Comparison of Pheochromocytoma-Specific Morbidity and Mortality Among Adults With Bilateral Pheochromocytomas Undergoing Total Adrenalectomy vs Cortical-Sparing Adrenalectomy.

Importance: Large studies investigating long-term outcomes of patients with bilateral pheochromocytomas treated with either total or cortical-sparing adrenalectomies are needed to inform clinical management. Objective: To determine the association of total vs cortical-sparing adrenalectomy with pheochromocytoma-specific mortality, the burden of primary adrenal insufficiency after bilateral adrenalectomy, and the risk of pheochromocytoma recurrence. Design, Setting, and Participants: This cohort study used data from a multicenter consortium-based registry for 625 patients treated for bilateral pheochromocytomas between 1950 and 2018. Data were analyzed from September 1, 2018, to June 1, 2019. Exposures: Total or cortical-sparing adrenalectomy. Main Outcomes and Measures: Primary adrenal insufficiency, recurrent pheochromocytoma, and mortality. Results: Of 625 patients (300 [48%] female) with a median (interquartile range [IQR]) age of 30 (22-40) years at diagnosis, 401 (64%) were diagnosed with synchronous bilateral pheochromocytomas and 224 (36%) were diagnosed with metachronous pheochromocytomas (median [IQR] interval to second adrenalectomy, 6 [1-13] years). In 505 of 526 tested patients (96%), germline mutations were detected in the genes RET (282 patients [54%]), VHL (184 patients [35%]), and other genes (39 patients [7%]). Of 849 adrenalectomies performed in 625 patients, 324 (52%) were planned as cortical sparing and were successful in 248 of 324 patients (76.5%). Primary adrenal insufficiency occurred in all patients treated with total adrenalectomy but only in 23.5% of patients treated with attempted cortical-sparing adrenalectomy. A third of patients with adrenal insufficiency developed complications, such as adrenal crisis or iatrogenic Cushing syndrome. Of 377 patients who became steroid dependent, 67 (18%) developed at least 1 adrenal crisis and 50 (13%) developed iatrogenic Cushing syndrome during median (IQR) follow-up of 8 (3-25) years. Two patients developed recurrent pheochromocytoma in the adrenal bed despite total adrenalectomy. In contrast, 33 patients (13%) treated with successful cortical-sparing adrenalectomy developed another pheochromocytoma within the remnant adrenal after a median (IQR) of 8 (4-13) years, all of which were successfully treated with another surgery. Cortical-sparing surgery was not associated with survival. Overall survival was associated with comorbidities unrelated to pheochromocytoma: of 63 patients who died, only 3 (5%) died of metastatic pheochromocytoma. Conclusions and Relevance: Patients undergoing cortical-sparing adrenalectomy did not demonstrate decreased survival, despite development of recurrent pheochromocytoma in 13%. Cortical-sparing adrenalectomy should be considered in all patients with hereditary pheochromocytoma.

Coexistence of VHL Disease and CPT2 Deficiency: A Case Report.

von Hippel-Lindau (VHL) disease is an inherited syndrome manifesting with benign and malignant tumors. Deficiency of carnitine palmitoyltransferase type II (CPT2) is a disorder of lipid metabolism that, in the muscle form, manifests with recurrent attacks of myalgias often associated with myoglobinuria. Rhabdomyolytic episodes may be complicated by life-threatening events, including acute renal failure (ARF). We report on a male patient who was tested, at 10 years of age, for VHL disease because of family history of VHL. He was diagnosed with VHL but without VHL-related manifestation at the time of diagnosis. During childhood, the patient was hospitalized several times for diffuse muscular pain, muscle weakness, and dark urine. These recurrent attacks of rhabdomyolysis were never accompanied by ARF. The patient was found to be homozygous for the mutation p.S113L of the CPT2 gene. To the best of our knowledge, this is the first report of the coexistence of VHL disease and CPT2 deficiency in the same individual. Based on findings from animal models, the case illustrates that mutations in the VHL gene might protect against renal damage caused by CPT2 gene mutations.

Intracranial internal carotid artery changes in acromegaly: a quantitative magnetic resonance angiography study.

PURPOSE: Although cerebrovascular mortality is increased up to eightfold in acromegaly, intracranial internal carotid artery (ICA) changes have not been well investigated. This is a magnetic resonance angiography (MRA) quantitative cross-sectional study of ICA tortuosity, ectasia and intercarotid distance in acromegalic patients with subsequent analysis of concomitant clinical, laboratory and neuroimaging findings. METHODS: One hundred seventy six acromegalic patients (mean-age 55 ± 14 years, age range 21-88, 92 females) and 104 subjects with headache or transient neurological deficits underwent MRA with the same 1.5 T scanner. Clinical data, laboratory and pituitary adenoma imaging findings were recorded. Using a commercially available software, we measured the tortuosity index [(curved/linear ICA length from C3-midpoint to intracranial bifurcation) - 1], ICA ectasia index (intracavernous/petrous ICA diameter) and intercarotid distance at C3 and C4 levels. RESULTS: Mean ICA tortuosity and ectasia indices were increased in acromegalic patients compared with controls (1.06 ± 0.29 vs 0.93 ± 0.26, p < 0.001; 1.02 ± 0.10 vs 0.92 ± 0.09, p < 0.001). Mean intercarotid distance was reduced at C3 and increased at C4 in acromegalic patients (16.7 ± 3.4 vs 17.9 ± 2.5 mm, p < 0.001; 16.7 ± 4.6 vs 15.4 ± 4.1 mm, p < 0.05; t test). ICA tortuosity and ectasia correlated neither with laboratory findings nor with previous or current treatment. On multivariate analysis, C3 intercarotid distance was reduced in patients on dopamine agonist treatment (p < 0.01) and increased in patients with GH-deficit (p = 0.01), while C4 intercarotid distance was increased with macroadenoma (p = 0.01) and reduced in patients under dopamine agonist (p < 0.01) or somatostatin analogue (p < 0.05) treatment. CONCLUSIONS: Intracranial ICA changes are common findings in acromegaly, and further studies focused on their possible clinical impact are needed.

Herniation of cerebellar tonsils in acromegaly: prevalence, pathogenesis and clinical impact.

Herniation of cerebellar tonsils (CTH) might occur in acromegaly patients and improve after acromegaly treatment. Our study investigated CTH prevalence in acromegaly, its relationship with clinical, laboratory and neuroimaging findings and its possible pathogenesis and clinical impact. 150 acromegaly patients (median-age 56 years, age-range 21-88, 83 females) underwent brain magnetic resonance imaging (MRI). Clinical data, laboratory and pituitary adenoma imaging findings were recorded. CTH, posterior cranial fossa area, tentorial angle, clivus, supraocciput and Twining's line length were measured in acromegaly patients and controls, who included MRI of 115 consecutive subjects with headache or transient neurological deficits (control group-1) and 24 symptomatic classic Chiari 1 malformation patients (control group-2). Acromegaly patients were interviewed for symptoms known to be related with CTH. 22/150 acromegaly patients (15 %) and 8/115 control group-1 subjects presented with CTH (p = 0.04). In acromegaly patients, CTH correlated positively with younger age and inversely with GH-receptor antagonist treatment. Control group-2 had a shorter clivus than CTH acromegaly patients (40.4 ± 3.2 mm vs 42.5 ± 3.3 mm, p < 0.05), while posterior fossa measures did not differ among acromegaly subgroups (with and without CTH) and control group-1. Headache and vision problems were more frequent in CTH acromegaly patients (p < 0.05); two acromegaly patients presented with imaging and neurological signs of syringomyelia. Despite no signs of posterior fossa underdevelopment or cranial constriction, CTH is more frequent in acromegaly patients and seems to contribute to some disabling neurological symptoms.

Increased rate of intracranial saccular aneurysms in acromegaly: an MR angiography study and review of the literature.

BACKGROUND: The concurrence of intracranial aneurysms and acromegaly has been reported and debated previously. Our study in a large number of patients aimed to verify whether acromegaly patients carry a higher risk of harboring intracranial saccular aneurysms and to evaluate the possible relationship using clinical, laboratory, and imaging techniques. MATERIALS AND METHODS: A total of 152 of 161 consecutive acromegaly patients (median age, 55.7 yr; 82 females) underwent neuroimaging evaluation of the circle of Willis. Clinical data (disease duration and disease control, hypertension, smoking history, diabetes and dyslipidemia, previous surgery or radiotherapy, previous or current pharmacological therapy), laboratory findings (GH and IGF-I at onset and shortly before examination), and pituitary adenoma imaging features (size and invasiveness of the cavernous sinus) were recorded. RESULTS: Twenty-six patients (17.3%) harbored 40 newly diagnosed intracranial aneurysms; two other patients had previously undergone aneurysm clipping due to subarachnoid hemorrhage. Ten patients had multiple aneurysms; most of the aneurysms were located in the intracranial tract of the internal carotid artery (67.5%); no aneurysms belonged to the vertebrobasilar circulation. The presence of intracranial aneurysms correlated with GH serum values at disease onset (P < 0.05) and showed a trend to a positive correlation with poor disease control (P = 0.06); no other laboratory, clinical, and radiological findings correlated with the presence of intracranial aneurysms. CONCLUSIONS: GH serum excess seems to carry an increased risk of developing intracranial aneurysms. A neuroradiological evaluation of the intracranial circulation might therefore be considered in the diagnostic work-up of patients affected with acromegaly.