scholarly journals Clinical and genetic heterogeneity of micronodular adrenal hyperplasia

2021 ◽  
Vol 15 (1) ◽  
pp. 27-35
Author(s):  
A. Chevais ◽  
D. G. Beltsevich ◽  
A. Yu. Abrosimov ◽  
D. A. Derkatch ◽  
A. A. Lazareva
Keyword(s):  
Cushing Syndrome ◽  
Gene Mutations ◽  
Carney Complex ◽  
Clinical Aspects ◽  
Adrenal Hyperplasia ◽  
Unilateral Adrenalectomy ◽  
Pathogenic Variants ◽  
Familial Form ◽  
Genes Encoding ◽  
Genetically Determined

Micronodular adrenal hyperplasia is a rare cause of ACTH-independent Cushing syndrome. It can be divided into two entities: primary pigmented nodular adrenocortical disease (PPNAD) and non-pigmented micronodular adrenocortical disease, among which familial and sporadic forms are distinguished. The most common is the genetically determined familial form PPNAD, as one of the components of Carney complex. The vast majority of patients have identifiable pathogenic variants in the PRKAR1A gene. In addition to the PRKAR1A gene mutations, inactivating mutations in the genes encoding phosphodiesterases (PDE11A4 and PDE8B), as well as PRKACA gene amplification, have been described in individuals with isolated forms. Despite the relative antiquity of the description of micronodular adrenal hyperplasia and the Carney comlex, a detailed study of pathophysiological mechanisms, genetic and clinical aspects of this pathology, nowadays, clinicians continue to face «atypical» cases. Thus, the nature of this disease is not well understood and requires further research. This review presents the accumulated data on micronodular adrenal hyperplasia, genetics aspects, and also describes 2 unique clinical cases of isolated PPNAD with unilateral adrenalectomy results.

scholarly journals Mifepristone Treatment in Four Cases of Primary Bilateral Macronodular Adrenal Hyperplasia (BMAH)

2019 ◽  
Vol 104 (12) ◽  
pp. 6279-6290 ◽  
Author(s):  
Pejman Cohan ◽  
Honey E East ◽  
Sandi-Jo Galati ◽  
Jennifer U Mercado ◽  
Precious J Lim ◽  
...  
Keyword(s):  
Treatment Duration ◽  
Cushing Syndrome ◽  
Signs And Symptoms ◽  
Response Assessment ◽  
Common Adverse Event ◽  
Adrenal Hyperplasia ◽  
Significant Weight Loss ◽  
Rare Form ◽  
Unilateral Adrenalectomy ◽  
Medical Practices

ContextPrimary bilateral macronodular adrenal hyperplasia (BMAH) is a rare form of adrenal Cushing syndrome conventionally treated with adrenalectomy. Medical treatment is often reserved for patients not eligible for surgery. However, to date there have been few studies about the efficacy of mifepristone for the treatment of BMAH associated with hypercortisolism.ObjectiveTo describe a series of patients with hypercortisolism due to BMAH treated with mifepristone from multiple medical practices.DesignWe retrospectively assessed four patients treated with mifepristone for hypercortisolism due to BMAH who had either failed unilateral adrenalectomy, declined surgery, or were poor surgical candidates.ResultsMifepristone induced clinical improvement and remission of the signs and symptoms of hypercortisolism in all described patients with BMAH. The median treatment duration at the time of efficacy response assessment was 5 months (range: 3 to 18 months). Improvement in cardiometabolic parameters was observed as early as 2 weeks after treatment was started. All patients achieved improvements in glycemic control and hypertension and had significant weight loss. The most common adverse event observed with mifepristone therapy was fatigue. Increases in TSH level occurred in two patients.ConclusionMifepristone can be an effective medical alternative to surgery in patients with hypercortisolism due to BMAH.

scholarly journals Cushing syndrome: uncovering Carney complex due to novel PRKAR1A mutation

2019 ◽  
Vol 2019 ◽  
Author(s):  
Catherine D Zhang ◽  
Pavel N Pichurin ◽  
Aleh Bobr ◽  
Melanie L Lyden ◽  
William F Young ◽  
...  
Keyword(s):  
Cushing Syndrome ◽  
Carney Complex ◽  
Pathogenic Variant ◽  
Endocrine Tumors ◽  
List Type ◽  
Pathogenic Variants ◽  
Adrenal Imaging ◽  
Unenhanced Computed Tomography ◽  
Learning Points ◽  
Tomography Scan

Summary Carney complex (CNC) is a rare multiple neoplasia syndrome characterized by spotty pigmentation of the skin and mucosa in association with various non-endocrine and endocrine tumors, including primary pigmented nodular adrenocortical disease (PPNAD). A 20-year-old woman was referred for suspected Cushing syndrome. She had signs of cortisol excess as well as skin lentigines on physical examination. Biochemical investigation was suggestive of corticotropin (ACTH)-independent Cushing syndrome. Unenhanced computed tomography scan of the abdomen did not reveal an obvious adrenal mass. She subsequently underwent bilateral laparoscopic adrenalectomy, and histopathology was consistent with PPNAD. Genetic testing revealed a novel frameshift pathogenic variant c.488delC/p.Thr163MetfsX2 (ClinVar Variation ID: 424516) in the PRKAR1A gene, consistent with clinical suspicion for CNC. Evaluation for other clinical features of the complex was unrevealing. We present a case of PPNAD-associated Cushing syndrome leading to the diagnosis of CNC due to a novel PRKAR1A pathogenic variant. Learning points: PPNAD should be considered in the differential for ACTH-independent Cushing syndrome, especially when adrenal imaging appears normal. The diagnosis of PPNAD should prompt screening for CNC. CNC is a rare multiple neoplasia syndrome caused by inactivating pathogenic variants in the PRKAR1A gene. Timely diagnosis of CNC and careful surveillance can help prevent potentially fatal complications of the disease.

scholarly journals Comprehensive Genetic Testing of CYP21A2: A Retrospective Analysis in Patients with Suspected Congenital Adrenal Hyperplasia

2021 ◽  
Vol 10 (6) ◽  
pp. 1183
Author(s):  
Madalina Nicoleta Nan ◽  
Rosa Roig ◽  
Susana Martínez ◽  
Jose Rives ◽  
Eulàlia Urgell ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Point Mutations ◽  
Gene Mutations ◽  
Pathogenic Variant ◽  
Adrenal Hyperplasia ◽  
Cyp21a2 Gene ◽  
Pathogenic Variants ◽  
New Variant ◽  
Allelic Distribution ◽  
Large Rearrangements

The most common form of congenital adrenal hyperplasia (CAH) results from a deficiency of the 21-hydroxylase enzyme (21-OHD), presenting with a broad spectrum of clinical phenotypes according to the CYP21A2 gene mutations. Of the 59 patients with suspected CAH, 62.7% presented a positive genetic result. Of them, 78.4% and 18.9% presented with non-classical and classical forms, respectively. An overall phenotype-genotype correlation of 88.9% was observed. Biochemically, 17-hydroxiprogesterone concentrations were significantly higher in genetically confirmed patients. Genetically, 36 patients presented with previously reported pathogenic variants, and one presented a new variant in homozygosis. Among the 74 alleles tested, point mutations were found in 89.2% and large rearrangements were found in the rest. The most prevalent pathogenic variant was p.(Val282Leu). The inclusion of relatives revealed one further case. Interestingly, 87.5% of relatives were carriers of a pathogenic variant, including two siblings initially classified as genetically positive. In addition, the study of male partners with gestational desire identified several carriers of mild mutations. Studying the allelic distribution of the variants also allowed for reclassifying one patient. In conclusion, a genetic approach including Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA) analysis, and allelic distribution of the pathogenic variants represents a beneficial tool for better classifying patients with 21-OHD.

scholarly journals Bilateral Adrenal Hyperplasia: Pathogenesis and Treatment

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1397
Author(s):  
Benjamin Chevalier ◽  
Marie-Christine Vantyghem ◽  
Stéphanie Espiard
Keyword(s):  
Carney Complex ◽  
Current Data ◽  
Adrenal Hyperplasia ◽  
Systematic Screening ◽  
Unilateral Adrenalectomy ◽  
Paracrine Regulation ◽  
Causal Genes ◽  
Bilateral Adrenal Hyperplasia ◽  
Pka Pathway

Bilateral adrenal hyperplasia is a rare cause of Cushing’s syndrome. Micronodular adrenal hyperplasia, including the primary pigmented micronodular adrenal dysplasia (PPNAD) and the isolated micronodular adrenal hyperplasia (iMAD), can be distinguished from the primary bilateral macronodular adrenal hyperplasia (PBMAH) according to the size of the nodules. They both lead to overt or subclinical CS. In the latter case, PPNAD is usually diagnosed after a systematic screening in patients presenting with Carney complex, while for PBMAH, the diagnosis is often incidental on imaging. Identification of causal genes and genetic counseling also help in the diagnoses. This review discusses the last decades’ findings on genetic and molecular causes of bilateral adrenal hyperplasia, including the several mechanisms altering the PKA pathway, the recent discovery of ARMC5, and the role of the adrenal paracrine regulation. Finally, the treatment of bilateral adrenal hyperplasia will be discussed, focusing on current data on unilateral adrenalectomy.

scholarly journals 17q22–24 Chromosomal Losses and Alterations of Protein Kinase A Subunit Expression and Activity in Adrenocorticotropin-Independent Macronodular Adrenal Hyperplasia

2006 ◽  
Vol 91 (9) ◽  
pp. 3626-3632 ◽  
Author(s):  
Isabelle Bourdeau ◽  
Ludmila Matyakhina ◽  
Sotirios G. Stergiopoulos ◽  
Fabiano Sandrini ◽  
Sosipatros Boikos ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Cushing Syndrome ◽  
Carney Complex ◽  
Chromosome 17 ◽  
Regulatory Subunit ◽  
Adrenal Tumors ◽  
Adrenal Hyperplasia ◽  
Subunit Expression ◽  
Kinase A

Abstract Context: Primary adrenocortical hyperplasias leading to Cushing syndrome include primary pigmented nodular adrenocortical disease and ACTH-independent macronodular adrenal hyperplasia (AIMAH). Inactivating mutations of the 17q22–24-located PRKAR1A gene, coding for the type 1A regulatory subunit of protein kinase A (PKA), cause primary pigmented nodular adrenocortical disease and the multiple endocrine neoplasia syndrome Carney complex. PRKAR1A mutations and 17q22–24 chromosomal losses have been found in sporadic adrenal tumors and are associated with aberrant PKA signaling. Objective: The objective of the study was to examine whether somatic 17q22–24 changes, PRKAR1A mutations, and/or PKA abnormalities are present in AIMAH. Patients: We studied fourteen patients with Cushing syndrome due to AIMAH. Methods: Fluorescent in situ hybridization with a PRKAR1A-specific probe was used for investigating chromosome 17 allelic losses. The PRKAR1A gene was sequenced in all samples, and tissue was studied for PKA activity, cAMP responsiveness, and PKA subunit expression. Results: We found 17q22–24 allelic losses in 73% of the samples. There were no PRKAR1A-coding sequence mutations. The RIIβ PKA subunit was overexpressed by mRNA, whereas the RIα, RIβ, RIIα, and Cα PKA subunits were underexpressed. These findings were confirmed by immunohistochemistry. Total PKA activity and free PKA activity were higher in AIMAH than normal adrenal glands, consistent with the up-regulation of the RIIβ PKA subunit. Conclusions: PRKAR1A mutations are not found in AIMAH. Somatic losses of the 17q22–24 region and PKA subunit and enzymatic activity changes show that PKA signaling is altered in AIMAH in a way that is similar to that of other adrenal tumors with 17q losses or PRKAR1A mutations.

Three-Quarters Adrenalectomy for Infantile-Onset Cushing Syndrome due to Bilateral Adrenal Hyperplasia in McCune-Albright Syndrome

2017 ◽  
Vol 88 (3-4) ◽  
pp. 285-290 ◽  
Author(s):  
Tomoyo Itonaga ◽  
Hironori Goto ◽  
Manabu Toujigamori ◽  
Yasuharu Ohno ◽  
Seigo Korematsu ◽  
...  
Keyword(s):  
Cushing Syndrome ◽  
Adrenal Crisis ◽  
Adrenal Hyperplasia ◽  
Unilateral Adrenalectomy ◽  
Mccune Albright Syndrome ◽  
Total Adrenalectomy ◽  
Bilateral Adrenal Hyperplasia ◽  
New Treatment ◽  
Albright Syndrome ◽  
Mccune Albright

Background: Bilateral adrenalectomy is performed in cases with infantile-onset Cushing syndrome due to bilateral adrenal hyperplasia in McCune-Albright syndrome (MAS) because severe Cushing syndrome with heart failure and liver dysfunction can have a lethal outcome. This procedure can completely ameliorate hypercortisolism, although lifetime steroid replacement therapy and steps to prevent adrenal crisis are necessary. Recently, the efficacy of unilateral adrenalectomy has been reported in adult cases of bilateral macronodular adrenal hyperplasia, but there is no consensus regarding the appropriate surgical treatment for bilateral adrenal hyperplasia in MAS. Objective: A 6-month-old girl presented with café-au-lait spots, short stature, central obesity, a moon face, and hypertension. Endocrinological tests and imaging studies led to the diagnosis of ACTH-independent Cushing syndrome due to bilateral adrenal hyperplasia induced by MAS. “Three-quarters adrenalectomy”, namely right-sided total adrenalectomy and left-sided half adrenalectomy, was carried out. An activating mutation of the GNAS1 gene (p.Arg201Cys) was identified in the adrenal tissues. Since the operation, our patient has been in a state of clinical remission for more than 2 years. Conclusion: Our original surgical intervention, three-quarters adrenalectomy, may be a new treatment option for Cushing syndrome associated with MAS.

Arrhythmogenic right ventricular cardiomyopathy: genetics

ESC CardioMed ◽  
2018 ◽  
pp. 1490-1495
Author(s):  
Petros Syrris ◽  
Alexandros Protonotarios
Keyword(s):  
Clinical Practice ◽  
Right Ventricular ◽  
Arrhythmogenic Right Ventricular Cardiomyopathy ◽  
Gene Mutations ◽  
Ventricular Cardiomyopathy ◽  
Pathogenic Variants ◽  
Gene Testing ◽  
Genes Encoding ◽  
Classic Form ◽  
Aids Diagnosis

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disorder of the heart muscle which is typically inherited in an autosomal dominant manner. It is believed to be familial in over 50% of cases. A recessive mode of inheritance has also been reported in syndromic cases with cardiocutaneous features. The classic form of the disorder is considered to be ‘a disease of the desmosome’ as pathogenic variants have been identified in five genes encoding key desmosomal proteins: plakoglobin, desmoplakin, plakophilin-2, desmoglein-2, and desmocollin-2. Mutations in these genes account for 30–50% of ARVC cases. A further eight non-desmosomal genes have also been implicated in the pathogenesis of the disorder but only account for rare cases. Studies of patients with ARVC-associated gene mutations have revealed marked genetic heterogeneity and very limited genotype–phenotype correlation. Disease expression often varies significantly amongst individuals carrying the same mutation. It has been proposed that the presence of more than one sequence variant is required to determine overt clinical disease and patients with multiple variants have a more severe phenotype compared to single variant carriers. Identification of a potentially pathogenic variant comprises a major criterion in the diagnosis of ARVC but informative integration of genetic testing into clinical practice remains challenging. Gene testing should be used to identify asymptomatic family members at risk and only aids diagnosis in cases of high suspicion for ARVC, along with other evident features of the disease already present. However, genetic findings should be used with caution in clinical practice and their interpretation must be performed in expert centres.

scholarly journals Cushing Syndrome in Carney Complex: Unilateral or Bilateral Adrenalectomy?

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A125-A125
Author(s):  
Géraldine Vitellius ◽  
Bruno Donadille ◽  
Bénédicte Decoudier ◽  
Sophie Deguelte ◽  
Jérôme Bertherat ◽  
...  
Keyword(s):  
Index Case ◽  
Cushing Syndrome ◽  
Carney Complex ◽  
Bilateral Adrenalectomy ◽  
Moderate Increase ◽  
Unilateral Adrenalectomy ◽  
Recommended Treatment ◽  
Post Surgery ◽  
Long Term Study ◽  
Low Cortisol

Abstract Carney Complex (CNC) is a rare multiple endocrine syndrome dueto PRKR1A germline mutations. Primary pigmented nodular adrenal disease (PPNAD), the most frequent manifestation of the disease is responsible for non-ACTH dependent Cushing syndrome and bilateral adrenalectomy is the recommended treatment. We had followed up a CNC family with mainly Cushing syndrome disease secondary to PPNAD for more than 40 years over 2 generations. Six members carry the disease and present a germline mutation of PRKR1A, 4 women and 2 men. One patient accidently died one year after surgery and the others 5 patients were regularly followed up. The index case, a 25 years woman, was diagnosed with Cushing syndrome in 1972 with hyperandrogenism, short stature and mild manifestations of hypercortisolism. Unilateral adrenalectomy was performed on the side of a nodular adrenal and pathology described PPNAD. Her sister was subsequently diagnosed and treated the same way. The 2 sisters did well, with pregnancies for both of them but different post surgery hormonal results. The index case had partial cortisol deficiency with persistent low cortisol level at 108 nmol/L. Her sister presented a moderate increase in cortisol in the evening or after dexamethasone at 306 nmol/L at last evaluation. The only events possibly associated to hypercortisolism in this patient were central overweight and three episodes of spontaneous pulmonary embolism and veinous thrombosis. Their 2 brothers were evaluated at 17 and 39 years while they developed cushing syndrome signs (round face, HTA, amyotrophy and fatigability). As CNC have been recognized at this time by Dr Carney, bilateral adrenalectomy was performed in one patient who died accidentally a few months later. His brother chose unilateral adrenalectomy on the side of the macronodular gland, recovered hypercortisolism signs and still needs adrenal substitution. The daughter of the index case demonstrated at 21 years old a mild Cushing syndrome and chose unilateral adrenalectomy like her mother. Symptoms resumed without any recurrence during 20 years follow up. The daughter of the patient II.2 was diagnosed earlier at seven years of age because she developed hyperandrogenism, central weight gain and growth arrest due to Cushing syndrome. Bilateral adrenalectomy was successfully performed and adrenal substitution was prescribed. Surprisingly, adrenal function seemed to recover 5 to 6 years post surgery and treatment was decreased then stopped. Adrenal CT scan did not show any residual gland but noriodocholesterol scintigraphy confirmed bilateral adrenal uptake. She is now mother of 2 and present a near normal cortisol circadian rythm without any treatment. Finally, we showed in this long-term study that unilateral adrenalectomy in PPNAD could be an option for the treatment of mild Cushing syndrome in adults. Recovery after bilateral adrenalectomy occurred in one patient.

Arrhythmogenic right ventricular cardiomyopathy: genetics

2018 ◽  
Author(s):  
Petros Syrris ◽  
Alexandros Protonotarios
Keyword(s):  
Clinical Practice ◽  
Right Ventricular ◽  
Arrhythmogenic Right Ventricular Cardiomyopathy ◽  
Gene Mutations ◽  
Sequence Variant ◽  
Ventricular Cardiomyopathy ◽  
Pathogenic Variants ◽  
Gene Testing ◽  
Genes Encoding ◽  
Classic Form

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disorder of the heart muscle which is typically inherited in an autosomal dominant manner. It is believed to be familial in over 50% of cases. A recessive mode of inheritance has also been reported in syndromic cases with cardiocutaneous features. The classic form of the disorder is considered to be ‘a disease of the desmosome’ as pathogenic variants have been identified in five genes encoding key desmosomal proteins: plakoglobin, desmoplakin, plakophilin-2, desmoglein-2, and desmocollin-2. Mutations in these genes account for 30–50% of ARVC cases. A further eight non-desmosomal genes have also been implicated in the pathogenesis of the disorder but only account for rare cases. Studies of patients with ARVC-associated gene mutations have revealed marked genetic heterogeneity and very limited genotype–phenotype correlation. Disease expression often varies significantly amongst individuals carrying the same mutation. It has been proposed that the presence of more than one sequence variant is required to determine overt clinical disease and patients with multiple variants have a more severe phenotype compared to single variant carriers. Identification of a potentially pathogenic variant comprises a major criterion in the diagnosis of ARVC but informative integration of genetic testing into clinical practice remains challenging. Gene testing should be used to identify asymptomatic family members at risk and only aids diagnosis in cases of high suspicion for ARVC, along with other evident features of the disease already present. However, genetic findings should be used with caution in clinical practice and their interpretation must be performed in expert centres.

Sign in / Sign up

Export Citation Format

Share Document