Carney complex - clinical case presentation and literature review

Introduction

Carney complex (CNC) is an extremely rare syndrome of multiple endocrine and non-endocrine neoplasia. Non-endocrine tumors manifestations include spotty pigmentation of the skin and mucous membranes, psammomatous melanocytic schwannomas, the presence of myxomas in the heart, skin, breast, and osteochondromyxomas. CNC also confers a predisposition to various tumors.  Endocrine manifestations include thyroid and gonadal tumors, growth hormone-secreting pituitary adenomas or somatotroph cell hyperplasia leading to acromegaly/gigantism, PPNAD (primary pigmented nodular adrenocortical disease) [1, 2].

The condition was first described in 1985 by Dr. J. Aidan Carney as the complex of myxomas, spotty pigmentation, and endocrine overactivity. In 1986 it was designated CNC, and in 1994 other authors used the term Carney syndrome [1-4]. Patients previously diagnosed with LAMB (lentigines, atrial myxoma, mucocutaneous myxoma, blue nevi) or NAME (nevi, atrial myxoma, myxoid neurofibroma, ephelides) are now more correctly classified as CNC [1]. By 2019, more than 750 cases had been reported worldwide [1, 5], of whom 63% were female and 37% male [1]. Age at diagnosis ranges from neonatal period to 50 years (median age is 20 years) [4]. The prevalence is estimated at approximately 1 in 200,000 and CNC is considered an orphan disease, with multiple diagnostic challenges, as a result, it is often under- or misdiagnosed [6].

Purpose of research. Presentation and analysis of a clinical case with Carney Complex, correlated with a systematic review of the specialty literature, to highlight the heterogeneity of clinical manifestations and facilitate early recognition of this rare pathology.

Case presentation

Patient X.Y,, a 54-year-old woman, was admitted to hospital in December 2022 with the following complaints: general weakness, dyspnea on moderate physical exertion, intermittent retrosternal discomfort, decreased visual acuity, vertigo, frequent headaches, apathy, and anxiety.

Disease history. The patient was diagnosed with acromegaly in March 2013. At that time, pituitary and peripheral hormone levels were measured, revealing an IGF-1 value of 871 ng/ml (reference range 101-267). Contrast-enhanced brain MRI revealed a mass in the left side of the adenohypophysis, measuring 9.5 mm in diameter, suggestive of a pituitary microadenoma with early invasion of the left cavernous sinus on the left, without signs of compression or infiltration of the internal carotid artery.

Resection of the pituitary adenoma was performed via a transfrontal approach. Postoperative histological examination, performed without immunohistochemistry, showed a pituitary adenoma composed of eosinophilic cells. One month postoperatively, IGF-1 was within the normal range. at 240 ng/ml (reference range 101-267). After 4 months, IGF-1 increases to 311 ng/ml (reference range 66-249) (Table 1) and Bromocriptine 2.5 mg/day was recommended. The patient discontinued the treatment on her own, because of worsening of headache and vertigo. Until 2022, the re-initiation of D2-agonists was attempted several times, because IGF-1 remained persistently slightly above the upper limit of the normal, however, the patient discontinued the administration each time for the same reasons. Whenever IGF-1 was measured (Table 2), contrast-enhanced pituitary MRI was also performed, followed by neurosurgical consultation, with no confirmation of recurrence. Other pituitary and peripheral hormones were measured over the years, with no abnormalities (Table 2). The outpatient chart was analyzed, revealing the periodic performance of several thyroid ultrasound examinations from 2013 to 2022, showing multiple cysts and 2-4 hypoechoic nodules in both lobes, without other abnormalities.

Abdominal and kidney ultrasonography in July 2015, showed a 13 mm hepatic cyst in segment VI and a 14 mm cyst in the right kidney. By December 2022, the hepatic cyst had increased to 31 mm and the right renal cyst to 20 mm.

In 2018, she consulted a cardiologist for the first time with the following complaints: dyspnea on moderate exertion, retrosternal discomfort, and elevated blood pressure (180/110 mm/Hg). Antihypertensive treatment was prescribed and she attended the cardiologist periodically for treatment adjustments.

Family history: mother died at 35 from breast cancer; her father died at 45 from a cardiovascular disease but could not specify the exact cause.

Physical examination on admission in December 2022: soft tissue hypertrophy of the face (nose, lips, tongue, and supraorbital region), mild bilateral proptosis, diastemas, mandibular prognathism, and elongation and thickening of the fingers. A moderate number of melanocytic nevi were diffusely distributed over the body surface. Cardiac auscultation revealed rhythmic and accentuated heart sounds, diastolic murmur at the mitral area with variable intensity depending on the patient’s position. Blood pressure was 170/100 mmHg and heart rate 110 bpm.

Paraclinical investigations in December 2022: TSH, free T4, prolactin, ACTH, basal serum cortisol were within reference ranges. Thyroid ultrasonography revealed multiple cysts with a maximum diameter of 3 to 5 mm, bilaterally and a 6 mm hypoechoic nodule, , with macrocalcifications in the right lobe. The laterocervical lymph nodes were unchanged. Renal ultrasonography revealed a 44 mm cystic lesion in the right kidney. The adrenal glands were not visualized. She was evaluated in hospital by a neurologist, who recommended nootropic and cerebrovascular agents; the neurological symptoms improved slightly by the end of the treatment course. Blood pressure nevertheless remained between 150 and 180 mmHg systolic and 100 and 110 mmHg diastolic on daily measurement, with the patient receiving four classes of antihypertensive drugs at maximum doses. Echocardiography performed during hospitalization detected a 20 × 30 mm mass attached to the interatrial septum, suggestive of a left atrial myxoma; ejection fraction was 63%, and no valvular regurgitation was identified (Figure 1). Following a multidisciplinary discussion with interventional cardiologists and cardiac surgeons, coronary angiography was recommended as a preoperative preparation procedure. She was discharged with recommendations to have IGF-1 measured and contrast-enhanced pituitary MRI performed to continue antihypertensive treatment prescribed by the cardiologist, and to return with results of the investigations. A syndrome of multiple endocrine and non-endocrine neoplasia, namely Carney complex, was suspected.

In January 2023, minimally invasive cardiac surgery was performed, with excision of the left atrial mass en bloc with the  interatrial septum is performed, followed by repair of the resulting of atrial septal defect with an autologous pericardial patch. Postoperative histopathological examination confirmed the diagnosis of cardiac myxoma. After the intervention, the patient was scheduled for a contrast-enhanced brain MRI, but did not undergo it, as she was unable to provide the radiologists with the discharge summary documenting the cardiac procedure and believed that a foreign body had been implanted to close the atrial septal defect. Non-contrast brain CT was performed instead (Figure 2) and showed no evidence of recurrence. IGF-1 was not measured due to lack of financial resources.

In July 2023, she developed acute calculous cholecystitis and underwent open cholecystectomy.

In March 2024, the patient was admitted again to the Endocrinology department. Her complaints on admission were headache, dizziness, vertigo, intermittent retrosternal discomfort, a slight change in facial features compared with the previous year, asthenia, and mood disturbances. On initial examination, in addition to the findings recorded at the previous admission, a keloid post-cholecystectomy scar was noted below the right costal margin (Figure 3). The patient reported that her facial changes had progressed over the past year, whereas her finger and shoe sizes had remained unchanged. Because IGF-1 is not covered by national health insurance, the urgent need to measure it in order to decide on medical treatment was discussed with her, and the absence of contraindications to contrast-enhanced pituitary MRI was explained.

Laboratory and imaging data from March 2024: TSH, free T4, anti-TPO antibodies, calcitonin, ACTH, basal serum cortisol and prolactin were within normal limits. C-peptide was elevated, HbA1C was 5.85% (normal range <5.6%) is in interval for prediabetes, HOMA IR-3.5 (normal <2.0-) indicating insulin resistance. On oral glucose tolerance testing, fasting glucose was 5.2 mmol/L, 1-hour glucose 10.9 mmol/L, and 2-hour glucose 8.4 mmol/L, the elevated 1-hour and 2-hour values confirming impaired glucose tolerance. In the suppression test with 1 mg of dexamethasone, basal serum cortisol was inhibited, presenting a value below 50 nmol/l. Abdominal ultrasonography showed a 40 mm cystic lesion in segment VI of the liver. Renal ultrasonography showed a 50 mm cyst at the lower pole of the right kidney. The adrenal glands were not visualized by ultrasound. In the right thyroid lobe, several cysts up to 6.5 mm and 2 subcentimeter hypoechoic nodules with central microcalcifications and perinodular vascularization were observed, classified as TIRADS 3. The cervical lymph nodes were not pathologically changed. Echocardiograghy was normal with no masses,  , interatrial septa defect or valvular regurgitation (Figure 4). IGF-1 was 218 ng/mL (reference range 67.3-201) (Table 2).

Discussion

CNC is caused by inactivating mutations in the tumor suppressor gene PRKAR1A, which encodes the type 1α regulatory subunit (R1α) of protein kinase A (PKA). Variants in PDE11A have also been implicated [7]. Activating mutations in the PRKACA and PRKACB genes have also been associated with CNC, the former being associated with Cushing's syndrome and the latter with acromegaly [8]. Inactivating mutations in the PRKAR1A gene on chromosome 17q22-24 are found in the majority of patients with CNC1 (Carney complex type 1), whereas a second locus on chromosome 2p16 is associated with CNC2 (Carney complex type 2). The condition is inherited in an autosomal dominant manner in 70% of cases, while up to 30% of cases arise sporadically from a de novo mutation [1, 9].

Endocrine manifestations. PPNAD. The most common endocrine manifestation of CNC is PPNAD, detected in 25 - 60% of cases [1, 9]. Of all patients with PPNAD, approximately 80% have CNC, while 20% have isolated PPNAD, where other lesions associated with CNC could not be detected [5]. The age of onset is usually in the second or third decade of life. Several cases of adrenocortical carcinoma have been diagnosed concomitantly. The true incidence of PPNAD is considered to be underestimated because almost all patients with CNC on histological examination following necropsy were identified as having PPNAD, despite the fact that 1 in 3 patients had normal adrenal appearance on computed tomography [3]. ACTH-independent Cushing's syndrome (CS) is estimated to occur in about half of patients with CNC [1]. Hypercortisolism develops progressively over the years and can be periodic: cyclic or atypical; subclinical ((more recently termed mild autonomous cortisol secretion, MACS) [1, 3]. PPNAD is characterized by adrenal glands of normal or enlarged size containing bilateral, pigmented nodules, smaller than 1 cm, delimited by atrophied adrenal cortical tissue. It occurs more frequently in women (71% of cases) with a average age of diagnosis of 30 years, but in men it is identified at an average age of 46 years. Over 80% of people with CNC and PPNAD have inactivating mutations of the PRKAR1A gene. Hypercortisolism can be diagnosed by measuring free urinary cortisol in 24-hour urine, salivary cortisol at midnight, 1 mg dexamethasone suppression test (Liddle test). Diagnosis can be more difficult in cases of cyclic Cushing syndrome (14%) or subclinical (19%) [5]. Drug treatment with ketoconazole or mitotane has rarely been used, most patients are treated radically by bilateral adrenalectomy [1].

Thyroid tumors. Thyroid involvement occurs more frequently in CNC than in the general population and can range from follicular hyperplasia and/or cystic changes to thyroid cancer. The average age of onset of thyroid changes is 10 years [7]. More than 60% of individuals with CNC have thyroid changes on ultrasonography [1], of which 75% have thyroid cysts and nodules in 25% with a malignancy rate of up to 10% [3]. Follicular and nodular hyperplasia, follicular adenoma, cystic changes, papillary and follicular thyroid cancer are the predominant types of thyroid tumors commonly associated with CNC. PRKAR1A mutation has been shown to have a direct impact on thyrocytes and also on other endocrine cells. Familial non-medullary thyroid carcinomas (FNMTC) account for 4–8% of all primary thyroid cancers. Patients may be asymptomatic, or may present with hyperthyroidism [7, 10]. Fine-needle aspiration of thyroid nodules is suggested in cases that appear suspicious, and thyroid cancer will be approached in relation to the histological type [7].

Pituitary tumors. Acromegaly occurs in up to 10–12% of patients of CNC. Up to 80% of individuals without evidence of pituitary adenoma on imaging have elevated GH, IGF-1, or prolactin levels and an abnormal GH response to a 75 g oral glucose load. Up to 64% of patients with CNC have concomitant secretion of GH and prolactin, but prolactinomas are rare [1]. GH-secreting adenomas usually do not become apparent before the third decade of life [3]. They are more common in women, developing one to two decades earlier than sporadic cases. Histologically, these somatotroph lesions may be either adenomas or hyperplasia [11]. Adenomas in CNC are more commonly microadenomas, often multiple and surrounded by hyperplasia, but there are also cases of very aggressive and invasive macroadenomas [5]. The treatment of choice for acromegaly is surgery, but drug treatment with a somatostatin analogue or a GH receptor antagonist may be considered [1, 12, 13], and cases resistant to drug treatment have also been described [11].

Ovarian impairment. Ovarian involvement in CNC occurs in 14-66% of cases, after puberty. The most common lesions are ovarian cysts and epithelial ovarian tumors (serous cystadenomas and cystic teratomas). Ovarian carcinomas (mucinous adenocarcinoma or endometrioid carcinoma) are rare [7].

Testicular tumors. Large cell calcifying Sertoli cell tumors (LCSCST) are stromal tumors present in at least 41% of men with CNC [7] and in some sources up to 75% [9]. Compared with sporadic LCSCST, LCSCST in CNC tends to be multicentric and bilateral. These tumors can be identified on ultrasonography as multiple homogeneous echogenic masses with smooth contours containing microcalcifications. LCSCST are usually asymptomatic, but occasionally they can be functional, favoring the appearance of gynecomastia by increasing the expression of P-450 aromatase [7]. The tumors gradually progress to replace normal testicular tissue, with reduced fertility and a malignant potential of up to 17% [9].

Non-endocrine manifestations of CNC

Skin damage. Skin damage is extremely important in CNC, as it can contribute to the identification of 3 major diagnostic criteria – cutaneous lentigines, pigmented nevi (blue or epithelioid blue nevi (EBN)), cutaneous myxoma.

Lentigines are identified in up to 80% of cases, they are brown to black, poorly circumscribed, flat, usually less than 0.5 cm in diameter, and are often distributed around the lips, eyelids, ears, and genital areas [1, 3]. Their clinical appearance of lentigines can vary depending on ethnicity, it has been observed that in African-Americans they can be slightly elevated, like papules, dark in color and resemble nevi. On histological examination, lentigines present with a hyperpigmentation of the basal cell layer associated with melanocytic hyperplasia and hypertrophy. They are histologically differentiated from ephelides because the pigmentation of ephelides is the result of increased melanin production without melanocytic hyperplasia. Lentigines can be the first sign of CNC since birth, but they do not present the typical characteristics and localization until prepuberty [3]. It is difficult to distinguish lentigines arising in CNC from those of solar etiology. However, compared with age-related skin lesions, lentigines associated with Carney complex tend to fade with age, especially after the age of 40 [1].

Blue nevi are seen in approximately 40% of patients. They are blue in color with an ovoid or star-shaped appearance, a smooth surface, and a variable distribution [14, 15]. EBN is a subtype of blue nevi that can be frequently seen in CNC, but is rare in the general population. They are intensely pigmented, have poorly circumscribed proliferative regions, and are associated with dermal fibrosis [1].

Cutaneous myxoma is a benign skin lesion that may be the first sign of CNC [16, 17], occurs in 30-55% of patients and usually appears before adulthood, but can recur in older patients [1]. Its incidence is probably underestimated, as it is often classified as a “common skin lesion” or an excess of collagen (fibromas, collagenomas). They are usually located on the eyelids, nipples, ears but can also be observed in other areas of the body. They are asymptomatic, small (often less than 1 cm in diameter) [16], opalescent or dark pink in color, and are diagnosed at an average age of 18 years [3]. However, in 2018, a case was reported with the largest cutaneous myxoma of 15 cm in a young patient (18 years) with CNC [14]. In more than 70% of patients, cutaneous myxomas have multiple locations and can recur. On histological examination, they are predominantly present in the dermis or extremely rarely in the subcutaneous tissues, they are well demarcated, with an abundant myxoid stroma, prominent capillaries, hypocellular and sometimes show lobulation. Early diagnosis is essential, because in over 80% of patients with CNC identified with life-threatening cardiac myxoma, the first manifestation of the disease was cutaneous myxoma. When a cutaneous myxoma is suspected, it is necessary to perform histological examination to confirm the diagnosis [3].

Other skin manifestations in CNC may include: café-au-lait spots that are usually less pigmented than those identified in McCune Albright syndrome; depigmented lesions that may be present at birth or develop during childhood; melanocytic and atypical nevi and the so-called Spitz nevus [3]. Any cutaneous and subcutaneous lesion, pigmented or not, or any focal swelling of unknown cause, requires a thorough dermatological examination, as dermatological elements are among the earliest and most easily detected lesions in CNC [10].

Cardiac tumors. Atrial myxoma is the most common benign cardiac tumor, often occurring sporadically, but sometimes occurring within the CNC [8]. It can be diagnosed in 20–40% of CNC cases [1, 15], at an average age of 20 years [1], but the age of onset can vary between 3 and 67 years [5]. They can occur in both sexes in any chamber of the heart and can be single or multiple [15] compared to sporadic ones that occur more frequently in the left atrium and in older women [2, 5]. Patients present with symptoms determined by embolic phenomena or intracardiac obstruction of blood flow that can subsequently lead to sudden death [1]. Cardiac myxomas are responsible for more than 50% of CNC mortality [1, 4]. Thus, they must be surgically removed, but have a high potential for recurrence (44%) despite surgical resection [9, 14].

Breast tumors. Breast involvement in CNC usually occurs after puberty and may include lobular or nodular myxomatosis, myxoid fibroadenomas, or ductal adenomas [9, 15]. Mammary myxomas occur in 20% of women with CNC and are frequently bilateral and multiple [1, 5, 15].

Bone tumors. Osteochondromyxoma is a rare myxomatous bone tumor that affects 1% of patients with CNC. They tend to be locally invasive and to recur after surgical removal [9]. They appear before the age of 2 years and have been observed to occur predominantly in long bones (diaphysis) and small flat bones (nasals) [1, 15]. Vertebral nodules may occur in 31.6% [9].

Psammomatous melanotic schwannoma. Psammomatous melanotic schwannomas (PMS) may be mistaken for malignant melanoma and occur in 8-10% of cases within the CNS. They can be located in any region of the central or peripheral nervous system, most commonly in the gastrointestinal tract (esophagus, stomach, rectum) and the paravertebral sympathetic chain. Symptoms of radicular pain caused by tumor compression of spinal nerves may occur [9]. It can metastasize in 10% of cases to the liver, lungs, brain [1, 15], in some sources up to 20% are potentially malignant [18]. PMS are difficult to treat tumors due to their location in the nerve roots along the spine, which makes them frequently inoperable [1].

Ocular manifestations. Ophthalmic involvement in CNC was first described by Kennedy et al. It is characterized by the appearance of facial and eyelid pigmented lesions (lentiginosis) in 70% of patients, pigmented lesions in the caruncle or semilunar fold of the conjunctiva in 27%, and palpebral myxomas in 16% of cases. Other ocular lesions identified in patients with CNC are conjunctival myxomas and rarely uveal melanotic schwannomas [9, 19].

Other tumors. Pancreatic neoplasms can be identified in up to 2.5% of cases of CNC and include acinar cell carcinoma, adenocarcinoma, intraductal pancreatic mucinous neoplasm. Other lesions that have been described in CNC include mixed parotid tumor, bronchogenic cyst, hepatocellular adenoma and carcinoma, colonic, gastric, and retroperitoneal fibrous histiocytomas, and most recently fibrolamellar carcinomas of the liver and hepatic and renal cysts [1].

The diagnosis of CNC is established when at least 2 major criteria  are present, but these must be confirmed biochemically, histologically and by imaging. The diagnosis can also be made when only one major criterion is present and the patient is identified as carrying a PRKAR1A gene mutation or has a diagnosed first-degree relative (Table 3) [3, 4, 7, 8].

Surveillance of patients with CNC differs according to age. In adolescents and adults, annual echocardiography (this investigation may be necessary twice a year in those with a history of excised myxoma), testicular or ovarian ultrasonography, thyroid ultrasonography, measurement of serum IGF-1 levels [2, 9], skin inspection, and measurement of prolactin, urinary free cortisol and other tests depending on symptoms and clinical manifestations [9]. In prepubertal children, annual echocardiography (every 6 months in those with a history of excised myxoma) and testicular ultrasonography in boys [2, 9], and monitoring of growth rate are recommended [9]. If assessment of growth rate and pubertal staging indicates other pathologies, it is recommended to perform tests appropriate to the suspected pathology. When PPNAD is suspected, salivary or urinary free cortisol measurement and/or the dexamethasone suppression test (Liddle test) and unenhanced adrenal computed tomography are indicated. For gigantism/acromegaly, serum IGF-1 measurements, contrast-enhanced pituitary MRI and GH suppression during glucose tolerance test are indicated. For psammomatous melanotic schwannoma, magnetic resonance imaging of the brain, spine, chest, abdomen, retroperitoneum and/or pelvis may be required [2].

Clinical and biochemical evaluation remains the cornerstone of the diagnosis of CNC. Genetic testing for PRKAR1A mutations is not currently recommended in all patients with CNC, but may be indicated for the detection of affected patients from families with known mutations of the same gene, to avoid unnecessary medical surveillance of non-carriers [2].

Prognosis. Cardiovascular involvement carries the highest risk of mortality in CNC (57%), particularly cardiac myxoma and cardiac surgical complications. Other important causes of death are metastatic or intracranial psammomatous melanotic schwannoma (14%), metastatic malignacy (14%), and non-cardiac postoperative complications (12%) [2].

In our patient, the features of CNC appeared later than is usually reported, but there are reports in the literature of CNC being diagnosed in the fourth and fifth decades of life [4]. [4]. Identification of patients with CNC is a real challenge for the endocrinologist, since it is an extremely rare disorder, with approximately 750 cases reported worldwide by 2019 [1, 5], and since the clinical criteria necessary for diagnosis may appear progressively throughout life and fall within the scope of several medical specialties.

The major criteria that initially formed the basis for establishing the diagnosis in this clinical case were the detection in 2013 of a GH-secreting pituitary adenoma, and later in 2022 of a left atrial myxoma, both formations being confirmed histologically postoperatively, a mandatory aspect for validating these criteria (Table 3).

Another major criterion identified is the ultrasonographic presence of hypoechoic nodules and multiple thyroid cysts [3], documented since 2013, when the diagnosis of acromegaly was made, without establishing the interconnection between these two nosological entities. To validate this criterion, evidence is required in a young subject (Table 3), in 2013 the patient was 46 years old, but the appearance of these nodules and cysts could have been long before the first ultrasonography in 2013.

Skin examination revealed a diffuse distribution of a moderate number of melanocytic nevi on the body surface, and retrospective analysis of medical documentation also identified surgical excision of a blue nevus. When the diagnosis of CNC was established in 2022, the patient was at an age at which, according to data from the specialized literature, pigment spots can fade, especially in people of 40 years old [1].

To identify PPNAD, another major criterion for the diagnosis of CNC, paraclinical screening for hypercorticism was performed using the 1 mg dexamethasone test, with cortisol being within the reference range (< 50 nmol/l), with the subsequent recommendation to perform a unenhanced CT of the adrenals. However, the apparently normal appearance of the adrenals on imaging investigations does not definitively exclude the presence of PPNAD because, according to some studies, almost all patients with CNC on histological examination following necropsy were identified as having PPNAD, despite the fact that 1 in 3 patients on computed tomography had normal adrenals [3]. Even a negative result on the 1 mg dexamethasone test does not exclude cyclic hypercorticism [1, 3]. Phenotypically, the patient does not present features of Cushing’s syndrome, but needs to be evaluated periodically to identify clinical manifestations suggestive of hypercorticism.

Follow-up is vital for patients with CNC for early detection of endocrine and non-endocrine neoplasms with subsequent decision-making on therapeutic management in order to increase quality and life expectancy.

According to surveillance recommendations, the patient underwent echocardiography every 6 months after minimally invasive cardiac surgery excision of the left atrial myxoma, aiming at early detection of a potential recurrence, which occurs in 44% of cases [9, 14]. Dynamic imaging results excluded recurrence of the cardiac myxoma.

The patient did not present any symptoms characteristic of hyperglycemia, but since elevated IGF-1 can induce diabetes mellitus associated with acromegaly, HbA1C (5.89%) and OGTT with values characteristic of prediabetes were measured. The elevated values, above the reference limits, of C-Peptide and the HOMA-IR index confirmed the presence of insulin resistance at a BMI of – 23.8 kg/m2. It was decided to intervene only by optimizing the lifestyle, with monitoring of HbA1C over 3-6 months, with subsequent reevaluation of the treatment.

Since CT is not the investigation of choice in the evaluation of pituitary mass formations, repeated evaluation of the pituitary structure by contrast-enhanced brain MRI is recommended. Analyzing the history of the disease, the patient presented with IGF-1 above the upper limit of normal for over 10 years, and repeated MRIs during this time interval did not reveal a relapse, there being the probability of pituitary somatotropic cell hyperplasia [11]. Although D2 agonists can be used as monotherapy in mild forms of acromegaly, the patient reported adverse reactions to the administration of both bromocriptine and cabergoline, with multiple discontinuations of treatment. For this reason, together with the development of a keloid scar at the cholecystectomy incision 6 months after surgery and the patient's report of a change in facial features, octreotide LAR 10 mg intramuscularly every 4 weeks was initiated, with IGF-1 to be measured 3 months after starting treatment. The therapeutic goal is normalization of IGF-1 for age [12, 13].

CNC is transmitted in an autosomal dominant manner, hereditary or through the sporadic occurrence of a de novo genetic mutation [1, 9]. In the context of the impossibility of performing genetic tests on the patient's parents, we cannot demonstrate Mendelian transmission, however, the sudden death of the father from cardiovascular causes, at a young age (45 years), raises suspicions. The probability that her descendants will also be identified with CNC is 50-100%. Genetic testing was recommended, if possible, to be performed by both the patient and first-degree relatives, despite the fact that genetic testing is found among the additional criteria for establishing the diagnosis (Table 3). At the same time, periodic clinical and paraclinical evaluation of first-degree relatives is recommended, for the early identification of the presence of characteristic CNC manifestations.

Conclusions

Carney complex is a rare multisystem syndrome that may remain unrecognized due to its heterogeneous presentation. Early recognition is crucial for timely screening for cardiac myxoma and appropriate long-term surveillance.

Reporting rare cases, together with synthesis of the available scientific data, may increase awareness of such conditions among medical professionals.

Competing interests

None declared

Authors’ contributions

BoE and GO conceived the study, conducted the literature review and analysis, and drafted the manuscript. BiE supervised the research as academic coordinator, contributed to the study design and data interpretation, and critically revised the manuscript. All authors reviewed and approved the final version of the manuscript.

Ethics approval

Not needed for this study

Acknowledgements and funding

No external funding.

Provenance and peer review

Not commissioned, externally peer reviewed.

Authors’ ORCID IDs

Borș Elena – https://orcid.org/0009-0001-7296-0620

Bivol Elena – https://orcid.org/0009-0004-4040-7048

Gușanu Olesea – https://orcid.org/0009-0002-4976-6579

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