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

Background Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy 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 nonendocrine 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 Twenty-five patients (23 families) were enrolled. Eleven distinct AIRE variants were identified, 2 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. Seventeen out of 25 patients were homozygote. The median number of clinical manifestations was 7; 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 natural killer 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 < .001), related to the severity of the disease. All tested sera (n = 18) were positive for anti-interferon-α, 15/18 for anti-IL-22 antibodies, and 13/18 for anti-IL-17F antibodies, without clear phenotypic correlation other than with CMC. Conclusion This first prospective cohort showed a high AIRE genotype variability, with 2 new gene variants. The prevalence of potentially life-threatening nonendocrine 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

Death in pediatric Cushing syndrome is uncommon but still occurs

Cushing syndrome (CS) in children is rare. Delayed diagnosis and treatment of CS may be associated with increased morbidity and, unfortunately, mortality. We performed a retrospective review of all patients with CS under the age of 18 referred to the NIH from 1998 to 2013 in order to describe deceased patients among cases of pediatric CS referred to the National Institutes of Health (NIH). The deaths of 4 children (3 females and 1 male), aged 7.5–15.5 years (mean age 11.2 years) with length of disease 2–4 years were recorded among 160 (2.5%) children seen at, or referred to the NIH over the last 15 years. All died at different institutions, prior to coming to the NIH (two of them) or after leaving NIH (two of them). Presenting symptoms included increasing weight and decreasing height gain, facial plethora, dorsocervical fat pad (webbed neck), striae, headache, vision disturbances and depression and other mood or behavior changes; there were no differences between how these patients presented and the others in our cohort. The causes of CS in the deceased patients were also not different, in fact, they spanned the entire spectrum of CS: pituitary disease (on of them), ectopic corticotropin production (one of them), and primary adrenal hyperplasia (1). In one patient, the cause of CS could not be verified. Three died of sepsis and one due to residual disease and complications of the primary tumor. CONCLUSIONS: Despite advances in early diagnosis and treatment of pediatric CS, a 2.5% mortality rate was identified in a large cohort of patients with this condition referred to an experienced, tertiary care referral center (although these deaths occurred elsewhere). Pediatricians need to recognize the possibility of death, primarily due to sepsis, in a patient with pediatric CS and act accordingly

Choosing wisely: the list of the group of study Endocrinology and Metabolic Diseases of Italian Society of Clinical Pathology and Laboratory Medicine

Background.: The need to promote the appropriateness of diagnostic and therapeutic procedures increased in the recent years in the world and in Italy. Scientific societies participated from the beginning in defining modes and tools to support the members in the “translation” of this need in the clinical practice, for example defining lists of the diagnostic and therapeutic procedures with the highest risk of inappropriateness. The most relevant projects at international and national levels were, respectively, Choosing wisely e Slow Medicine. SIPMeL is supporting Slow Medicine and presented at 2015 SIPMel National Congress the list of the 5 procedures with the highest risk of inappropriateness in Laboratory Medicine. Methods.: In 2015 a survey has been carried out among the members of the Group of study Endocrinology-Metabolic diseases that were asked to vote (score 1–10) the five procedures with the highest risk of inappropriateness supporting their score with a short comment and essential references. Results.: The final list was obtained from the sum of the scores and includes: (1) optimal assessment of thyroid function; (2) optimal diagnostics of Cushing syndrome; (3) optimal diagnostics of pheocromocytoma; (4) optimal diagnostics for autoimmune thyroid disease; (5) assessment of 25 (OH) vitamin D. Conclusions.: The top five procedures have been presented at 2015 SIPMel National Congress and will be available in the Society website. We propose that also the other SIPMel groups of study prepare similar list and make them available within the Society and profession in a similar way