Abstract
Background/Aim: Carney complex (CNC) is a rare autosomal dominant tumor-predisposition syndrome with variable expression. Its main features are pigmentary skin lesions, soft-tissue myxomas, and endocrine overactivity or tumors. There is occasional overlap with other syndromes, and oligosymptomatic cases may escape diagnosis. This report describes the long journey of a patient until the diagnosis of CNC was finally made after a thorough diagnostic workup. Case Report: The female patient was referred for treatment of a subcutaneous tumor of the lower abdomen. Medical reports detailed previous excisions of fibroma, neurofibroma and myxoma, and a malignant tumor of the cerebellopontine angle. The resected subcutaneous tumor was a myxoma. The identification of a previously unknown frameshift mutation in the gene for protein kinase cAMP-dependent type I regulatory subunit alpha (PRKAR1A) in the patient confirmed the diagnosis of CNC. Conclusion: Patients with CNC may have highly variable clinical findings. Some rare lesions in CNC are more commonly recorded in other syndromes, making early diagnosis difficult in some cases. Genetic testing greatly facilitates diagnosis.
The rare diseases grouped under the umbrella term ‘Carney complex’ (CNC) are primarily myxomas, spotty pigmentation, and endocrine overactivity or tumors (1). The phenotype of the autosomal dominant inherited disease is highly variable. Oligosymptomatic patients may escape diagnosis. Diagnosis is predominantly made based on differently weighted symptoms and findings (1, 2). However, individual findings known in other and more common genetic disorders which have overlapping phenotypes may hamper diagnosis of CNC (3, 4). Molecular genetics have significantly improved CNC diagnosis (2). A particular type of nerve sheath tumor, psammomatous melanotic schwannoma (MS), arises in about 10% of patients with CNC. In an individual with unusual findings assuming a CNC diagnosis, published diagnostic criteria should be applied (1, 2). This report documents the phenotype of the disease in a particular case, the verification of CNC diagnosis, and the treatment measures taken.
Case Report
A 35-year-old female patient had developed an abdominal subcutaneous tumor that had grown slowly over the previous years and was limiting her physical mobility. The mass had repeatedly been suspected to represent a neurofibroma during follow-up (inspection, imaging). However, previous assessments of the patient had not shown any other clinical findings supporting the diagnosis of neurofibromatosis. Notably, the patient had experienced several unusual tumors that made a genetic cause of the disease probable. The current admission was for surgical treatment of the abdominal lesion and for diagnosis of the underlying disease.
Medical history. In childhood, “fibromas” of the eyelid, palate, and chin had been removed. Histological findings of these lesions were not available. Several cutaneous neurofibromas with myxoid stromal component (localization: mons pubis, abdomen, right thigh) were excised at the age of 22 and 27 years. Several times, the medical reports favored the diagnosis of neurofibromatosis from the summary of reports and respective current findings. At the age of 27 years, multiple fibromas of both breasts were excised. The breast fibromas also had a pronounced myxoid stromal component. At the age of 21 years, cranial magnetic resonance imaging (MRI) was performed because the patient had complained of increasing tingling paresthesia for about 2-3 months. There was a facial hyperesthesia in the region of the first and second branches of the right trigeminal nerve, without other neurological deficits. MRI revealed a T2-weighted inhomogeneous hyperintense, T1-weighted clearly hyperintense mass of the cerebellopontine angle (CPA), which had an hourglass shape located around the origin of the right trigeminal nerve and extended from the posterior to the middle cranial fossa. After contrast application, the tumor exhibited homogeneous enhancement. The tumor was adjacent to the aqueduct from the lateral side. The fourth ventricle appeared slightly compressed. There was no evidence of liquor circulatory disturbance. Radiological findings were judged to be trigeminal neurinoma. One month later, the lesion was resected (R2). Intraoperatively, the tumor arose in the meninges of the right CPA and Meckel’s cave and was diagnosed a melanocytic tumor. Immunohistochemical examination characterized the tumor as epithelial membrane antigen (EMA)-negative, cluster of differentiation 57 (CD57)-negative, melan A, human melanoma black 45 (HMB45)-positive, and the Molecular Institute Borstel clone no. 1 (MIB1) index was high (≤20%). From these findings, the final diagnosis of malignant melanoma (MM) was inferred. Therefore, the affected region was externally irradiated (39 Gy, single dose 3 Gy) followed by chemotherapy (temozolomide). Ten years later, the patient developed a cerebral infarction in the supply area of the left posterior cerebral artery. While initial dysarthria completely regressed after rapid lysis therapy, the ophthalmological examination confirmed permanent quadrant anopsia of the right side. During the search for causes of thromboembolic cerebral vascular insult, a mass of the left atrium was discovered by echocardiography (3×1.3 cm2). The tumor was removed and histologically classified as myxoma. In the further course, the patient developed repeated vertigo and had oppressive headaches. Finally, idiopathic intracranial hypertension was diagnosed. Endocrinological assessment showed type 2 diabetes mellitus, adrenocorticotropic hormone-independent hypercortisolism, vitamin D deficiency, and elevated blood pressure. Sonography of the euthyroid thyroid gland showed an organ with a volume in the normal range, and several small cysts.
Physical findings. On admission, the obese patient (79.9 kg, with a height of 156 cm) had an unsteady gait. The patient did not have any of the skin findings of neurofibromatosis. Cutaneous and subcutaneous tumors were palpable in the periareolar region of both breasts. A prominent tumor was visible on the left side of the mons pubis. A small pedunculated cutaneous tumor was present on the left labium minus.
Imaging. A whole-body positron-emission tomography-computed tomography performed 4 years earlier detected a left para-medial subcutaneous hypogastric/inguinal tumor (size: 5.8×5.3 cm2, standardized uptake value=3.5). The lesion was classified a neurofibroma. Small thickenings of the medial and lateral limbs of the right adrenal gland (probably micro-nodules) were identified on computed tomography.
Postoperative residues but no local tumor recurrence were evident on current cranial computed tomography. Newly diagnosed, small convex lesions on the left parietal and right frontal regions were suspected of being meningioma. Current cranial MRI showed multiple old infarctions of the posterior circulation on both sides in the cerebellum, thalamus and on the left lateral ventricle.
Therapy. Under general anesthesia, the inguinal tumor was completely removed. Protrusions on the surface resembled a multi-cystic lesion. The cut surfaces of the bisected spherical tumor showed extensive layers of organized hemorrhage (marginal and central). The small pedunculated solid tumor of the vulva had a homogeneous smooth white cut surface resembling schwannoma. Healing was uneventful.
Histology. The lesions comprised lobular, hypocellular tumors consisting of spindle-cells with round to oval nuclei without significant atypia or mitotic activity (MIB1 index: <1%, CD34+; EMA, pan-cytokeratin AE1/AE3, smooth muscle actin, desmin, S100, C-kinase potentiated protein phosphatase-1 inhibitor 17, and erythroblast transformation-specific related gene: all negative). Both tissue specimens were diagnosed as superficial angiomyxoma. Extensive, organized hemorrhage was confirmed in the inguinal tumor.
Genetics. A DNA sample from blood leukocytes was exome-sequenced on a NextSeq550 (Illumina, San Diego, CA, USA) after enrichment using a Twist Human Core Exome plus RefSeq Panel (TWIST Bioscience, San Francisco, CA, USA). Targeted analysis of several clinical candidate genes [HUGO Gene Nomenclature Committee HGNC: multiple endocrine neoplasia 1 (MEN1), myosin heavy chain 8 (MYH8), neurofibromin 1 (NF1), merlin (NF2), leucine zipper-like transcription regulator 1 (LZTR1), protein kinase cAMP-dependent type I regulatory subunit alpha (PRKAR1A), serine/threonine kinase 11 (STK11)] was performed using the varvis 1.17.1 software package (Limbus Medical Technologies GmbH, Rostock, Germany). A novel heterozygous frameshift variant of the PRKAR1A gene was detected (chr17: 66521060; NM_212472.2: c514dup, p.(Asp172Glyfs*2), which was classified as pathogenic, thereby confirming the diagnosis of CNC, type 1 (#160980). All other genes examined had no pathogenic findings.
The patient consented to the examinations in accordance with the German Genetic Diagnostics Act (Gendiagnostikgesetz – GenDG) and the publication of the anonymized data. The examinations were carried out in accordance with the Declaration of Helsinki and were approved by local laws (HmbKHG, §12 - Hamburg Health Service Act).
Discussion
The report describes the long-term disease course of a patient suffering from CNC. Several manifestations in this case were unusual for CNC (2-4) and gave reason to extend the diagnostic measures. Identification of a pathogenic PRKAR1A mutation and exclusion of pathogenic variants in genes related to diseases with partially similar phenotype confirmed the CNC diagnosis.
The overview of the findings suggested that a type of neurofibromatosis was unlikely (3, 4). Tentative diagnosis was CNC based on medical history and current findings. However, in the patient’s youth, several skin tumors had been excised and were repeatedly diagnosed as neurofibroma. This type of lesion is not expected in CNC (2). Multiple neurofibromas are a hallmark of neurofibromatosis type 1 (NF1). A particular type of nerve sheath tumor, psammomatous MS, is well documented in CNC (2). This tumor must be distinguished from MM. Syndromic tumors of the CPA are most likely to be schwannoma associated with NF2. Furthermore, pigmented lesions of the skin and mucosa are common in CNC [>80%, (2)] and neurofibromatoses (3, 4) and are considered diagnostic criteria. Therefore, it was decided to combine surgical therapy and genetic diagnostics in the treatment.
Skin lesions in CNC. The absence of pigmentary skin abnormalities in the present case is intriguing. It is likely that her lack of pigmentary disorders contributed to the late consideration of CNC. However, the absence of characteristic pigmentation disorders in this case was also a reason for considering the diagnosis of “neurofibromatosis” unlikely.
The patient has developed several cutaneous and subcutaneous tumors since childhood for which no histological findings are available, and which are defined in the records as fibromas or neurofibromas. Histological findings revealed fibroma (breast) on one side and neurofibroma with a conspicuous myxoid stroma on the other side (trunk, extremities). The breast tumors are an indicator of CNC. However, the reported nerve sheath tumors are not a diagnostic sign of CNC. On the other hand, cutaneous neurofibroma may also occur in NF2 (4, 5). Hybrid tumors consisting of neurofibroma, and schwannoma have been detected relatively frequently in NF2 and schwannomatosis (5). Differentiation of atypical neurofibroma and schwannoma from myxoma can be challenging. However, it should also be considered that the patient’s cutaneous tumors may already have been myxomas.
Pigmented malignant tumor of CPA. Detection of melanoma in CPA is suspicious for metastasis (6). However, both primary melanoma and melanoma metastasis of the CPA are rare (7). Imaging of cerebral metastatic MM may cause difficulty in distinguishing this tumor from multifocal central nervous system lesions in NF2 (8). Indeed, evidence of CPA tumors is a main diagnostic criterion of NF2 (4). However, in NF2, vestibular schwannoma is expected in this localization. The presumed cells of origin in MM, i.e. melanocytes, also originate from the neural crest cells like Schwann cells (9). Pigmentation disorders of the skin are among the findings of NF2 (4); the focus is on two-dimensional hyperpigmentation with predominantly rounded borders (Café-au-lait spots, much more frequent in NF1). However, MM is rarely reported in NF2 (10) and in NF1 (11), and obviously favors certain localizations in these diseases (9). On the other hand, MS may arise in NF2 (12) and CNC (13). In some patients with CNC, pigmented meningeal melanocytoma originated in Meckel’s cave (14) and from the trigeminal nerve (15). Nevertheless, Meckel’s cave is a preferred site for the development of intracranial MS (16). In summary, a pigmented tumor of the CPA raises the suspicion of metastatic disease or association with a syndrome, especially NF2. Reports of intracerebral MS are generally anecdotal and do not allow for cause-related therapeutic guidelines. Radiation therapy is an important adjuvant of therapy (17). These tumors have an uncertain prognosis (12). MS was diagnosed in 8% of patients with CNC (18); however, the localizations of MS of this study are not mentioned. Four out of 28 patients with CNC with MS died due to metastatic tumors (18).
The majority of MS cases are S100-positive (13). In the present case, no morphological examination results are available for a possible S100 reaction of the CPA tumor. The expression of HMB45 is not a reliable discriminator between MM and MS (13). Increased recurrence rates are expected in vestibular schwannoma with a MIB1 index of 3.5 and higher (19). Ki67 labeling index did not exceed 10% in any case of MS (13). The very high proliferation index of our case (20%) was a decisive factor in the assessment of the lesion as MM. In retrospect, malignant de-differentiated MS of the CPA in CNC cannot be excluded. Somatic mutations of the NF2 gene have been reported in sporadic MM (20, 21).
PRKAR1A gene. The PRKAR1A gene coding for the cAMP-dependent protein kinase type I-alpha regulatory subunit is mutated in about 73% of CNC cases (18). PRKAR1A haploinsufficiency causes excess cellular cAMP signaling in affected tissues (2). Data suggest that PRKAR1A is a tumor-suppressor gene because tumors of patients with CNC frequently (but not in all cases) show both germline mutation and loss of heterozygosity of the 17q22-24 PRKAR1A locus (2).
Detection of a PRKAR1A mutation is an important criterion for CNC diagnosis. There is an obvious link between the loss of function of the gene and the development of angiomyxoma in general. Sporadic angiomyxomas were PRKAR1A-negative in 80% of cases on immunohistochemistry (22).
The PRKAR1A variant demonstrated in the present case has not yet been described in international databases (23). This is, however, not surprising, as the pathogenic mechanism of PRKAR1A mutations is loss of function and many families have their own “private” mutations, while only a few changes in this gene are recurrent ones.
Conclusion
Clinical diagnosis of CNC can be difficult in individual cases. Diagnostic guidelines facilitate the classification of findings in an individual suspected of being affected by CNC. The increasing availability of molecular genetic testing can significantly improve the diagnosis of the syndrome and its differentiation from other diseases.
Acknowledgements
The Authors thank Lan Kluwe, PhD, Tumor Biology Laboratory, Department of Neurology and Department of Maxillofacial Surgery, UKE, Hamburg, for performing the mutation analysis of the NF2 and LZTR1 gene; Andreas M. Luebke, MD, PhD, Institute of Pathology, for detailed histological evaluation of the tumors; and Professor Christian Hagel, MD, PhD, Institute of Neuropathology, for critical review of the article.
Footnotes
Authors’ Contributions
Treatment of the patient, drafting the manuscript: REF; molecular genetics, checking and correcting the article: MZ, approval of article for publication: All Authors.
Conflicts of Interest
There are no conflicts of interest to disclose.
- Received October 6, 2022.
- Revision received October 21, 2022.
- Accepted October 27, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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