{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T12:55:59Z","timestamp":1776344159941,"version":"3.51.2"},"reference-count":38,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:00:00Z","timestamp":1776297600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>This case highlights a novel genotype\u2013phenotype correlation in the field of endocrinology. Specific endocrine and imaging assessment, in addition to next-generation sequencing (NGS), was performed on the Illumina MiSeq platform, using a TruSight One Sequencing Panel kit for genomic analysis of coding regions of 4813 genes. A 54-year-old female was confirmed with a papillary thyroid carcinoma after total thyroidectomy and underwent radioiodine ablative therapy. Three years later, a left femoral enchondroma of almost 3 cm was identified at computed tomography (CT) scan and magnetic resonance imaging (MRI). She experienced hypertension (in addition to obesity, dyslipidaemia and impaired glucose tolerance) and was later confirmed with ACTH-independent cortisol excess [lack of cortisol suppression at 1 mg dexamethasone testing of 13.9 (normal &lt; 1.8 \u00b5g\/dL)], noting bilateral adrenal tumors, of 4.7 cm (right), respectively, and of 1.6 cm (left) at CT. Right laparoscopic adrenalectomy was performed with post-operative adrenal insufficiency, requiring glucocorticoid replacement and stopping the anti-hypertensive medication. Pathology report confirmed an adrenocortical adenoma (a Ki67 proliferation index of 2%). Noting the unusual association of the mentioned conditions, NGS was performed in the peripheral blood and identified a heterozygote missense variant of the APC gene (c.5759G&gt;A, p.Arg1920Gln), a heterozygote missense variant of the MSH6 gene (c.2092C&gt;G, p.Gln698Glu), and an incidental additional finding: a heterozygote stop gain pathogenic variant of the CACNA1S gene (c.2707C&gt;T, p.Arg903*). The first two are currently classified as variants of uncertain significance. Whether the co-presence of a triple mutation may change the clinical picture and the life-long outcomes across reciprocal influence is still an open matter. Further research will point out the clinical implications of this genotype\u2013phenotype association, which, to our best knowledge, has not been previously reported.<\/jats:p>","DOI":"10.3390\/diagnostics16081185","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T11:35:42Z","timestamp":1776339342000},"page":"1185","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Papillary Thyroid Carcinoma, Bilateral Macronodular Adrenal Cortical Disease-Related Cortisol Excess, and Femoral Enchondroma: A Novel Phenotype\u2013Genotype Based on Next-Generation Sequencing (Variants of APC, MSH6, and CACNA1S Genes)"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8585-3835","authenticated-orcid":false,"given":"Mara","family":"Carsote","sequence":"first","affiliation":[{"name":"Department of Endocrinology, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 020021 Bucharest, Romania"},{"name":"Department of Clinical Endocrinology V, \u201cC.I. Parhon\u201d National Institute of Endocrinology, 011863 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4886-2174","authenticated-orcid":false,"given":"Sorina Violeta","family":"Schipor","sequence":"additional","affiliation":[{"name":"Department of Research, \u201cC.I. Parhon\u201d National Institute of Endocrinology, 011863 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anda","family":"Dumitrascu","sequence":"additional","affiliation":[{"name":"Department of Radiology and Medical Imaging, \u201cC.I. Parhon\u201d National Institute of Endocrinology, 011863 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5970-3701","authenticated-orcid":false,"given":"Ana-Maria","family":"Gheorghe","sequence":"additional","affiliation":[{"name":"Department of Clinical Endocrinology V, \u201cC.I. Parhon\u201d National Institute of Endocrinology, 011863 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oana-Claudia","family":"Sima","sequence":"additional","affiliation":[{"name":"Department of Clinical Endocrinology V, \u201cC.I. Parhon\u201d National Institute of Endocrinology, 011863 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9190-837X","authenticated-orcid":false,"given":"Dana","family":"Manda","sequence":"additional","affiliation":[{"name":"Department of Research, \u201cC.I. Parhon\u201d National Institute of Endocrinology, 011863 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mihai","family":"Costachescu","sequence":"additional","affiliation":[{"name":"PhD School of \u201cCarol Davila\u201d University of Medicine and Pharmacy, 020021 Bucharest, Romania"},{"name":"Department of Radiology and Medical Imaging, \u201cDr. Carol Davila\u201d Central Military University Emergency Hospital, 010825 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrei","family":"Muresan","sequence":"additional","affiliation":[{"name":"Department of Research, \u201cC.I. Parhon\u201d National Institute of Endocrinology, 011863 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9991-7052","authenticated-orcid":false,"given":"Emi Marinela","family":"Preda","sequence":"additional","affiliation":[{"name":"Department of Radiology, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Radiology and Medical Imaging, \u201cFoisor\u201d Clinical Hospital of Orthopaedics, Traumatology and Osteoarticular TB, 021382 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dana","family":"Terzea","sequence":"additional","affiliation":[{"name":"Department of Pathology, \u201cC.I. Parhon\u201d National Institute of Endocrinology, 011863 Bucharest, Romania"},{"name":"Oncoteam Diagnostics, 012244 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,16]]},"reference":[{"key":"ref_1","unstructured":"(2026, March 09). Available online: https:\/\/franklin.genoox.com."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3515","DOI":"10.1016\/j.radcr.2025.04.027","article-title":"A journey with Maffucci syndrome: From skull base chondrosarcoma to multiorgan management: A case report and literature review","volume":"20","author":"Dibas","year":"2025","journal-title":"Radiol. Case Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1210\/js.2016-1018","article-title":"Maffucci Syndrome Associated With Adrenocorticotropic Hormone-Independent Bilateral Macronodular Adrenal Hyperplasia","volume":"1","author":"Battaglia","year":"2017","journal-title":"J. Endocr. Soc."},{"key":"ref_4","first-page":"166","article-title":"Emphysematous cystitis: An unreported complication after pancreaticoduodenectomy","volume":"119","author":"Dumitrascu","year":"2015","journal-title":"Med.-Surg. J."},{"key":"ref_5","first-page":"S387","article-title":"Multiple endocrine neoplasia type 2 syndrome and osteoporosis","volume":"35","author":"Nistor","year":"2023","journal-title":"Aging Clin. Exp. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s13000-022-01205-8","article-title":"Thorahcic SMARCA4-deficient undifferentiated tumors with ganglioneuroma and enchondroma: Implications for SLC7A11 and ARID1A expression: A case report","volume":"17","author":"Kito","year":"2022","journal-title":"Diagn. Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.5858\/arpa.2018-0570-RA","article-title":"Familial Adenomatous Polyposis Syndrome: An Update and Review of Extraintestinal Manifestations","volume":"143","author":"Dinarvand","year":"2019","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Antohi, C., Haba, D., Caba, L., Ciofu, M.L., Drug, V.L., B\u0103rboi, O.B., Dobrov\u0103\u021b, B.I., P\u00e2nzaru, M.C., Gorduza, N.C., and Lupu, V.V. (2021). Novel Mutation in APC Gene Associated with Multiple Osteomas in a Family and Review of Genotype-Phenotype Correlations of Extracolonic Manifestations in Gardner Syndrome. Diagnostics, 11.","DOI":"10.3390\/diagnostics11091560"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Ditonno, I., Novielli, D., Celiberto, F., Rizzi, S., Rendina, M., Ierardi, E., Di Leo, A., and Losurdo, G. (2023). Molecular Pathways of Carcinogenesis in Familial Adenomatous Polyposis. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24065687"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1186\/s12957-023-02951-9","article-title":"De novo familial adenomatous polyposis associated thyroid cancer with a c.2929delG frameshift deletion mutation in APC: A case report and literature review","volume":"21","author":"Xu","year":"2023","journal-title":"World J. Surg. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"309348","DOI":"10.1155\/2015\/309348","article-title":"FAP Associated Papillary Thyroid Carcinoma: A Peculiar Subtype of Familial Nonmedullary Thyroid Cancer","volume":"2015","author":"Cetta","year":"2015","journal-title":"Pathol. Res. Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/s10689-019-00146-4","article-title":"A unique case of two somatic APC mutations in an early onset cribriform-morular variant of papillary thyroid carcinoma and overview of the literature","volume":"19","author":"Aydemirli","year":"2020","journal-title":"Fam. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"119","DOI":"10.3892\/or.2024.8778","article-title":"Cribriform morular thyroid carcinoma: Clinicopathological and molecular basis for both a preventive and therapeutic approach for a rare tumor","volume":"52","year":"2024","journal-title":"Oncol. Rep."},{"key":"ref_14","unstructured":"(2026, March 09). Available online: https:\/\/www.ncbi.nlm.nih.gov\/clinvar\/variation\/185443\/."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1007\/s10014-023-00461-w","article-title":"Lynch syndrome-associated chordoma with high tumor mutational burden and significant response to immune checkpoint inhibitors","volume":"40","author":"Shinojima","year":"2023","journal-title":"Brain Tumor Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1038\/s41416-022-02059-z","article-title":"Lynch syndrome, molecular mechanisms and variant classification","volume":"128","author":"Abildgaard","year":"2023","journal-title":"Br. J. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.giec.2021.09.002","article-title":"Identification of Lynch Syndrome","volume":"32","author":"Maratt","year":"2022","journal-title":"Gastrointest. Endosc. Clin. N. Am."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Williams, M.H., Hadjinicolaou, A.V., Norton, B.C., Kader, R., and Lovat, L.B. (2023). Lynch syndrome: From detection to treatment. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1166238"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1111\/cen.15248","article-title":"Genetic Testing Referral Rates for Pheochromocytoma and Paraganglioma in an Academic Tertiary Centre","volume":"103","author":"Ruhle","year":"2025","journal-title":"Clin. Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1210\/js.2019-00050","article-title":"Adrenal Cortical Carcinoma Associated With Lynch Syndrome: A Case Report and Review of Literature","volume":"3","author":"Kaur","year":"2019","journal-title":"J. Endocr. Soc."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Spinelli, I., Moffa, S., Fianchi, F., Mezza, T., Cinti, F., Di Giuseppe, G., Marmo, C., Ianiro, G., Ponziani, F.R., and Tortora, A. (2024). Lynch Syndrome and Thyroid Nodules: A Single Center Experience. Genes, 15.","DOI":"10.3390\/genes15070859"},{"key":"ref_22","first-page":"79","article-title":"Prevalence of germline mutations of hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6 genes in 75 French kindreds with nonpolyposis colorectal cancer","volume":"105","author":"Wang","year":"1999","journal-title":"Hum. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s10689-008-9199-3","article-title":"Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population","volume":"8","author":"Nilbert","year":"2009","journal-title":"Fam. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Loizidou, M.A., Neophytou, I., Papamichael, D., Kountourakis, P., Vassiliou, V., Marcou, Y., Kakouri, E., Ioannidis, G., Philippou, C., and Spanou, E. (2014). The mutational spectrum of Lynch syndrome in Cyprus. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0105501"},{"key":"ref_25","unstructured":"(2026, March 09). Available online: https:\/\/www.ncbi.nlm.nih.gov\/clinvar\/variation\/89251\/."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1136\/jmedgenet-2019-106163","article-title":"Genetic T-type calcium channelopathies","volume":"57","author":"Weiss","year":"2020","journal-title":"J. Med. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e230061","DOI":"10.1530\/ERC-23-0061","article-title":"Genetic variants and down-regulation of CACNA1H in pheochromocytoma","volume":"31","author":"Svahn","year":"2024","journal-title":"Endocr.-Relat. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1186\/s13023-021-01850-0","article-title":"Calcium channelopathies and intellectual disability: A systematic review","volume":"16","author":"Kessi","year":"2021","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Zhou, W., Zhao, P., Gao, J., and Zhang, Y. (2023). A novel CACNA1S gene variant in a child with hypokalemic periodic paralysis: A case report and literature review. BMC Pediatr., 23.","DOI":"10.1186\/s12887-023-04326-1"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"17562864251317961","DOI":"10.1177\/17562864251317961","article-title":"CACNA1S-associated triadopathy presenting with myalgia, muscle weakness, and asymptomatic hyperCKemia","volume":"18","author":"Luo","year":"2025","journal-title":"Ther. Adv. Neurol. Disord."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1007\/s00424-020-02368-3","article-title":"Skeletal muscle CaV1.1 channelopathies","volume":"472","author":"Flucher","year":"2020","journal-title":"Pfl\u00fcgers Arch. Eur. J. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Yang, B., Yang, Y., Tu, W., Shen, Y., and Dong, Q. (2014). A rare case of unilateral adrenal hyperplasia accompanied by hypokalaemic periodic paralysis caused by a novel dominant mutation in CACNA1S: Features and prognosis after adrenalectomy. BMC Urol., 14.","DOI":"10.1186\/1471-2490-14-96"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1177\/0004563218785395","article-title":"Does thyrotoxic periodic paralysis have a genetic predisposition? A case report","volume":"55","author":"Rasheed","year":"2018","journal-title":"Ann. Clin. Biochem."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Mao, X., Tang, L., Li, H., Zhang, W., Liu, L., Wang, H., and Headar, A. (2023). Functional enrichment analysis of mutated genes in children with hyperthyroidism. Front. Endocrinol, 14.","DOI":"10.3389\/fendo.2023.1213465"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"101454","DOI":"10.1016\/j.gim.2025.101454","article-title":"ACMG SF v3.3 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG)","volume":"27","author":"Lee","year":"2025","journal-title":"Genet. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1002\/mgg3.142","article-title":"Novel pathogenic variants and genes for myopathies identified by whole exome sequencing","volume":"3","author":"Hunter","year":"2015","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1007\/s00401-016-1656-8","article-title":"Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy","volume":"133","author":"Schartner","year":"2017","journal-title":"Acta Neuropathol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/s12022-022-09710-8","article-title":"Overview of the 2022 WHO Classification of Adrenal Cortical Tumors","volume":"33","author":"Mete","year":"2022","journal-title":"Endocr. Pathol."}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/16\/8\/1185\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T11:51:05Z","timestamp":1776340265000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/16\/8\/1185"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,16]]},"references-count":38,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["diagnostics16081185"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics16081185","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,16]]}}}