An Unusual Early Oral Presentation of Acromegaly: A Case Report

Acromegaly is a devastating chronic slowly progressive disease. Its early diagnosis is a challenging issue that necessitates clinical suspicion of signs and symptoms as a first step. This report introduces an unusual early sign in the oral cavity that lead to the early diagnosis of an acromegaly case. A case of a healthy 40-year-old male patient presented with progressively growing multiple hard swellings in the upper and lower jaws. Clinical examination revealed bony hard multiple small spiky exostosis-like swellings, located at the maxillary and mandibular alveolar bones. An array of investigations revealed a 2-mm diameter pituitary tumour in MRI of sella. To the best of the author’s knowledge, this is the first report of spiky exostosis-like growths in the alveolar bone as an early sign of acromegaly. In this case, thorough examination of oral signs and symptoms was the first step for early diagnosis and hence, better prognosis for acromegaly.

Unusual location of osteochondroma in the temporal region in a patient with functional pituitary adenoma

Osteochondromas are common in the long bones and relatively rare in the head and neck regions. We herein report a case of a solitary temporal bone osteochondroma associated with a functional pituitary adenoma hypersecreting prolactin. The patient was a 48-year-old man with progressive, painless temporal swelling associated with gradual visual loss, gynaecomastia, erectile dysfunction, and loss of libido. A brain computed tomography scan with bone windows showed right temporal sessile bony expansion and a pituitary tumour. A pituitary function test revealed hyperprolactinaemia. His symptoms resolved with medical management, and excisional biopsy of the temporal tumour confirmed an osteochondroma. To the best of our knowledge, this is the first reported case of a solitary temporal bone osteochondroma with a functional pituitary adenoma hypersecreting prolactin.

Cardiovascular risk in patients with Cushing’s disease – an interdisciplinary problem

Cushing’s disease is a chronic endogenous hypercortisolaemia associated with overproduction of adrenocorticotropic hormone by a pituitary adenoma, leading to multiple systemic complications that significantly increase morbidity and mortality, as well as reduce the quality of life as a result of prolonged tissue exposure to excess cortisol. Hypercortisolaemia in Cushing’s disease is associated with significant functional and constitutional disorders of the entire body. The consequences of chronic hypercortisolaemia include haemodynamic disorders associated with excessive vascular contraction and increased blood pressure, obesity, carbohydrate metabolism disorders, dyslipidaemia, and coagulopathies, which may contribute to significant cardiovascular remodelling. Cardiovascular disorders have a particular impact on long-term prognosis and quality of life in Cushing’s disease. If left untreated, Cushing’s disease significantly increases the cardiovascular risk and limits the treatment options for secondary organ complications. Cardiovascular mortality (myocardial infarction, heart failure, stroke) is several times higher in patients with Cushing’s disease than in the general population. Early diagnosis of the corticotropic pituitary tumour, as well as a thorough morphological and functional cardiovascular assessment seem essential in risk stratification. Normalisation of cortisol levels after combined neurosurgical and/or pharmacological treatment reduces mortality and the risk of cardiovascular and respiratory complications. The aim of this study is to present the complexity of clinical problems in patients with Cushing’s disease, who are in a particular need of interdisciplinary care.

More than a decade of real-world experience of pegvisomant for acromegaly: ACROSTUDY

Objective: To report the final long-term safety and efficacy analyses of patients with acromegaly treated with pegvisomant from the ACROSTUDY. Design: Global (15 countries), multicentre, non-interventional study (2004-2017). Methods: The complete ACROSTUDY cohort comprised patients with acromegaly, who were being treated with pegvisomant (PEGV) prior to the study or at enrolment. Main endpoints were long-term safety (comorbidities, adverse events [AEs], pituitary tumour volumes, liver tests) and efficacy (IGF-1 changes). Results: Patients (n = 2221) were treated with PEGV for a median of 9.3 years (range, 0-20.8 years) and followed up for a median of 7.4 years (range, 0-13.9 years). Before PEGV, 96.3% had received other acromegaly treatments (surgery/radiotherapy/medications). Before PEGV treatment, 87.2% of patients reported comorbidities. During ACROSTUDY, 5567 AEs were reported in 56.5% of patients and of these 613 were considered treatment-related (in 16.5% of patients) and led to drug withdrawal in 1.3%. Pituitary imaging showed a tumour size increase in 7.1% of patients; the majority (71.1%) reported no changes. Abnormal AST or ALT liver tests occurred in 3.2% of patients. IGF-1 normalization rate improved over time, increasing from 11.4% at PEGV start to 53.7% at year 1, and reaching 75.4% at year 10 with use of ≥30 mg PEGV/day in an increasing proportion of patients. Conclusion: This comprehensive review of the complete cohort in ACROSTUDY confirmed the overall favourable benefit-to-risk profile and high efficacy of PEGV as mono- and combination therapy in patients with an aggressive course/uncontrolled/active acromegaly requiring long-term medical therapy for control.

Spontaneous intracranial hypotension presenting with progressive cognitive decline

A 63-year-old woman presented with headache, progressive somnolence, neurocognitive decline and urinary incontinence through a year. Medical history was unremarkable except for hypertension and hypercholesterolaemia. Neurological examination was normal. Brain MRI showed findings typical for spontaneous intracranial hypotension (subdural fluid collection, pachymeningeal enhancement, brain sagging) and pituitary tumour. The patient’s complaints improved dramatically but temporarily after treatment with each of repeated targeted as well as non-targeted blood patches and a trial with continuous intrathecal saline infusion. Extensive work up including repeated MRI-scans, radioisotope cisternographies, CT and T2-weighted MR myelography could not localise the leakage, but showed minor root-cysts at three levels. Finally, lateral decubitus digital subtraction dynamic myelography with subsequent CT myelography identified a tiny dural venous fistula at the fourth thoracic level. After surgical venous ligation, the patient fully recovered. Awareness of spontaneous dural leaks and their heterogeneous clinical picture are important and demands an extensive workup.

Recurrent cavernous sinus thrombosis: a rare complication of Cushing disease

A 14-year-old girl who presented in 2017 with headache, unilateral right eye ptosis and secondary amenorrhoea had an initial workup consistent with non-functioning pituitary macroadenoma. She underwent debulking of pituitary tumour in October 2017. Postoperatively, she developed recurrent cavernous sinus thrombosis. In view of recurrent thrombosis, she was reinvestigated and was found to have adrenocorticotropic hormone-dependent Cushing. Follow-up MRI 1 year after initial presentation showed that there was structural recurrence of pituitary macroadenoma. She subsequently underwent a petrosal craniotomy for debulking of tumour. Postsurgery she remained biochemically Cushingnoid. MRI 5 months after second surgery showed an enlarging pituitary mass which was deemed inoperable. A multidisciplinary meeting discussion consensus for treatment included radiotherapy and somatostatin analogue, pasireotide. She completed 30 cycles of radiotherapy and MRI post radiotherapy showed reduction in the size of the macroadenoma. Currently, she is waiting for pasereotide initiation.

MIF Inhibition Suppresses Cell Viability and Induces Apoptosis via the ATF4-CHOP Pathway in Mouse Pituitary AtT-20 Cells

Cushing’s disease (CD) is characterized by cortisol overproduction due to ACTH hypersecretion from a pituitary tumour (PT). With an incidence of approximately 1.2 to 2.4 cases per million per year, CD patients have higher rates of morbidity and mortality than the general population. Surgical management is currently the first therapeutic option. However, remission rates vary between studies, and patients may suffer from complications caused by hormonal abnormalities from remnant PT tissues, the surgery itself, as medical treatment options are limited. Macrophage migratory inhibitory factor (MIF) is a cytokine expressed in various tumors, including ACTH-producing PTs, and has been found to play a crucial role in tumorigenesis. Previous studies demonstrate that MIF regulates cell growth via the signal transducer and activator of transcription 3 (STAT3) pathway, the mammalian target of rapamycin (mTOR) pathway, and autophagy. Together, these indicate MIF as a potential therapeutic target for PTs. However, the role of MIF in ACTH-producing PTs remains unknown. Using mouse ACTH-producing PT cells, AtT-20 cells as a model, we established that MIF overexpression led to increased cell growth. In contrast, pharmacological MIF inhibition by 4-iodo-6-phenylpyrimidine (4-IPP) and (S,R)-3-(4-Hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid (ISO-1) and genetic MIF downregulation by siRNA both suppressed cell viability and induced apoptosis, suggesting an anti-apoptotic role of MIF. Genetic MIF downregulation also increased the expression of apoptosis-inducible genes such as activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP), and reduced ACTH production. However, pharmacological MIF inhibition had no effect on ACTH production, which suggests that the mechanism of pharmacological MIF inhibition may be different from MIF downregulation. Neither MIF upregulation nor downregulation affected cell signalling pathways such as the STAT3 pathway, the mTOR pathway, or autophagy. Our findings suggest that MIF inhibition can be a viable therapeutic approach for ACTH-producing PTs.