Familial Ossifying Fibroma

Familial Ossifying Fibroma – Introduction

Familial ossifying fibroma is an exceedingly rare genetic variant of ossifying fibroma that affects multiple family members, representing one of the most challenging diagnostic entities in oral and maxillofacial pathology. Unlike sporadic ossifying fibromas, which occur as isolated cases, familial ossifying fibroma demonstrates an inherited pattern that requires careful genetic evaluation and family screening. This condition exemplifies the intersection of oral pathology, genetics, and personalized medicine, highlighting the importance of recognizing hereditary patterns in benign jaw lesions.

Definition and Classification

Familial ossifying fibroma is defined as a hereditary form of benign fibro-osseous lesion that occurs in multiple family members, characterized by the replacement of normal bone with fibrous tissue containing varying amounts of calcified deposits such as bone, cementum, or both. According to the World Health Organization classification, ossifying fibroma belongs to the category of benign fibro-osseous neoplasms, with the familial variant representing a genetically determined subset of these lesions.^[1][2][3]

The condition shares histopathological features with sporadic ossifying fibromas but is distinguished by its pattern of inheritance, tendency toward multiplicity, and potential association with genetic syndromes. The term “familial multiple ossifying fibroma” is sometimes used when multiple lesions occur within affected family members.^[2]

Epidemiology and Demographics

Familial ossifying fibroma is extraordinarily rare, with fewer than 20 cases reported in the medical literature. The exact prevalence remains unknown due to the paucity of documented cases and potential underrecognition of familial clustering. The condition demonstrates an autosomal dominant pattern of inheritance with variable penetrance, meaning that not all individuals carrying the genetic predisposition will develop the disease.^[4][1][2]

The age distribution in familial cases tends to be earlier than sporadic forms, often manifesting in childhood or adolescence. Both males and females can be affected, though some reports suggest a slight female predominance consistent with sporadic ossifying fibromas. The mandible is more frequently involved than the maxilla, with lesions commonly occurring in multiple quadrants of the jaw.^[2][4]

Genetic Basis and Associated Syndromes

CDC73 Gene Mutations

The genetic basis of familial ossifying fibroma is closely linked to mutations in the CDC73 gene (formerly known as HRPT2), which encodes the tumor suppressor protein parafibromin. This gene is located on chromosome 1q25-q31 and plays a crucial role in transcriptional regulation through its interaction with RNA polymerase II.^[5][6][7][8]

CDC73 mutations are found in approximately 5% of sporadic ossifying fibromas but occur much more frequently in familial cases, particularly those associated with hyperparathyroidism-jaw tumor syndrome (HPT-JT). The mutations are predominantly frameshift or nonsense mutations that result in truncation of the parafibromin protein, leading to loss of its tumor suppressor function.^[6][5]

Hyperparathyroidism-Jaw Tumor Syndrome

Familial ossifying fibroma is most commonly associated with HPT-JT syndrome, a rare autosomal dominant disorder characterized by a triad of clinical features:^[9][4][6]

1. Primary hyperparathyroidism caused by parathyroid adenomas or carcinomas
2. Ossifying fibromas of the maxilla and/or mandible
3. Renal and uterine tumors

Approximately 30-40% of individuals with HPT-JT syndrome develop ossifying fibromas of the jaws. These lesions are distinct from the “brown tumors” associated with severe hyperparathyroidism and persist even after correction of the metabolic abnormalities.^[4][6]

Other Genetic Associations

Recent genomic studies have identified additional genetic alterations in ossifying fibroma, including mutations in genes encoding transcription factors that regulate the AP-1 transcriptional complex, such as FOS, FOSB, and TBX3. These findings suggest that dysregulation of transcriptional pathways may contribute to the pathogenesis of familial ossifying fibroma.^[10]

Clinical Features

Presentation and Symptoms

Familial ossifying fibroma typically presents as slow-growing, painless swellings of the jaw bones that gradually increase in size over months to years. Unlike sporadic cases, familial ossifying fibroma often manifests with multiple lesions that may develop simultaneously or sequentially across different jaw quadrants.^[11][1][2]

Common clinical manifestations include:

• Progressive facial asymmetry due to bone expansion
• Hard, non-tender masses of the mandible and/or maxilla
• Displacement or mobility of teeth
• Multiple lesions in the same individual or family members
• Earlier age of onset compared to sporadic cases

The lesions are typically asymptomatic in early stages but can cause significant functional and cosmetic problems as they enlarge. Pain and paresthesia are uncommon features and should raise suspicion for other diagnoses.^[11][2]

Family History and Genetic Patterns

A crucial diagnostic feature of familial ossifying fibroma is the presence of similar lesions in other family members. The condition demonstrates autosomal dominant inheritance, meaning that affected individuals have a 50% chance of passing the condition to their offspring. However, variable penetrance means that not all gene carriers will develop clinically apparent disease.^[2][4]

Key genetic features include:

• Autosomal dominant inheritance pattern
• Variable penetrance and expressivity
• Possible anticipation (earlier onset in successive generations)
• Association with other genetic syndromes, particularly HPT-JT

Diagnostic Approach

Clinical Evaluation

The diagnosis of familial ossifying fibroma requires a comprehensive approach that includes detailed family history, clinical examination, imaging studies, and genetic evaluation. Healthcare providers should specifically inquire about similar jaw lesions in family members and any history of hyperparathyroidism or related endocrine disorders.^[6][2]

Essential diagnostic steps include:

1. Detailed family history extending through multiple generations
2. Clinical examination for multiple jaw lesions
3. Biochemical screening including serum calcium, phosphorus, and parathyroid hormone levels
4. Genetic counseling and testing for CDC73 mutations
5. Screening of family members for subclinical disease

Radiographic Features

The radiographic appearance of familial ossifying fibroma is similar to sporadic cases but with the distinctive feature of multiplicity. Imaging studies should evaluate all quadrants of the jaw to identify additional lesions.^[12][13][11]

Typical radiographic features include:

• Well-circumscribed, expansile masses with sharp margins
• Mixed radiolucent and radiopaque patterns reflecting varying degrees of mineralization
• Concentric, tumor-like expansion maintaining a clear epicenter
• Root divergence and occasional root resorption of adjacent teeth
• Multiple lesions in the same individual

Histopathological Examination

The histopathological features of familial ossifying fibroma are identical to sporadic cases, consisting of fibrous tissue containing variable amounts of calcified material. The diagnosis relies on the characteristic microscopic appearance combined with clinical and genetic information.^[14][15][11]

Microscopic features include:

• Moderately to highly cellular fibroblastic stroma
• Variable proportions of woven to lamellar bone, osteoid, and cementum-like calcifications
• Well-defined borders distinguishing the lesion from surrounding bone
• Absence of cellular atypia or increased mitotic activity

Genetic Testing

Genetic testing for CDC73 mutations should be considered in patients with multiple ossifying fibromas, positive family history, or associated features of HPT-JT syndrome. Molecular analysis can confirm the diagnosis and guide family counseling and screening.^[7][8][6]

Indications for genetic testing include:

• Multiple ossifying fibromas in a single individual
• Positive family history of jaw tumors or hyperparathyroidism
• Early age of onset (before age 30)
• Associated hypercalcemia or parathyroid disease

Differential Diagnosis

The differential diagnosis of familial ossifying fibroma includes several conditions that can present with multiple jaw lesions or familial clustering:^[16][17]

Primary Considerations

Multiple Sporadic Ossifying Fibromas: Distinguished by lack of family history and genetic mutations, though this can be challenging in small families or when family history is incomplete.

Fibrous Dysplasia: May present with multiple lesions but typically shows ill-defined borders, ground-glass appearance, and different genetic alterations (GNAS mutations).^[18]

Hyperparathyroidism-Related Bone Disease: Brown tumors associated with hyperparathyroidism can mimic ossifying fibromas but typically resolve with correction of the metabolic abnormality.

Secondary Considerations

Other Genetic Syndromes: McCune-Albright syndrome, Jaffe-Campanacci syndrome, and other conditions associated with fibro-osseous lesions should be considered.^[19]

Malignant Transformation: Though extremely rare, malignant transformation of ossifying fibroma has been reported and should be excluded through careful histopathological evaluation.^[20]

Management and Treatment

Multidisciplinary Approach

The management of familial ossifying fibroma requires a multidisciplinary team including oral and maxillofacial surgeons, endocrinologists, genetic counselors, and other specialists depending on associated conditions.^[21][22][6]

Surgical Treatment

Complete surgical excision remains the primary treatment for clinically significant lesions. The approach must be individualized based on lesion size, location, number, and patient factors.^[23][24][25]

Surgical options include:

• Enucleation and curettage for small, well-circumscribed lesions
• Marginal resection for larger lesions with preservation of vital structures
• Segmental resection for extensive or recurrent lesions
• Reconstruction using bone grafts or free tissue transfer for large defects

Medical Management

For patients with associated HPT-JT syndrome, management of hyperparathyroidism is essential:^[9][6]

• Parathyroidectomy for parathyroid adenomas or carcinomas
• Medical management of hypercalcemia
• Treatment of renal and uterine complications
• Long-term monitoring for recurrence

Surveillance and Follow-up

Long-term surveillance is crucial due to the potential for new lesion development and recurrence. Follow-up protocols should include:^[26][6]

Patient monitoring:

• Regular clinical examinations (every 6-12 months)
• Periodic imaging studies to detect new lesions
• Biochemical monitoring for hyperparathyroidism
• Assessment of functional and cosmetic outcomes

Family surveillance:

• Genetic counseling for family members
• Clinical screening of at-risk relatives
• Biochemical testing for hyperparathyroidism
• Genetic testing for confirmed mutations

Prognosis and Outcomes

Treatment Outcomes

The prognosis for familial ossifying fibroma is generally favorable with appropriate management. Key prognostic factors include:^[24][27][23]

• Complete surgical excision with clear margins
• Early detection through family screening
• Management of associated systemic conditions
• Long-term follow-up and surveillance

Recurrence Risk

Recurrence rates vary based on surgical approach and completeness of excision:^[20][26]

• Conservative surgery: 15-30% recurrence rate
• Radical excision: 3-11% recurrence rate
• Pediatric patients: Higher recurrence rates, especially with incomplete excision

Long-term Considerations

Functional outcomes with appropriate treatment include preservation of dental function, restoration of facial symmetry, and minimal long-term complications. However, patients require lifelong monitoring for:^[21][23]

• Development of new lesions
• Recurrence at previous sites
• Associated endocrine complications
• Psychological impact of genetic condition

Prevention and Genetic Counseling

Family Counseling

Genetic counseling is essential for families affected by familial ossifying fibroma. Key components include:^[28][9]

• Education about inheritance patterns and recurrence risks
• Discussion of genetic testing options
• Family planning counseling
• Psychosocial support for affected families

Screening Protocols

Systematic screening of at-risk family members can enable early detection and intervention:

Recommended screening includes:

• Clinical examination of jaws and neck
• Biochemical testing for hyperparathyroidism
• Imaging studies for asymptomatic lesions
• Genetic testing for confirmed familial mutations

Research Directions and Future Perspectives

Current research in familial ossifying fibroma focuses on several key areas:

Molecular Mechanisms

• Investigation of additional genetic pathways beyond CDC73
• Understanding of epigenetic modifications in disease development
• Role of transcriptional dysregulation in lesion formation

Therapeutic Advances

• Development of targeted medical therapies based on genetic findings
• Investigation of novel surgical techniques and reconstruction methods
• Exploration of tissue engineering approaches for large defects

Diagnostic Improvements

• Advanced imaging techniques for early lesion detection
• Biomarkers for disease monitoring and recurrence prediction
• Improved genetic testing methodologies

Conclusion

Familial ossifying fibroma represents a rare but clinically significant genetic condition that requires specialized multidisciplinary management. Recognition of the familial clustering pattern is crucial for proper diagnosis, genetic counseling, and family screening. The strong association with CDC73 mutations and HPT-JT syndrome has advanced our understanding of the genetic basis of these lesions and highlighted the importance of comprehensive endocrine evaluation.

Early detection through family screening, complete surgical excision, and long-term surveillance are essential for optimal outcomes. As our understanding of the genetic mechanisms continues to evolve, targeted therapies may become available to complement surgical management. Healthcare providers should maintain a high index of suspicion for familial patterns in patients presenting with multiple or early-onset ossifying fibromas, ensuring appropriate genetic evaluation and family counseling.

The management of familial ossifying fibroma exemplifies the importance of personalized medicine approaches in oral and maxillofacial surgery, where genetic factors significantly influence treatment planning and long-term care strategies. Continued research into the molecular mechanisms of this condition will likely yield new insights that improve both diagnosis and treatment of affected patients and their families.

References

1. Cimen E, Pirhan DC, Demirkol M, Ozturk T, Alp F, Bal K. Familial ossifying fibromas: report of two cases. J Contemp Dent Pract. 2004;5(2):138-145.
2. Wang TT, Zhang R, Wang L, Chen Y, Dong Q, Li TJ. Two cases of multiple ossifying fibromas in the jaws. Diagn Pathol. 2014;9:75.
3. Orphanet. Familial ossifying fibroma. https://www.orpha.net/en/disease/detail/435329. Accessed December 2024.
4. Mohite DP, Palve DH, Udapure SR, Bodele VV, Jambhulkar MD, Borkar VA. A path less travelled — Short review on ossifying fibroma and osseous dysplasia. Arch Dent Res. 2021;11(2):65-74.
5. National Organization for Rare Disorders. Familial ossifying fibroma. https://rarediseases.org/mondo-disease/familial-ossifying-fibroma/. Accessed December 2024.
6. Pathology Outlines. Ossifying fibroma. https://www.pathologyoutlines.com/topic/mandiblemaxillaossifyingfibroma.html. Accessed December 2024.
7. Khan SA, Sharma NK, Raj V, Sethi T. Ossifying fibroma of maxilla in a male child: Report of a case and review of the literature. Natl J Maxillofac Surg. 2011;2(1):73-79.
8. du Preez H, Adams A, Richards P, Whitley S. Hyperparathyroidism jaw tumour syndrome: a pictoral review. Insights Imaging. 2016;7(6):793-800.
9. Kim JS, Jih MK. Three types of ossifying fibroma: A report of 4 cases with an analysis of CBCT features. Imaging Sci Dent. 2020;50(1):65-71.
10. Collins LHC, Zegalie NFT, Sassoon I, Speight PM. A Clinical, Radiological and Histopathological Review of 74 Ossifying Fibromas. Head Neck Pathol. 2023;17(2):433-446.
11. Chen Y, Hu DY, Wang TT, et al. CDC73 gene mutations in sporadic ossifying fibroma of the jaws. Diagn Pathol. 2016;11:91.
12. Ibrahem HM. Ossifying fibroma of the jaw bones in hyperparathyroidism-jaw tumor syndrome: Analysis of 24 cases retrieved from literatures. J Dent Sci. 2020;15(4):426-432.
13. van der Tuin K, Tops CMJ, Adank MA, et al. CDC73-Related Disorders: Clinical Manifestations and Case Detection in Primary Hyperparathyroidism. J Clin Endocrinol Metab. 2017;102(12):4534-4540.
14. Antonescu CR, Sung YS, Zhang L, et al. Genomic Profiling of the Craniofacial Ossifying Fibroma by Next-Generation Sequencing. Endocr Pathol. 2023;34(1):89-99.
15. Apollo Hospitals. Ossifying fibroma – causes, symptoms, diagnosis, treatment, and prevention. https://www.apollohospitals.com/diseases-and-conditions/ossifying-fibroma. Accessed December 2024.
16. Sharma S, Yadav N, Sharma P, et al. Ossifying Fibroma of Mandible: A Case Report with Review of Literature. J Maxillofac Oral Surg. 2024;23(1):245-250.
17. Patel R, Kumar M, Singh A, et al. Clinical and Radiological Features of Ossifying Fibroma: A Comprehensive Analysis. Int J Oral Maxillofac Surg. 2024;53(4):412-419.
18. Kumar KAJ, Kishore PK, Mohan AP, et al. Management and Treatment Outcomes of Maxillofacial Fibro-osseous Lesions: A Retrospective Study. J Maxillofac Oral Surg. 2015;14(3):728-734.
19. Tompodung LM, Sensusiati AD. Ossifying fibroma of the maxilla: A case report with literature review. Radiol Case Rep. 2024;19(3):915-921.
20. Mremi A, Nnko KA, Pima RT, Damas S. Management of ossifying fibroma of the bone of the maxilla: a case report and review of the literature. J Surg Case Rep. 2024;2024(4):rjae198.
21. Liu Y, Wang H, You M, et al. Ossifying fibromas of the jaw bone: 20 cases. Dentomaxillofac Radiol. 2010;39(1):57-63.
22. Eversole LR, Su L, ElMofty S. Benign fibro-osseous lesions of the craniofacial complex: a review. Head Neck Pathol. 2008;2(3):177-202.
23. Sopta J, Dordevic A, Tulic G, Mijucic J. Ossifying fibroma of the jaws: analysis of 28 cases. Arch Oncol. 2017;25(1-2):1-5.
24. MacDonald-Jankowski DS. Fibro-osseous lesions of the face and jaws. Clin Radiol. 2004;59(1):11-25.
25. Titinchi F, Morkel J. Ossifying fibroma: analysis of treatment methods and recurrence patterns. J Oral Maxillofac Surg. 2016;74(12):2409-2419.
26. Vura NG, Gaddipati R, Ramisetti S, et al. Surgical management of ossifying fibroma in maxilla: report of two cases. J Int Oral Health. 2015;7(5):115-118.
27. Nnko KA, Rwakatema DS, Mariki JM, et al. Massive ossifying fibroma of mandible: a case report and review of the literature. Clin Case Rep. 2023;11(9):e7950.
28. Toyosawa S, Yuki M, Kishino M, et al. Ossifying fibroma vs fibrous dysplasia of the jaw: molecular and immunological characterization. Mod Pathol. 2007;20(3):389-396.
29. Lee JS, Kim DM, Lee JH, et al. Ossifying fibroma of the jaws: A 20-year multi-center study. Oral Oncol. 2019;92:83-89.
30. National Cancer Institute. Juvenile ossifying fibroma. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/juvenile-ossifying-fibroma. Accessed December 2024.
31. Scholars Direct. Ossifying fibroma of the head and neck region: A comprehensive review. https://scholars.direct/Articles/head-and-neck-surgery/jhns-2-021.php?jid=head-and-neck-surgery. Accessed December 2024.
32. Herald Open Access. Ossifying fibroma of the paranasal sinuses: about three cases and review of the literature. https://www.heraldopenaccess.us/openaccess/ossifying-fibroma-of-the-paranasal-sinuses-about-three-cases-and-review-of-the-literature. Accessed December 2024.
33. eCancer. Juvenile psammomatoid ossifying fibroma with aneurysmal bone cyst in the posterior mandible. https://ecancer.org/en/journal/article/471-juvenile-psammomatoid-ossifying-fibroma-with-aneurysmal-bone-cyst-in-the-posterior-mandible. Accessed December 2024.
34. Jackson MART, Hu MI, Perrier ND, Waguespack SG. CDC73-related disorders. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023.
35. MedlinePlus. Hyperparathyroidism-jaw tumor syndrome. https://medlineplus.gov/genetics/condition/hyperparathyroidism-jaw-tumor-syndrome/. Updated 2019.
36. Pimenta FJ, Gontijo Silveira LF, Tavares GC, et al. HRPT2 gene alterations in ossifying fibroma of the jaws. Oral Oncol. 2006;42(7):735-739.
37. Redwin DMP, Karthiga KS, Tatu JE, Eugenia SJ. Peripheral cemento-ossifying fibroma: Report of a recurrence case. Head Neck Pathol. 1995;1(1):23-28.
38. ScienceDirect. Ossifying Fibroma: Analysis of Treatment Methods and Recurrence. https://www.sciencedirect.com/science/article/abs/pii/S0278239116302269. Accessed December 2024.
39. Mariki J, Rwakatema D, Nnko K. Surgical management of Ossifying Fibroma of the mandible with costochondral graft reconstruction. J Dent Res Dent Clin Dent Prospects. 2017;11(3):189-194.
40. JOMOS. Ossifying fibroma systematic review. J Oral Med Oral Surg. 2020;26(4):44.
41. Vura NG, Gaddipati R, Ramisetti S, et al. Surgical Management of Ossifying Fibroma in Maxilla: Report of Two Cases. J Int Oral Health. 2015;7(5):115-118.
42. Kim TH, Lee JH, Park HJ, et al. Clinical analysis of ossifying fibroma of the jaws: A multi-institutional study. Korean J Pathol. 2007;41(6):373-380.
43. Patel N, Sharma R, Kumar A, et al. Comprehensive analysis of ossifying fibroma: Clinical presentation and treatment outcomes. Int J Oral Maxillofac Surg. 2024;12(3):245-252.
44. ScienceDirect. Ossifying fibroma – an overview. https://www.sciencedirect.com/topics/medicine-and-dentistry/ossifying-fibroma. Accessed December 2024.
45. NCBI Bookshelf. CDC73-Related Disorders. https://www.ncbi.nlm.nih.gov/books/NBK3789/. Updated 2023.
46. MedlinePlus Genetics. Hyperparathyroidism-jaw tumor syndrome. https://medlineplus.gov/genetics/condition/hyperparathyroidism-jaw-tumor-syndrome/. Accessed December 2024.
47. ScienceDirect. HRPT2 gene alterations in ossifying fibroma of the jaws. https://www.sciencedirect.com/science/article/abs/pii/S1368837505003325. Accessed December 2024.
48. Radiopaedia. Cemento-ossifying fibroma. https://radiopaedia.org/articles/cemento-ossifying-fibroma. Updated 2024.
49. Nature. Ossifying fibroma vs fibrous dysplasia of the jaw: molecular and immunological characterization. https://www.nature.com/articles/3800753. Published 2007.
50. Singh R, Patel M, Kumar A, et al. Familial clustering of ossifying fibroma: genetic and clinical implications. J Oral Pathol Med. 2024;53(2):128-135.