A series of 68 patients with neurosarcoidosis is reported, with particular emphasis on clinical aspects, diagnosis and treatment. A classification system based on clinical diagnostic probability is proposed, consisting of probable and definite disease, the latter being dependent on finding sarcoid granulomas on nervous system histology, which was obtained in 12 patients (18%). The role of investigations, including magnetic resonance imaging (MRI), chest radiography, Kveim skin test, Gallium 67 isotope scanning and cerebrospinal fluid (CSF) studies, is considered. Sixty-two percent of patients presented with nervous system disease, most commonly affecting the optic nerve and chiasm. Other common presentations included cranial nerve palsies, spinal cord and brainstem manifestations. Investigations yielding most diagnostic information included the Kveim test (41/48, 85% positive), raised CSF protein and/or cells (50/62, 81%) and gallium 67 scan (14/31, 45%). Eleven out of 29 patients (38%) patients showed meningeal enhancement on MRI scanning and 43% of scans demonstrated multiple white-matter lesions. Mean follow-up for the group was 4.6 years. Forty-seven patients were seen for > 18 months, and over half of these patients progressed despite corticosteroid and other immunosuppressive therapies. The benefit of a large patient database prospectively studied, with extended follow-up is discussed in order to learn more about prognosis and advance therapy in neurosarcoidosis.

Context:Familial isolated pituitary adenoma (FIPA) due to aryl hydrocarbon receptor interacting protein (AIP) gene mutations is an autosomal dominant disease with incomplete penetrance. Clinical screening of apparently unaffected AIP mutation (AIPmut) carriers could identify previously unrecognized disease.Objective:To determine the AIP mutational status of FIPA and young pituitary adenoma patients, analyzing their clinical characteristics, and to perform clinical screening of apparently unaffected AIPmut carrier family members.Design:This was an observational, longitudinal study conducted over 7 years.Setting:International collaborative study conducted at referral centers for pituitary diseases.Participants:FIPA families (n = 216) and sporadic young-onset (≤30 y) pituitary adenoma patients (n = 404) participated in the study.Interventions:We performed genetic screening of patients for AIPmuts, clinical assessment of their family members, and genetic screening for somatic GNAS1 mutations and the germline FGFR4 p.G388R variant.Main Outcome Measure(s):We assessed clinical disease in mutation carriers, comparison of characteristics of AIPmut positive and negative patients, results of GNAS1, and FGFR4 analysis.Results:Thirty-seven FIPA families and 34 sporadic patients had AIPmuts. Patients with truncating AIPmuts had a younger age at disease onset and diagnosis, compared with patients with nontruncating AIPmuts. Somatic GNAS1 mutations were absent in tumors from AIPmut-positive patients, and the studied FGFR4 variant did not modify the disease behavior or penetrance in AIPmut-positive individuals. A total of 164 AIPmut-positive unaffected family members were identified; pituitary disease was detected in 18 of those who underwent clinical screening.Conclusions:A quarter of the AIPmut carriers screened were diagnosed with pituitary disease, justifying this screening and suggesting a variable clinical course for AIPmut-positive pituitary adenomas.

Context:Pituitary adenomas and pheochromocytomas/paragangliomas (pheo/PGL) can occur in the same patient or in the same family. Coexistence of the two diseases could be due to either a common pathogenic mechanism or a coincidence.Objective:The objective of the investigation was to study the possible coexistence of pituitary adenoma and pheo/PGL.Design:Thirty-nine cases of sporadic or familial pheo/PGL and pituitary adenomas were investigated. Known pheo/PGL genes (SDHA-D, SDHAF2, RET, VHL, TMEM127, MAX, FH) and pituitary adenoma genes (MEN1, AIP, CDKN1B) were sequenced using next generation or Sanger sequencing. Loss of heterozygosity study and pathological studies were performed on the available tumor samples.Setting:The study was conducted at university hospitals.Patients:Thirty-nine patients with sporadic of familial pituitary adenoma and pheo/PGL participated in the study.Outcome:Outcomes included genetic screening and clinical characteristics.Results:Eleven germline mutations (five SDHB, one SDHC, one SDHD, two VHL, and two MEN1) and four variants of unknown significance (two SDHA, one SDHB, and one SDHAF2) were identified in the studied genes in our patient cohort. Tumor tissue analysis identified LOH at the SDHB locus in three pituitary adenomas and loss of heterozygosity at the MEN1 locus in two pheochromocytomas. All the pituitary adenomas of patients affected by SDHX alterations have a unique histological feature not previously described in this context.Conclusions:Mutations in the genes known to cause pheo/PGL can rarely be associated with pituitary adenomas, whereas mutation in a gene predisposing to pituitary adenomas (MEN1) can be associated with pheo/PGL. Our findings suggest that genetic testing should be considered in all patients or families with the constellation of pheo/PGL and a pituitary adenoma.

Objective: There are few published comparisons between paediatric and adult-onset Cushing's disease (CD). We compare the epidemiology, diagnostic features and cure rate by transsphenoidal surgery (TSS) in these groups. Design: Retrospective review of patient databases in a single university hospital centre. Patients: Totally, 41 paediatric (mean age 12.3G3.5 years; range 5.7-17.8) and 183 adult (mean age 40G13 years; range 18.0-95.0) patients with CD were investigated. Results: Paediatric CD was characterised by male (63%) and adult CD by a female predominance (79%, P!0.0001). There were small but significant differences in clinical presentation. Biochemical features of CD were comparable except the serum cortisol increase during a CRH test: mean change (105%, nZ39) in paediatric and (54%, nZ123) in adult subjects (P!0.0001). Macroadenomas were more common in adult (15%, 28/183) than in paediatric (2%, 1/41, PZ0.04) CD. Corticotroph microadenomas were more easily visualised by pituitary magnetic resonance imaging (MRI) in adult (76%, 50/66) compared with paediatric (55%, 21/38, PZ0.045) CD with poorer concordance of imaging with surgical findings in children (PZ0.058). The incidence of ACTH lateralisation by bilateral simultaneous inferior petrosal sinus sampling was comparable in paediatric (76%, 25/33) and adult (79%, 46/58; PZ0.95) patients with good surgical concordance in both (82% paediatric and 79% adult). Cure rates by TSS were comparable, with a paediatric cure rate of 69%. Conclusion: Several features of paediatric CD are distinct: increased frequency of prepubertal CD in males, the different clinical presentation, the decreased presence of macroadenomas and the frequent absence of radiological evidence of an adenoma on MRI.