Nelson syndrome is a rare disorder, characterized by clinical features arising from an adrenocorticotropic hormone (ACTH)-secreting pituitary macroadenoma after bilateral adrenalectomy. Common symptoms of Nelson syndrome include weight gain, vision problems, and skin hyperpigmentation, among many others. In this case report, a 58-year-old Asian female who displayed clinical features akin to Nelson syndrome despite not undergoing bilateral adrenalectomy is investigated. The patient has a past history of an ACTH-secreting pituitary macroadenoma, for which a transsphenoidal resection was performed along with radiation therapy. A year following this, she displayed severe facial and neck hyperpigmentation. According to the laboratory results obtained, the patient displayed initial high ACTH levels and low-normal AM cortisol levels, which are signs of partial adrenal insufficiency. A brain MRI was performed, which confirmed stable residual tumor tissue in the cavernous sinus. The results pointed to the adrenal glands as the cause of the hyperpigmentation, and the patient was diagnosed with primary adrenal insufficiency. To bring her ACTH levels and low-normal AM cortisol into the proper range, she was given low-dose hydrocortisone and monitored for five years. Over this time period, her hyperpigmentation improved significantly and eventually resolved entirely, and her ACTH levels were lowered, indicating that hydrocortisone was the appropriate treatment for normalizing ACTH levels. In this case, it was determined that unresponsive adrenal glands lead to high ACTH levels, which resulted in an atypical case of Nelson syndrome and the physical symptom of hyperpigmentation.

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Nelson syndrome is a rare and potentially life-threatening complication of treatment with total bilateral adrenalectomy for women with Cushing disease. A successful term pregnancy following fertility treatment in a patient with Nelson syndrome is presented. Our study provides guidance in the prenatal and intrapartum management of this condition. A case report and a systematic review of 14 papers describing 50 pregnancies are presented. An electronic database search included Medline (1946 to September 2022), Embase (1980 to September 2022), Cochrane Library, and UKOSS. A small number of pregnancies in women with Nelson syndrome are reported in literature, but there are no guidelines. Some authors detail the prenatal care provided to their patients. Four studies report prenatal monitoring with visual field checks and two report monitoring with X-rays. Five studies report the use of parenteral hydrocortisone at the time of delivery. Where described, women delivered appropriately grown newborns at term, with timing and mode of delivery dictated by obstetric indications. Preconception counseling and optimization of maternal health status improve pregnancy outcomes in women with Nelson syndrome. Multidisciplinary review in a combined obstetric-endocrine prenatal clinic is ideal. Awareness about potential complications during pregnancy and the postnatal period is crucial in providing optimal care to the mother and baby.

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Nelson\'s syndrome is a potentially severe condition that may develop in patients with Cushing\'s disease treated with bilateral adrenalectomy. Its management can be challenging. Pituitary surgery followed or not by radiotherapy offers the most optimal tumour control, whilst pituitary irradiation alone needs to be considered in cases requiring intervention and are poor surgical candidates. Observation is an option for patients with small lesions, not causing mass effects to vital adjacent structures but close follow-up is required for a timely detection of corticotroph tumour progression and for further treatment if required. To date, no medical therapy has been consistently proven to be effective in Nelson\'s syndrome. Pharmacotherapy, however, should be considered when other management approaches have failed. A subset of patients with Nelson\'s syndrome may develop further tumour growth after primary treatment, and, in some cases, a truly aggressive tumour behaviour can be demonstrated. In the absence of evidence-based guidance, the management of these cases is individualized and tailored to previously offered treatments. Temozolomide has been used in patients with aggressive Nelson\'s with no consistent results. Development of tumour-targeted therapeutic agents are an unmet need for the management of aggressive cases of Nelson\'s syndrome.

Corticotroph tumor progression after bilateral adrenalectomy/Nelson\'s syndrome (CTP-BADX/NS) is a severe complication of bilateral adrenalectomy (BADX). The aim of our study was to investigate the prevalence, presentation and outcome of CTP-BADX/NS in patients with Cushing\'s disease (CD) included in the European Registry on Cushing\'s Syndrome (ERCUSYN). We examined data on 1045 CD patients and identified 85 (8%) who underwent BADX. Of these, 73 (86%) had follow-up data available. The median duration of follow-up since BADX to the last visit/death was 7 years (IQR 2-9 years). Thirty-three patients (45%) experienced CTP-BADX/NS after 3 years (1.5-6) since BADX. Cumulative progression-free survival was 73% at 3 years, 66% at 5 years and 46% at 10 years. CTP-BADX/NS patients more frequently had a visible tumor at diagnosis of CD than patients without CTP-BADX/NS (P < 0.05). Twenty-seven CTP-BADX/NS patients underwent surgery, 48% radiotherapy and 27% received medical therapy. The median time since diagnosis of CTP-BADX/NS to the last follow-up visit was 2 years (IQR, 1-5). Control of tumor progression was not achieved in 16 of 33 (48%) patients, of whom 8 (50%) died after a mean of 4 years. Maximum adenoma size at diagnosis of CD was associated with further tumor growth in CTP-BADX/NS despite treatment (P = 0.033). Diagnosis of CTP-BADX/NS, older age, greater UFC levels at diagnosis of CD and initial treatment predicted mortality. In conclusion, CTP-BADX/NS was reported in 45% of the ERCUSYN patients who underwent BADX, and control of tumor growth was reached in half of them. Future studies are needed to establish effective strategies for prevention and treatment.

Corticotroph cells give rise to aggressive and rare pituitary neoplasms comprising ACTH-producing adenomas resulting in Cushing disease (CD), clinically silent ACTH adenomas (SCA), Crooke cell adenomas (CCA) and ACTH-producing carcinomas (CA). The molecular pathogenesis of these tumors is still poorly understood. To better understand the genomic landscape of all the lesions of the corticotroph lineage, we sequenced the whole exome of three SCA, one CCA, four ACTH-secreting PA causing CD, one corticotrophinoma occurring in a CD patient who developed Nelson syndrome after adrenalectomy and one patient with an ACTH-producing CA. The ACTH-producing CA was the lesion with the highest number of single nucleotide variants (SNV) in genes such as USP8, TP53, AURKA, EGFR, HSD3B1 and CDKN1A. The USP8 variant was found only in the ACTH-CA and in the corticotrophinoma occurring in a patient with Nelson syndrome. In CCA, SNV in TP53, EGFR, HSD3B1 and CDKN1A SNV were present. HSD3B1 and CDKN1A SNVs were present in all three SCA, whereas in two of these tumors SNV in TP53, AURKA and EGFR were found. None of the analyzed tumors showed SNV in USP48, BRAF, BRG1 or CABLES1. The amplification of 17q12 was found in all tumors, except for the ACTH-producing carcinoma. The four clinically functioning ACTH adenomas and the ACTH-CA shared the amplification of 10q11.22 and showed more copy-number variation (CNV) gains and single-nucleotide variations than the nonfunctioning tumors.

Pituitary adenomas produce a complex collection of disorders. Some are incidental findings. Some distort local anatomical structures which can lead to disorders of vision or hormone production. Some produce excesses of hormones which can be either life threatening or clinically distressing. The management requires the expertise of a variety of experts who plan together. No single treatment is universally successful in controlling these conditions. Medical, biochemical, surgical and radiosurgical management can all have parts to play. Coordinate co-operation between specialists will provide patients with the best available treatment.

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BACKGROUND: Nelson\'s syndrome (NS) is a rare complication involving enlargement of an adrenocorticotropic hormone (ACTH) producing tumor in the pituitary following bilateral adrenalectomy in Cushing\'s syndrome. Here, we explore the epidemiology, complication profiles, and readmission statistics of 63 patients diagnosed with NS.
METHODS: The Nationwide Readmission Database was retrospectively queried for all patients diagnosed with NS (n = 63) or receiving total bilateral adrenalectomy (TBA) surgery (n = 275) between 2016 and 2017. Complications, demographics, and predictive factors were queried for all patients involved. Statistical analysis used Mann-Whitney U nonparametric testing was to compare basic demographics and gaussian-fitted multivariable regression analysis with post hoc odds ratios to compare patient predictors of development of NS and complication rates between the two cohorts.
RESULTS: We report the largest contemporary patient series of NS through a nationally-representative inpatient database and explore the clinical characteristics of modern NS patients. Modeling revealed that the absence of primary hypertension served as a significant predictor for NS when compared to the TBA control cohort (OR = 0.88; 95%CI = 0.79-0.99; p = 0.037). In addition, analysis of complications between NS and TBA cohortsrevealed that NS patients have significantly higher rates of hypoosmolarity/hyponatremia (OR = 1.42; 95%CI = 1.19-1.71; p = 0.00021), hypopituitarism (OR = 1.94; 95%CI = 1.60-2.36; p < 0.0001), and sepsis (OR = 1.51; 95%CI = 1.14-2.00; p = 0.0046).
CONCLUSIONS: Contemporary NS is a rare complication of TBA, and modern cases of NS may differ significantly from cases of NS reported in the mid-1900s. As such, a thorough understanding of patient complications and predictive factors for NS are necessary to fully guide patient management in the modern era.