Multifocal extracardiac rhabdomyomas: extending the phenotype of Birt–Hogg–Dubé syndrome
Authors: D. S. Bajwa, S. Cook, R. Winn, I. M. Winship, A. McQueen, A. Husain, N. Rajan
Journal: British Journal of Dermatology (2021)

Dear Editor, Birt–Hogg–Dubé (BHD) syndrome is characterized by a triad of benign skin tumours, pulmonary cysts with an attendant risk of pneumothorax and renal cancer. BHD is caused by heterozygous pathogenic variants in folliculin (FLCN), a tumour suppressor gene. Single cardiac and extracardiac rhabdomyomas have been infrequently reported1 in patients with BHD, but not conclusively linked as part of the phenotype as these may have been coincidental events. Here we report a case of a patient with BHD with multifocal extracardiac rhabdomyomas, adding evidence to support rhabdomyomas as part of the BHD phenotype. A 63-year-old man presented complaining of fullness in the submandibular region. He had multiple facial fibrofolliculomas and trichodiscomas (Figure 1a), for which he previously received ablative laser therapy. He was known to carry a familial heterozygous germline pathogenic variant in FLCN [NM_144997.5: c.469_471delTTC (p.Phe157del)] and had two brothers who were also carriers of the pathogenic variant. This variant segregated with the BHD phenotype in this family and has been reported in several prior BHD syndrome pedigrees.1 One affected brother had a history of unilateral human papillomavirus-positive tonsillar squamous cell carcinoma, which had metastasized to the lymph nodes. Ultrasound and computed tomography studies of the head and neck in the proband demonstrated three homogeneous soft-tissue masses within the left submandibular and bilateral sublingual spaces (Figure 1b). A percutaneous ultrasound-guided core biopsy was obtained from the left submandibular tumour. Histological examination revealed large eosinophilic cells with occasional cross-striations, interspersed with pale areas. Immunohistochemistry demonstrated strong positivity for desmin in keeping with rhabdomyoma (Figure 1c). Rhabdomyoma DNA analysis demonstrated loss of heterozygosity (LOH) at the site of the patient's FLCN pathogenic variant, compared with control tissue (Figure 1d). Subsequent imaging has shown these tumours to have remained static over a 4-year period. Extracardiac rhabdomyomas are categorized as adult, fetal and genital types.2 Adult-type extracardiac rhabdomyomas have a predominance in men (average age of presentation 65 years) with the head and neck being the main site.3 Patients may present with dysphagia and hoarseness, and other symptoms may include pain and new-onset snoring. Multifocal extracardiac rhabdomyomas are rare, with 33 cases ever reported, predominantly in male patients over the age of 50 years.3 Such cases are suggestive of a genetic predisposition; however, unlike cardiac rhabdomyomas which have been reported in tuberous sclerosis and Möbius syndrome,4 a genetic basis has not been elucidated.3, 5 It is of interest that in one case of multifocal extracardiac rhabdomyomas,3 multiple perinasal papules were noted; however, BHD was not considered and a skin biopsy was not performed. There have been prior reports of BHD and single extracardiac rhabdomyomas reported in the larynx2 and parathyroid glands.6 In addition, a case of two cardiac rhabdomyomas has been reported in a 5-month-old boy, presenting with an out-of-hospital cardiac arrest. Notably, that child carried the same pathogenic variant in FLCN as our patient, and had no pathogenic variants in the tuberous sclerosis genes TSC1 or TSC2.1 Finally, in the Nihon rat model of BHD (which carries a germline FLCN pathogenic variant), cardiac rhabdomyomas are reported in 12% of heterozygote rats.1 FLCN is located on chromosome 17 and plays a role in regulating diverse metabolic and cellular pathways, including the mammalian target of rapamycin (mTOR) signalling pathway.7 As the TSC1/TSC2 complex also regulates mTOR signalling, it has been suggested that deregulated mTOR signalling may account for rhabdomyoma formation in both tuberous sclerosis and BHD syndrome.2 LOH, a frequent genetic event in tumour predisposition syndromes, is seen to involve FLCN in BHD-related renal cancer, but has not been demonstrated in the keratinocytes of fibrofolliculomas.8 Our case reporting the multifocal presentation of extracardiac rhabdomyomas, and the demonstration of LOH of FLCN in rhabdomyoma tissue, adds support to rhabdomyoma being an infrequent but linked phenotypic feature in BHD. Patients with multifocal rhabdomyomas may benefit from phenotypic assessment to determine whether they satisfy clinical diagnostic criteria for BHD syndrome. If confirmed to carry a pathogenic variant in FLCN following genetic testing, they may benefit from genetic counselling, advice regarding the risk of pneumothorax and renal cancer surveillance. Dalvir Bajwa: Conceptualization (equal); Investigation (equal); Writing-original draft (equal); Writing-review & editing (equal). Sam Cook: Investigation (equal); Validation (equal); Writing-review & editing (equal). Remus Winn: Investigation (equal). Ingrid. Winship: Conceptualization (supporting); Writing-review & editing (equal). Andrew McQueen: Investigation (equal); Methodology (equal); Writing-original draft (equal); Writing-review & editing (equal). Akhtar Husain: Conceptualization (lead); Investigation (equal); Methodology (equal); Writing-original draft (equal); Writing-review & editing (equal). Neil N Rajan: Conceptualization (equal); Data curation (equal); Formal analysis (equal); Funding acquisition (equal); Investigation (equal); Methodology (equal); Project administration (equal); Supervision (equal); Validation (equal); Writing-original draft (equal); Writing-review & editing (equal).