PAM variants in patients with thyrotrophinomas, cyclical Cushing’s disease and prolactinomas

IntroductionGermline loss-of-function variants in PAM, encoding peptidylglycine α-amidating monooxygenase (PAM), were recently discovered to be enriched in conditions of pathological pituitary hypersecretion, specifically: somatotrophinoma, corticotrophinoma, and prolactinoma. PAM is the sole enzyme responsible for C-terminal amidation of peptides, and plays a role in the biosynthesis and regulation of multiple hormones, including proopiomelanocortin (POMC).MethodsWe performed exome sequencing of germline and tumour DNA from 29 individuals with functioning pituitary adenomas (12 prolactinomas, 10 thyrotrophinomas, 7 cyclical Cushing’s disease). An unfiltered analysis was undertaken of all PAM variants with population prevalence <5%.ResultsWe identified five coding, non-synonymous PAM variants of interest amongst seven individuals (six germline, one somatic). The five variants comprised four missense variants and one truncating variant, all heterozygous. Each variant had some evidence of pathogenicity based on population prevalence, conservation scores, in silico predictions and/or prior functional studies. The yield of predicted deleterious PAM variants was thus 7/29 (24%). The variants predominated in individuals with thyrotrophinomas (4/10, 40%) and cyclical Cushing’s disease (2/7, 29%), compared to prolactinomas (1/12, 8%).ConclusionThis is the second study to demonstrate a high yield of suspected loss-of-function, predominantly germline, PAM variants in individuals with pathological pituitary hypersecretion. We have extended the association with corticotrophinoma to include the specific clinical entity of cyclical Cushing’s disease and demonstrated a novel association between PAM variants and thyrotrophinoma. PAM variants might act as risk alleles for pituitary adenoma formation, with a possible genotype-phenotype relationship between truncating variants and altered temporal secretion of cortisol

Trochlear nerve schwannomas occurring in patients without neurofibromatosis: case report and review of the literature

OBJECTIVE AND IMPORTANCE: Despite their predilection for sensory nerves, intracranial schwannomas have been reported in a number of mixed and purely motor cranial nerves, especially in association with Type 2 neurofibromatosis. We report the rare occurrence of a trochlear nerve schwannoma in a patient without neurofibromatosis and review 17 other case reports from the literature. CLINICAL PRESENTATION: A 35-year-old woman presented with an 8-week history of evolving left hemiparesis, bilateral bulbar paresis, and out-of-character emotional lability. INTERVENTION: She underwent a left temporal craniotomy and a subtemporal, transtentorial approach to the tentorial hiatus, with complete excision of a cisternal trochlear nerve schwannoma. CONCLUSION: Postoperative complications included temporary oculomotor and abducens nerve palsies and temporary right hemiparesis and mild expressive dysphasia, which were resolved at 23-month follow-up. Pre-operative symptoms and signs completely resolved, but a postoperative complete trochlear nerve palsy required inferior oblique myectomy for correction of diplopia. A review of the literature showed no preoperative trochlear nerve involvement in at least 45% of cases. The tumor is isointense on T1- and T2-weighted magnetic resonance images and enhances brightly with gadolinium. The most frequently used approach for surgical excision is the subtemporal approach, and the tumor is almost always totally excised. Long-term follow-up suggests recovery of preoperative deficit, and persisting or new trochlear nerve palsy is the rule.Stephen Santoreneos, Ahmed Hanieh and Ruth E. Jorgense

Modified transoral approach for resection of skull base chordomas in children

Purpose: Chordomas are rare slow growing, locally destructive tumours originating from remnants of the primitive notocord and are found most commonly in the clivus and saccrococcygeal region. These tumours usually present in early adult life but on occasion can present in childhood. The combination of the skull base location and paediatric patient size makes access to these tumours particularly challenging. Methods and results: We report a multidisciplinary technique used in two cases in children where a modified extended palatal split was undertaken to allow greater access for tumour excision. Conclusion: This approach allows for good access to the skull base region to allow for maximal tumour resection. This technique also appears to have minimal impact on palatal function and no adverse effects on the upper airway management.Xenia Doorenbosch, Stephen Santoreneos, Cindy J. Molloy, David J. David and Peter J. Anderso