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].

• Pain

  We describe the case of a 7-year-old boy with no significant past medical or family history who initially presented as an emergency with acute left testicular pain and a scrotal exploration was performed. [urologyannals.com]

  Systemic symptoms such as fever, joint pains, and a lupus -like butterfly facial rashes may accompany the myxomas (and may be due to the production of the proinflammatory cytokine interleukin-6 by the myxoma). [medicinenet.com]

  At 32 weeks of gestation, she was admitted to our Department of Obstetrics with hypertension and severe back pain. In addition, she had unusual pigmentation and typical cushingoid features. [ncbi.nlm.nih.gov]

• Weight Gain

  CASE REPORT: We report the case of a 20-year-old patient with a history of weight gain, hirsutism, acne, secondary amenorrhea and facial lentiginosis. [ncbi.nlm.nih.gov]

  This syndrome causes weight gain in the face and upper body, slowed growth in children, fragile skin, fatigue, and other health problems. [ghr.nlm.nih.gov]

  Cushing syndrome usually presents in adolescence or young adult life with its classic features such as abnormal fat distribution, striae, easy bruising and hypertension; in children it may cause weight gain and growth arrest. [dermatologyadvisor.com]

• Congestive Heart Failure

  Although primary tumors of the heart are rare in all age groups, they are still important to consider in differential diagnoses of valvular disease, congestive heart failure, and arrhythmia. [emedicine.medscape.com]

  Congestive heart failure. Endocrine tumors may be characterized as disorders like over activity of the gland. The most common one is an ACTH-independent Cushing's syndrome caused by PPNAD. [epainassist.com]

• Short Stature

  Soljak MA, Aftimos S, Gluckman PD : A new syndrome of short stature, joint limitation and muscle hypertrophy. Clin Genet 1983; 23 : 441–446. 28. [nature.com]

  stature, craniofacial dysmorphism, and congenital heart defects B3GAT3 Muscular dystrophy-dystroglycanopathy FKTN Myelodysplastic syndrome, somatic TET2 Myoclonus Dystonie SGCE Myopathy due to myoadenylate deaminase deficiency AMPD1 Myotonia Congenita [meduniwien.ac.at]

• Surgical Procedure

  Medical Treatment Surgical Procedures Physical Modalities Excision of cutaneous myxomas, blue nevi and suspicious flat pigmented lesions Optimal Therapeutic Approach for this Disease The dermatologic management of Carney complex is straightforward. [dermatologyadvisor.com]

  Her mother’s past medical history included three other surgical procedures, including the removal of a lipoma on her back at the age of 18 months, right mastectomy for intraductal mammary carcinoma at the age of 52 years, and hysterectomy with bilateral [karger.com]

• Dyspnea

  They may thus cause cardiac outflow obstruction with symptoms ranging from fatigue and dyspnea to heart failure and sudden death; historically reported as high as 16% in CNC families. [jacc.org]

  He reported having worsening dyspnea on exertion for the preceding 2 to 3 months and was only able to walk a few feet without dyspnea. [amjcaserep.com]

  To the Editor: An 18-year-old man presented with right-sided weakness, exertional dyspnea, and palpitations. His medical history was significant for a left atrial myxoma that was excised 5 years before his current presentation. [amjmed.com]

  Case Presentation A 21-year-old female patient presented with progressive exertional dyspnea and irregular palpitations for 3 months. She had past surgical history significant for excision of a cutaneous myxoma in her left arm. [hindawi.com]

  Case 1 A 29-year-old woman with palpitations and dyspnea. The echocardiogram showed 2 tumors in the right ventricle (Figure 1), which were surgically resected. The histopathologic study confirmed the diagnosis of myxomas. [revespcardiol.org]

• Respiratory Distress

  He was a well-appearing man without respiratory distress. [amjcaserep.com]

  distress (SMARD1) IGHMBP2 Spinale Muskelatrophie (SMA) SMN1 Spinale und bulbäre Muskelatrophie Kennedy AR Spinocerebelläre Ataxie SCA1, SCA2, SCA3, SCA6, SCA7, SCA17 Spondylocostal dysostosis (AR) DLL3 Spondyloepiphyseal dysplasia with congenital joint [meduniwien.ac.at]

• Heart Failure

  The cardiac tumors are myxomas which can arise in any chamber of the heart. Although almost always benign, cardiac myxomas are associated with stroke from tumor embolism and with heart failure from obstruction of a valve. [medicinenet.com]

  The surgery was complicated by post-cardiotomy heart failure requiring an intra-aortic balloon pump, however she made a full recovery. [jacc.org]

  Cardiac myxomas - Although myxomas are benign tumors, they can completely abolish intracardiac flow and cause heart failure, stroke, or sudden death. For this reason, almost 50% of deaths in CNC are attributed to these tumors. [symptoma.com]

  Intracardiac myxomas in Carney complex are significant causes of cardiovascular morbidity and mortality through embolic stroke and heart failure. [ncbi.nlm.nih.gov]

  Up to 75–80% of these myxomas originate within the left atrium and can result in emboli, heart failure, or non-specific constitutional symptoms. [amjcaserep.com]

• Diastolic Murmur

  A III/IV mid-diastolic murmur was heard at the apex. Neurologic examination revealed right-sided hemiplegia, ipsilateral upper motor neuron facial nerve palsy, and expressive aphasia. [amjmed.com]

  Auscultation of the heart revealed a loud first heart sound and a mid-diastolic murmur with a soft systolic murmur at the mitral area, which increased on expiration, suggestive of predominant mitral stenosis and mitral regurgitation. [ijpmonline.org]

  Physical examination revealed a high jugular venous pressure and a diastolic murmur. An electrocardiogram showed atrial fibrillation. Laboratory investigations were within normal limits except for a low TSH and elevated free T3 and T4. [hindawi.com]

  A cardiac exam revealed normal heart rate and regular rhythm, normal S1 and S2 heart sounds without tumor plop, but a 2/4 low-pitch, rumbling diastolic murmur was appreciated at the left lower sternal border. [amjcaserep.com]

• Heart Murmur

  The physical examination revealed a heart murmur and a CT scan indicated multiple cerebral infarcts. [revespcardiol.org]

  Additional heart abnormalities that may occur in individuals with Carney complex include palpitations, diastolic heart murmurs and “tumor plop”, which is a distinctive sound related to the movement of a tumor within the heart. [rarediseases.org]

• Arthralgia

  The systemic symptoms (eg, fever, arthralgia, elevated sedimentation rate, lupuslike rashes) that accompany some myxomas may be due to the production of the proinflammatory cytokine interleukin-6 by the myxoma. [emedicine.medscape.com]

  Cardiac myxomas may lead to Arthralgia, fever, shortness of breath, joint pain, tumor plop, mitral regurgitation, signs of anemia, and diastolic rumble. [epainassist.com]

• Fracture

  We present a novel PRKAR1A gene germline mutation in a patient with severe osteoporosis and recurrent vertebral fractures. Clinical case report. [ncbi.nlm.nih.gov]

  Radiologic imaging revealed T8-T10 and L3-L5 vertebral compression fractures. [hormones.gr]

  A 21-year-old man was referred for evaluation with multiple spinal compression fractures and adenomas affecting both adrenal glands. [ekjm.org]

  Rev Chim. 70:3660–3662. 2019. 54 Sandru F, Dumitrascu MC, Albu SE, Carsote M and Valea A: Obesity and osteoporotic fractures. [spandidos-publications.com]

• Skin Lesion

  Specific for the disease skin lesions are present in more than half of the CNC patients. [ncbi.nlm.nih.gov]

  […] tags or other skin lesions, including lipomas and angiofibromas. [oxfordmedicine.com]

  Skin lesions are the most common CNC manifestation: lentigines are present in 70 to 75% of patients with CNC. Blue nevi are also typical of CNC. [genome.jp]

• Freckles

  The most characteristic features in this case are posterior laryngeal cleft and the presence of numerous freckles and lentigines in childhood. [ncbi.nlm.nih.gov]

  Suggestive or associated with CNC findings but not diagnostic are: (1) intense freckling (without darkly pigmented spots or typical distribution); (2) multiple blue nevi of common type; (3) café-au-lait spots or other ‘birthmarks’; and (4) multiple skin [oxfordmedicine.com]

  Carney complex variant: Families with trismus, pseudocamptodactyly, freckling and cardiac myxomas have been described with mutations in the MYH8 (myosin heavy chain 8) gene. [dermatologyadvisor.com]

  An autosomal dominant multiple neoplasia and lentiginosis syndrome, first described as the association of: (1) primary pigmented nodular adrenocortical disease (PPNAD), a pituitary-independent, primary form of hyperadrenocortisolism; (2) lentigines, freckles [medical-dictionary.thefreedictionary.com]

  Ephelides (freckles[6]). Pronounced e-FEE-le-DEEs.[7] LAMB LAMB: Lentigines. Focal melanocyte hyperplasia. Atrial myxomas. Mucocutaneous myxomas. Blue nevi. [librepathology.org]

• Hyperpigmentation

  […] 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]

  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]

  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]

  Tissue Neoplasms, Connective and Soft Tissue Neoplasms by Histologic Type Neoplasms Heart Neoplasms Thoracic Neoplasms Neoplasms by Site Heart Diseases Cardiovascular Diseases Abnormalities, Multiple Congenital Abnormalities Skin Abnormalities Melanosis Hyperpigmentation [clinicaltrials.gov]

• 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]

• Stroke

  We studied patients with strokes and cardiac myxomas that were hospitalized in our institution and elsewhere; a total of 7 patients with 16 recurrent atrial myxomas and >14 episodes of strokes were identified. [ncbi.nlm.nih.gov]

  Although almost always benign, cardiac myxomas are associated with stroke from tumor embolism and with heart failure from obstruction of a valve. Myxomas also may occur in the breast, testis, thyroid, brain, or adrenal gland. [medicinenet.com]

  Post clot retrieval, she was admitted into the stroke unit for supportive management. [heraldopenaccess.us]

  Women with Carney complex may be at a high risk for recurrent atrial myxomas that lead to multiple strokes. [22] Early identification of a female patient with Carney complex may facilitate stroke prevention. [emedicine.medscape.com]

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].

• Cortisol Increased

  However, 6 months after operation, 24- hour urine-free cortisol increased slightly (129.6 ug/day), causing us to consider resecting the contralateral adrenal gland. [kjim.org]

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]

Treatment of acromegaly with somatostatin analogs may also be used either as a primary treatment or as an adjuvant to trans-sphenoidal surgery. [statpearls.com]

The patient was examined for persistence of hypersomatotropism after partial resection of growth hormone secreting pituitary adenoma, followed by radiation treatment with Leksell γ knife and treated by somatostatin analogues. [endocrine-abstracts.org]

This patient received treatment with cabergoline and octreotide, but blood tests revealed high serum levels of growth hormone and insulin-like growth factor 1. [ccjm.org]

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

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

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

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]

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]

The discussion covers the phenotype spectrum, epidemiology, mode of inheritance, pathogenesis, and clinical profile of each condition, all of which is accompanied by a wealth of illustrations. [books.google.com]

[…] 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]

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]

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]

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

Bertherat, Molecular Analysis of the Cyclic AMP-Dependent Protein Kinase A (PKA) Regulatory Subunit 1A (PRKAR1A) Gene in Patients with Carney Complex and Primary Pigmented Nodular Adrenocortical Disease (PPNAD) Reveals Novel Mutations and Clues For Pathophysiology [onlinelibrary.wiley.com]

Similar articles Adrenal pathophysiology: lessons from the Carney complex. Groussin L, Cazabat L, René-Corail F, Jullian E, Bertherat J. Groussin L, et al. Horm Res. 2005;64(3):132-9. doi: 10.1159/000088586. Epub 2005 Sep 27. Horm Res. 2005. [pubmed.ncbi.nlm.nih.gov]

Prevention of secondary complications: Medical or surgical treatment of endocrine manifestations may prevent the metabolic abnormalities from Cushing syndrome or arthropathy and complications from acromegaly. [pubmed.ncbi.nlm.nih.gov]

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]

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