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BACKGROUND: Multiple endocrine neoplasia type 2B is a rare syndrome caused mainly by Met918Thr germline RET mutation, and characterised by medullary thyroid carcinoma, phaeochromocytoma, and extra-endocrine features. Data are scarce on the natural history of multiple endocrine neoplasia type 2B. We aimed to advance understanding of the phenotype and natural history of multiple endocrine neoplasia type 2B, to increase awareness and improve detection. METHODS: This study was a retrospective, multicentre, international study in patients carrying the Met918Thr RET variant with no age restrictions. The study was done with registry data from 48 centres globally. Data from patients followed-up from 1970 to 2016 were retrieved from May 1, 2016, to May 31, 2018. Our primary objectives were to determine overall survival, and medullary thyroid carcinoma-specific survival based on whether the patient had undergone early thyroidectomy before the age of 1 year. We also assessed remission of medullary thyroid carcinoma, incidence and treatment of phaeochromocytoma, and the penetrance of extra-endocrine features. FINDINGS: 345 patients were included, of whom 338 (98%) had a thyroidectomy. 71 patients (21%) of the total cohort died at a median age of 25 years (range <1-59). Thyroidectomy was done before the age of 1 year in 20 patients, which led to long-term remission (ie, undetectable calcitonin level) in 15 (83%) of 18 individuals (2 patients died of causes unrelated to medullary thyroid carcinoma). Medullary thyroid carcinoma-specific survival curves did not show any significant difference between patients who had thyroidectomy before or after 1 year (comparison of survival curves by log-rank test: p=0·2; hazard ratio 0·35; 95% CI 0.07-1.74). However, there was a significant difference in remission status between patients who underwent thyroidectomy before and after the age of 1 year (p<0·0001). There was a significant difference in remission status between patients who underwen

Primary adrenal insufficiency (PAI) is a potentially life-threatening condition that can present with nonspecific features and can be difficult to diagnose. We undertook next generation sequencing in a cohort of children and young adults with PAI of unknown etiology from around the world and identified a heterozygous missense variant (rs6161, c.940G.A, p.Glu314Lys) in CYP11A1 in 19 individuals from 13 different families (allele frequency within undiagnosed PAI in our cohort, 0.102 vs 0.0026 in the Genome Aggregation Database; P, 0.0001). Seventeen individuals harbored a second heterozygous rare disruptive variant in CYP11A1 and two had very rare synonymous changes in trans (c.990G.A, Thr330 =; c.1173C.T, Ser391 =). Although p.Glu314Lys is predicted to be benign and showed no loss-of-function in an Escherichia coli assay system, in silico and in vitro studies revealed that the rs6161/c.940G.A variant, plus the c.990G.A and c.1173C.T changes, affected splicing and that p.Glu314Lys produces a nonfunctional protein in mammalian cells. Taken together, these findings show that compound heterozygosity involving a relatively common and predicted “benign” variant in CYP11A1 is a major contributor to PAI of unknown etiology, especially in European populations. These observations have implications for personalized management and demonstrate how variants that might be overlooked in standard analyses can be pathogenic when combined with other very rare disruptive changes.

1. Clinical assessment of Graves’ orbitopathy Graves’ orbitopathy (GO) is the most frequent extrathyroid complication in Graves’ disease. Natural history, described by Rundle, features an initial inflammatory or active phase in which acute episodes and spontaneous remissions alternate, then a fibrotic phase, with regression within 12–18 months. Diagnosis is based on symptoms and ocular signs. Clinical examination must therefore be rigorous; in case of doubt, the ophthalmologist's opinion is determining. Various classifications assess clinical signs: most widely used are the EUGOGO (European Group Of Graves’ Orbitopathy) and VISA (Vision, Inflammation, Strabismus, Appearance) classifications, the former (http://www.eugogo.eu.proxy.bib.ucl.ac.be) in Europe and the latter (http://www.thyroideyedisease.org.proxy.bib.ucl.ac.be) more often in the US and Canada. Both have limitations; they are not interchangeable, and each patient must consistently be monitored on one or the other. Expert discussions are ongoing, and alternative classifications are offered to improve assessment [1], [2]. Delayed diagnosis and treatment impair ocular progression [3]. Optimal treatment depends on activity status and severity [4]. Clinical activity score (CAS) ≥3/7 indicates active status. Severity is graded as mild, moderate-to-severe or very severe (sight-threatening). Table 1 shows activity and severity criteria. [...]