A rare case of familial Cushing’s syndrome with a common presentation of weight gain due to a mutation of the PRKAR1A gene causing isolated primary pigmented nodular adrenocortical disease

Poukoulidou, Thekla; Maiter, Dominique; Bertherat, Jérôme; Beauloye, Véronique

doi:10.1515/jpem-2014-0018

Cited by 6 publications

(7 citation statements)

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“…While the best first-line screening test for CS is the UFC excretion, this test may not always be consistent in PPNAD and several measurements are often necessary. The loss of normal circadian rhythm of cortisol secretion is a reliable finding [2, 3, 19]. Tirosh et al [20] recently compared AM/PM ratios of plasmatic cortisol levels in 105 patients with confirmed CS from different endogenous causes (Cushing disease and ACTH-independent CS) in order to analyze its utility to establish the etiology.…”

Section: Discussionmentioning

confidence: 99%

“…CNC is associated with inactivating germline mutations of the PRKAR1A gene, coding for the regulatory subunit R1A of the PKA and located on 17q22.2–24.3 [3, 4, 11-13]. PKA is the main mediator of the effects of cAMP in the eukaryotic cells.…”

Section: Discussionmentioning

confidence: 99%

“…The clinical presentation in children is often insidious. Weight gain – the most common presenting symptom – concomitant with growth arrest are the hallmarks of CS in childhood [1-3]. Other manifestations include headaches, purple striae, acanthosis nigricans, facial plethora, hypertension, delayed pubertal development, hirsutism, and other signs of virilization.…”

Section: Introductionmentioning

confidence: 99%

“…PPNAD is a rare genetic disease that may be isolated (12% of cases) but mostly associated with myxomas, lentigines, and multiple endocrine gland disorders, integrating an autosomal dominant disorder known as the Carney complex (CNC), caused by germline mutations of the regulatory subunit type 1A (RIα) of cAMP-dependent protein kinase ( PRKAR1A ) gene [1, 3, 6, 7]. The mutation detection rate was 41% in the CNC phenotype [8] and up to 82% for patients with PPNAD [9, 10].…”

Section: Introductionmentioning

confidence: 99%

“…Hypercortisolism may be cyclic, with sudden large excretion periods followed by spontaneous regression. Therefore, the urinary free cortisol (UFC) is usually increased but may be variable [3, 14]. Moreover, patients with PPNAD may have a paradoxical rise of cortisol in response to high-dose dexamethasone suppression test [1, 12, 14, 15].…”

Section: Introductionmentioning

confidence: 99%

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Familial Forms of Cushing Syndrome in Primary Pigmented Nodular Adrenocortical Disease Presenting with Short Stature and Insidious Symptoms: A Clinical Series

et al. 2018

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Cushing syndrome (CS) is a rare disease in children, frequently associated with subtle or periodic symptoms that may delay its diagnosis. Weight gain and growth failure, the hallmarks of hypercortisolism in pediatrics, may be inconsistent, especially in ACTH-independent forms of CS. Primary pigmented nodular adrenocortical disease (PPNAD) is the rarest form of ACTH-independent CS, and can be associated with endocrine and nonendocrine tumors, forming the Carney complex (CNC). Recently, phenotype/genotype correlations have been described with particular forms of CNC where PPNAD is isolated or associated only with skin lesions. We present four familial series of CS due to isolated PPNAD, and compare them to available data from the literature. We discuss the clinical and molecular findings, and underline challenges in diagnosing PPNAD in childhood.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Familial Forms of Cushing Syndrome in Primary Pigmented Nodular Adrenocortical Disease Presenting with Short Stature and Insidious Symptoms: A Clinical Series

et al. 2018

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Syndromes associated with abnormalities in the adrenal cortex

Chen¹,

Hunt²

2017

Diagnostic Histopathology

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Protein Kinase A Alterations in Adrenocortical Tumors

2014

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Stimulation of the cAMP pathway by adrenocorticotropin (ACTH) is essential for adrenal cortex maintenance, glucocorticoid and adrenal androgens synthesis, and secretion. Various molecular and cellular alterations of the cAMP pathway have been observed in endocrine tumors. Protein kinase A (PKA) is a central key component of the cAMP pathway. Molecular alterations of PKA subunits have been observed in adrenocortical tumors. PKA molecular defects can be germline in hereditary disorders or somatic in sporadic tumors. Heterozygous germline inactivating mutations of the PKA regulatory subunit RIα gene (PRKAR1A) can be observed in patients with ACTH-independent Cushing's syndrome (CS) due to primary pigmented nodular adrenocortical disease (PPNAD). PRKAR1A is considered as a tumor suppressor gene. Interestingly, these mutations can also be observed as somatic alterations in sporadic cortisol-secreting adrenocortical adenomas. Germline gene duplication of the catalytic subunits Cα (PRKACA) has been observed in patients with PPNAD. Furthermore, exome sequencing revealed recently activating somatic mutations of PRKACA in about 40% of cortisol-secreting adrenocortical adenomas. In vitro and in vivo functional studies help in the progress to understand the mechanisms of adrenocortical tumors development due to PKA regulatory subunits alterations. All these alterations are observed in benign oversecreting tumors and are mimicking in some way cAMP pathway constitutive activation. On the long term, unraveling these alterations will open new strategies of pharmacological treatment targeting the cAMP pathway in adrenal tumors and cortisol-secretion disorders.

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A rare case of familial Cushing’s syndrome with a common presentation of weight gain due to a mutation of the PRKAR1A gene causing isolated primary pigmented nodular adrenocortical disease

Abstract: It is exceptional for PPNAD to be an isolated phenomenon as well as being revealed by progressive weight gain in adolescence.

Cited by 6 publications

References 4 publications

Familial Forms of Cushing Syndrome in Primary Pigmented Nodular Adrenocortical Disease Presenting with Short Stature and Insidious Symptoms: A Clinical Series

Familial Forms of Cushing Syndrome in Primary Pigmented Nodular Adrenocortical Disease Presenting with Short Stature and Insidious Symptoms: A Clinical Series

Syndromes associated with abnormalities in the adrenal cortex

Protein Kinase A Alterations in Adrenocortical Tumors

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