Common variable immunodeficiency (CVID) with central adrenal insufficiency is a recently defined clinical syndrome caused by mutations in the nuclear factor kappa-B subunit 2 (NFKB2) gene. We present the first case of NFKB2 mutation in Asian population. An 18-year-old Chinese female with adrenocorticotropic hormone (ACTH) deficiency was admitted due to adrenal crisis and pneumonia. She had a history of recurrent respiratory infections since childhood and ectodermal abnormalities were noted during physical examination. Immunologic tests revealed panhypogammaglobulinemia and deficient natural killer (NK)-cell function. DNA sequencing of NFKB2 identified a heterozygous nonsense mutation (c.2563 A>T, p.855: Lys>*) in the patient but not her parents. Clinicians should be alert to comorbidities of adrenal insufficiency and ectodermal dysplasia in CVID patients as these might suggest a rare hereditary syndrome caused by NFKB2 mutation.

Purpose: This pilot study investigated the performance of C-X-C motif chemokine receptor 4 (CXCR4) molecular imaging (⁶⁸Ga-pentixafor PET/CT) in Cushing syndrome (CS) and the correlation between CXCR4 signaling interactions and glucose metabolism in adrenocorticotropin-cortisol pathway. Methods: We retrospectively evaluated 31 patients (16 patients with CS and 15 patients with nonfunctioning pituitary or adrenal adenomas). All patients underwent ⁶⁸Ga-pentixafor PET/CT, and 11 with pituitary adenoma also underwent ¹⁸F-FDG PET/CT. The diagnosis accuracy of ⁶⁸Ga-pentixafor PET/CT was calculated. The correlation between radiouptake along the pituitary-adrenal axis and hormone levels was calculated. Results: Patients with Cushing disease characterized a focal uptake in adrenocorticotropic hormone–producing pituitary adenoma (ACTH-PA). In ACTH-independent CS, there was increased uptake of ⁶⁸Ga-pentixafor in adrenal lesions but not in the pituitary fossa. The nonfunctioning pituitary or adrenal adenomas showed negative ⁶⁸Ga-pentixafor signal. The one patient with metastatic ectopic ACTH syndrome had multiple ⁶⁸Ga-pentixafor–avid lesions. Using the threshold of SUV_max >8.5 in the adrenal lesions, the sensitivity and specificity of ⁶⁸Ga-pentixafor PET/CT to diagnose cortisol-producing adenoma were 100% and 84.9%. A cutoff SUV_max value of 3.0 on ⁶⁸Ga-pentixafor PET/CT had 100% sensitivity and specificity for differentiating ACTH-PA. The corresponding hormone level was significantly correlated with uptake of ⁶⁸Ga-pentixafor in pituitary adenoma and adrenal tissue but not with glucose metabolism. Conclusion: We have characterized the performance of ⁶⁸Ga-pentixafor in different subtypes of CS. ⁶⁸Ga-pentixafor PET/CT is promising in the differential diagnosis of both ACTH-independent and ACTH-dependent CS. Activated CXCR4 molecular signaling along the pituitary-adrenal axis was found in patients with Cushing disease.

Our objective was to investigate the clinical value of ⁶⁸Ga-pentixafor PET/CT in subtype diagnosis of primary aldosteronism (PA) patients with adrenal micronodules less than 1 cm in diameter and compare it with the routine clinical methods. Methods: We used prospective enrollment of PA patients with adrenal micronodules identified by adrenal CT scans to undergo ⁶⁸Ga-pentixafor PET/CT. Patients were divided into surgically eligible and ineligible groups based on surgical pathology and postoperative follow-up or adrenal venous sampling (AVS) results. Patient management was discussed by a multidisciplinary team. The semiquantitative parameters of PET/CT included SUV_max for adrenal lesion and SUV ratios for lesion to liver and lesion to normal adrenal gland. Results: In total, 123 PA patients with adrenal micronodules were examined using ⁶⁸Ga-pentixafor PET/CT, and 104 patients who underwent surgery or successful AVS were included in the analysis (48 ± 10 y old). The sensitivity, specificity, and accuracy of visual analysis using ⁶⁸Ga-pentixafor PET/CT to identify surgically eligible patients were 90.2%, 72.7%, and 86.5%, respectively, which were significantly higher than those of adrenal CT (73.1%, 53.8%, and 68.3%, respectively) and yielded consistent results in different CT morphologic or age subgroups. In 36 patients who had both AVS and ⁶⁸Ga-pentixafor PET/CT, the tests showed a 66.7% concordance rate. However, PET/CT was significantly more concordant with surgical outcomes than was AVS in 17 patients who underwent adrenalectomy (82.4% vs. 68.86%). Among the 183 adrenal micronodules included in the study, the semiquantitative diagnostic thresholds for 92 lesions eligible for surgical treatment were an SUV_max of at least 4.55, an SUV ratio of at least 2.17 for lesion to liver, and an SUV ratio of at least 1.90 for lesion to normal adrenal gland. All patients benefited from surgical removal of ⁶⁸Ga-pentixafor–avid microlesions. Conclusion: In PA patients with adrenal micronodules, ⁶⁸Ga-pentixafor PET/CT demonstrated promising diagnostic accuracy in classification and appeared to perform better than adrenal CT. Furthermore, there was also a suggestion of some potential in predicting postoperative efficacy compared with AVS, although these observations require further investigation and verification in larger cohorts. Visual Abstract