Clinical, pathological, and molecular correlation of folliculocystic and collagen hamartoma: A new potential diagnostic criterion for tuberous sclerosis complex?

Abstract

Folliculocystic and collagen hamartoma (FCCH) is a rare entity with only 18 reported cases worldwide. Of them, most are found in patients diagnosed with tuberous sclerosis complex (TSC). FCCH has distinctive histopathologic features, including collagen deposition in the dermis, perifollicular fibrosis, and comedones with keratincontaining cysts lined by infundibular epithelium. We report three patients with a definitive TSC clinical diagnosis in whom clinical, histopathologic, and molecular features were studied to establish if there exists a genotype-phenotype correlation. The molecular results showed different heterozygous pathogenic variants (PV) in TSC2 in each patient: NM_000548.4:c.5024C>T, NG_005895.1:c.1599+1G>T, and NM_000548.4:c.2297_2298dup, to our knowledge; the latter PV has not been reported in public databases. The same PVs were identified as heterozygous in the tumor tissue samples, none of which yielded evidence of a TSC2 second hit. Because all FCCH patients with available molecular diagnosis carry a pathogenic genotype in TSC1 or TSC2, we suggest that FCCH should be considered as a new and uncommon diagnostic manifestation in the TSC consensus international diagnostic criteria. The early recognition of FCCH by clinicians could prompt the identification of new TSC cases. Interestingly, our molecular findings suggest that one of the patients described herein is a probable case of somatic mosaicism. K E Y W O R D S cutaneous genetic mosaicism, cutaneous hamartoma, folliculocystic and collagen hamartoma, TSC1 and TSC2 gene sequencing, tuberous sclerosis complex 1 | INTRODUCTION Tuberous sclerosis complex (TSC) is a multisystemic disease caused by pathogenic variants (PV) in the TSC1 (MIM #191100) and TSC2 (MIM #613254) genes, leading to over-activation of the mTOR pathway and the subsequent formation of hamartomas. 1 The most recently described hamartoma is folliculocystic and collagen hamartoma (FCCH). Torrelo et al 2 published six patients with FCCH, which is a rare cutaneous hamartoma presenting unique histopathologic features, including the deposition of dermal collagen, follicular-sebaceous cystic dilation, and peri-infundibular inflammation. Eight other cases of this type of hamartoma have been reported. 3-11 Thirteen of fifteen

Uncommon Large and Bilateral Fibrous Cephalic Plaques in a Patient with TSC2-Related Tuberous Sclerosis Complex

“…FCPs and FCCHs share some histopathologic features, such as collagen deposits, capillary dilation, and concentric fibrosis around follicles. However, FCCHs are also characterized by dilatation of the infundibular portion of the follicle and the presence of comedo-like openings [6]. Histopathologic evaluation of the present patient indicated that the large and bulky lesions were diagnostic of FCPs.…”

“…Skin biopsies showed normal epidermis with abundant collagen fibers forming nodules surrounding the gland ducts, hair follicles, and vessels in the deep dermis. These findings were compatible with FCP, as no follicular comedo-like openings or follicularsebaceous cystic dilations were present [4,6].…”

“…FCPs should also be differentiated from other dermatologic lesions, such as folliculocystic and collagen hamartomas (FCCHs), which have been described as exophytic plaques with an elastotic consistency and comedo-like openings, and are thought to be considered a new clinical manifestation of TSC [6]. FCPs and FCCHs share some histopathologic features, such as collagen deposits, capillary dilation, and concentric fibrosis around follicles.…”

Giant Genital Mass: Unveiling a Unique Case of Folliculocystic and Collagen Hamartoma

“…The prevailing theory suggests the involvement of TSC1/TSC2 genes and sex hormones in its pathogenesis, yet the emergence of cases in females and those without tuberous sclerosis contradicts this hypothesis [ 5 ]. A case series studying patients with FCCH in tuberous sclerosis patients identified heterozygous pathogenic variants in the TSC2 gene in tumor tissue samples, without evidence of a TSC2 second hit, suggesting a potential genotype-phenotype correlation [ 2 ].…”

“…Proposed as an atypical variant of collagen hamartoma, FCCH demonstrates unique histopathological and clinical features [ 1 ]. The disease typically presents as an exophytic plaque with an elastotic consistency and comedo-like openings, with over half of the cases appearing in infancy or early childhood [ 2 ]. The head is the most common site of involvement, with genital involvement never previously reported.…”