Nailing the diagnosis of the BAP1 tumor predisposition syndrome

By Warren R. Heymann, MD, FAAD
June 5, 2024
Vol. 6, No. 23

I never imagined that I would be writing another commentary on onychopapillomas (Ops) so soon. The initial commentary was devoted to rare malignant Ops. (1) Unsurprisingly, additional reports of malignant Ops have been reported. (2) What else could warrant another commentary? The observation that multiple Ops appear to be associated with the BAP1-tumor predisposition syndrome (BAP1-TPDS).

According to West et al., “The BRCA1-associated protein 1 (BAP1) tumor suppressor gene is located on chromosome 3p21.3 and encodes a protein involved in multiple critical cellular functions, including cell proliferation and division, cell death, and DNA damage repair. The protein is a deubiquitinase enzyme (DUB) that regulates the ubiquitinproteasome pathway, which is responsible for the degradation of unnecessary or damaged proteins within the cell. It acts as a negative regulator in this pathway by removing ubiquitin, a tag that marks proteins for degradation from other proteins thereby stabilizing the proteins within the cell. The BAP1 protein resides in both the cytoplasm and nucleus of the cell, with different functions: it is involved in DNA repair mechanisms in the nucleus, while it regulates apoptosis in the cytoplasm. BAP1 also plays a prominent role in regulating the tumor suppressor protein p53, which prevents the development of cancerous cells.” (3)

BAP1 was first identified as a tumor suppressor gene in 2008. Germline pathogenic variants in BAP1 have subsequently been associated with various tumors resulting in the recognition of BAP1-TPDS (OMIM 614327). Patients with this autosomal dominant syndrome are at risk for uveal melanoma (30-34%), malignant mesothelioma of the pleura and the peritoneum (20-25%), cutaneous melanoma (13%), renal cell carcinoma (10%) and specific non-malignant neoplasms of the skin. Additional tumors including meningioma, cholangiocarcinoma, and hepatocellular carcinoma, have been suggested as possible associations with BAP1-TPDS. (3,4).

Turbeville and Hand assert, “BAP1-inactivated benign melanocytic nevi present as well-marginated, skin-colored to red/brown, pedunculated or dome-shaped papules typically distributed most commonly on the head and neck, followed by trunk and extremities. Multiple lesions are characteristically present in individuals with germline mutations (ranging from 5 to 50 lesions in individual members of affected families). Dermatoscopic findings associated with these lesions have been reported. Interestingly, structureless with eccentric dots/globules pattern and network with raised structureless areas pattern was significantly associated with germline mutations. Ultimately, diagnosis relies on the histopathologic evaluation of biopsy specimen.” (5) Dermatopathologists play a crucial role in diagnosing BAP1-TPDS; dermal nevi with sheets of Spitzoid epithelioid melanocytes suggest the diagnosis, which is confirmed by the loss of BAP1. (6) Once a diagnosis is established, genetic testing should be considered if a patient has a history of multiple such lesions, a strong family history of such lesions exists, or the lesion is diagnosed in a young patient. (5)

It is easy to miss the diagnosis of BAP1–TPDS. Clinically, lesions often appear banal, with no reason to remove or biopsy them. Unless there is a detailed family history noting associated malignancies, the syndrome may not be recognized. Are there any clinical clues that may alert the dermatologist to consider the diagnosis of BAP1-TPDS?

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Lebensohn et al. performed a prospective cohort study in individuals who were known carriers of pathogenic BAP1 germline variants, evaluating them for nail abnormalities among 47 participants aged 13 to 72 years from 35 families. Nail abnormalities were detected in 41 patients (87.2%), including leukonychia, splinter hemorrhage, onychoschizia, and distal nail hyperkeratosis. Clinical findings consistent with Ops were detected in 39 patients (83.0%), including 35 of 40 individuals aged 30 years or older (87.5%). A nail bed biopsy was performed on 5 patients and was consistent with Ops. Polydactylous involvement with Ops was detected in nearly all patients with nail involvement (38 of 39 patients [97.4%]). (7) Studies in the general population confirm that most Ops are monodactylous. (8) Lebensohn et al. concluded that BAP1-TPDS is associated with a high rate of nail abnormalities consistent with Ops in adult disease carriers. “Findings suggest that this novel cutaneous sign may facilitate detection of the syndrome in family members who are at risk and patients with cancers associated with BAP1 given that multiple onychopapillomas are uncommon in the general population and may be a distinct clue to the presence of a pathogenic germline variant in the BAP1 gene.” Further studies are necessary to determine if the BAP1-TPDS Ops are at risk for becoming malignant; in the 5 patients evaluated histologically, the Ops demonstrated an inconsistent loss of BAP1 expression. Any change or symptoms (pain) in these lesions warrants further clinical assessment (7) and possible nail biopsy.

Patients identified with BAP1-TPDS require ongoing surveillance for malignancy screening. Identifying affected family members is essential. The recognition of the association of polydactylous Ops with BAP1-TPDS is a seminal observation that will save lives.

Point to Remember: Patients with polydactylous onychopapillomas mandate evaluation for the BAP1-tumor predisposition syndrome.

Our expert’s viewpoint

Edward W. Cowen, MD, MHsc, FAAD
Senior Clinician
Head, Dermatology Consultation Service
Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases

We have probably all seen a patient with BAP1 TPDS. More than likely — if the patient was an adult — our data suggest this patient probably had nail findings suggestive of onychopapilloma (we don’t currently have enough data regarding age of onset of nail changes in younger patients). How did we miss this diagnostic clue for so long? Although BAP1 TPDS is a ‘melanoma’ syndrome, as Dr. Heymann notes, cutaneous melanoma is less penetrant than many of the other malignancies associated with germline BAP1 pathogenic variants and will develop in a minority of patients. BAP1 inactivated melanocytomas are also an important cutaneous sign but require biopsy confirmation and may not be sampled without a prior index of suspicion due to their banal clinical appearance.

Similarly, the nail changes in BAP1 TPDS often present with subtle thin leukonychia bands (rather than erythronychia or splinter hemorrhage) and are often asymptomatic. So, even when detected, nail changes in this setting are unlikely to be biopsied. Nevertheless, we believe this clinical finding may be a particularly helpful clue to a diagnosis of BAP1 TPDS because polydactylous onychopapilloma appears to be uncommon in the general population. Ultimately, careful skin and nail evaluation together with a thorough personal and family cancer history provide the best context for consideration of BAP1 genetic evaluation.

Lastly, our report was the product of the concerted effort of a dedicated group of clinicians studying the syndrome at the NIH but would not have been possible without the contribution of our patients, particularly those who allowed us to biopsy their nails. Several patients were simultaneously dealing with a serious cancer diagnosis — their willingness to help us confirm nail disease as a new diagnostic marker will facilitate the future diagnosis of BAP1 TPDS in others and their contribution is greatly appreciated.

1. Heymann WR. When to see red in linear erythronychia – Malignant onychopapilloma. Dermatology World Insights and Inquiries, Vol 4, No. 26, June 29, 2022. https://staging.aad.org/dw/dw-insights-and-inquiries/archive/2022/linear-erythronychia-malignant-onychopapilloma

2. Haynes D, Haneke E, Rubin AI. Clinical, onychoscopic, nail clipping, and histopathological findings of malignant onychopapilloma. J Cutan Pathol. 2024 Apr 2. doi: 10.1111/cup.14620. Epub ahead of print. PMID: 38563529.

3. West EC, Chiappetta M, Mattingly AA, Congedo MT, Evangelista J, Campanella A, Sassorossi C, Flamini S, Rossi T, Pistoni M, Abenavoli L, Margaritora S, Lococo F, Boccuto L. BRCA1-associated protein 1: Tumor predisposition syndrome and KuryIsidor syndrome, from genotype-phenotype correlation to clinical management. Clin Genet. 2024 Jun;105(6):589-595. doi: 10.1111/cge.14507. Epub 2024 Mar 20. PMID: 38506155.

4. Lalloo F, Kulkarni A, Chau C, Nielsen M, Sheaff M, Steele J, van Doorn R, Wadt K, Hamill M, Torr B, Tischkowitz M; Delphi respondents; Hanson H. Clinical practice guidelines for the diagnosis and surveillance of BAP1 tumour predisposition syndrome. Eur J Hum Genet. 2023 Nov;31(11):1261-1269. doi: 10.1038/s41431-023- 01448-z. Epub 2023 Aug 22. PMID: 37607989; PMCID: PMC10620132.

5. Turbeville JG, Hand JL. Pediatric Cutaneous Oncology: Genodermatoses and Cancer Syndromes. Dermatol Clin. 2023 Jan;41(1):175-185. doi: 10.1016/j.det.2022.07.013. Epub 2022 Oct 28. PMID: 36410977.

6. Heymann WR. Becoming Wiser About the Wiesner Nevus. Skinmed. 2016 Oct 1;14(5):379-380. PMID: 27871353.

7. Lebensohn A, Ghafoor A, Bloomquist L, Royer MC, Castelo-Soccio L, Karacki K, Hathaway O, Maglo T, Wagner C, Agra MG, Blakely AM, Schrump DS, Hassan R, Cowen EW. Multiple Onychopapillomas and BAP1 Tumor Predisposition Syndrome. JAMA Dermatol. 2024 May 17:e241804. doi: 10.1001/jamadermatol.2024.1804. Epub ahead of print. PMID: 38759225; PMCID: PMC11102040.

8. Kim TR, Bae KN, Son JH, Shin K, Kim HS, Ko HC, Kim BS, Kim MB. Onychopapilloma: its clinical, dermoscopic and pathologic features. J Eur Acad Dermatol Venereol. 2022 Nov;36(11):2235-2240. doi: 10.1111/jdv.18461. Epub 2022 Aug 4. PMID: 35869667.

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