Primary pigmented nodular adrenocortical disease

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Primary pigmented nodular adrenocortical disease
Other namesPPNAD
PPNAD2.jpg
Macroscopic appearance of adrenal gland in PPNAD following adrenalectomy

Primary pigmented nodular adrenocortical disease (PPNAD) was first coined in 1984 by Carney et al. It often occurs in association with Carney complex (CNC). CNC is a rare syndrome that involves the formation of abnormal tumours that cause endocrine hyperactivity.

Contents

PPNAD arises due to the enlargement of the cortex of the adrenal glands, resulting in Cushing's syndrome that is independent of the pituitary hormone ACTH. [1]

Signs and symptoms

Diagram of Cushing's symptoms Cushing's syndrome (vector image).svg
Diagram of Cushing's symptoms
Picture of lentigines associated with Carney Complex LEOPARD Synd5.jpg
Picture of lentigines associated with Carney Complex

PPNAD is a rare cause of high cortisol levels in the blood and often manifests as ACTH-independent Cushing's syndrome. [2] [3] The effects of PPNAD can often be cyclical so the symptoms of Cushing's syndrome will not always be as severe, which may complicate diagnosis. [4] The classic symptoms of Cushing's syndrome include rapid central weight gain, a puffy red face and a buffalo hump at the back of the neck due to fat deposits. Skin changes in Cushing's syndrome include thinning and bruising easily, developing striae and hyperpigmentation at skin folds. The hormonal changes can lead to hirsutism, males developing breast tissue, females no longer having periods and both sexes may become infertile. High cortisol levels can lead to psychological disturbances such as anxiety or depression and insomnia. Bone health can deteriorate, leading to an increased fracture risk in people with Cushing's syndrome. [5] PPNAD is unique as it often causes Cushing's at a young age, in children and adolescents. [3] In addition to the other symptoms of Cushing's syndrome, the patient may have a short stature due to interrupted growth because of ACTH suppression. [5]

In 90% of people with PPNAD it is associated with Carney Complex.[ citation needed ] Carney Complex is usually inherited, however it can also occur sporadically. [6] A visible sign of Carney complex is abnormal skin hyperpigmentation. There may also be myxomas which can appear as lumps in the skin and breast as well as often being present in the heart, which can lead to multiple cardiovascular problems. [7] The majority of people with PPNAD will have some of these signs/symptoms due to the strong association between PPNAD and Carney Complex.[ citation needed ]

Causes

PPNAD, the endocrine manifestation that comes from Carney Complex (CNC), can be syndromic or isolated. The main cause of isolated PPNAD is a mutation of PRKAR1α, located at 17q22-24, which is the gene encoding the regulatory R1α subunit of protein kinase A. Germline heterozygous PRKAR1α inactivation mutations are present in 80% of CNC patients affected by Cushing's syndrome. [8] There are over 117 mutations of the PRKAR1α gene that can cause CNC, with many of these mutations producing premature stop codons, thus resulting in the complete loss of PRKAR1α protein. CNC patients have also been discovered with an unusually shortened PRKAR1α protein, detected in tumours and leukocytes, following a splice-site mutation, which causes exon-6 skipping. [9] Therefore, both haploinsufficiency and the complete loss of PRKAR1α can lead to the increased PKA activity observed in PPNAD patients, due to the disruption of the cAMP signalling pathway.[ citation needed ]

Sahut-Barnola et al. used a mouse model to cre-lox knockout the Prkar1a gene specifically from cells of the adrenal cortex and observed that the mice subsequently developed Cushing syndrome that is independent of the pituitary. They also observed that the mutation caused increased PKA activity.[ citation needed ]

The R1α loss caused the adult adrenal gland became hyperactive and hyperplastic on both sides, as seemingly the foetal adrenal cells within it were not maintained and thus expanded. This established tumoral growths. This mouse KO model phenocopies what happens in human cases of PPNAD. [10]

Inactivation of PDE11A4, located at 2q31-5, has also been identified in PPNAD patients without PRKAR1α mutations. PDE11A4 is the gene encoding phosphodiesterase 11A4, another participant of the cAMP signalling pathway. [11]

Diagnosis

Diagnosis usually occurs upon investigation of a cause for already suspected Cushing's syndrome. High levels of cortisol observed in patients with PPNAD are not suppressed upon administration of dexamethasone (dexamethasone suppression test), and upon MRI or CT imaging, the pituitary will show no abnormalities. Measuring ACTH will confirm that the cause of the patients Cushing's syndrome is ACTH independent. The nature of Cushing's syndrome itself is periodic, which can make diagnosing PPNAD increasingly difficult. [12]

Diagnosis of PPNAD can be difficult to determine preoperatively as CT scan findings can be variable i.e. appear normal or suggest unilateral adrenal lesions therefore impeding the correct diagnosis. NP-59 scintigraphy may be particularly useful in identifying the bilateral nature of the disease. [13]

Gene studies are not necessary for diagnosis as there are clear gross and histological diagnostic markers, as the nodules can usually be seen clearly in both cases A positive family history of PPNAD has been shown to be associated with abnormal histological findings, e.g. mitotic figures, which may further hinder diagnosis. At the point where abdominal CT scanning and pituitary fossa MRI show no clear abnormalities, adrenalectomy may be performed. [12]

Treatment

After diagnosis, it is important for patients to be continually monitored. The most common treatment for PPNAD is bilateral laparoscopic adrenalectomy; the process by which both adrenal glands are removed by a small incision. [2] Patients who have received this treatment will be prescribed mineralocorticoid and glucocorticoid steroids as they are no longer being naturally produced. [14] This is a treatment which has been used and refined since 1984. [15]

Related Research Articles

<span class="mw-page-title-main">Adrenocorticotropic hormone</span> Pituitary hormone

Adrenocorticotropic hormone is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important component of the hypothalamic-pituitary-adrenal axis and is often produced in response to biological stress. Its principal effects are increased production and release of cortisol and androgens by the zona fasiculata and zona reticularis, respectively. ACTH is also related to the circadian rhythm in many organisms.

<span class="mw-page-title-main">Cushing's syndrome</span> Symptoms from excessive exposure to glucocorticoids such as cortisol

Cushing's syndrome is a collection of signs and symptoms due to prolonged exposure to glucocorticoids such as cortisol. Signs and symptoms may include high blood pressure, abdominal obesity but with thin arms and legs, reddish stretch marks, a round red face due to facial plethora, a fat lump between the shoulders, weak muscles, weak bones, acne, and fragile skin that heals poorly. Women may have more hair and irregular menstruation or loss of menses, with the exact mechanisms of why still unknown. Occasionally there may be changes in mood, headaches, and a chronic feeling of tiredness.

Cushing's disease is one cause of Cushing's syndrome characterised by increased secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary. This is most often as a result of a pituitary adenoma or due to excess production of hypothalamus CRH that stimulates the synthesis of cortisol by the adrenal glands. Pituitary adenomas are responsible for 80% of endogenous Cushing's syndrome, when excluding Cushing's syndrome from exogenously administered corticosteroids. The equine version of this disease is Pituitary pars intermedia dysfunction.

<span class="mw-page-title-main">Adrenal insufficiency</span> Insufficient production of steroid hormones by the adrenal glands

Adrenal insufficiency is a condition in which the adrenal glands do not produce adequate amounts of steroid hormones. The adrenal glands—also referred to as the adrenal cortex—normally secrete glucocorticoids, mineralocorticoids, and androgens. These hormones are important in regulating blood pressure, electrolytes, and metabolism as a whole. Deficiency of these hormones leads to symptoms ranging from abdominal pain, vomiting, muscle weakness and fatigue, low blood pressure, depression, mood and personality changes to organ failure and shock. Adrenal crisis may occur if a person having adrenal insufficiency experiences stresses, such as an accident, injury, surgery, or severe infection; this is a life-threatening medical condition resulting from severe deficiency of cortisol in the body. Death may quickly follow.

Corticotropic cells, are basophilic cells in the anterior pituitary that produce pro-opiomelanocortin (POMC) which undergoes cleavage to adrenocorticotropin (ACTH), β-lipotropin (β-LPH), and melanocyte-stimulating hormone (MSH). These cells are stimulated by corticotropin releasing hormone (CRH) and make up 15–20% of the cells in the anterior pituitary. The release of ACTH from the corticotropic cells is controlled by CRH, which is formed in the cell bodies of parvocellular neurosecretory cells within the paraventricular nucleus of the hypothalamus and passes to the corticotropes in the anterior pituitary via the hypophyseal portal system. Adrenocorticotropin hormone stimulates the adrenal cortex to release glucocorticoids and plays an important role in the stress response.

<span class="mw-page-title-main">Hypopituitarism</span> Medical condition

Hypopituitarism is the decreased (hypo) secretion of one or more of the eight hormones normally produced by the pituitary gland at the base of the brain. If there is decreased secretion of one specific pituitary hormone, the condition is known as selective hypopituitarism. If there is decreased secretion of most or all pituitary hormones, the term panhypopituitarism is used.

<span class="mw-page-title-main">Metyrapone</span> Chemical compound

Metyrapone, sold under the brand name Metopirone, is a medication which is used in the diagnosis of adrenal insufficiency and occasionally in the treatment of Cushing's syndrome (hypercortisolism). It is part of the steroidogenesis inhibitor class of drugs.

<span class="mw-page-title-main">Pituitary adenoma</span> Tumor of the pituitary gland

Pituitary adenomas are tumors that occur in the pituitary gland. Most pituitary tumors are benign, approximately 35% are invasive and just 0.1% to 0.2% are carcinomas. Pituitary adenomas represent from 10% to 25% of all intracranial neoplasms, with an estimated prevalence rate in the general population of approximately 17%.

<span class="mw-page-title-main">Adrenocortical carcinoma</span> Cancer of the adrenal cortex

Adrenocortical carcinoma (ACC) is an aggressive cancer originating in the cortex of the adrenal gland.

Nelson's syndrome is a disorder that occurs in about one in four patients who have had both adrenal glands removed to treat Cushing's disease. In patients with pre-existing adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas, loss of adrenal feedback following bilateral adrenalectomy can trigger the rapid growth of the tumor, leading to visual symptoms and hyperpigmentation. The severity of the disease is dependent upon the effect of ACTH release on the skin, pituitary hormone loss from mass compression, as well as invasion into surrounding structures around the pituitary gland.

<span class="mw-page-title-main">Adrenocorticotropic hormone deficiency</span> Medical condition

Adrenocorticotropic hormone deficiency is a rare disorder characterized by secondary adrenal insufficiency with minimal or no cortisol production and normal pituitary hormone secretion apart from ACTH. ACTH deficiency may be congenital or acquired, and its symptoms are clinically similar to those of glucocorticoid deficiency. Symptoms consist of weight loss, diminished appetite, muscle weakness, nausea, vomiting, and hypotension. Low blood sugar and hyponatremia are possible; however, blood potassium levels typically remain normal because affected patients are deficient in glucocorticoids rather than mineralocorticoids because of their intact renin-angiotensin-aldosterone system. ACTH may be undetectable in blood tests, and cortisol is abnormally low. Glucocorticoid replacement therapy is required. With the exception of stressful situations, some patients with mild or nearly asymptomatic disease may not require glucocorticoid replacement therapy. As of 2008 about two hundred cases have been described in the literature.

<span class="mw-page-title-main">Carney complex</span> Medical condition

Carney complex and its subsets LAMB syndrome and NAME syndrome are autosomal dominant conditions comprising myxomas of the heart and skin, hyperpigmentation of the skin (lentiginosis), and endocrine overactivity. It is distinct from Carney's triad. Approximately 7% of all cardiac myxomas are associated with Carney complex.

Pseudo-Cushing's syndrome or non-neoplastic hypercortisolism is a medical condition in which patients display the signs, symptoms, and abnormal cortisol levels seen in Cushing's syndrome. However, pseudo-Cushing's syndrome is not caused by a problem with the hypothalamic-pituitary-adrenal axis as Cushing's is; it is mainly an idiopathic condition, however a cushingoid appearance is sometimes linked to excessive alcohol consumption. Elevated levels of total cortisol can also be due to estrogen found in oral contraceptive pills that contain a mixture of estrogen and progesterone. Estrogen can cause an increase of cortisol-binding globulin and thereby cause the total cortisol level to be elevated.

<span class="mw-page-title-main">Adrenocortical adenoma</span> Benign tumor of the adrenal gland

An adrenocortical adenoma or adrenal adenoma is commonly described as a benign neoplasm emerging from the cells that comprise the adrenal cortex. Like most adenomas, the adrenocortical adenoma is considered a benign tumor since the majority of them are non-functioning and asymptomatic. Adrenocortical adenomas are classified as ACTH-independent disorders, and are commonly associated with conditions linked to hyperadrenalism such as Cushing's syndrome (hypercortisolism) or Conn's syndrome (hyperaldosteronism), which is also known as primary aldosteronism. In addition, recent case reports further support the affiliation of adrenocortical adenomas with hyperandrogenism or florid hyperandrogenism which can cause hyperandrogenic hirsutism in females. "Cushing's syndrome" differs from the "Cushing's disease" even though both conditions are induced by hypercortisolism. The term "Cushing's disease" refers specifically to "secondary hypercortisolism" classified as "ACTH-dependent Cushing's syndrome" caused by pituitary adenomas. In contrast, "Cushing's syndrome" refers specifically to "primary hypercortisolism" classified as "ACTH-independent Cushing's syndrome" caused by adrenocortical adenomas.

The ACTH test is a medical test usually requested and interpreted by endocrinologists to assess the functioning of the adrenal glands' stress response by measuring the adrenal response to adrenocorticotropic hormone or another corticotropic agent such as tetracosactide or alsactide (Synchrodyn). ACTH is a hormone produced in the anterior pituitary gland that stimulates the adrenal glands to release cortisol, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and aldosterone.

Hypoadrenocorticism in dogs, or, as it is known in people, Addison's disease, is an endocrine system disorder that occurs when the adrenal glands fail to produce enough hormones for normal function. The adrenal glands secrete glucocorticoids such as cortisol and mineralocorticoids such as aldosterone; when proper amounts of these are not produced, the metabolic and electrolyte balance is upset. Mineralocorticoids control the amount of potassium, sodium, and water in the body. Hypoadrenocorticism is fatal if left untreated.

<span class="mw-page-title-main">Adrenal gland disorder</span> Medical condition

Adrenal gland disorders are conditions that interfere with the normal functioning of the adrenal glands. Your body produces too much or too little of one or more hormones when you have an adrenal gland dysfunction. The type of issue you have and the degree to which it affects your body's hormone levels determine the symptoms.

<span class="mw-page-title-main">Carney triad</span> Multiple neoplasia syndrome

Carney triad (CT) is characterized by the coexistence of three types of neoplasms, mainly in young women, including gastric gastrointestinal stromal tumor, pulmonary chondroma, and extra-adrenal paraganglioma. The underlying genetic defect remains elusive. CT is distinct from Carney complex and Carney-Stratakis syndrome.

Inferior petrosal sinus sampling, is a diagnostic medical procedure used to determine whether excess adrenocorticotropic hormone (ACTH) is coming from the pituitary gland or from a source outside the pituitary. The procedure is usually reserved for patients with consistent ACTH-dependent Cushing's syndrome without a clear cut lesion on pituitary MRI.

<span class="mw-page-title-main">Adrenalism</span>

Adrenalism describes the condition of an excessive or substandard secretion of hormones related to the adrenal glands, which are found directly superior to the kidneys. Adrenalism can be further distinguished as hyperadrenalism, referring to the excessive secretion of hormones, and hypoadrenalism, referring to the insufficient secretion of hormones.

References

  1. ↑ Larsen, Jennifer L; Cathey, W.J; Odell, William D (1986). "Primary adrenocortical nodular dysplasia, a distinct subtype of cushing's syndrome. Case report and review of the literature". The American Journal of Medicine. 80 (5): 976–84. doi:10.1016/0002-9343(86)90648-0. PMID   3010718.
  2. 1 2 Choi, Kyung Mook; Seu, Jae Hong; Kim, Yong Hyun; Lee, Eun Jong; Kim, Sang Jin; Baik, Sei Hyun; Choi, Dong Seop (1995). "Cushing's Syndrome Due to Primary Pigmented Nodular Adrenocortical Disease - A Case Report Reviews of the Literature-". The Korean Journal of Internal Medicine. 10 (1): 68–72. doi:10.3904/kjim.1995.10.1.68. PMC   4532033 . PMID   7626560.
  3. 1 2 Courcoutsakis, Nikos; Prassopoulos, Panos; Stratakis, Constantine A (2010). "CT Findings of Primary Pigmented Nodular Adrenocortical Disease: Rare Cause of ACTH-Independent Cushing Syndrome". American Journal of Roentgenology. 194 (6): W541. doi:10.2214/AJR.09.4056. PMID   20489078.
  4. ↑ Stratakis, Constantine A; Kirschner, Lawrence S; Carney, J. Aidan (2001). "Clinical and Molecular Features of the Carney Complex: Diagnostic Criteria and Recommendations for Patient Evaluation". The Journal of Clinical Endocrinology & Metabolism. 86 (9): 4041–6. doi: 10.1210/jcem.86.9.7903 . PMID   11549623.
  5. 1 2 Wagner-Bartak, Nicolaus A; Baiomy, Ali; Habra, Mouhammed Amir; Mukhi, Shalini V; Morani, Ajaykumar C; Korivi, Brinda R; Waguespack, Steven G; Elsayes, Khaled M (2017). "Cushing Syndrome: Diagnostic Workup and Imaging Features, with Clinical and Pathologic Correlation". American Journal of Roentgenology. 209 (1): 19–32. doi:10.2214/AJR.16.17290. PMID   28639924.
  6. ↑ Stratakis, Constantine A; Kirschner, Lawrence S; Carney, J. Aidan; Pack, Svetlana D; Taymans, Susan E; Giatzakis, Christoforos; Cho, Yee Sook; Cho-Chung, Yoon S (2000). "Mutations of the gene encoding the protein kinase a type I-alpha regulatory subunit in patients with the Carney complex". Nature Genetics. 26 (1): 89–92. doi:10.1038/79238. PMID   10973256. S2CID   36818715.
  7. ↑ Jain, Sonia; Maleszewski, Joseph J; Stephenson, Christopher R; Klarich, Kyle W (2015). "Current diagnosis and management of cardiac myxomas". Expert Review of Cardiovascular Therapy . 13 (4): 369–75. doi:10.1586/14779072.2015.1024108. PMID   25797902. S2CID   6935363.
  8. ↑ Bertherat, Jérôme (2006). "Carney complex (CNC)". Orphanet Journal of Rare Diseases. 1: 21. doi: 10.1186/1750-1172-1-21 . PMC   1513551 . PMID   16756677.
  9. ↑ Gangoda, L; Doerflinger, M; Srivastava, R; Narayan, N; Edgington, L E; Orian, J; Hawkins, C; O'Reilly, L A; Gu, H; Bogyo, M; Ekert, P; Strasser, A; Puthalakath, H (2014). "Loss of Prkar1a leads to Bcl-2 family protein induction and cachexia in mice". Cell Death and Differentiation. 21 (11): 1815–24. doi:10.1038/cdd.2014.98. PMC   4211378 . PMID   25012505.
  10. ↑ Sahut-Barnola, Isabelle; De Joussineau, Cyrille; Val, Pierre; Lambert-Langlais, Sarah; Damon, Christelle; Lefrançois-Martinez, Anne-Marie; Pointud, Jean-Christophe; Marceau, Geoffroy; Sapin, Vincent; Tissier, Frédérique; Ragazzon, Bruno; Bertherat, Jérôme; Kirschner, Lawrence S; Stratakis, Constantine A; Martinez, Antoine (2010). "Cushing's Syndrome and Fetal Features Resurgence in Adrenal Cortex–Specific Prkar1a Knockout Mice". PLOS Genetics. 6 (6): e1000980. doi: 10.1371/journal.pgen.1000980 . PMC   2883593 . PMID   20548949.
  11. ↑ Cazabat, Laure; Ragazzon, Bruno; Groussin, Lionel; Bertherat, Jérôme (2006). "PRKAR1A mutations in primary pigmented nodular adrenocortical disease". Pituitary. 9 (3): 211–9. doi:10.1007/s11102-006-0266-1. PMID   17036196. S2CID   95749.
  12. 1 2 Manipadam, Mariet; Sen, Sudipta; Abraham, Rachel; Simon, Anna (2011). "Primary pigmented nodular adrenocortical disease". Journal of Indian Association of Pediatric Surgeons. 16 (4): 160–2. doi: 10.4103/0971-9261.86881 . PMC   3221162 . PMID   22121318.
  13. ↑ Vezzosi, Delphine; Tenenbaum, Florence; Cazabat, Laure; Tissier, Frédérique; Bienvenu, Marie; Carrasco, Carmen A; Laloi-Michelin, Marie; Barrande, Gaëlle; Lefebvre, Hervé; Hiéronimus, Sylvie; Tabarin, Antoine; Bertagna, Xavier; Legmann, Paul; Vantyghem, Marie-Christine; Bertherat, Jérôme (2015). "Hormonal, Radiological, NP-59 Scintigraphy, and Pathological Correlations in Patients with Cushing's Syndrome Due to Primary Pigmented Nodular Adrenocortical Disease (PPNAD)". The Journal of Clinical Endocrinology & Metabolism. 100 (11): 4332–8. doi: 10.1210/jc.2015-2174 . PMID   26390100.
  14. ↑ Liu, James K; Fleseriu, Maria; Delashaw, Johnny B; Ciric, Ivan S; Couldwell, William T (2007). "Treatment options for Cushing disease after unsuccessful transsphenoidal surgery". Neurosurgical Focus. 23 (3): E8. doi: 10.3171/foc.2007.23.3.10 . PMID   17961031.
  15. ↑ Shenoy, B. V; Carpenter, P. C; Carney, J. A (1984). "Bilateral primary pigmented nodular adrenocortical disease. Rare cause of the Cushing syndrome". The American Journal of Surgical Pathology. 8 (5): 335–44. doi:10.1097/00000478-198405000-00002. PMID   6329005.
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