Adrenocortical carcinoma and succinate dehydrogenase gene mutations: an observational case series

Objective Germline loss-of-function mutations in succinate dehydrogenase (SDHx) genes results in rare tumor syndromes that include pheochromocytoma, paraganglioma, and others. Here we report a case series of patients with adrenocortical carcinoma (ACC) that harbor SDHx mutations. Patients and results We report four unrelated patients with ACC and SDHx mutations. All cases presented with Cushing syndrome and large adrenal masses that were confirmed to be ACC on pathology. All four ACC specimens were found to have truncating mutations in either SDHC or SDHA, while cases 1, 2 and 3 also had the mutations confirmed in the germline: Case 1: SDHC c.397C > T, pR133X; Case 2: SDHC c.43C > T, p.R15X; Case 3: SDHA c.91C > T, p.R31X; Case 4: SDHA c.1258C > T, p.Q420X. Notably, Case 1 had a father and daughter who both harbored the same SDHC germline mutation, and the father had a paraganglioma and renal cell carcinoma. A combination of next generation sequencing, and/or immunohistochemistry, and/or mass spectroscopy was used to determine whether there was loss of heterozygosity and/or loss of SDH protein expression or function within the ACC. Potential evidence of loss of heterozygosity was observed only in Case 2. Conclusions We observed truncating mutations in SDHA or SDHC in the ACC and/or germline of four unrelated patients. Given how statistically improbable the concurrence of ACC and pathogenic germline SDHx mutations is expected to be, these observations raise the question whether ACC may be a rare manifestation of SDHx mutation syndromes. Further studies are needed to investigate the possible role of SDH deficiency in ACC pathogenesis.

Download Full-text

Succinate dehydrogenase gene mutations are strongly associated with paraganglioma of the organ of Zuckerkandl

Endocrine Related Cancer ◽

10.1677/erc-10-0004 ◽

2010 ◽

Vol 17 (3) ◽

pp. 581-588 ◽

Cited By ~ 25

Author(s):

Maya B Lodish ◽

Karen T Adams ◽

Thanh T Huynh ◽

Tamara Prodanov ◽

Alex Ling ◽

...

Keyword(s):

Succinate Dehydrogenase ◽

Mesenteric Artery ◽

Chromaffin Cells ◽

Clinical Characteristics ◽

Inferior Mesenteric Artery ◽

Clinical Presentation ◽

Gene Mutations ◽

Aortic Bifurcation ◽

Dehydrogenase Gene ◽

Genes Encoding

Organ of Zuckerkandl paragangliomas (PGLs) are rare neuroendocrine tumors that are derived from chromaffin cells located around the origin of the inferior mesenteric artery extending to the level of the aortic bifurcation. Mutations in the genes encoding succinate dehydrogenase subunits (SDH) B, C, and D (SDHx) have been associated with PGLs, but their contribution to PGLs of the organ of Zuckerkandl PGLs is not known. We aimed to describe the clinical presentation of patients with PGLs of the organ of Zuckerkandl and investigate the prevalence of SDHx mutations and other genetic defects among them. The clinical characteristics of 14 patients with PGL of the organ of Zuckerkandl were analyzed retrospectively; their DNA was tested for SDHx mutations and deletions. Eleven out of 14 (79%) patients with PGLs of the organ of Zuckerkandl were found to have mutations in the SDHB (9) or SDHD (2) genes; one patient was found to have the Carney–Stratakis syndrome (CSS), and his PGL was discovered during surgery for gastrointestinal stromal tumor. Our results show that SDHx mutations are prevalent in pediatric and adult PGLs of the organ of Zuckerkandl. Patients with PGLs of the organ of Zuckerkandl should be screened for SDHx mutations and the CSS; in addition, asymptomatic carriers of an SDHx mutation among the relatives of affected patients may benefit from tumor screening for early PGL detection.

Download Full-text

A review of the tumour spectrum of germline succinate dehydrogenase gene mutations: Beyond phaeochromocytoma and paraganglioma

Clinical Endocrinology ◽

10.1111/cen.14289 ◽

2020 ◽

Vol 93 (5) ◽

pp. 528-538 ◽

Cited By ~ 2

Author(s):

James MacFarlane ◽

Keat Cheah Seong ◽

Chad Bisambar ◽

Basetti Madhu ◽

Kieren Allinson ◽

...

Keyword(s):

Succinate Dehydrogenase ◽

Gene Mutations ◽

Dehydrogenase Gene ◽

Tumour Spectrum

Download Full-text

Succinate Dehydrogenase Gene Mutations in Cardiac Paragangliomas

The American Journal of Cardiology ◽

10.1016/j.amjcard.2015.03.020 ◽

2015 ◽

Vol 115 (12) ◽

pp. 1753-1759 ◽

Cited By ~ 15

Author(s):

Victoria L. Martucci ◽

Abbas Emaminia ◽

Jaydira del Rivero ◽

Ronald M. Lechan ◽

Bindiya T. Magoon ◽

...

Keyword(s):

Succinate Dehydrogenase ◽

Gene Mutations ◽

Dehydrogenase Gene

Download Full-text

Use of Steroidogenic Precursors for Evaluation of Adrenocortical Carcinoma in Adrenal Masses: A Case Series

Consultant ◽

10.25270/con.2020.10.00008 ◽

2020 ◽

Vol 60 ◽

Author(s):

Adnan Haider ◽

Nadia Barghouthi ◽

Jennifer Turner ◽

Vladimer Bakhutashvili

Keyword(s):

Adrenocortical Carcinoma ◽

Case Series ◽

Adrenal Masses

Download Full-text

Recurrent Cushing Syndrome Secondary to Metastatic Adrenocortical Carcinoma in a Patient With Previously Resected Adenoma

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.2011 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A983-A983

Author(s):

Noor Addasi ◽

Emily Christine Silverman ◽

Apar Ganti ◽

Anupam Kotwal

Keyword(s):

Cancer Progression ◽

Adrenocortical Carcinoma ◽

Cushing Syndrome ◽

Adrenal Adenoma ◽

Local Therapy ◽

Close Monitoring ◽

Liver Lesions ◽

Loss Of Function ◽

Late Night ◽

Recommended Treatment

Abstract Background: ACTH-independent causes of Cushing Syndrome (CS) have mostly benign etiologies. For the majority of these conditions, surgery is the recommended treatment and is nearly 100% curative. Current guidelines do not specify follow up imaging recommendations in patients with resected adenomas. We present a case of severe CS secondary to an adrenal adenoma that was completely resected, and presented later as a metastatic adrenocortical carcinoma (ACC). Clinical Case: A 34- year-old woman presented with worsening confusion, weight gain and new onset diabetes and hypertension. Her history was significant for a 7 cm left adrenal mass and ACTH- independent CS previously treated with left adrenalectomy 2 years prior to this presentation. She was following with an endocrinologist who weaned her hydrocortisone to 10-5 mg. She completed a successful pregnancy but had worsening depression. Her steroids were stopped on admission and evaluation showed hypokalemia [2.9 mmol/L (n 3.5-5.1)], hypercortisolemia [29.9 mcg/dL (n 6.7-22.6)], and ACTH <12 pg/mL (n<46). This was followed with 1 and 8 mg dexamethasone suppression tests that she failed with cortisol levels of 37.8 and 41.6 mcg/dL respectively, late-night salivary cortisol of 0.974 ug/dL (n <0.181), and extremely elevated 24-hr urinary cortisol of 3,700.2 ug/d (n<45). Of the steroid hormone precursors, 11 deoxycortisol was elevated at 725 ng/dL (n<32) and DHEA-S was 29mcg/dL (n 35-430). A CT scan revealed multiple liver lesions, and no residual nodularity in the left adrenalectomy bed. Liver lesions were PET-avid, and biopsy confirmed metastatic ACC. Due to the extensive hepatic involvement, she was not a candidate for local therapy. She was started on mitotane and metyrapone for CS. She was treated with doxorubicin, cisplatin and etoposide chemotherapy every 4 weeks. Due to insurance issues; metyrapone was replaced by mifepristone. Over 8 weeks, mitotane level became therapeutic at 20 mcg/mL, hepatic masses decreased in size, and she transitioned form CS to adrenal insufficiency (AI) with am cortisol of 3 mcg/dL with accompanying nausea and improved glycemic control without medication. Next generation sequencing studies of the liver biopsy specimen revealed a frameshift loss of function mutation in FH that encodes the protein fumarase (c.912_918del p.F305fs; variant allele fraction - 67.8%). Conclusion: Metastatic ACC presenting with life-threatening CS presents a diagnostic and management challenge. Combination therapy with mitotane and chemotherapy demonstrated benefit in our patient. The transition from severe CS to AI due to mitotane was challenging to monitor biochemically due to mifepristone use. Loss of function FH mutation is associated with cancer progression. Patients with resected large adrenal adenomas require close monitoring to identify malignant behavior.

Download Full-text

Atypical manifestation of adrenocortical carcinoma - case series

Endocrine Abstracts ◽

10.1530/endoabs.56.p113 ◽

2018 ◽

Author(s):

Karolina Nowak ◽

Agnieszka Lebek-Szatanska ◽

Radoslaw Samsel ◽

Andrzej Cichocki ◽

Katarzyna Roszkowska-Purska ◽

...

Keyword(s):

Adrenocortical Carcinoma ◽

Case Series ◽

Atypical Manifestation

Download Full-text

A Melanocortin-4 Receptor Agonist Induces Skin and Hair Pigmentation in Patients with Monogenic Mutations in the Leptin-Melanocortin Pathway

Skin Pharmacology and Physiology ◽

10.1159/000516282 ◽

2021 ◽

pp. 1-10

Author(s):

Varvara Kanti ◽

Lia Puder ◽

Irina Jahnke ◽

Philipp Maximilian Krabusch ◽

Jan Kottner ◽

...

Keyword(s):

Leptin Receptor ◽

Skin Pigmentation ◽

Gene Mutations ◽

Continuous Treatment ◽

Whole Body ◽

Hair Color ◽

Phase 2 ◽

Loss Of Function ◽

The Impact ◽

Over Time

Background and Objectives: Gene mutations within the leptin-melanocortin signaling pathway lead to severe early-onset obesity. Recently, a phase 2 trial evaluated new pharmacological treatment options with the MC4R agonist setmelanotide in patients with mutations in the genes encoding proopiomelanocortin (POMC) and leptin receptor (LEPR). During treatment with setmelanotide, changes in skin pigmentation were observed, probably due to off-target effects on the closely related melanocortin 1 receptor (MC1R). Here, we describe in detail the findings of dermatological examinations and measurements of skin pigmentation during this treatment over time and discuss the impact of these changes on patient safety. Methods: In an investigator-initiated, phase 2, open-label pilot study, 2 patients with loss-of-function POMC gene mutations and 3 patients with loss-of-function variants in LEPR were treated with the MC4R agonist setmelanotide. Dermatological examination, dermoscopy, whole body photographic documentation, and spectrophotometric measurements were performed at screening visit and approximately every 3 months during the course of the study. Results: We report the results of a maximum treatment duration of 46 months. Skin pigmentation increased in all treated patients, as confirmed by spectrophotometry. During continuous treatment, the current results indicate that elevated tanning intensity levels may stabilize over time. Lips and nevi also darkened. In red-haired study participants, hair color changed to brown after initiation of setmelanotide treatment. Discussion: Setmelanotide treatment leads to skin tanning and occasionally hair color darkening in both POMC- and LEPR-deficient patients. No malignant skin changes were observed in the patients of this study. However, the results highlight the importance of regular skin examinations before and during MC4R agonist treatment.

Download Full-text

NCMP-17. MISMATCH REPAIR MUTATIONS AND THE CENTRAL NERVOUS SYSTEM: A CASE SERIES OF GERMLINE MUTATIONS AND CNS MALIGNANCY

Neuro-Oncology ◽

10.1093/neuonc/noaa215.528 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii126-ii126

Author(s):

Amber Ruiz ◽

Jerome Graber

Keyword(s):

Treatment Response ◽

Mismatch Repair ◽

Case Series ◽

Germline Mutations ◽

Molecular Characteristics ◽

Loss Of Function ◽

Dna Mismatch ◽

Mutational Burden ◽

Increased Risk ◽

Tumor Mutational Burden

Abstract Our understanding of genetic predispositions for malignancy is continually evolving. One family of germline mutations well described in the literature is that of the DNA mismatch repair mechanism (MMR). Lynch syndrome (LS) is due to a loss of function mutation of several MMR genes- MSH2, MLH1, MSH6, and PMS2. Germline MMR mutations lead to microsatellite instability and loss of genomic integrity resulting in an increased risk for various cancers (colorectal, genitourinary, etc). LS may be as common as 1 in 400 people and some MMR mutations have been associated with gliomas. There is a paucity of information regarding frequency of glioma subtypes as well as tumor genetic and molecular characteristics which have important clinical implications. We describe a case series of 6 individuals with germline MMR mutations and brain tumors. Those with MSH2 and PMS2 mutations (n=3) developed glioblastomas at a mean age at diagnosis of 48 years. These tumors expressed MGMT hyper-methylation and high tumor mutational burden. Only one had IDH-1 mutation. Those with MLH1 mutations (n=3), did not develop gliomas. This raises the question of differential glioma subtype development based on MMR gene. It also highlights the possibility of Lynch-associated gliomas having more favorable treatment response due to MGMT methylation and potential response to immunotherapy based on high tumor mutational burden. Though the sample size is small, there appears to be a preponderance of women compared to men (5:1 respectively). Larger studies are needed to verify CNS involvement in germline MMR mutations. In doing so, we hope to identify factors that may influence clinical management and lead to a better understanding of treatment response and disease prognosis.

Download Full-text

Functional characterization of a loss-of-function mutant I324M of arginine vasopressin receptor 2 in X-linked nephrogenic diabetes insipidus

Scientific Reports ◽

10.1038/s41598-021-90736-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Lixia Wang ◽

Weihong Guo ◽

Chunyun Fang ◽

Wenli Feng ◽

Yumeng Huang ◽

...

Keyword(s):

Diabetes Insipidus ◽

Arginine Vasopressin ◽

Nephrogenic Diabetes Insipidus ◽

Functional Characterization ◽

Gene Mutations ◽

Biochemical Properties ◽

Vasopressin Receptor ◽

Inherited Disease ◽

Loss Of Function ◽

Gene Encoding

AbstractX-linked nephrogenic diabetes insipidus (X-linked NDI) is a rare inherited disease mainly caused by lost-of-function mutations in human AVPR2 gene encoding arginine vasopressin receptor 2 (V2R). Our focus of the current study is on exploration of the functional and biochemical properties of Ile324Met (I324M) mutation identified in a pedigree showing as typical recessive X-linked NDI. We demonstrated that I324M mutation interfered with the conformation of complex glycosylation of V2R. Moreover, almost all of the I324M-V2R failed to express on the cell surface due to being captured by the endoplasmic reticulum control system. We further examined the signaling activity of DDAVP-medicated cAMP and ERK1/2 pathways and the results revealed that the mutant receptor lost the ability in response to DDAVP stimulation contributed to the failure of accumulation of cAMP and phosphorylated ERK1/2. Based on the characteristics of molecular defects of I324M mutant, we selected two reagents (SR49059 and alvespimycin) to determine whether the functions of I324M-V2R can be restored and we found that both compounds can significantly “rescue” I324M mutation. Our findings may provide further insights for understanding the pathogenic mechanism of AVPR2 gene mutations and may offer some implications on development of promising treatments for patients with X-linked NDI.

Download Full-text

Atopic Dermatitis: Case Series of Individualized Homoeopathic Treatment

International Journal of Health Sciences and Research ◽

10.52403/ijhsr.20211114 ◽

2021 ◽

Vol 11 (11) ◽

pp. 115-123

Author(s):

Mousumi Das

Keyword(s):

Atopic Dermatitis ◽

Family History ◽

Case Series ◽

Calcineurin Inhibitors ◽

Loss Of Function ◽

Key Words Atopic Dermatitis ◽

Topical Calcineurin Inhibitors ◽

History Of ◽

Allergic Disorders ◽

Positive Results

Atopic dermatitis is a common, chronic, intensely pruritic, relapsing inflammatory skin disease that affects both children and adults. Atopic dermatitis is often the originating of a series of allergic disorders, mentioned as the "atopic march".There are numerous risk factors correlated with AD development. However, only two have always been related, and they are (1) family history of atopy and (2) loss of function mutations in the FLG gene. Topical anti-inflammatory therapy with topical corticosteroids or topical calcineurin inhibitors treatment are available in conventional therapy but sometimes it has been reported that patients are also benefited from Homoeopathic treatment. Four patients who presented at the outpatient department at National Institute of Homoeopathy, Saltlake, Kolkata with Atopic dermatitis and a family history of asthma, allergic rhinitis were treated with constitutional homoeopathic medicine. Details of consultations, treatment and assessment are summarized. A constitutional treatment thus eliminates the symptoms locally and internally as well as long-lasting relief from complaints. Common remedies include Mercuris Solubilis, Sulphur. This case series shows positive results of homoeopathy in the treatment of Atopic dermatitis. Key words: Atopic dermatitis, Family history, Individualized Homoeopathic treatment, Case series, repertorisation.

Download Full-text