Dermatological and endocrine elements in Carney complex (Review)
FLORICA SANDRU1,2, MIHAI CRISTIAN DUMITRASCU3,4, AIDA PETCA3,5, MARA CARSOTE6,7, RAZVAN-COSMIN PETCA8,9 and DIANA LORETA PAUN6,7
1Department of Dermatology, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest; 2Department of Dermatology, ‘Elias’ Emergency Hospital, 011461 Bucharest;
3Department of Obstetrics and Gynecology, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest; 4Department of Obstetrics and Gynecology, University Emergency Hospital Bucharest, 050098 Bucharest; 5Department of Obstetrics and Gynecology, ‘Elias’ Emergency Hospital, 022461 Bucharest; Department of Endocrinology, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest;
“Department of Endocrinology, ‘C. I. Parhon’ National Institute of Endocrinology, 011863 Bucharest;
8Department of Urology, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest;
9Department of Urology, ‘Prof. Dr. Theodor Burghele’ Clinical Hospital, 061344 Bucharest, Romania
Received July 23, 2021; Accepted August 23, 2021
DOI: 10.3892/etm.2021.10748
Abstract. Carney complex (CNC) is a very rare, autosomal dominant, hereditary syndrome. Seventy percent of individuals with CNC have germline inactivating or deleting mutations of the CNC1 gene [currently known as protein kinase cAMP-dependent type I regulatory subunit a (PRKARIA), located at the 17q22-24 chromosome level], with 30% of cases presenting with phosphodiesterase gene mutations. A member of the lentiginosis family, dermatological features include: skin pigmentation, cutaneous/mucosal myxomas, usually diagnosed by the age of 20 years (neonatal presentation is exceptional, requiring a meticulous differential diagnosis). Melanocyte-derived tumors such as epithelioid blue nevi (with different levels of pigmentation) and pigmented epithelioid melanocytoma (previously ‘animal-type melanoma’) are often found. Myxomas, mesenchymal tumors with mostly a benign pattern, may be recurrent. Primary cutaneous melanotic schwannoma are atypical, while non-skin sites are frequent. Corticotropinomas or somatotropinomas are part of the
hereditary syndrome-related pituitary adenomas (representing 5% of all). Primary pigmented nodular adrenocortical disease involves bilateral cortical hyperplasia causing Cushing syndrome (CS) at an earlier age than non-CNC cases; osteoporotic fractures seem more prevalent compare to CS of other etiologies. Typically benign, a few cases of adrenocortical carcinoma have been identified. A total of 5% of familial non-medullary thyroid cancer is syndromic, also including CNC. CNC-related thyroid frame includes: hyperthyroidism, follicular hyperplasia/adenomas, follicular carcinoma (usually aggressive, bilateral or multifocal). Large cell calcifying Sertoli cell tumors of the testes have malignant behavior in adults; in children these may induce precocious puberty. Two particular mammary tumors are found: myxoid fibroadenomas and breast myxomatosis. Cutaneous/subcutaneous lesions, pigmented or not, or any focal swelling of non-identified cause needs careful examination, since dermatological elements are among the earliest and most discernable by which to detect lesions in CNC, a systemic condition with multi-level endocrine involvement.
Correspondence to: Dr Mihai Cristian Dumitrascu, Department of Obstetrics and Gynecology, ‘Carol Davila’ University of Medicine and Pharmacy, 8 Eroilor Sanitari Street, 050474 Bucharest, Romania E-mail: drdumitrascu@yahoo.com
Abbreviations: CNC, Carney complex; ACTH, adrenocorticotropic hormone; FNMTC, familial non-medullary thyroid cancer; GH, growth hormone
Key words: Carney complex, pigmented spot, lentiginosis, PRKAR1A gene, acromegaly, Cushing syndrome, thyroid tumor, adrenal tumor, testicular tumor, primary pigmented nodular adrenocortical disease
Contents
1. Introduction
2. Aim of the review
3. Lentiginosis
4. Myxomas
5. Schwannomas
6. Pituitary adenomas
7. Adrenal disease
8. Thyroid conditions
9. Testicular tumors
10. Mammary tumors
11. Discussion
12. Conclusions
1. Introduction
Carney complex (CNC) is a very rare autosomal-dominant hereditary syndrome with high penetrance with underlying endocrine elements such as primary pigmented nodular adrenocortical disease at the level of the adrenal cortex [clinically associated with Cushing syndrome (CS)] pituitary adenomas secreting adrenocorticotropic hormone (ACTH) and growth hormone (GH) thus causing Cushing disease, respective gigantism or acromegaly or giganto-acromegaly, and thyroid pathology of tumor type in addition to non-endocrine findings of various types (1). Among them, we mention myxomas located in the skin, mucosa, heart, and breast (2). In addition, at the skin level there are pigmented cutaneous lesions or lentiginosis (the core elements for diagnostic are pigmented maculas, myxoma, and primary pigmented nodular adrenocortical disease) (3,4). Moreover, schwannomas such as psammomatous melanotic type are related to the syndrome (5). Some tumors have a highly malignant potential such as osteochondromyxomas or adult types of testicular tumors (for instance, the malignant cases of large cell calcifying Sertoli cell tumors) (6,7).
CNC was identified in 1985 while two decades ago the associated mutations were beginning to be identified (8). A total 70% of individuals have a germline mutation of the CNC1 gene [which today is called protein kinase cAMP-dependent type I regulatory subunit a (PRKARIA) gene, located at the 17q22-24 chromosome level]; the mutation includes an inactivating type or large deletions, while the gene encodes cyclic AMP-dependent protein kinase A (at the level of subunit la or RIA) (9). Genotype-phenotype correlations have been described in PRKAR1A gene mutations (10). Defects of catalytic subunits (PRKACA) are related to adrenal hyperplasia while other subunits such as PRKACB are connected to the presence of hypophyseal tumors, pigmented skin lesions and myxomas (11). A total of 30% of subjects have mutations of the phosphodiesterase genes, also of an inactivating type (12). These genetic aspects may be linked to particular adrenal tumors and testicular neoplasia in individuals with CNC (13).
No particular therapy has addressed the hereditary complex of diseases; once the mutation is identified starting from any type of lesion, then gene testing is indicated; a multidisciplinary team is required to adequately screen and approach further elements of CNC that are more likely to express later in life (14,15).
2. Aim of the review
We aimed to introduce a brief narrative presentation of skin lesions in CNC in addition to the overall picture, especially the endocrine panel.
The instrumentation of research was PubMed starting from several key words in different combinations as mentioned in the specific ‘Key words’ section. A number of 82 papers are cited; they were published between 2021 and 2012. We included the papers with the most clinical relevance; the approach of the presentation was multidisciplinary. As expected, due to the rarity of the syndrome, the level of statistical evidence involving most of the cited papers was low.
3. Lentiginosis
CNC is a type of genodermatoses, hereditary syndromes with skin involvement and tumorigenic findings, some of them being highly malignant (16). Skin pigmentation and myxomas are usually diagnosed in CNC by the age of 20 years, although neonatal presentation has been rarely reported and a specific panel of differential diagnosis is required at early ages (17). Spotty skin pigmentation are described with a disposition all over the body (18).
Different melanocyte-derived tumors have been identified such as epithelioid blue nevi and pigmented epithelioid melanocytoma (19,20). Pigmented epithelioid melanocytoma was previously termed ‘animal-type melanoma’ (21). Despite being linked to this hereditary syndrome, blue nevus-derived tumors, underlying different grades of pigmentation, do not typically have a neonatal presentation (22). Congenital, epithelioid and spindle cell-derived neoplasia are described in sporadic cases even in multiple sites accounting for up to 1,000 lesions per individual in some cases (23). Acquired cases of epithelioid blue nevus are described in individuals with chronic sun exposure and associated skin damage (24).
Any cutaneous and subcutaneous lesion, pigmented or not or any focal swelling of non-identified cause needs careful dermatological evaluation since dermatological elements are among the earliest and most easy to detect lesions in an otherwise multi-organ disease (25).
4. Myxomas
Myxoma is a mesenchymal tumor which usually has a benign behavior; the most frequent sites being the skin, mucosa, and heart in relationship with CNC (26). Recurrence of skin myxomas is found in some cases (27). In 2018, the largest skin myxoma of 15 cm was reported in an 18-year-old patient (28).
Rarely do they embrace other scenarios such as intra-oral myxomas and facio-oral deformations that need to be differentiated from acromegaly-related changes if the co-presence of a somatotropinoma is also confirmed (29). Atypical presentations or the identification of a myxoma in patients who are not yet diagnosed with CNC requires differentiation upon clinical and mainly histological findings in addition to gene testing; for instance, an eyelid myxoma may be mistaken as a chalazion or a superficial angiomyxoma (a benign tumor with underlying multiple vessels and a large matrix) (30,31).
Cardiac myxoma may lead to atypical cardio-embolic stroke in individuals with CNC or it may be incidentally detected at autopsy (32). In other cases, a massive embolic event may cause sudden death (33). Recurrent atrial presentation has also been reported (34). In 2020, a series of 41 cases with pediatric presentation in addition to arterial ischemic stroke was reported (a median age of 11 years; 56% male predominance) in subjects with CNC (35).
5. Schwannomas
Subjects with CNC may develop a particular neoplasia, melanotic schwannoma, derived from the spinal nerves and ganglia, a very rare tumor (36). This is a tumor with two
subtypes: Psammomatous or non-psammomatous; overall, the neoplasia is malignant in one out of 10 patients and aggressive profile is less likely to be predicted from the initial diagnosis (37). The tumor may be developed in sporadic cases and in PRKAR1A carriers(38). Cases with a primary cutaneous location have been reported in individuals confirmed with CNC (39).
6. Pituitary adenomas
CNC includes the presentation of pituitary adenomas, as seen in other hereditary syndromes such as multiple endocrine neoplasia type 1, Lynch syndrome, neurofibromatosis type 1, and rarely in von Hipple-Lindau disease (40,41). A total of 95% of pituitary adenomas are sporadic; the others involve the mentioned inherited syndromes as well as isolated pituitary conditions as seen in individuals with AIP mutations (42). CNC-related pituitary tumors are secretors: corticotropinoma or somatotropinoma (43).
7. Adrenal disease
In individuals with CND, one in 10 adults has a tumor at the level of the adrenal cortex, mostly an age-dependent, so called ‘adrenal incidentaloma’ (44). Adrenal tumor-related genetic backup is identified with regard to channel anomalies as found in some cases of primary hyperaldosteronism; in TP53 mutations (such as Li-Fraumeni syndrome) causing adrenocortical carcinoma, especially in pediatric individuals, or pigmented adrenal lesions induced by CNC (45,46). Other syndromic circumstances associated with an adrenal tumor involves multiple endocrine neoplasia type 2A, neurofibromatosis type 1, McCune-Albright syndrome, Beckwith-Wiedemann syndrome, and von Hipple-Lindau disease (47).
PRKARIA gene-associated tumors are typically benign; yet in 2012 the first case of adrenal cancer was reported in one family (48). Generally, adrenocortical carcinoma is regarded as a highly aggressive tumor and prompt intervention is required to achieve a better prognosis but the overall prognosis remains very poor (49).
Most of the cases diagnosed with primary bilateral hyperplasia of micronodular adrenocortical type at imaging scan are associated with the hormonal picture of Cushing syndrome (50). The typical picture of tumor-related hyper- cortisolemia is expected such as cardiovascular risk, obesity, and osteoporosis (51,52). The age of diagnosis is decreased when compared with other types of adrenal Cushing syndromes (50,53). A paper published in 2020 found, based on two retrospective studies, a higher risk of osteoporotic fractures vs. Cushing syndrome of other causes (50,54). Since the gene-related adrenal masses are bilateral, unilateral adrenalectomy rarely cures the persistent hypercorticism (55).
8. Thyroid conditions
Familial non-medullary thyroid cancer (FNMTC) involves one affected individual and at least two of his first-degree relatives (56). It represents 3-9% of all primary thyroid cancers (57). A total of 95% are non-syndromic (for instance,
mutations of FOXE1 or TTF1 genes) which, in the absence of gene testing, have a presentation very similar with sporadic cases (58). A total of 5% of individuals with FNMTC are syndromic with underlying driven germline mutations similar to CNC, but also Gardner syndrome, Cowden syndrome or DICER1 syndrome (59).
In CNC, thyroid gland involvement may be completely asymptomatic or associated with hyperthyroidism (60). Benign lesions are follicular hyperplasia and adenomas while follicular carcinoma is more aggressive than usual with bilateral and multifocal presentation and early lymph node metastases (60).
9. Testicular tumors
As seen in Peutz-Jaghers syndrome, large cell calcifying Sertoli cell tumors, even very rare, are associated with CNC (61). They are identified either in pediatric or in adult individuals (62). No particular endocrine constellation is expected, unless precocious puberty is developed in chil- dren; while local pain may be present, including a bilateral pattern (63). The echoic aspect of testicular calcifications is very suggestive (64). Testes-sparing surgery is indicated in cases that are not suggestive for a malignant behavior (which is mostly seen in adults, not in children) (65,66).
10. Mammary tumors
In females with CNC, mammary tumors with particular histolog- ical features have been reported, namely myxoid fibroadenomas that are distinctive from traditional fibroadenomas (67). Breast myxomatosis has also been reported (68).
11. Discussion
CNC needs to be differentiated from Carney triad which is a very rare combination of unknown cause, associated with three different types of tumors: pulmonary chondroma, gastric leiomyosarcoma [very similar to gastrointestinal stromal tumor (GIST) presentation] and paraganglioma (69,70).
Other tumorigenic risks have been reported in CNC including melanoma; yet currently it is considered incidental, but a clear histological and immunohistochemically differen- tiation from melanotic schwannoma is required (71,72). Uveal melanoma has also been reported in cases with CNC, but the association is not typical (73).
When it comes to skin changes in individuals with CNC, many of these are actually related to the hormone excess of endocrine tumors such as acromegaly, Cushing syndrome/disease, and thyrotoxicosis (74,75). Cortisol or GH excess may be complicated with secondary diabetes mellitus, and chronic hyperglycemia-related dermatological findings are precisely connected to the endocrine disease control (76,77). Endocrine tumors may be the first step that helps denote the findings of CNC or they may be revealed in subjects with skin lesions suggestive of a lentiginosis or in carriers of a PRKAR1A mutation (78). One multicenter trial on 70 patients (with a median age of 35.4 years) that were either known with Carney complex or with primary pigmented bilateral hyperplasia or they were PRKAR1A carriers identified acromegaly in 11.4% of all the cases. Also, in this cohort
there was one subject confirmed with testicular lesions and two individuals identified with heart myxomas. Overall, the interval of follow-up was 36 months (78).
Another distinctive aspect is the fact that acromegalic patients, especially with long-term undetected or uncontrolled disease, are traditionally described as having a higher risk than the general population for presenting with associated second non-pituitary tumor, either benign such as nodular goiter, colonic polyps, even testicular tumors and mammary fibro-adenomas in females, or malign such as thyroid cancer (79,80). In these cases, evaluation of dermatological elements is a valuable clue for implementing PRKACA gene testing in order to differentiate a cluster of tumors related to GH excess or related to CNC itself (81,82).
12. Conclusions
Cutaneous manifestations such as skin myxomas and pigmented lesions are essential clues for identifying individuals with Carney complex. The endocrine panel of manifestations varies from pituitary, adrenal, and thyroid glands to testicular tumors and breast anomalies in females. Despite being a rare entity, close multidisciplinary work is required on a lifelong basis, and early tumor identification improves the overall prognosis.
Acknowledgements
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Funding
No funding was received.
Availability of data and materials
All information presented in this review is documented by relevant references.
Authors’ contributions
FS drafted the manuscript and critically revised the final form in light of the literature data. MCD is the corresponding author and helped the revision of the literature data. AP researched the literature data, and MC drafted the manuscript in light of the literature findings. RCP drafted the manuscript in light of the literature findinds and DLP approved the final form after reviewing all the literature data. All authors read and approved the final manuscript for publication.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare they have no competing interests.
References
1. Bouys L and Bertherat J: Management of endocrine disease: Carney complex: Clinical and genetic update 20 years after the identification of the CNC1 (PRKARIA) gene. Eur J Endocrinol 184: R99-R109, 2021.
2. Samanidis G, Khoury M, Balanika M and Perrea DN: Current challenges in the diagnosis and treatment of cardiac myxoma. Kardiol Pol 78: 269-277, 2020.
3. García-Guzmán B, Portocarrero-Ortiz L, Dorantes-Argandar AA and Mercado M: Hereditary pituitary tumor syndrome: Genetic and clinical aspects. Rev Invest Clin 72: 8-18, 2020.
4. Li S, Duan L, Wang FD, Lu L and Jin ZY: Carney complex: Two case reports and review of literature. World J Clin Cases 6: 800-806, 2018.
5. Chikkannaiah P, Boovalli MM, Nathiyal V and Venkataramappa S: Morphological spectrum of peripheral nerve sheath tumors: An insight into World Health Organization 2013 classification. J Neurosci Rural Pract 7: 346-354, 2016.
6. Dağdeviren Çakır A, Turan H, Celkan T, Çomunoğlu N, Ercan O and Evliyaoğlu O: An unusual presentation of Carney complex. J Clin Res Pediatr Endocrinol 12: 117-121, 2020.
7. Courcoutsakis N, Prassopoulos P and Stratakis C: Carney complex: One more entity with skin and bone manifestations. Radiographics 35: 296-297, 2015.
8. Anik A and Abaci A: Endocrine cancer syndromes: An update. Minerva Pediatr 66: 533-547, 2014.
9. Bosco Schamun MB, Correa R, Graffigna P, de Miguel V and Fainstein Day P: Carney complex review: Genetic features. Endocrinol Diabetes Nutr (Engl Ed) 65: 52-59, 2018 (In English, Spanish).
10. Espiard S and Bertherat J: Carney complex. Front Horm Res 41: 50-62, 2013.
11. Correa R, Salpea P and Stratakis CA: Carney complex: An update. Eur J Endocrinol 173: M85-M97, 2015.
12. Hannah-Shmouni F, Faucz FR and Stratakis CA: Alterations of phosphodiesterases in adrenocortical tumors. Front Endocrinol (Lausanne) 7: 111, 2016.
13. Libé R, Horvath A, Vezzosi D, Fratticci A, Coste J, Perlemoine K, Ragazzon B, Guillaud-Bataille M, Groussin L, Clauser E, et al: Frequent phosphodiesterase 11A gene (PDE11A) defects in patients with Carney complex (CNC) caused by PRKAR1A mutations: PDE11A may contribute to adrenal and testicular tumors in CNC as a modifier of the phenotype. J Clin Endocrinol Metab 96: E208-E214, 2011.
14. Rodriguez FJ, Stratakis CA and Evans DG: Genetic predis- position to peripheral nerve neoplasia: Diagnostic criteria and pathogenesis of neurofibromatoses, Carney complex, and related syndromes. Acta Neuropathol 123: 349-367, 2012.
15. Siordia JA: Medical and surgical management of Carney complex. J Card Surg 30: 560-567, 2015.
16. Ladd R, Davis M and Dyer JA: Genodermatoses with malignant potential. Clin Dermatol 38: 432-454, 2020.
17. Bilkhu AS and Sunderesan R: Newborn infant with congenital lentigines as a manifestation of Carney complex. BMJ Case Rep 14: e239259, 2021.
18. Attri B, Aggarwal A, Mattoo S and Kulshreshtha B: Cushing’s syndrome due to primary pigmented nodular adrenal disease in two brothers with Carney complex. Pediatr Endocrinol Diabetes Metab 26: 155-158, 2020.
19. Isales MC, Mohan LS, Quan VL, Garfield EM, Zhang B, Shi K, Arva N, Beaubier N, Yazdan P, White K, et al: Distinct genomic patterns in pigmented epithelioid melanocytoma: A molecular and histologic analysis of 16 cases. Am J Surg Pathol 43: 480-488, 2019.
20. Cohen JN, Joseph NM, North JP, Onodera C, Zembowicz A and LeBoit PE: Genomic analysis of pigmented epithelioid melanocytomas reveals recurrent alterations in PRKARIA, and PRKCA genes. Am J Surg Pathol 41: 1333-1346, 2017.
21. Gavriilidis P, Michalopoulou I, Chatzikakidou K and Nikolaidou A: Pigmented epithelioid melanocytoma: A new concept encompassing animal-type melanoma and epithelioid blue nevus. BMJ Case Rep 2013: bcr-2013-008865, 2013.
22. Blebea C, Li D, Castelo-Soccio L and Chu EY: Generalized congenital epithelioid blue nevi (pigmented epithelioid melanocytomas) in an infant: Report of case and review of the literature. J Cutan Pathol 46: 954-959, 2016.
23. Shi G, Zhou Y, Li SJ and Fan YM: Clinicopathologic features of an infant with generalized congenital epithelioid blue nevi. Pediatr Dev Pathol 16: 442-446, 2013.
24. Yazdan P, Haghighat Z, Guitart J and Gerami P: Epithelioid and fusiform blue nevus of chronically sun-damaged skin, an entity distinct from the epithelioid blue nevus of the Carney complex. Am J Surg Pathol 37: 81-88, 2013.
25. Lanjewar DN, Bhatia VO, Lanjewar SD and Carney JA: Cutaneous myxoma: An important clue to Carney complex. Indian J Pathol Microbiol 57: 460-462, 2014.
26. Leventhal JS and Braverman IM: Skin manifestations of endocrine and neuroendocrine tumors. Semin Oncol 43: 335-340, 2016.
27. Shirinpour Z, Farhangiyan Z, Akiash N and Rashidi H: Recurrent cardiac and skin myxomas along with acromegaly: A case report of Carney complex. ARYA Atheroscler 16: 146-150, 2020.
28. Karegar M, Sarwate M, Kothari K, Rojekar A and Naik L: Cytologic diagnosis of unusual, large multiple cutaneous myxomas in a case of Carney complex. J Lab Physicians 10: 354-356, 2018.
29. Mariz BALA, Tager EMJR, Fernandez CC, de Almeida OP and Carlos R: Palatal soft tissue myxoma in a patient with Carney complex. Head Neck Pathol 15: 1023-1030, 2021.
30. Joshi A, Jakati S and Ali MJ: A rare case of recurrent isolated eyelid myxoma: Case report and review of literature. Orbit: Dec 15, 2020 (Epub ahead of print).
31. Iwashita W, Kurabayashi A, Tanaka C, Naganuma S, Kawamura T, Aki F and Furihata M: Superficial angiomyxoma of the nipple in a Japanese woman: A case report and review of literature. Int J Surg Pathol 28: 683-687, 2020.
32. Chatzikonstantinou S, Kazis D, Giannakopoulou P, Poulios P, Pikou O, Geroukis T, Lyssikatos C, Stratakis CA and Bostanjopoulou S: Carney complex syndrome manifesting as cardioembolic stroke: A case report and review of the literature. Int J Neurosci: Nov 10, 2020 (Epub ahead of print).
33. Dell’Aquila M, Carbone A, Pennacchia I, Stigliano E, Oliva A and Arena V: Sudden death by massive systemic embolism from cardiac myxoma. Role of the clinical autopsy and review of literature. Cardiovasc Pathol 49: 107244, 2020.
34. Cervantes-Molina LA, Ramírez-Cedillo D, Masini-Aguilera ID, López-Taylor JG, Machuca-Hernández M and Pineda-De Paz DO: Recurrent atrial myxoma in a patient with Carney complex. A case report and literature review. Arq Bras Cardiol 114 (4 Suppl 1): S31-S33, 2020 (In English, Portuguese).
35. Tona C, Nosadini M, Pelizza MF, Pin JN, Baggio L, Boniver C, Gabrieli JD, Causin F, Toldo I and Sartori S: Cardiac myxoma as a rare cause of pediatric arterial ischemic stroke: Case report and literature review. Neuropediatrics 51: 389-396, 2020.
36. Sarfo A, Helm K and Flamm A: Cutaneous myxomas and a psammomatous melanotic schwannoma in a patient with Carney complex. J Cutan Pathol 46: 93-96, 2019.
37. Shanmugam S, Ghosh M, Niamathullah S and Ghosh S: Psammomatous melanotic schwannoma as a component of Carney complex. Indian J Pathol Microbiol 58: 368-370, 2015.
38. Topf MC, Pham QH, D’Souza JN, Chaskes M, Tuluc M, Cognetti DM and Luginbuhl AJ: Pigmented melanotic schwan- noma of the neck: Report of 2 cases and review of the literature. Ear Nose Throat J 98: 102-106, 2019.
39. Cohen JN, Yeh I and LeBoit PE: Melanotic schwannoma of the vulva: a case report and review of the literature. Am J Dermatopathol 42: 46-51, 2020.
40. Chang M, Yang C, Bao X and Wang R: Genetic and epigenetic causes of pituitary adenomas. Front Endocrinol (Lausanne) 11: 596554, 2021.
41. Sandru F, Carsote M, Valea A, Albu SE, Petca RC and Dumitrascu MC: Somatostatinoma: Beyond neurofibromatosis type 1 (Review). Exp Ther Med 20: 3383-3388, 2020.
42. Dénes J and Korbonits M: The clinical aspects of pituitary tumour genetics. Endocrine 71: 663-674, 2021.
43. Kiefer FW, Winhofer Y, Iacovazzo D, Korbonits M, Wolfsberger S, Knosp E, Trautinger F, Höftberger R, Krebs M, Luger A and Gessl A: PRKARIA mutation causing pituitary-dependent Cushing disease in a patient with Carney complex. Eur J Endocrinol 177: K7-K12, 2017.
44. Glazer DI and Mayo-Smith WW: Management of incidental adrenal masses: An update. Abdom Radiol (NY) 45: 892-900, 2020.
45. Juhlin CC, Bertherat J, Giordano TJ, Hammer GD, Sasano H and Mete O: What did we learn from the molecular biology of adrenal cortical neoplasia? From histopathology to translational genomics. Endocr Pathol 32: 102-133, 2021.
46. Lam AK: Adrenocortical carcinoma: Updates of clinical and pathological features after renewed world health organisation classification and pathology staging. Biomedicines 9: 175, 2021.
47. Kamilaris CDC, Hannah-Shmouni F and Stratakis CA: Adrenocortical tumorigenesis: Lessons from genetics. Best Pract Res Clin Endocrinol Metab 34: 101428, 2020.
48. Anselmo J, Medeiros S, Carneiro V, Greene E, Levy I, Nesterova M, Lyssikatos C, Horvath A, Carney JA and Stratakis CA: A large family with Carney complex caused by the S147G PRKAR1A mutation shows a unique spectrum of disease including adrenocortical cancer. J Clin Endocrinol Metab 97: 351-359, 2012.
49. Paragliola RM, Corsello A, Locantore P, Papi G, Pontecorvi A and Corsello SM: Medical approaches in adrenocortical carcinoma. Biomedicines 8: 551, 2020.
50. Maillet M, Bourdeau I and Lacroix A: Update on primary micronodular bilateral adrenocortical diseases. Curr Opin Endocrinol Diabetes Obes 27: 132-139, 2020.
51. Poiană C, Carșote M, Neamțu MC, Avramescu ET, Vasilescu F, Terzea D, Păun D, Trifănescu R and Dănciulescu Miulescu R: Well-differentiated neuroendocrine tumor and osteoporosis: Incidental findings? Rom J Morphol Embryol 54: 1169-1171, 2013.
52. Kamilaris CDC, Faucz FR, Andriessen VC, Nilubol N, Lee CR, Ahlman MA, Hannah-Shmouni F and Stratakis CA: First somatic PRKAR1A defect associated with mosaicism for another PRKAR1A mutation in a patient with Cushing syndrome. J Endocr Soc 5: bvab007, 2021.
53. Dumitrascu MC, Stanescu AMA, Bejan C, Sandru F, Toader DO, Radavoi DG, Cotirlet A, Judea Pusta CT and Diaconu CC: Obesity and its implications on stress urinary incontinence. Rev Chim 70: 3660-3662, 2019.
54. Sandru F, Dumitrascu MC, Albu SE, Carsote M and Valea A: Obesity and osteoporotic fractures. Rom J Mil Med 123: 166-171, 2020.
55. Meloche-Dumas L, Mercier F and Lacroix A: Role of unilateral adrenalectomy in bilateral adrenal hyperplasias with Cushing’s syndrome. Best Pract Res Clin Endocrinol Metab 35: 101486, 2021.
56. Cirello V, Colombo C, Karapanou O, Pogliaghi G, Persani L and Fugazzola L: Clinical and genetic features of a large monocentric series of familial non-medullary thyroid cancers. Front Endocrinol (Lausanne) 11: 589340, 2021.
57. Peiling Yang S and Ngeow J: Familial non-medullary thyroid cancer: Unraveling the genetic maze. Endocr Relat Cancer 23: R577-R595, 2016.
58. Hińcza K, Kowalik A and Kowalska A: Current knowledge of germline genetic risk factors for the development of non-medul- lary thyroid cancer. Genes (Basel) 10: 482, 2019.
59. Cirello V: Familial non-medullary thyroid carcinoma: Clinico-pathological features, current knowledge and novelty regarding genetic risk factors. Minerva Endocrinol (Torino) 46: 5-20, 2021.
60. Carney JA, Lyssikatos C, Seethala RR, Lakatos P, Perez-Atayde A, Lahner H and Stratakis CA: The spectrum of thyroid gland pathology in Carney complex: The importance of follicular carcinoma. Am J Surg Pathol 42: 587-594, 2018.
61. Potić Floranović M, Ristić Petrović A, Stojnev S, Potić M, Petrović F and Janković Veličkovic L: Large-cell calcifying sertoli cell tumour with macrocalcification in partially resected testis of young adult patient. Malays J Pathol 40: 343-348, 2018.
62. Rosenblum F, Koenig RG, Mikhail FM, Porterfield JR, Nix JW and Eltoum IA: An adolescent with large cell calcifying sertoli cell tumor of the testis and undiagnosed Carney complex: A case report. Diagn Cytopathol 45: 634-639, 2017.
63. Alleemudder A and Pillai R: A case of Carney complex presenting as acute testicular pain. Urol Ann 8: 360-362, 2016.
64. Li G, Lee MS, Kraft KH and Heider A: Prepubertal malignant large cell calcifying sertoli cell tumor of the testis. Urology 117: 145-149, 2018.
65. Pelit ES, Erol B, Zenginkinet T and Çaşkurlu T: Testis-sparing surgery of unilateral testicular large-cell calcifying sertoli cell tumor: A sporadic case. Turk J Urol 44: 370-372, 2018.
66. Freire MJ, Nunes P, Sousa LS and Figueiredo A: Organ-sparing surgery for large cell calcifying sertoli cell tumour in a patient with Carney complex. BMJ Case Rep 2017: bcr2017219557, 2017.
67. Lozada JR, Burke KA, Maguire A, Pareja F, Lim RS, Kim J, Gularte-Merida R, Murray MP, Brogi E, Weigelt B, et al: Myxoid fibroadenomas differ from conventional fibroadenomas: A hypothesis-generating study. Histopathology 71: 626-634, 2017.
68. Courcoutsakis NA, Tatsi C, Patronas NJ, Lee CC, Prassopoulos PK and Stratakis CA: The complex of myxomas, spotty skin pigmen- tation and endocrine overactivity (Carney complex): Imaging findings with clinical and pathological correlation. Insights Imaging 4: 119-133, 2013.
69. Fraile Alonso I and López Pardo R: Carney triad: A case report, characteristics and literature review of this rare entity. Int J Surg Case Rep 79: 14-17, 2021.
70. Iliesiu A, Ungureanu IA, Petca A, Constantin MM, Petca RC, Sandru F, Constantin T and Dumitrascu MC: Paraganglioma presenting as a mesenteric cystic mass: A case report. Exp Ther Med 20: 2489-2492, 2020.
71. Mubarak F, Tanwir A and Nizamani WM: A rare case of melanotic schwannoma: Utility of susceptibility weighted sequences in preoperative imaging. Cureus 10: e3068, 2018.
72. Sandru F, Draghici CC, Predescu T, Magdalena Constantin M, Petca RC, Constantin T, Petca A and Dumitrașcu MC: Regressive melanoma in a female patient: A case report. Exp Ther Med 20: 87-90, 2020.
73. Salomão DR, Ida CM, Greipp PT and Carney JA: Case report with review of the literature: Uveal melanoma in a patient with Carney complex-another rare component of the syndrome? Ocul Oncol Pathol 6: 311-317, 2020.
74. Geurts JL, Strong EA, Wang TS, Evans DB and Clarke CN: Screening guidelines and recommendations for patients at high risk of developing endocrine cancers. J Surg Oncol 121: 975-983, 2020.
75. Cuny T, Mac TT, Romanet P, Dufour H, Morange I, Albarel F, Lagarde A, Castinetti F, Graillon T, North MO, et al: Acromegaly in Carney complex. Pituitary 22: 456-466, 2019.
76. Valea A, Carsote M, Ghervan C and Georgescu C: Glycemic profile in patients with acromegaly treated with somatostatin analogue. J Med Life 8 (Spec Issue): 82-86, 2015.
77. Valea A, Ghervan C, Carsote M, Morar A, Iacob I, Tomesc F, Pop DD and Georgescu C: Effects of combination therapy: Somatostatin analogues and dopamine agonists on GH and IGF1 levels in acromegaly. Clujul Med 88: 310-313, 2015.
78. Espiard S, Vantyghem MC, Assié G, Cardot-Bauters C, Raverot G, Brucker-Davis F, Archambeaud-Mouveroux F, Lefebvre H, Nunes ML, Tabarin A, et al: Frequency and incidence of Carney complex manifestations: A prospective multicenter study with a three-year follow-up. J Clin Endocrinol Metab 105: dgaa002, 2020.
79. Matyjaszek-Matuszek B, Obel E, Lewicki M, Kowalczyk-Bołtuć J and Smoleń A: Prevalence of neoplasms in patients with acromegaly-the need for a national registry. Ann Agric Environ Med 25: 559-561, 2018.
80. Terzolo M, Puglisi S, Reimondo G, Dimopoulou C and Stalla GK: Thyroid and colorectal cancer screening in acromegaly patients: Should it be different from that in the general population? Eur J Endocrinol 183: D1-D13, 2020.
81. Ronchi CL, Peverelli E, Herterich S, Weigand I, Mantovani G, Schwarzmayr T, Sbiera S, Allolio B, Honegger J, Appenzeller S, et al: Landscape of somatic mutations in sporadic GH-secreting pituitary adenomas. Eur J Endocrinol 174: 363-372, 2016.
82. Loughrey PB and Korbonits M: Genetics of pituitary tumours. Exp Suppl 111: 171-211, 2019.