Stemming from mutations of genes responsible for the activity of protein kinase A (a vital molecule for regulation of cell growth and proliferation of endocrine cells), the Carney complex (CNC) is a rare genetic disease with a diverse clinical presentation [1] [2] [3]. The autosomal dominant pattern of inheritance is established as the primary mode of disease transmission across generations, although de novo mutations have been described as well [1] [2] [4] [5]. The diagnosis is usually made around 20 years of age, and the following conditions constitute this clinical entity [1] [2] [3] [4] [5] [6] [7]:

• Cutaneous lesions - One of the first and most frequent manifestations of CNC is the appearance of small, flat, brown or black macules (termed lentigines) developing in the facial and genital area, including the mucous membranes, is encountered in almost 80% of patients [1] [2] [3]. In addition, epithelioid blue nevi (domed, smooth-surfaced bluish papules) and cutaneous myxomas (subcutaneous non-pigmented nodules) are frequently seen as well, with the eyelid, the external ear canal, the genitalia and the breast nipples being their main locations [2] [3] [4] [5] [7]. Less common findings include café-au-lait spots, spitz nevi, and depigmentation [1].
• Cardiac myxomas - Although myxomas are benign tumors, they can completely abolish intracardiac flow and cause heart failure, stroke, or sudden death [1] [5] [6] [7]. For this reason, almost 50% of deaths in CNC are attributed to these tumors [1] [6]. They are present in 20-40% of cases and recur in a substantial proportion of individuals even after appropriate therapy [1].
• Endocrine tumors - Certain authors classify CNC as multiple endocrine neoplasias, as many endocrine tumors of different organs and tissues have been discovered in these patients. Somatomammotroph hyperplasia, growth-hormone (GH) producing adenomas that could result in acromegaly, prolactinomas, and asymptomatic elevations of GH, insulin-growth-factor 1 (IGF-1) are pathologies of the pituitary gland seen in CNC [2] [3] [4] [7]. Additional neoplastic malformations are those of the suprarenal glands (primary pigmented nodular adrenocortical disease - PPNAD), thyroid gland (thyroid nodules, cysts, benign adenomas or papillary and follicular carcinomas), breast, pancreas (although rare), testes (large cell calcifying sertoli cell tumors -LCCSCT), ovaries, the skeletal system (osteochondromyxoma), and the nervous system (psammomatous melanotic schwannomas - PMS) [1] [2] [4] [5] [6] [7].

• Cushingoid

  After the second adrenalectomy, the Cushingoid features disappeared, and cortisol levels returned to normal. Carney complex is a rare disease that lacks consistent genotype-phenotype correlations. [ncbi.nlm.nih.gov]

  The patient did not exhibit acromegalic or cushingoid features. Figure 1 Figure 2 Laboratory data.—A complete blood count, chemistry profile, and liver functions tests were normal. [escholarship.org]

• Thrombosis

  Heterozygosity for Prkaca rescued the embryonic lethality of the R1a-CKO, although mice had a shorter than normal lifespan and died from cardiac failure with atrial thrombosis. [ncbi.nlm.nih.gov]

• Osteopenia

  During the postoperative period the severe back pain persisted, and radiographic evaluation revealed a collapse of L(2)/L(3) with severe osteopenia. A CT scan showed a mass in the right suprarenal area. [ncbi.nlm.nih.gov]

  ~ O ~ Osteopenia This Topic on the Message Boards. Osteoporosis This Topic on the Message Boards. ~ P ~ Panhypopituitarism This Topic on the Message Boards. PCOS This Topic on the Message Boards. [cushieblog.com]

  Severe osteopenia in young adults associated with Cushing’s syndrome due to micronodular adrenal disease. J Clin Endocrinol Metab 1974; 39: 1138–47. 12. [journals.lww.com]

• Hyperpigmentation

  We report an illustrated case of a 61-year-old woman with multiple atrial myxomas and cutaneous hyperpigmentation as part of the Carney complex. [ncbi.nlm.nih.gov]

  […] hormone receptors.8 Hyperpigmentation does not occur in patients with adrenal Cushing syndrome because overproduction of cortisol suppresses ACTH secretion.8 PATIENT’S TREATMENT This patient received treatment with cabergoline and octreotide, but blood [ccjm.org]

  Michael Gibson, M.S., M.D. [1] Overview Carney complex is an autosomal dominant condition comprising myxomas of the heart and skin, hyperpigmentation of the skin (lentiginosis), and endocrine overactivity (Carney et al, 1985; McCarthy et al, 1986). [wikidoc.org]

  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. [en.wikipedia.org]

  Note hyperpigmentation of lips as well as large nevus on right temple (arrowhead). Later in life, this individual also developed recurrent intracardiac myxomas. [circ.ahajournals.org]

• Hirsutism

  Abstract A woman with Carney complex presented at the age of 22 years with abdominal pain and hirsutism. [ncbi.nlm.nih.gov]

  Some affected women may experience disturbances of their menstrual cycles and a male pattern of hair growth (hirsutism). [rarediseases.org]

• Photosensitivity

  Disorders/diagnosis* Photosensitivity Disorders/genetics Skin/pathology Skin/radiation effects Skin Neoplasms/diagnosis* Skin Neoplasms/genetics Skin Neoplasms/metabolism Sunlight/adverse effects* Substances Biomarkers, Tumor Cyclic AMP-Dependent Protein [ncbi.nlm.nih.gov]

• Testicular Swelling

  We report on a child who presented with a 2-year history of gynecomastia with associated bilateral testicular swellings and discuss a novel treatment strategy for managing bilateral testicular tumors in the context of the Carney complex. [ncbi.nlm.nih.gov]

• Radiculopathy

  The spinal tumors occurred in adults (mean age 32 years, range 18-49 years) who presented with pain and radiculopathy. [ncbi.nlm.nih.gov]

  It usually affects either the gastrointestinal tract (60%) or the paraspinal sympathetic tract (30%) where it can present with easily misdiagnosed painful radiculopathy in young adults. [dermatologyadvisor.com]

  Depending upon their location psammomatous melanotic schwannomas can cause pain or discomfort as well as damage to one or more nerves (radiculopathy). In rare cases, these tumors can become malignant. [rarediseases.org]

• Sciatica

  The authors describe a patient with Carney's complex who presented with sciatica due to a lumbar nerve root sheath tumor. A far-lateral approach was used to resect a nonpsammomatous melanotic schwannoma. [ncbi.nlm.nih.gov]

The diagnosis of CNC mandates a detailed clinical investigation that will be able to establish definite diagnostic criteria for this rare genetic disease, which includes the presence of two or more of the mentioned cardiac, cutaneous, or endocrine pathologies. One of the key elements in the workup that could significantly raise clinical suspicion is a positive family history, as studies have shown that one of the parents suffers from the disease in up to 70% of cases [3]. After a thorough physical examination, which can confirm the presence of the cutaneous lesions by inspection of the skin and certain tumors by palpation (eg. the testes or breasts), a detailed imaging workup should follow. Ultrasonography is highly useful in detecting testicular and thyroid tumors, and cardiac ultrasonography is vital in determining the presence of intracardiac lesions, such as myxomas [2] [5] [6] [7]. Furthermore, computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen, the thorax, and the endocranium may be crucial for identifying pituitary, adrenal, ovarian, uterine or breast tumors [1] [2] [3]. On the other hand, serum levels of IGF-1, prolactin, and a complete hormonal panel should be performed. In addition to clinical and imaging criteria, genetic studies are also included in the diagnostic criteria for CNC, and confirmation of PRKAR1A gene mutations in patients who present with any of the mentioned manifestations provides strong evidence to make the diagnosis of CNC [4] [5] [6].

Although radical orchiectomy is the gold standard for the treatment of testicular neoplasms, a conservative approach with partial orchiectomy or tumourectomy may be the best treatment option for these patients, allowing the preservation of endocrine function [ncbi.nlm.nih.gov]

Management and treatment Cardiac myxomas require surgical removal. [orpha.net]

Prognosis of all melanotic schwannomas is usually poor due to local recurrences or metastases. [ncbi.nlm.nih.gov]

(Outcomes/Resolutions) The prognosis for Carney Complex depends upon the location and type of tumors and the combination of signs and symptoms in any given individual In general, the presence of cardiac myxomas indicates a poorer prognosis, with an average [dovemed.com]

Abstract Cardiac myxomas are the most common primary tumors of the heart, although little is known about their etiology. [ncbi.nlm.nih.gov]

Etiology One of the putative CNC genes located on 17q22-24, ( PRKAR1A ), has been found to encode the regulatory subunit (R1A) of protein kinase A. [orpha.net]

[…] myxoma breast testis thyroid brain adrenal gland: primary pigmented nodular adrenocortical disease (PPNAD) pituitary adenoma psammomatous melanotic schwannoma testicular tumors Sertoli cell tumors: most common osteochondromyxoma On this page: Article: Epidemiology [radiopaedia.org]

NIH), Bethesda, Maryland, USA. 2 National Institute of Child Health and Human Development (NICHD)NIH, Bethesda, Maryland, USA Department of PediatricsGeorgetown University Hospital, Washington, District of Columbia, USA. 3 Biostatistics and Clinical Epidemiology [ncbi.nlm.nih.gov]

Summary Epidemiology The prevalence of CNC is unknown but it is a rare disease with around 160 index cases identified so far. Clinical description Skin pigmentation anomalies include lentigines and blue nevi. [orpha.net]

Terminology Carney complex appears to be preferred over Carney syndrome Epidemiology Incidence of 70 cases per 100,000 individuals Usually white, no gender preference Mean age at diagnosis is 10 - 20 years ( eMedicine: Carney Complex ) Clinical features [pathologyoutlines.com]

This review summarizes older and recent findings on the genetics and pathophysiology of MiBAH, PPNAD, and related disorders. Copyright © 2018. Published by Elsevier Masson SAS. [ncbi.nlm.nih.gov]

Pathophysiology Cardiac myxomas, while histologically benign, may cause embolic phenomena, valvular obstruction, and heart failure. Myxomas are also found in the thyroid and adrenal glands, brain, breasts, and testes. [accesspediatrics.mhmedical.com]

(See Pathophysiology and Etiology.) [emedicine.com]

[…] culture may apply) | Oral Rinse Billing References Groussin et al., Molecular analysis of the cyclic AMP-dependent protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene in patients with Carney complex and PPNAD reveals novel mutations and clue for pathophysiology [genedx.com]

Although treatment guidelines for this rare tumor do not exist, radiotherapy was performed in our patient to prevent possible recurrence or regrowth of this malignant tumor. [ncbi.nlm.nih.gov]

1. Correa R, Salpea P, Stratakis C. Carney Complex: an update. Eur J Endocrinol. 2015;173(4):M85-M97.
2. Bertherat J. Carney complex (CNC). Orphanet J Rare Dis. 2006;1:21.
3. Stratakis CA, Kirschner LS, Carney JA. Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation. J Clin Endocrinol Metab. 2001;86(9):4041-4046.
4. Salpea P, Stratakis CA. Carney Complex and McCune Albright Syndrome: An overview of clinical manifestations and human molecular genetics. Mol Cell Endocrinol. 2014;386(0):85-91.
5. Zhang YL, Wang XC, Yu W, et al. A case of familial Carney complex. Arch Iran Med. 2015;18(5):324-328.
6. Havrankova E, Stenova E, Olejarova I, Sollarova K, Kinova S. Carney complex with biatrial cardiac myxoma. Ann Thorac Cardiovasc Surg. 2014;20 Suppl:890-892.
7. Courcoutsakis NA, Tatsi C, Patronas NJ, Lee C-CR, Prassopoulos PK, Stratakis CA. The complex of myxomas, spotty skin pigmentation and endocrine overactivity (Carney complex): imaging findings with clinical and pathological correlation. Insights Imaging. 2013;4(1):119-133.