Brooke-Spiegler Syndrome in Japanese Siblings with an R758X Mutation: A Case Report

Abstract

Introduction

Brooke-Spiegler syndrome is a rare hereditary skin disorder characterized by the development of multiple adnexal tumors, such as trichoepitheliomas and cylindromas, with a higher prevalence in females.

Case Presentation

We report a rare case involving two male siblings who developed facial lesions consistent with this condition. Both patients presented with tumors on the nasal ala, which were successfully treated with carbon dioxide (CO₂) laser therapy. Genetic testing confirmed the diagnosis of Brooke-Spiegler syndrome, consistent with autosomal dominant inheritance.

Conclusion

This case underscores the importance of family history and genetic evaluation in the diagnosis and management of this syndrome. Repeated CO₂ laser therapy may provide effective long-term cosmetic control of facial lesions.

Introduction

Brooke-Spiegler syndrome (BSS) is a rare autosomal dominant genetic disorder characterized by the development of multiple skin appendage tumors, most notably cylindromas, trichoepitheliomas, and spiradenomas [1]. These benign adnexal neoplasms most commonly arise on the scalp, face, and neck – areas rich in pilosebaceous units. BSS is caused by germline mutations in the CYLD gene located on chromosome 16q12.1, which encodes a tumor suppressor protein involved in the negative regulation of the NF-κB signaling pathway [2, 3]. Loss of CYLD function leads to dysregulated cell proliferation and tumor development in adnexal structures.

Although BSS can affect both sexes, it predominantly manifests in females and typically presents during the second or third decade of life [1]. The number and size of lesions can vary considerably, ranging from a single nodule to hundreds of tumors, some of which may coalesce into large, disfiguring masses. Cylindromas are generally small (0.5–3 cm), but giant variants exceeding 7 cm have been reported, particularly on the scalp, sometimes forming so-called “turban tumors” [4]. While most tumors are histologically benign, malignant transformation – especially to cylindrocarcinoma – can occur, necessitating close clinical surveillance in cases of rapid enlargement, ulceration, or bleeding.

From a clinical standpoint, BSS poses both cosmetic and functional challenges, particularly when tumors are numerous or located in cosmetically sensitive areas. The psychosocial burden associated with facial and scalp tumors can be profound. Treatment typically involves surgical excision, although recurrence is common. Other modalities, such as laser ablation, electrosurgery, or targeted molecular therapies (e.g., NF-κB inhibitors), have been explored with varying success [5]. Genetic counseling is essential owing to the hereditary nature of the disease, and identification of affected family members can facilitate early diagnosis and intervention.

Although familial cases of BSS have been documented, reports involving multiple affected siblings remain scarce. Here, we present a unique case of two Japanese brothers diagnosed with BSS, both carrying a known pathogenic CYLD variant and exhibiting typical clinical features. This case highlights the importance of family history in the diagnostic approach and contributes to the limited literature on BSS in East Asian populations.

Case Report

A 29-year-old male (the older brother) presented with multiple asymptomatic, smooth, round, well-defined skin-colored tumors on his face. The tumors first appeared at 5 years of age and rapidly expanded since approximately the age of 20 years. His younger brother (aged 28 years) presented with multiple well-defined, round, skin-colored tumors in the nasal and nasolabial areas and had a similar age of onset (Fig. 1). Both patients had no prior medical history, but their sister (20 years), mother, maternal aunt, and maternal grandmother had similar nasal tumors.

Fig. 1.

Appearance of the patients before treatment. a Older brother. b Younger brother.

Chest CT scans of both patients showed no pulmonary nodules or metastatic lesions. Salivary gland evaluation by physical examination and ultrasonography findings were also unremarkable. Given the risk of malignant transformation associated with CYLD mutations, the use of radiotherapy was explicitly discouraged. Alternative treatment options such as surgical excision and electrosurgery were considered. However, due to the facial location, multiplicity, and cosmetic sensitivity of the lesions, both patients opted for carbon dioxide (CO₂) laser therapy, which offers greater precision and reduced scarring.

The tumors were treated with a scanner-equipped continuous wave CO₂ laser therapy (1–3 W, 1–3 sessions) after application of an anesthetic cream. The lesions were excised by cauterization of the superficial dermis, resulting in significant reduction in the lesions and improvement in their appearance (Fig. 2). Patients were counseled on the importance of strict photoprotection as a preventive measure against UV-induced tumor development.

Fig. 2.

Appearance of the older brother after CO₂ laser cauterization treatment (3 sessions).

Both patients were subjected to genetic analysis using HaloPlex analysis and Sanger sequencing to identify any CYLD mutations; both were found to have a heterozygous nonsense mutation in the CYLD gene at c.2272C>T, p.Arg758Ter, consistent with an autosomal dominant inheritance pattern.

Pathological examination revealed that hair follicle-like cells proliferated in a nodular pattern in the deep layers of the epidermis, surrounded by fibrous stroma, forming fibroepithelial units. Multiple keratin cysts were present in the dermis, consistent with a hair follicle epithelial tumor (Fig. 3). No obvious nuclear atypia or mitotic figures were observed, and there were no signs of malignancy. Based on these results, a diagnosis of multiple trichoepithelioma was made. Given the presence of multiple trichoepitheliomas involving the facial area in both brothers, a strong maternal family history of similar lesions, and identification of a pathogenic CYLD mutation, the overall clinical and genetic features supported the diagnosis of BSS. Although only trichoepitheliomas were confirmed histologically, the combination of tumor type, anatomical distribution, and inheritance pattern favored BSS over multiple familial trichoepithelioma or familial cylindromatosis, which are considered phenotypic variants within the CYLD cutaneous syndrome spectrum. The patients were advised to undergo regular dermatological follow-up every 6 months to monitor for the development of new lesions. The patients were satisfied with cosmetic improvements and requested continued treatment for other regions or minor recurrence. Furthermore, genetic counseling was recommended for at-risk family members, especially first-degree relatives, in light of the autosomal dominant inheritance pattern of CYLD-associated disorders.

Fig. 3.

Histopathological findings. Small basal cells resembling hair germ cells proliferated in nests from the deep epidermis to the dermis, with numerous keratin cysts forming around them.

Discussion

BSS is a genetic disorder characterized by a combination of cylindromas and follicular epithelial tumors. It typically presents during puberty and affects several members of the same family, with a higher incidence in females than that in males [1]. The tumors gradually grow, causing significant esthetic changes accompanied by psychological, social, and occupational side effects.

Biopsy specimens are essential for the diagnosis of BSS. Most lesions are histologically single; however, tumors with mixed features, such as spiradenocylindromas, spiradenoma-trichoepitheliomas, and cylindroma-trichoepitheliomas, may also occur [6]. The CYLD tumor suppressor gene on chromosome 16 has been implicated in the etiology of BSS and its phenotypic variants, and genetic mutation testing may confirm the diagnosis in some cases [7]. No correlation has been reported between the genotype and phenotype with respect to disease severity, potential for malignancy, or the occurrence of extracutaneous lesions. In this case, a c.2272C>T, p.Arg758Ter nonsense mutation was identified, which is primarily detected in Hungarian and Anglo-Saxon families [1]. The clinical severity in our patients, characterized by early childhood onset, lesion progression during adulthood, and strong familial aggregation, was comparable to that reported in these families. In Japanese individuals, this mutation has only been detected in a single sporadic case, and another case was associated with a c.1681_1682delTT, p.Leu561Serfs*8 mutation accompanied by giant hemangiomas [8]. To our knowledge, this is the first reported case of R758X mutation-induced BSS in male Japanese siblings. Although there are ethnic and geographic differences, the phenotypic expression of CYLD mutations appears relatively consistent across populations. However, the pathogenesis of BSS in patients with large CYLD gene rearrangements remains unclear.

BSS is a rare disease, with no consensus regarding optimal treatment strategies. Treatment options that have demonstrated efficacy include skin peeling, electrosurgery, cryotherapy, radiation therapy, neodymium-doped YAG laser, erbium YAG laser, CO₂ laser ablation, photodynamic therapy, combination of sodium salicylate and prostaglandin A1, combination of aspirin and adalimumab, and topical imiquimod [1]. In patients with multiple small lesions, as in this case, multiple CO₂ laser ablation treatments may be appropriate, with consideration of the balance between surgical invasiveness and scar formation. CO₂ laser therapy is widely used for cosmetic reduction of adnexal tumors in CYLD-associated syndromes. To the best of our knowledge, as of May 2025, eight studies have reported on the treatment of follicular epithelioma with laser therapy [5, 9–14]. These studies reported no recurrence of lesions during the 2-year follow-up period except for one study [14].

In conclusion, BSS is a rare, inherited cutaneous disorder that can lead to extensive disfigurement and psychosocial distress. Although it is more common in females, this report highlights a rare presentation in male siblings of Japanese descent. Accurate diagnosis requires histological confirmation and genetic testing. Identification of pathogenic CYLD variants, such as c.2272C>T (p.Arg758Ter), can facilitate diagnosis and family screening. Repeated CO₂ laser therapy is an effective management option for patients with multiple lesions. Long-term follow-up is essential for detecting recurrence and monitoring for potential malignant transformation.

Statement of Ethics

Written informed consent was obtained from the patients prior to study participation, including consent to participate and to publish the findings. Ethical approval was not required for this study in accordance with national ethical guidelines. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000548697).

Conflict of Interest Statement

The authors declare no conflicts of interest associated with this article.

Funding Sources

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Author Contributions

Conceptualization, clinical management, and literature review: K.T. and S.S. Data curation and writing – original draft: K.T. Writing – review and editing: S.S. Supervision: K.K.

Funding Statement

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Data Availability Statement

All clinical and imaging data relevant to this case report are included in the article. There are no restrictions on data availability. Further inquiries can be directed to the corresponding author.