Recklinghausen– Engel syndrome and tumor-like skeletal lesions in hyperparathyroidism: literature review and clinical case

Aim of the study: to provide a contemporary overview of the nomenclature and terminology of Recklinghausen– Engel syndrome (parathyroid osteodystrophy), its pathogenesis, and characteristic morphological and radiological manifestations. Special attention is paid to the differential diagnosis between brown tumor and skeletal giant cell tumor. The study aims to present the clinical and morphological criteria for distinguishing these conditions, systematized in a comparative table.

Material and Methods. A literature search was conducted in the Medline, PubMed, Elibrary, and other databases. Of the 100 identified publications, 30 were included in this systematic review. We report a case of a resected brown tumor of the femur in a 58-year-old man with previously undiagnosed hyperparathyroidism, detailing the morphological diagnostic features and the disease course.

Results. Recklinghausen-Engel syndrome (parathyroid osteodystrophy) is a rare but clinically significant metabolic skeletal disorder that develops in the setting of hyperparathyroidism. It is characterized by marked osteoclastic activity, the formation of cystic lesions, subperiosteal resorption, and so-called brown tumors. Despite its benign nature, this syndrome often mimics aggressive giant cell bone tumors, which complicates the interpretation of clinical, radiological, and morphological data and increases the risk of diagnostic errors.

Conclusion. This article discusses the diagnostic challenges in the absence of overt clinical symptoms of hyperparathyroidism and emphasizes the key role of the pathomorphologist within a multidisciplinary team. Timely detection of parathyroid hormone hypersecretion and radical removal of the hyperplastic or neoplastic parathyroid gland lead to the regression of bone lesions and a favorable prognosis.

1. Diacinti D., Cipriani C., Biamonte F., Pepe J., Colangelo L., Kripa E., Iannacone A., Orlandi M., Guarnieri V., Diacinti D., Minisola S. Imaging technologies in the differential diagnosis and follow-up of brown tumor in primary hyperparathyroidism: Case report and review of the literature. Bone Rep. 2020; 14: 100745. doi: 10.1016/j.bonr.2020.100745.

2. Tariq M.U., Din N.U., Qureshi M.B., Park Y.K. Chondroblastoma of foot bones; a clinicopathological study of 29 cases confirming the diagnostic utility of H3K36M and H3G34W antibodies at an uncommon site. Ann Diagn Pathol. 2023; 65: 152135. doi: 10.1016/j.anndiagpath.2023.152135.

3. Walsh H., Crane H., Hunter K.D. Giant cell lesions of the jaws. Diagn. Histopathol. 2022; 28(5): 217–27. doi: 10.1016/j.mpdhp.2022.02.002.

4. Unni K.K., Inwards C.Y. Dahlin’s bone tumors: general aspects and data on 10,165 cases. 6th ed. Philadelphia: Wollters Kluwer/Lippincott Williams & Wilkins Health, 2010. 402 p.

5. Zhong Y., Huang Y., Luo J., Ye Y. Misdiagnosis of brown tumour caused by primary hyperparathyroidism: a case report with literature review. BMC Endocr Disord. 2022; 22(1): 66. doi: 10.1186/s12902-022-00971-2.

6. Aghaghazvini L., Sharifian H., Rasuli B. Primary Hyperparathyroidism Misdiagnosed as Giant Cell Bone Tumor of Maxillary Sinus: A Case Report. Iran J Radiol. 2016; 13(1): e13260. doi: 10.5812/iranjradiol.13260.

7. Borbolla-Pertierra A.M., Guinto-Arcos E., Rodríguez-Reyes A., Moreno G.G., Olvera-Morale O. Brown tumour involving the orbit: case report and review of the literature. Can J Ophthalmol. 2016; 51(4): 125–27. doi: 10.1016/j.jcjo.2016.02.020.

8. Hameed M. Giant cell-rich lesions of bone. Diagn Histopathol. 2020. 26(10): 474–83. doi: 10.1016/j.mpdhp.2020.07.005.

9. Hatipoglu E., Eskazan A.E., Celik O., Kantarci F., Kadioglu P. Diagnostic dilemma: metastatic bone malignancy or primary hyperparathyroidism with brown tumor. Open J Intern. Med. 2013; 3: 60–62.

10. Mascarenhas L.S., Marchionni A.M.T., Rebouças D.S., Neri J.S.V., Ribeiro A., Medrado A.P. Brown tumor as a result of secondary hyperparathyroidism in chronic renal disease. J Oral Diag. 2016; 1. doi: 10.5935/2525-5711.20160021.

11. Öç Y., Kılınç B.E., Gültekin O., Yazar E.A., Varol A., Özdemir H.M. Brown tumor and hyperparathyroidism in orthopaedic surgery. Turk J Osteoporos. 2021; 27(1): 24–29. doi: 10.4274/tod.galenos.2020.72677.

12. Proimos E., Chimona T.S., Tamiolakis D., Tzanakakis M.G., Papadakis C.E. Brown tumor of the maxillary sinus in a patient with primary hyperparathyroidism: a case report. J Med Case Rep. 2009; 3: 7495. doi: 10.4076/1752-1947-3-7495.

13. Rao D.S., Kalappanavar A.N., Annigeri R.G. Normocalcemic hyperparathyroidism manifesting as brown tumor of mandible: a case report. J Orofac Sci. 2016; 8(1): 71–73. doi: 10.4103/0975-8844.181933.

14. Wu Y., Cheng W., Zhang X., Li Z., Liu Y., Bai W. Neurofibromatosis type I-associated malignant peripheral nerve sheath tumors: a case report and literature review. Arch Med Sci. 2020; 16(6): 1476–82. doi: 10.5114/aoms.2020.100309.

15. Paramita R.D., Rahardjo P. Multiple brown tumor in late adolescence mimicking bone metastasis: A challenging case report. Radiol Case Rep. 2024; 19(10): 4266–72. doi: 10.1016/j.radcr.2024.07.008.

16. Choi J.H., Kim K.J., Lee Y.J., Kim S.H., Kim S.G., Jung K.Y., Choi D.S., Kim N.H. Primary Hyperparathyroidism with Extensive Brown Tumors and Multiple Fractures in a 20-Year-Old Woman. Endocrinol Metab (Seoul). 2015; 30(4): 614–19. doi: 10.3803/EnM.2015.30.4.614.

17. Rossi B., Ferraresi V., Appetecchia M.L., Novello M., Zoccali C. Giant cell tumor of bone in a patient with diagnosis of primary hyperparathyroidism: a challenge in differential diagnosis with brown tumor. Skeletal Radiol. 2014; 43(5): 693–97. doi: 10.1007/s00256-013-1770-9.

18. Shetty A.D., Namitha J., James L. Brown tumor of mandible in association with primary hyperparathyroidism: a case report. J Int Oral Health. 2015; 7(2): 50–52.

19. Selvi F., Cakarer S., Tanakol R., Guler S.D., Keskin C. Brown tumour of the maxilla and mandible: a rare complication of tertiary hyperparathyroidism. Dentomaxillofac Radiol. 2009; 38(1): 53–58. doi: 10.1259/dmfr/81694583.

20. Aljabri K.S.J., Bokhari A.A., Bokhari S.A., Alshareef M.A., Alhumidi A., Aljabri B.K. Wide spread skeletal bones involvements of brown tumors in a patient with an ectopic mediastinal parathyroid adenoma: a case report and review of literature. Med Case Rep. 2016; 2(3): 32. doi: 10.21767/2471-8041.1000032.

21. Rekhi B., Dave V., Butle A., Dharavath B., Khetale S., Redhu A.K., Singh R., Dutt A. Immunohistochemical expression of H3.3 G34W in 100 giant cell tumors of bone and its diagnostic mimics, including its value in resolving uncommon diagnostic scenarios: A single institutional study at a tertiary cancer referral center, India. Indian J Pathol Microbiol. 2024; 67(3): 542–52. doi: 10.4103/ijpm.ijpm_886_23.

22. Tumors and tumor-like lesions of bone: for surgical pathologists, orthopedic surgeons and radiologists. Ed. by E. Santini-Araujo, R.K. Kalil, F. Bertoni, Y.K. Park. London; New York: Springer, 2015. 994 p. ISBN: 978-1-4471-6577-4. doi: 10.1007/978-1-4471-6578-1.

23. Priyanthan T., Hermann A.P., Bojsen J.A., Krøigaard A.B., Bistrup C., Pedersen E.B. Multiple Focal Brown Tumors (Osteitis Fibrosa Cystica) in a Renal Transplant Recipient. Case Rep Nephrol. 2022; 4675041. doi: 10.1155/2022/4675041.

24. Jakubowski J.M., Velez I., McClure S.A. Brown tumor as a result of hyperparathyroidism in an end-stage renal disease patient. Case Rep Radiol. 2011; 415476. doi: 10.1155/2011/415476.

25. Kamal A.F., Isdianto P.A., Abdullah A., Kodrat E. Brown tumors of hyperparathyroidism misdiagnosed as multifocal giant cell tumors of bone: a case report. Hum Pathol: Case Rep. 2020; 21: 200385. doi: 10.1016/j.ehpc.2020.200385.

26. Manzil F.F.P., Bhambhvani P., Vattoth S., Subedi S.K., Bag A.K., O’Malley J.P. Primary hyperparathyroidism–related brown tumors mimicking other giant cell–containing skeletal tumors: role of correlative imaging in diagnosis. J Nucl Med Technol. 2013; 41(1): 46–48. doi: 10.2967/jnmt.112.115204.

27. Ito K., Ikuta K., Nishida Y., Sakai T., Imagama S. Spontaneous regression of brown tumor in a patient treated with peritoneal dialysis. Cureus. 2021; 13(8): e17078. doi: 10.7759/cureus.17078.

28. Vaishya R., Agarwal A., Singh H., Vijay V. Multiple ‘brown tumors’ masquerading as metastatic bone disease. Cureus. 2015; 7(12): e431. doi: 10.7759/cureus.431.

29. Shooshtarizadeh T., Rahimi M., Movahedinia S. P63 expression as a biomarker discriminating giant cell tumor of bone from other giant cellrich bone lesions. Pathol Res Pract. 2016; 212(10): 876–79. doi:10.1016/j.prp.2016.07.007.

30. Yamamoto H., Iwasaki T., Yamada Y., Matsumoto Y., Otsuka H., Yoshimoto M., Kohashi K., Taguchi K., Yokoyama R., Nakashima Y., Oda Y. Diagnostic utility of histone H3.3 G34W, G34R, and G34V mutantspecific antibodies for giant cell tumors of bone. Hum Pathol. 2018; 73: 41–50. doi: 10.1016/j.humpath.2017.11.020.