Dear Editor, Tuberous sclerosis complex (TSC) is an autosomal dominant disorder, with an incidence between 1 in 6,000 and 1 in 10,000 live births. It is caused by mutations in the TSC1 (9q34) or TSC2 (16p13.3) genes, which encode the proteins hamartin and tuberin, respectively.1 Mutations in these tumor suppressor genes disrupt the inhibitory functions of hamartin and tuberin, leading to abnormal activation of the mammalian target of rapamycin (mTOR) pathway - a key regulator of cell growth and metabolism. Among the two multimeric complexes mTORC1 and mTORC2, mTORC1 is responsible for integrating signals from growth factors, amino acids, energy levels, and hypoxia stressors, resulting in hyperproliferation of cells and leading to the formation of solid tumors and hamartomas. This can affect multiple organs, including the brain, skin, heart, kidneys, liver, and lungs, potentially compromising their function.2 Here, we report a case of folliculocystic and collagen hamartoma (FCCH) on the knee in a patient with TSC, an unusual site of presentation that expands the spectrum of its clinical manifestations. A 7-year-old boy was referred from the surgery department to the dermatology outpatient department with asymptomatic, well-defined, skin-colored, dome-shaped outgrowths with ulceration on his left knee. These lesions had been present since birth, were non-tender, and had shown slow progression, gradually increasing in size over the past four years. Dermatological examination of the left knee revealed a 15 × 10 cm plaque on lateral aspect with multiple dome-shaped swellings (1 × 1 cm to 5 × 4 cm), comedone-like openings, and ulceration Figure 1a, 1b, and 1c. There was no history of discharge from these lesions. Further clinical examination revealed multiple red, angiofibroma-like lesions on both cheeks and nose, which had also been present since birth Figure 2a. Additionally, a firm, skin-colored plaque resembling orange peel was present on the lower back Figure 2b. Notably, the boy also had a history of seizure episodes since infancy. Routine investigations were performed, and a 4 mm punch biopsy was taken from the cystic growth present on the left knee. Differential diagnoses of FCCH, neurofibroma, epidermal inclusion cyst, steatocystoma multiplex, and lipoma were considered and the differentiating features between these entities are enumerated in Table 1.3,4 Histopathological examination revealed a cyst located in the dermis Figure 3a. The epidermis was thinned-out with fibroplasia in the dermis with an intradermal cyst having a flattened wall containing lamellated keratin, and perifollicular concentric fibrosis Figure 3b. A diagnosis of folliculocytic and collagen hamartoma was made. Dermoscopy showed orange-red plugs in follicular openings, perifollicular scaling, and empty follicular openings, which are characteristic features of FCCH.Figure 1: (a–c) Multiple dome-shaped, firm cystic outgrowths, with few having comedone-like openings and ulcerations on lateral aspect of left kneeFigure 2: (a) Multiple angiofibromas on the mid-face and cheeks. (b) A shagreen patch present on the lower backTable 1: Differentiating features between neurofibroma, epidermal inclusion cyst, steatocystoma multiplex, folliculocystic collagen hamartoma, and lipoma 3 , 4 Figure 3: (a) Histopathological image showing a cyst located in the dermis, with increased collagen deposition (blue cross) and pericystic fibrosis (red dot) Hematoxylin & eosin, 10×. (b) Image depicting a keratin-filled cyst in the dermis (black cross) and perifollicular fibrosis (green cross) Hematoxylin & eosin, 10×A diagnosis of tuberous sclerosis was established based on the fulfillment of two major criteria from the consensus international diagnostic guidelines: the presence of a shagreen patch and two or more angiofibromas. FCCH has also been found to be associated with TSC, further supporting the diagnosis. Topical sirolimus 0.1%, an mTOR inhibitor, was recommended as a treatment option to reduce the size and progression of FCCH. This association underscores the need to consider FCCH as a potential diagnostic criterion in future revisions of the consensus guidelines. While FCCH has typically been reported as skin-colored plaques with comedone-like openings, primarily on the scalp, this case presented with an unusual localization on the left knee. Other possible sites of presentation include the thighs, back, and face. Surgical line of management was advised. Notably, malignant transformation of FCCH has not been reported.5 FCCH is a rare and complex hamartoma characterized by significant collagen deposition, concentric perifollicular fibrosis, and keratin-filled infundibular cysts, as observed in histopathological analysis. To date, only 18 cases of FCCH associated with TSC have been reported worldwide. Table 2 highlights the previously reported cases of FCCH and its varied clinical presentations.4,6-15 A review of 18 reported cases revealed a strong male predominance (88.9%), with the scalp being the most commonly involved site (44.4%), followed by the abdomen (16.7%) and thigh (11.1%). Histologically, thickened dermal collagen was the most consistent finding (83%), along with perifollicular fibrosis (72%), keratin-filled infundibular cysts (67%), and cystic dilation of follicles (50%). Ruptured cysts with granulomatous inflammation were seen in 33% of cases, and subcutaneous extension was noted in nearly half. Clinically, lesions presented as slowly progressive plaques or tumors with comedone-like openings, typically present from birth or early childhood.Table 2: Previously reported cases of folliculocystic and collagen hamartoma and its varied clinical presentationEarly recognition of FCCH may facilitate the diagnosis of previously unrecognized cases of TSC. All reported FCCH patients with available molecular data have demonstrated a pathogenic variant in TSC2, suggesting FCCH as a potential novel cutaneous manifestation of TSC. This finding supports the consideration for its inclusion in the international TSC consensus diagnostic criteria. Prompt identification of TSC, followed by continuous monitoring and multidisciplinary management, is vital to reduce associated morbidity and mortality. Recognition of FCCH as a rare but informative clinical feature can significantly enhance early detection and comprehensive care in affected individuals. Authors’ contributions We confirm that all authors have read and approved the manuscript for submission. All authors meet authorship criteria, and the manuscript represents honest work. Declaration of patient consent The authors certify that they have obtained all appropriate parent consent forms. In the form a parent has given their consent for his images and other clinical information to be reported in the journal. The parent understands that his name and initials will not be published. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. Statement on use of artificial intelligence in manuscript preparation/editing We have not used artificial intelligence.
Kalchuri et al. (Mon,) studied this question.