Normocortisolemic Cushing’s Syndrome Initially Presenting with Increased Glucocorticoid Receptor Numbers1

Newfield, Ron S.; Kalaitzoglou, George; Licholai, Teresa; Chilton, David; Ashraf, Javed; Thompson, E. Brad; New, Maria I.

doi:10.1210/jcem.85.1.6220

Cited by 15 publications

(5 citation statements)

References 16 publications

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“… 56 Another case showed increased numbers of GRs per cell (observed in peripheral lymphocytes) with normal binding affinity. 57 Interestingly, GC hypersensitivity seems to predominantly affect the peripheral tissues but not the hypothalamus and pituitary glands; hence, the negative feedback loop is largely intact, and suppression of the HPA axis is disproportional to the clinical signs. 54 These cases illustrate the need for clinical awareness of GC hypersensitivity in patients suspected of Cushing's syndrome, when cortisol levels are low and exogenous GC use is excluded.…”

Section: Genetic Mutations and Polymorphisms In Association With Gc S...mentioning

confidence: 99%

Variation in glucocorticoid sensitivity and the relation with obesity

et al. 2021

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Summary Increasing evidence points to a relation between increased glucocorticoid (GC) exposure and weight gain. In support, long‐term cortisol measurements using hair analysis revealed that many individuals with obesity appear to have cortisol values in the high physiological range. The mechanisms behind this relationship need to be determined in order to develop targeted therapy to reach sustainable weight loss in these subgroups. The effect of GCs is not only determined by the plasma concentration of GCs but also by individual differences in GC sensitivity and the target tissue, which can be analyzed by functional GC assays. GC sensitivity is influenced by multiple genetic and acquired (e.g., disease‐related) factors, including intracellular GC availability, hormone binding affinity, and expression levels of the GC receptors and their isoforms, as well as factors involved in the modulation of gene transcription. Interindividual differences in GC sensitivity also play a role in the response to exogenous GCs, with respect to both therapeutic and adverse effects. Accordingly, in this review, we summarize current knowledge on mechanisms that influence GC sensitivity and their relationships with obesity and discuss personalized treatment options targeting the GC receptor.

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Section: Genetic Mutations and Polymorphisms In Association With Gc S...mentioning

confidence: 99%

Variation in glucocorticoid sensitivity and the relation with obesity

et al. 2021

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“… 4 10.8 F Americian – – central obesity, moon face, buffalo hump, violaceous striae, osteopenia, learning disability, early puberty 304.18 ± 15.28 6.09 ± 2.35 normal normal mifepristone remission Nicolaides et al [ 4 ]. 5 9 F Greek – – central obesity, moon face, buffalo hum, violaceous striae, acanthosis nigricans, hirsutism 0.45–7.79 1.00 9.00 normal no spontaneous remission Su, et al [ 6 ] 6 child NM Chinses – – central obesity, moon face, buffalo hum, violaceous striae, hirusm, hypertension, growth retardation, ostalgia Low Normal Low normal NM NM Iida et al [ 14 ] 7 54 M Japanese + – central obesity, moon face, buffalo hump, DM 20.00 ± 19.00 <2.00 40.00–50.00 normal NM NM Krysiak et al [ 21 ] 8 28 F Polish – – Obesity, hypertension, prediabetes, osteopenia 120.31 <2.00 272.4–317.8 adrenal gland atrophy ketoconazole, cabergoline death because of an accident Liu., et al [ 22 ] 9 27 M Chinses + – central obesity, moon face, buffalo hum, violaceous striae, osteopenia 10.75 <0.22 11.95...…”

Section: Discussionmentioning

confidence: 99%

“…The affinity of mifepristone is 18 times that of cortisol, and mifepristone can effectively improve the clinical syndrome caused by hypercortisolism. In addition to an adult female patient with PGGH who used ketoconazole because mifepristone was not available [ 21 ], a 27-year-old male patient and a 13.75-year-old girl with PGGH were treated with mifepristone, and their symptoms were improved [ 5 , 22 ]. The experience with mifepristone in children is very limited.…”

Section: Discussionmentioning

confidence: 99%

Two cases of infantile-onset primary generalized glucocorticoid hypersensitivity and the effect of mifepristone

Zhao

et al. 2022

BMC Pediatr

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Background Primary generalized glucocorticoid hypersensitivity (PGGH) is a very rare disease caused by terminal organ hypersensitivity to glucocorticoids for which the aetiology is unknown. The incidence of PGGH is extremely rare, especially in children. To date, the literatures about the etiology, prognosis and treatment of PGGH are scarce. Aim of the study is describing the cases of two Chinese children with infantile-onset PGGH in one family, one of whom died and one who was treated with mifepristone. They are the two youngest children with PGGH reported in the literature. Case presentation Two siblings with infantile-onset PGGH were affected in this family. The main manifestations of patient 1 were typical Cushing’s syndrome-like manifestations, significantly aggravated symptoms after physiological doses of glucocorticoids and very low levels of serum cortisol and adrenocorticotropin hormone (ACTH) during attacks. After being diagnosed with PGGH, he was given guidance to avoid glucocorticoids and took mifepristone therapy for 5 months, and his symptoms improved. Patient 2 was the younger brother of patient 1, with similar manifestations to his brother at the age of 4 months. Patient 2 ultimately died at the age of 9 months. Conclusion PGGH is a very rare disease that can lead to death if not diagnosed and treated in a timely manner. This article describes the cases of the two youngest children with PGGH reported in the literature, one of whom improved after mifepristone treatment, and increases the knowledge of the clinical manifestations of and the treatment experience in PGGH.

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“…However, the mutation D401H did not alter the affinity of the mutant receptor for the ligand, had no effect on the time required to complete its cytoplasmic to nucleus translocation, did not affect its ability to bind to GREs of target genes, and did not change its ability to interact with the GRIP1 coactivator [ 90 ]. Notably, a number of cases with primary generalized glucocorticoid hypersensitivity syndrome and no mutated NR3C1 gene have also been reported [ 91 , 92 , 93 , 94 , 95 ].…”

Section: Primary Generalized Glucocorticoid Hypersensitivity Syndromementioning

confidence: 99%

Primary Generalized Glucocorticoid Resistance and Hypersensitivity Syndromes: A 2021 Update

Nicolaides

Charmandari

2021

IJMS

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Glucocorticoids are the final products of the neuroendocrine hypothalamic–pituitary—adrenal axis, and play an important role in the stress response to re-establish homeostasis when it is threatened, or perceived as threatened. These steroid hormones have pleiotropic actions through binding to their cognate receptor, the human glucocorticoid receptor, which functions as a ligand-bound transcription factor inducing or repressing the expression of a large number of target genes. To achieve homeostasis, glucocorticoid signaling should have an optimal effect on all tissues. Indeed, any inappropriate glucocorticoid effect in terms of quantity or quality has been associated with pathologic conditions, which are characterized by short-term or long-lasting detrimental effects. Two such conditions, the primary generalized glucocorticoid resistance and hypersensitivity syndromes, are discussed in this review article. Undoubtedly, the tremendous progress of structural, molecular, and cellular biology, in association with the continued progress of biotechnology, has led to a better and more in-depth understanding of these rare endocrinologic conditions, as well as more effective therapeutic management.

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Normocortisolemic Cushing’s Syndrome Initially Presenting with Increased Glucocorticoid Receptor Numbers1

Cited by 15 publications

References 16 publications

Variation in glucocorticoid sensitivity and the relation with obesity

Variation in glucocorticoid sensitivity and the relation with obesity

Two cases of infantile-onset primary generalized glucocorticoid hypersensitivity and the effect of mifepristone

Primary Generalized Glucocorticoid Resistance and Hypersensitivity Syndromes: A 2021 Update

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