto-immune disease. This autosomal recessive disorder is caused by mutations in the auto-immune regulator (AIRE) gene, and leads to autoimmunity targeting peripheral tissues. There is a wide variability in clinical phenotypes in patients with APSI, with auto-immune endocrine and non-endocrine disorders, and chronic mucocutaneous candidiasis. These patients suffer from oral diseases such as dental enamel hypoplasia and candidiasis. Both are frequently described, and in recent series, enamel hypoplasia and candidiasis are even the most frequent components of APS1 together with hypoparathyroidism. Both often occur during childhood (before 5 years old for canrdidiasis, and before 15 years old for enamel hypoplasia). Oral candidiasis is recurrent all life long, could become resistant to azole antifungal after years of treatment, and be carcinogenic, leading to severe oral squamous cell carcinoma. Oral components of APS1 should be diagnosed and rigorously treated. Dental enamel hypoplasia and/or recurrent oral candidiasis in association with auto-immune diseases in a young child should prompt APS1 diagnosis.

Group 6. Modalities and frequency of monitoring of patients with adrenal insufficiency. Patient education.

Patients with adrenal insufficiency require regular, specialised monitoring in order to optimise their replacement therapy, to detect signs of under- and over-dosage, and to examine for possible associated disorders (auto-immune disorders in the case of auto-immune primary adrenal insufficiency either isolated or as part of auto-immune polyendocrinopathy syndrome type 1; illnesses with underlying monogenic causes). The transition period between adolescence and adulthood represents an added risk of a breakdown in monitoring which requires particular attention from medical teams and coordination between adult and pediatric medical teams. It is essential to encourage patient autonomy in the management of their illness, notably their participation in treatment education programs, in particular programs that target avoidance of, or early treatment of acute adrenal insufficiency. The principal educational objectives for patients in such programs are: to be in possession of, and carry the necessary tools for their treatment in an emergency; to be able to identify situations of increased risk and the early signs of adrenal crisis; to know how to adjust their oral glucocorticoid treatment; to be capable of administering hydrocortisone by subcutaneous injection; to be able to predict and therefore adjust treatment to different situations (heat, physical exercise, travel) and to be able to correctly use the appropriate resources of the healthcare services. Other programs could also be developed to respond to needs and expectations of patients, notably concerning the adjustment of hydrocortisone dosage to avoid overdose in the context of chronic fatigue syndrome.

Serological proteome analysis reveals new specific biases in the IgM and IgG autoantibody repertoires in autoimmune polyendocrine syndrome type 1.

OBJECTIVE: Autoimmune polyendocrine syndrome type 1 (APS 1) is caused by mutations in the AIRE gene that induce intrathymic T-cell tolerance breakdown, which results in tissue-specific autoimmune diseases. DESIGN: To evaluate the effect of a well-defined T-cell repertoire impairment on humoral self-reactive fingerprints, comparative serum self-IgG and self-IgM reactivities were analyzed using both one- and two-dimensional western blotting approaches against a broad spectrum of peripheral tissue antigens. METHODS: Autoantibody patterns of APS 1 patients were compared with those of subjects affected by other autoimmune endocrinopathies (OAE) and healthy controls. RESULTS: Using a Chi-square test, significant changes in the Ab repertoire were found when intergroup patterns were compared. A singular distortion of both serum self-IgG and self-IgM repertoires was noted in APS 1 patients. The molecular characterization of these antigenic targets was conducted using a proteomic approach. In this context, autoantibodies recognized more significantly either tissue-specific antigens, such as pancreatic amylase, pancreatic triacylglycerol lipase and pancreatic regenerating protein 1α, or widely distributed antigens, such as peroxiredoxin-2, heat shock cognate 71-kDa protein and aldose reductase. As expected, a well-defined self-reactive T-cell repertoire impairment, as described in APS 1 patients, affected the tissue-specific self-IgG repertoire. Interestingly, discriminant IgM reactivities targeting both tissue-specific and more widely expressed antigens were also specifically observed in APS 1 patients. Using recombinant targets, we observed that post translational modifications of these specific antigens impacted upon their recognition. CONCLUSIONS: The data suggest that T-cell-dependent but also T-cell-independent mechanisms are involved in the dynamic evolution of autoimmunity in APS 1.

Long-term efficacy of modified-release recombinant human thyrotropin augmented radioiodine therapy for benign multinodular goiter: results from a multicenter, international, randomized, placebo-controlled, dose-selection study.

BACKGROUND: Enhanced reduction of multinodular goiter (MNG) can be achieved by stimulation with recombinant human thyrotropin (rhTSH) before radioiodine ((131)I) therapy. The objective was to compare the long-term efficacy and safety of two low doses of modified release rhTSH (MRrhTSH) in combination with (131)I therapy. METHODS: In this phase II, single-blinded, placebo-controlled study, 95 patients (57.2 ± 9.6 years old, 85% women, 83% Caucasians) with MNG (median size 96.0 mL; range 31.9-242.2 mL) were randomized to receive placebo (n=32), 0.01 mg MRrhTSH (n=30), or 0.03 mg MRrhTSH (n=33) 24 hours before a calculated (131)I activity. Thyroid volume (TV) and smallest cross-sectional area of trachea (SCAT) were measured (by computed tomography scan) at baseline, six months, and 36 months. Thyroid function and quality of life (QoL) was evaluated at three-month and yearly intervals respectively. RESULTS: At six months, TV reduction was enhanced in the 0.03 mg MRrhTSH group (32.9% vs. 23.1% in the placebo group; p=0.03) but not in the 0.01 mg MRrhTSH group. At 36 months, the mean percent TV reduction from baseline was 44 ± 12.7% (SD) in the placebo group, 41 ± 21.0% in the 0.01 mg MRrhTSH group, and 53 ± 18.6% in the 0.03 mg MRrhTSH group, with no statistically significant differences among the groups, p=0.105. In the 0.03 mg MRrhTSH group, the subset of patients with basal (131)I uptake <20% had a 24% greater TV reduction at 36 months than the corresponding subset of patients in the placebo group (p=0.01). At 36 months, the largest relative increase in SCAT was observed in the 0.03 mg MRrhTSH group (13.4 ± 23.2%), but this was not statistically different from the increases observed in the placebo or the 0.01 mg MRrhTSH group (p=0.15). Goiter-related symptoms were reduced and QoL improved, without any enhanced benefit from using MRrhTSH. At three years, the prevalence of permanent hypothyroidism was 13%, 33%, and 45% in the placebo, 0.01 mg, and 0.03 mg MRrhTSH groups respectively. The overall safety profile of the study was favorable. CONCLUSIONS: When used as adjuvant to (131)I, enhanced MNG reduction could not be demonstrated with MRrhTSH doses ≤ 0.03 mg, indicating that the lower threshold for efficacy is around this level.

Thyroid autoimmunity and polyglandular endocrine syndromes.

Even though autoimmune thyroiditis is considered as the most emblematic type of organ-specific autoimmune disorder of autoimmunity, autoimmune thyroid diseases can be associated with other autoimmune endocrine failures or non-endocrine diseases (namely vitiligo, pernicious anemia, myasthenia gravis, autoimmune gastritis, celiac disease, hepatitis). Thyroid disorders, which are the most frequent expression of adult polyendocrine syndrome type 2, occur concomitantly with or secondarily to insulinodependent diabetes, premature ovarian failure, Addison's disease (Schmidt syndrome, or Carpenter syndrome if associated with diabetes). Testicular failure and hypoparathyroidism are unusual. The disease is polygenic and multifactorial. Disorders of thyroid autoimmunity are, surprisingly, very rare in polyendocrine syndrome type 1 (or APECED) beginning during childhood. They are related to mutations of the AIRE gene that encodes for a transcriptional factor implicated in central and peripheral immune tolerance. Hypothyroidism can also be observed in the very rare IPEX and POEMS syndromes.

Polyglandular autoimmune syndrome type I.

Polyglandular Autoimmune Syndrom type 1 (PAS-1) or Autoimmune PolyEndocrinopathy Candidiasis-Ectodermal-Dystrophy (APECED) is a rare recessive autosomal disease related to Autoimmune Regulator (AIRE) gene mutations. AIRE is mainly implicated in central and peripheric immune tolerance. Diagnosis was classically based on presence of at least two out of three "majors" criterions of Whitaker's triad (candidiasis, autoimmune hypoparathyroidism and adrenal insufficiency). Presence of one criterion was sufficient when a sibling was previously diagnosed. However, some atypic or poorly symptomatic variants do not correspond to these criterions. As a matter of fact, digestive (malabsorption, pernicious anemia, hepatitis), cutaneous (alopecia, vitiligo, enamel dysplasia) or ophtalmological (keratitis) components could prevail. In these cases, diagnosis could be made by molecular genetics. Prognosis is influenced by genetic (AIRE mutations, HLA), hormonal and environmental (infections) factors. Potentially letal components (hepatitis and severe malabsorption) could be treated by immunosuppressors. Candidiasis and other infections should be carefully screened and treated before beginning those therapies, in order to avoid severe systemic infections.

Precocious hypothyroidism mechanisms after radioiodine treatment in Graves' disease.

OBJECTIVE: Hypothyroidism can occur after radioiodine treatment for Graves' disease. It may happen precociously and transiently in the first year after treatment. The purpose of this study was to understand the mechanisms responsible for precocious hypothyroidism. METHODS: 36 patients treated for Graves disease by radiodiodine were prospectively studied; The following variables were included in the analysis: age, gender, attendance for Graves' orbitopathy (GO), delay before radioiodine treatment, number of recurrences, previous treatments, corticosteroid therapy, thyroid mass, and (131)I dose. The titres of free T4 (FT4), thyroid-stimulating hormone (TSH), anti-TSH receptor antibodies (TRAb), anti-thyroid peroxydase antibodies (TPOAb) and anti-thyroglobulin antibodies (TGAb) were monitored. Thyroid stimulating (TSAb) and blocking (TBAb) antibodies were determined and (123)I uptake was measured when hypothyroidism occurred. RESULTS: 23 patients became precociously hypothyroid (group A) while 13 patients did not (group B). The initial TGAb titre was higher in group A (p=0.0024), and corticosteroid therapy was used more frequently to avoid aggravating GO in group B (p=0.0276). TPOAb and TGAb titres increased significantly only in group A (p=0.0112 and p=0.0202, respectively). When hypothyroidism occurred, TBAb was present in 13 patients. Transient hypothyroidism due to TBAb was observed in 1 patient. No iodide organification impairment was disclosed by the perchlorate test. CONCLUSION: Radioinduced thyroiditis appears to be the main mechanism involved in the pathogenesis of precocious hypothyroidism. A higher TGAb titre before treatment is associated with precocious hypothyroidism, suggesting the prognostic value of TGAb. Transient hypothyroidism directly due to TBAb remains rare.

[Apeced syndrome or autoimmune polyendocrine syndrome Type 1]. / Syndrome Apeced ou polyendocrinopathie auto-immune de type 1.

Apeced syndrome is a rare disease, with autosomal recessive transmission and associated with mutations of the AIRE gene, which is involved in central and peripheral immune tolerance mechanisms. Its diagnosis is classically based on the combination of any two of the following three major criteria: chronic mucocutaneous candidiasis, hypoparathyroidism and autoimmune chronic adrenocortical insufficiency (Addison disease). One single criterion is sufficient to diagnosis a sibling of a patient already diagnosed. Because of its great phenotypic variability, some atypical or oligosymptomatic forms may not be recognized. In the presence of one of the three major criteria, it is thus important to look for other clinical manifestations--digestive, cutaneous (including keratinized appendages) and ophthalmological (until then considered minor). In these atypical forms, the diagnosis depends on molecular genetics. Prognosis is influenced by different factors that may be genetic (AIRE mutations, HLA), hormonal (sex) or environmental (infections). Potentially fatal disease (hepatitis or severe malabsorption) requires immunosuppressant therapy. Before beginning this aggressive treatment, underlying infectious foci, especially of candidiasis, must be sought and treated to prevent the development of extremely serious systemic infections in this context. A workup for splenic atrophy is also recommended.