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Carney Complex

Lamb Len/atr+muco+blue Naev

Carney complex is a rare genetic disease comprised of various cutaneous lesions, multiple endocrine tumors, atrial myxomas and other associated features. A detailed and comprehensive clinical, biochemical, and imaging workup is necessary in order to identify the constitutive features of this condition and make the diagnosis.


Presentation

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]
  • […] hyperplasia and adenomas not dependent on growth hormone–releasing hormone Signs and symptoms Skin: Pigmentation, including blue nevi of the face, lips, sclera, trunk, or genital mucosa Cutaneous myxomas Generalized hyperpigmentation, obesity, striae, or cushingoid[emedicine.com]
Collapse
  • 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]
Plethora
  • Complete regression of seborrhea, acne, and plethora was observed after 8 weeks of treatment (cumulative dose 95 g). Regular menses returned after 13 weeks (cumulative dose 197 g, plasma MT 8 microg/ml).[ncbi.nlm.nih.gov]
Aspiration
  • We present a unique case and literature review of CNC in which two neoplasms characteristic of this complex were initially diagnosed through cytological fine needle aspirate specimens, leading to the identification of CNC, with subsequent surgical and[ncbi.nlm.nih.gov]
Abdominal Pain
  • Abstract A woman with Carney complex presented at the age of 22 years with abdominal pain and hirsutism.[ncbi.nlm.nih.gov]
  • pain Total pancreatectomy c.891 3 a g heterozygous Skip exon 10 c.891 3a g homozygous Lentiginosis, large-cell calcifying Sertoli cell tumor Deceased at 67 3 F/75 Abdominal pain None (biopsy–autopsy) No mutation (polymorphism variant: c.349 5dup) NA[doi.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]
Diplopia
  • A 34-year-old woman presented with odontalgia, right V3 hypoesthesia, V2 paresthesia, and diplopia. Magnetic resonance imaging scans of the brain revealed a small tumor with homogenous contrast in the right trigeminal pathway.[ncbi.nlm.nih.gov]
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]
  • 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]
  • 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]
  • ., autosomal dominant condition characterized by spotty skin, hyperpigmentation or lentiginosis; myxomas (mostly benign) mainly in skin and heart, noncancerous connective tissue tumors; nerve sheath tumors or schwannomas and cancerous or benign tumors[epainassist.com]
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]
Paresthesia
  • A 34-year-old woman presented with odontalgia, right V3 hypoesthesia, V2 paresthesia, and diplopia. Magnetic resonance imaging scans of the brain revealed a small tumor with homogenous contrast in the right trigeminal pathway.[ncbi.nlm.nih.gov]

Workup

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].

Nephrolithiasis
  • Medical history was significant for chronic hypertension, nephrolithiasis, and an atrial myxoma excised in 2011. She had Cushingoid features, an elevated 24-hour urine free cortisol, and a cutaneous myxoma.[ncbi.nlm.nih.gov]

Treatment

  • 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

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

Etiology

Epidemiology

  • 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]
  • (See Epidemiology and DDx.) While myxomas are usually sporadic, several familial, autosomal dominant conditions that combine lentiginosis and cardiac myxomas have been described.[emedicine.medscape.com]
Sex distribution
Age distribution

Pathophysiology

  • 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]
  • ., 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: Augmented PKA signaling is associat Horvath et[genedx.com]

Prevention

  • 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]

References

Article

  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.

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Last updated: 2019-06-28 12:26