Onychomatricoma with Tuberous Sclerosis: A Novel Association?

Dear Editor,

Tuberous sclerosis complex (TSC), or Bourneville’s disease, is a rare autosomal dominant genetic disorder characterized by benign tumors in multiple organ systems, including the skin, brain, kidneys, heart, lungs, and eyes. Dermatological manifestations include angiofibromas, shagreen patches, hypopigmented macules, and periungual fibromas (Koenen tumors). TSC is caused by mutations in the TSC1 or TSC2 genes, which encode the tumor suppressors hamartin and tuberin, respectively. These mutations can be either inherited or sporadic.[1] To the best of our knowledge, the occurrence of onychomatricoma (OM) in TSC patients has not been previously documented.

A 15-year-old boy presented to the dermatology outpatient department with multiple facial lesions, progressing slowly for six years. The patient was on phenytoin for seizure disorder for the past eight years. Clinical examination revealed multiple facial angiofibromas, multiple collagenomas on the back and forehead, and multiple periungual fibromas of various sizes. The right great toenail showed widening and onychodystrophy involving the medial half [Figure 1]. Onychoscopy of the dystrophic medial great toenail lesion showed multiple whitish concentric lamellae with brown spots in the center [Figure 2], suggestive of ‘woodworm appearance.’ Intraoperatively, the removal of the overlying dystrophic nail plate revealed a proximally originating nodular mass with villous projections, [Figure 3]. Histopathology of the nail plate specimen revealed a thickened nail plate with lacunae [Figure 4a]. The villous mass was composed of papillary projections with connective tissue stroma, extending deep into the dermis [Figure 4b]. These projections were covered by matrix epithelium [Figure 4c]. The findings were suggestive of onychomatricoma. Immunohistochemical or genetic analysis could not be done due to resource constraints.

Figure 1.

Onychodystrophy involving the medial half of the right great toenail. Additional Koenen’s tumors can be seen in the fifth digit

Figure 2.

Onychoscopy [AM7115MZT Dino-Lite Edge 3.0 digital microscope] of the dystrophic medial great toenail lesion showing multiple whitish concentric lamellae with brown spots in the center (black arrows), suggestive of “woodworm appearance” (polarized, 70x)

Figure 3.

Intraoperative appearance of the nodular mass with villous projections

Figure 4.

Histological section showing (a) a thickened nail plate with lacunae (H and E, 40x); (b) a villous mass composed of papillary projections with connective tissue stroma, extending deep into the dermis (H and E, 100x); (c) a high-power view shows projections to be covered by matrix epithelium (H and E, 400x)

Onychomatricoma is a rare, benign nail unit tumor that predominantly occurs in adults. Clinically, it is characterized by thickening of the nail plate, chromonychia (leukonychia, xanthonychia, or leukoxanthonychia), and surface irregularities such as longitudinal ridging. Although the exact origin of onychomatricoma is unclear, potential causative factors include localized trauma, onychomycosis, or chromosomal alterations, particularly involving chromosome 11.[2] However, no previous association between onychomatricoma and TSC has been reported, despite TSC being associated with various other skin tumors. Multiple periungual fibromas, or Koenen tumors, are the most common nail unit tumors in TSC. These are often asymptomatic but occasionally cause pain or deformity. Although TSC is associated with a predisposition to multiple benign tumors, periungual fibromas remain the only nail tumors previously described in TSC. This raises questions about the potential link between TSC-related genetic mutations and the development of onychomatricoma. In our case, the clinical, onychoscopic, and histological features were consistent with onychomatricoma, although differentiation from fibrokeratomas was inconclusive due to the lack of immunohistochemical analysis.

Cañueto et al.[3] conducted a genome-wide analysis of DNA copy number variations in onychomatricoma, revealing a total of 34 regions with altered DNA copy numbers. Notably, losses were more common than gains, with significant losses observed in chromosomes 6q14, 11p14–p15, and 11q21–q22. Among these, the deletion of 11p15.4, housing the STIM1 gene, is particularly significant. Decreased STIM1 levels have been associated with accelerated progression of TSC-related tumors due to reinstated AKT1 function and increased angiogenesis.[4] Losses involving chromosome 11 and decreased STIM1 levels may explain the co-occurrence of onychomatricoma with TSC. A comprehensive genomic analysis of onychomatricoma by Perrin et al.[5] also reported recurrent loss of chromosome 13, including the RB1 (retinoblastoma 1) gene, in all cases. Interestingly, retinoblastoma has been documented with TSC, showing a mutation in the RB1 gene with a heterozygous loss of the 17^th exon in TSC2.[6] Many reports of p53 mutations identified in onychomatricoma cases suggest an interplay between p53 and TSC contributing to tumorigenesis.[1,2,3,4,5,7] Mutations in TSC2 or p53 may prevent normal autophagy, leading to tumorigenesis.[1] Genetic testing could have been valuable in our case, but could not be performed due to a lack of resources. Like Koenen tumors, onychomatricoma is also a fibroepithelial tumor, albeit of matricial origin, characterized by a complex structure of fibrous and epithelial elements. This similarity underscores the need for further research into their pathogenesis, especially in the context of TSC.

In conclusion, our case presents a novel association between onychomatricoma and TSC. A potential genetic predisposition warrants further research. Clinicians should be aware of this possibility, as it adds to the spectrum of dermatological manifestations of TSC. Investigating the molecular pathogenesis of this association may provide valuable insights into the development of this uncommon nail tumor.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient’s mother has given consent for the images and other clinical information to be reported in the journal. The patient’s mother understands that the name and initials of the child will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Use of artificial intelligence (AI)

We have not used artificial intelligence in the preparation of this manuscript.

Funding Statement

Nil.