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E-IJD® - CORRESPONDENCE |
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| Year : 2022 | Volume
: 67
| Issue : 6 | Page : 836 |
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| An atypical cutaneous symptom in tuberous sclerosis complex: A case report and systematic review of the literature |
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Xiaochao Zhang1, Yabing Hu2, Yongchu Huang1
1 Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong, University of Science and Technology, Wuhan, China
2 Department of Dermatology, Tongji Hospital; Department of Laboratory Medicine, Wuhan No.1 Hospital, Tongji Medical College, Huazhong, University of Science and Technology, Wuhan, China
| Date of Web Publication | 23-Feb-2023 |
Correspondence Address:
Yongchu Huang
Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong, University of Science and Technology, Wuhan
China
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/ijd.ijd_560_21
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How to cite this article:
Zhang X, Hu Y, Huang Y. An atypical cutaneous symptom in tuberous sclerosis complex: A case report and systematic review of the literature. Indian J Dermatol 2022;67:836 |
How to cite this URL:
Zhang X, Hu Y, Huang Y. An atypical cutaneous symptom in tuberous sclerosis complex: A case report and systematic review of the literature. Indian J Dermatol [serial online] 2022 [cited 2023 Mar 29];67:836. Available from: https://www.e-ijd.org/text.asp?2022/67/6/836/370322 |
Sir,
Tuberous sclerosis complex (TSC) is an autosomal dominant, multisystem disorder that is classically characterized by abnormal proliferation of cells and tissues.[1],[2],[3] It was first described by Desire-Magloire Bourneville in 1880. TSC could occur in all kinds of people, regardless of race, gender.[1] In the past years the incidence of TSC is low, estimation of 1/6000-10,000 newborns annually. About 2 million people are disturbed by it in the world.[4] The clinical characters of TSC include tumorigenesis in kidneys, heart, lungs, brain and skin, and neurologic and behavioral abnormalities, including cognitive disability, autism spectrum disorder and seizures. All patients with TSC carry inherited or de novo mutations in TSC1 or TSC2 genes, both of which belong to tumor-suppressor genes.[5] The main skin manifestations of tuberous sclerosis complex are: facial angiofibromas, ungual fibromas, fibrous cephalic plaques, shagreen patches and focal hypopigmentation changes. Whereas atypical symptoms are occasionally found in patients with tuberous sclerosis complex. Here, for the first time we reported one TSC patient with an atypical facial cutaneous rash, folliculocystic and collagen hamartoma, different from typical facial angiofibromas. Furthermore, we review the recent literature on the TSC, which indicates TSC have other atypical symptoms. Many patients with TSC may have a near normal life, but poor prognosis and considerable mortality are the character of TSC.[6] Hence, familiarity with the spectrum of clinical manifestations of tuberous sclerosis complex for early diagnosis and treatment is significant for all physicians, containing dermatologists.
 Case Report | |  |
A 31-year-old woman came to our department for erythema and nodules in the face, neck, and oral cavity for more than 30 years. Just after her birth, erythema began to appear on the face, neck, and mouth, the red nodules of grain size developed on the surface and gradually expanded. The patient did not feel itching and painful. Twenty-five years ago, she found several grain-sized hypopigmentation spots with rough surface in lumbar, slowly increasing.
In 2010, she underwent “partial facial tumor resection” surgery for the facial rash. In 2015, genetic testing of TSC1 and TSC2 genes in her whole blood sample showed c. 3691_3694 delCTGT frameshift mutation in TSC2 gene, resulting in early termination of the coding protein sequence, and truncated protein or degradation. Depending on the rashes (erythema and nodules in the oral cavity, lumbodorsal hypopigmented macules of rough surface) and genetic sequencing results, she was diagnosed with TSC. In 2016, her fetus also showed a TSC2 gene mutation by prenatal genetic testing, and “artificial labor induction and laparoscopic placental extraction” were performed. In 2018, a chest CT scan showed bronchial disease and right upper lobe nodules. In 2018, an MRI scan of the head and upper abdomen showed both sides of the lateral ventricle subependymal and bilateral frontotemporal parietal, right occipital lobe with more abnormal signals, tuberous sclerosis, and multiple small cysts in the left kidney were considered. The patient had no history of epilepsy, intellectual disability, or developmental delay, and she had no family history of similar skin changes.
The physical examination showed dark erythema, soft and painless nodules of different sizes, with a broad base on the chin, right mandibular region, right neck, and oral cavity [Figure 1]a and [Figure 1]b, and lumbodorsal several peanut-sized hypopigmentation macules of rough surface [Figure 1]c. In our department, she was preliminarily diagnosed with TSC. However, we wondered what the nature of facial erythema and nodules were, and whether the rashes were cutaneous symptoms of TSC or not. With the patient's informed consent, most of the skin lesions of the face and neck were excised after the preoperative examination. Although there was no improvement in the other region, improvement in the face and neck tumors was observed after the operation [Figure 2]a and [Figure 2]b. On the 14th day after the operation, with the redness and swelling of the facial incision subsided significantly, the face and neck tumors were not noticeable [Figure 2]c and [Figure 2]d. The patient was also very satisfied with the operation. | Figure 1: Cutaneous symptoms: dark erythema, soft and painless nodules of different sizes, with a broad base on the right neck, chin, right mandibular region (a), and oral cavity (b). (c) Lumbodorsal several peanut-sized hypopigmentation macules of rough surface
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 | Figure 2: The condition of operation wound on 5 days after the operation (a and b). Operation wound on 14 days after operation (c and d)
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Histopathological examination of facial lesions showed normal epidermis, a cystic structure in the middle dermis, with epidermis as the wall, sebaceous cells as the wall, sebum as the content, collagen and vascular smooth muscle around the wall, the change of folliculocystic and collagen hamartoma, a large number of collagen fibers proliferated and thickened [Figure 3]. Combined with facial clinical presentation, we considered facial erythema and nodules as folliculocystic and collagen hamartoma. Based on the medical history and histopathological changes, we speculated that folliculocystic and collagen hamartoma might be an atypical cutaneous symptom of TSC patients. | Figure 3: Histopathological examination (stained with hematoxylin and eosin) of facial lesions showed that normal epidermis, a cystic structure in the middle dermis, with epidermis as the wall, sebaceous cells as the wall, sebum as the content, collagen and vascular smooth muscle around the wall, the change of folliculocystic and collagen hamartoma, a large of collagen fibers proliferated and thickened. (Scale bars: a–c = 500 μm and 40×, d–f = 200 μm and 100×, g–i = 100 μm and 200×)
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| Discussion | | |
Tuberous sclerosis complex (TSC) is a rare, multisystem, autosomal dominant syndrome that affects multiple organ systems.[1],[2] It was first described by Desire-Magloire Bourneville in 1880. In the world, TSC is estimated to affect approximately 2 million people.[4] Although the incidence rate of TSC is not high and no difference in the morbidity between sex or ethnicity, there are many patients with mild symptoms and due toa relatively poor understanding of this disease, they might remain not to be diagnosed for years. In 2012, experts in the International Tuberous Sclerosis Complex Consensus group revised the diagnostic criteria for TSC, consisting of mutation analysis and the improved identification of the related clinical characteristics, for the use of doctors in clinical work.[7] However, few people use the revised diagnostic criteria to do epidemiological studies of TSC since 1999. For doctors, diagnosing TSC is challenging because of its low incidence rate. Especially, for those patients with atypical symptoms, the diagnosis is more difficult. A typical cutaneous reaction, caused by TSC, isa vital sign for its diagnosis. In the one case presented here, we described one patient with tuberous sclerosis complex, with an atypical cutaneous symptom, but including typical other multisystem disorders. The patient was diagnosed with tuberous sclerosis complex in her 20s, after genetic testing revealing mutations in the TSC2 gene.
All TSC individuals have germline mutations in either TSC1 or TSC2, both of which belong to tumor-suppressor genes. Patients with TSC carry inherited or de novo mutations in TSC1 or TSC2 genes.[5] It was reported that a unique TSC2 mutation resulted in an atypical clinical presentation.[8] In our case, genetic testing showed c. 3691_3694 delCTGT frameshift mutation in the TSC2 gene, which rarely occurs in normal people. Moreover, the mutation in TSC2 is likely pathogenic, not reported. We conjectured that the TSC2 mutation might lead to the atypical rash, folliculocystic and collagen hamartoma in the face.
The pathological mechanism of tumors in TSC is clear, which is due to the inactivation of either the TSC1 or TSC2 gene.[6],[9],[10],[11],[12],[13],[14] TSC1 and TSC2 proteins form the TSC protein complex to inhibit the activity of the mTORC1 signaling pathway.[14] The overactivation of the mTORC1 signaling pathway leads to abnormal proliferation of cells and tissues, and tissue dysplasia in TSC, which leads to hamartomas seen in multiple system organs of TSC patients. It was reported that mTORC1 could regulate anabolic and catabolic processes. The activation of the mTORC1 signaling promotes nucleotide synthesis and protein translation, lipid synthesis, gluconeogenesis, invasiveness, angiogenesis and lymphangiogenesis, and ATP production, whereas inhibiting autophagy, apoptosis.[15] In the case presented here, the patient showed lipocytes tumor on the face, an atypical cutaneous symptom for TSC, which may be associated with the overactivation of the mTORC1 signaling pathway, due to TSC2 gene mutation. Moreover, the folliculocystic and collagen hamartoma is pathologically similar to hamartomas, due to a cystic structure, sebaceous cells as the wall, sebum as the content, collagen and vascular smooth muscle around the wall, a large number of collagen fibers proliferated and thickened.
The clinical characters of TSC include tumorigenesis in kidneys, heart, lungs, brain, and skin, and neurologic and behavioral abnormalities, including cognitive disability, autism spectrum disorder, and seizures.[15],[16] The clinical features of TSC vary widely between different individuals, even in the same family. Among neurologic manifestations, there are epilepsy (90% of patients suffering from), subependymal nodule (about 80%–90% of patients), subependymal giant cell astrocytomas (10%–15% of individuals with TSC), tuberous sclerosis complex-associated neuropsychiatric disorder (about 90% of patients), intellectual disability (about 50% of patients), autism spectrum disorder (about 40% of patients). cardiac manifestations includecardiac rhabdomyoma (about 90% of patients in infants and about 20% of patients in adults). Renal manifestations include angiomyolipoma (about 70% of patients), simple multiple cysts (about 35% of patients), polycystic kidney disease (about 5% of patients), and renal cell carcinoma (about 2%–3% of patients). Pulmonary manifestations include, in women, there are asymptomatic lymphangioleiomyomatosis (LAM) (about 80% of patients), symptomatic LAM, which can lead to respiratory failure (about 5%–10% of patients), and in men and women, there is multifocal micronodular pneumocyte hyperplasia (about 10% of patients). Other manifestations include oral fibromas (about 50% of patients) and retinal astrocytic hamartomas (about 50% of patients).[15] Except for these typical symptoms, there were a few reports that TSC had other atypical presentations. An atypical tuberous sclerosis complex phenotype was shown as familial renal cell carcinoma with leiomyomatous stroma.[17] Ocular coloboma was reported as an atypical ocular lesion in TSC.[18] These reports indicated that TSC patients may develop atypical symptoms in all organ systems.
Dermatologic manifestations include angiofibroma (about 75% of patients), ungual fibroma (about 20-80% of patients), fibrous cephalic plaques (about 25% of patients), shagreen patches (>50% of patients), and focal hypopigmentation (about 90% of patients). In many cases, multiple forms of TSC erythra can coexist, and atypical erythra may be found in TSC patients.[15] Although the patient presented here suffered from a typical rash (focal hypopigmentation), she also developed an atypical cutaneous symptom on the face, namely folliculocystic and collagen hamartoma, different from facial angiofibromas. One of the most typical dermatologic manifestations of TSC is facial angiofibroma. The changes are common forms of skin features. Facial angiofibroma consists of connective and adipose tissue.[19],[20] It often occurs on the center of the face, which patients are concerned with.[21] But in the case presented here, the folliculocystic and collagen hamartoma developed on the chin, right mandibular region, and right neck. Based on facial dermatologic manifestations for 30 years and recurrence, we considered that folliculocystic and collagen hamartoma may be an atypical cutaneous symptom in TSC patients. However, future investigation and more case reports will be needed.
Keloid and collagenoma are the differential diagnosis of the atypical facial cutaneous rash, folliculocystic and collagen hamartoma in our case. Keloid usually displays solid papules, nodules, or plaques, mostly occurring on the chest, with shiny smooth surface, the edge extending around in the shape of crab foot or earthworm. Histopathology shows that tightly packed collagen fibers with hyaline degeneration, accumulate in the lesions, without cystic structure.[22] Collagenoma is a type (with dominant dermal collagen) of connective tissue nevus, usually occurring over the upper trunk, soles, arms, thighs, and back. But it rarely occurs on the face.[23] Collagenoma is divided into four types (two inherited and two acquired). Two inherited collagenoma are familial cutaneous collagenomas and shagreen patches of tuberous sclerosis which is one of the main skin manifestations of tuberous sclerosis complex, generally located in the lumbosacral region. Two acquired collagenoma are eruptive collagenoma when multiple and isolated collagenoma when solitary.[23] Histopathology shows that in the dermis, dense, coarse collagen fibers accumulate excessively, and elastic fibers appear diminished in number or normal, but with no cystic structure.[24]
Clinical manifestations, imaging examinations, and genetic testing may be used to diagnose TSC. The long-term outcome of mTOR inhibition therapy for TSC is absolutely uncertain because rapamycin, an mTOR inhibition, began to be used for TSC clinical trials in 2003.[15] However, rapamycin has been used for a long time as an immunosuppressant for transplant patients and for tumor patients. There are many potential adverse effects, such as wound-healing complications and some cutaneous issues, stomatitis, delayed sexual maturation and infertility, metabolic adverse effects.[25],[26],[27],[28] selective arterial embolization, and radiofrequency ablation; hence, topical rapamycin and operation are some means of symptomatic treatment for TSC.[29],[30] In the case presented here, the patient had received the operation for improving her appearance. Better treatment needs further research.
In conclusion, we describe one case of TSC, with an atypical cutaneous eruption, which is rarely seen among TSC patients in the world. TSC should be taken into account with uncommon skin manifestations and other systemic symptoms, especially for the patients who have a TSC family history. Early diagnosis and treatment can improve the prognosis of TSC patients with prevention of the progress of TSC.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her/consent for her images and other clinical information to be reported in the journal. The patient understands that her names and initials will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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