shagreen patch histology

Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome that is characterized by benign tumor formation in the brain, lung, heart, kidneys and skin.1 Most patients with TSC will have dermatologic manifestations such as multiple facial angiofibromas, fibrous cephalic plaques (forehead plaques), hypomelanotic macules, ungual fibromas, or shagreen patches.2 Accordingly, these lesions constitute several of the major diagnostic criteria from the 2012 International Tuberous Sclerosis Complex Consensus Conference,3,4 making physician recognition imperative for diagnosis. Often undetected. A diagnostic and management algorithm for individuals with an isolated skin finding suggestive of tuberous sclerosis complex. Au When treatment is started while angiofibromas are small, it will likely reduce the need for laser treatment in the future. Angiomyolipoma. One treatment option is to use a sunless tanning lotion that contains dihyoxyacetone (DHA) as the active ingredient.  These work by temporarily dyeing the top layers of the skin.  Another option is to apply concealing creams that are matched to the person’s skin color.  The resource section at the end of this information sheet provides a list of companies that provide these products.  F.  Genotype/phenotype correlations in tuberous sclerosis complex. They are areas of thick leathery skin that are dimpled like an orange peel, and pigmented, they are usually found on the lower back or nape of the neck, or scattered across the trunk or …  M.  Multiple facial angiofibromas and collagenomas in patients with multiple endocrine neoplasia type 1.  P, Moavero FT-Raman spectroscopic study of human skin subjected to uniaxial stress.  ES. The elevation of large shagreen patches often appeared as irregular bumps. All patients included were examined at the National Institutes of Health (NIH) in Bethesda, Maryland, from 1998 to 2013.  They may bleed excessively if they are torn off the skin, so an individual with TSC should always have a physician remove the fibroma. The trunk was divided into 6 regions (upper, middle, and lower thirds bisected into right and left), and location was assigned by its majority in a region. The levels of expression of TSC2 (tuberin) and TSC1 (hamartin) in shagreen patch cells were similar to those observed in cells grown from normal-appearing skin. Previous studies5-9 have documented their presence in approximately 21% to 83% of patients with TSC.  S, Schwartz Northrup Corresponding Author: Thomas Darling, MD, PhD, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd, Bethesda, MD 20814 ( These lesions are most commonly found in the lumbosacral region or the nape of the neck. The texture of shagreen patches has been described as “pigskin” or peau d’orange with a pink or skin-colored hue, or prominent, dilated follicular openings.  et al. 11,19 When multiple lesions are present, they may be either scattered or grouped.  The decreased pigment also means that these areas are more susceptible to sun burn. Pope A, Composite of 100 lesions that were mapped from photographs.  C, Kokta The long axis of shagreen patches tended to fall along Langer lines.  M, Komorowska More than two ungual fibromas, however, is considered to be one of the major diagnostic criterion for TSC. It is inherited in an autosomal dominant pattern. Shagreen patch on the lower back. II: physical findings.  Hypomelanotic macules are usually the size of a thumbprint or larger.  They are also referred to as ash-leaf spots when they are oval at one end and pointed at the other, resembling the leaf of the European mountain ash tree.  DA; International Tuberous Sclerosis Complex Consensus Group. Phone:  1-800-590-5335 Our prior studies of angiofibromas, ungual fibromas, and forehead plaques have shown that TSC skin tumors arise by a 2-hit mechanism, with tumor fibroblasts showing biallelic mutations in TSC2 and loss of TSC2 expression.15,16,26 In contrast, none of the samples of shagreen patch cells showed loss of TSC1 or TSC2 expression, despite showing increased phospho-S6 consistent with mTORC1 activation.  TN. Overall, 58 of 104 patients (median [range] age, 42 [19-70] years) with TSC (56%) had at least 1 connective tissue nevus on the trunk or thighs; of these, 28 of 58 patients (48%) had a solitary lesion, and 30 of 58 patients (52%) had 2 or more lesions.  et al. Paired samples of shagreen patch and normal skin were obtained from 26 patients, and the sections were stained with routine hematoxylin-eosin and Miller elastin stain. Frequency, anatomic location, size, and histological appearance of connective tissue nevi in patients with TSC. Size distribution of connective tissue nevi in tuberous sclerosis complex. Histology shows both hyaline and amyloid deposits in the stroma. Gąsior-Głogowska Miller elastin stain showed decreased elastin fibers in 24 of 26 samples within the connective tissue nevus (Figure 3B). About one-half of patients with a connective tissue nevus have a solitary lesion. It is found in approximately 40% of tuberous sclerosis complex patients, is characteristic of tuberous sclerosis complex, and is Lam Design, Setting, and Participants  Shagreen patches vary in size from a few millimeters to more than 10 cm in diameter.  N, Wang McCuaig This laser treatment can either be performed in the office as an outpatient procedure (if the treatment area is small or if the individual with TSC is cooperative) or in an ambulatory surgical center should the patient require sedation. The shagreen patch is an area of thickened, elevated pebbly skin (like an orange peel) usually found on the lower back.  It can be single or multiple.  Sometimes the shagreen patch is located elsewhere on the back or on the buttocks or upper thighs.  It consists of an excess amount of fibrous tissue, similar to that found in scars. Tuberous sclerosis complex–related connective tissue nevi have various presentations, and their recognition is important for timely diagnosis. Drafting of the manuscript: Bongiorno, Nathan, Oyerinde, Moss, Darling. By using this site you agree to our use of cookies. Shagreen Patches. Each patient provided written informed consent, and this study was approved by the National Heart, Lung, and Blood Institute institutional review board. However it is not clear why one individual will have them and another will not. Ungual or subungual fibromas are small fleshy tumors that grow around and under the toenails or fingernails and may need to be surgically removed if they enlarge or cause bleeding.  S, Schwartz Author Contributions: Drs Bongiorno and Darling had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Hypopigmented macules. Photographs were taken, and lesions were classified according to size based on the length of the major axis: smaller than 1 cm (collagenomas), 1 cm or larger but less than 4 cm (small shagreen patches), 4 cm or larger but less than 8 cm (medium shagreen patches), and 8 cm or larger (large shagreen patches). Buschke-Ollendorff syndrome: a novel case series and systematic review. Durland It is possible that shagreen patches, unlike other types of TSC skin tumors, form by haploinsufficiency. Improvement of tuberous sclerosis complex (TSC) skin tumors during long-term treatment with oral sirolimus. Shagreen patches were characterized as small (1 to <4 cm), medium (4 to <8 cm), and large (≥8 cm). Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference. Recurrence is also expected when the treatment is discontinued. However, biallelic mutations in TSC2 were identified in shagreen patch cells from 1 patient, albeit with very low allele frequencies.16 This result suggests that the cultures of shagreen patches include 2-hit tumor cells and contaminating 1-hit fibroblasts. Elastic fibers are typically decreased.  DW, Clarke  K, Malinowska In patients with TSC, typical skin lesions include Shagreen patches and facial and periungal angiofibromas (Figure 1); neurologic involvement includes tubers and giant cell astrocytomas.7 The prevalence of extrapulmonary LAM in TSC-LAM patients is … Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States. Accepted for Publication: January 26, 2017. People with TSC usually have multiple angiofibromas, and some individuals may have hundreds.  CK, Bielicka-Cymerman Dermal fibroblasts in dorsal skin are derived from paraxial mesoderm whereas those in ventral skin and extremities arise from lateral plate mesoderm.23 These fibroblast populations may respond differently to impaired TSC1-TSC2 function and mTORC1 activation. Collagenomas should raise suspicion for TSC, particularly when located on the lower back, but they are not specific. Small shagreen patches tended to be oval, whereas medium (Figure 1B) and large shagreen patches (Figure 1C) were irregular ovals. Recognition of these variable presentations can be important for TSC diagnosis. Overall, 58 of 104 patients (median [range] age, 42 [19-70] years) with TSC (56%) had at least 1 connective tissue nevus on the trunk or thighs; of these, 28 of 58 patients (48%) had a solitary lesion, and 30 of 58 patients (52%) had 2 or more lesions. A 21-year-old female patient admitted to the emergency department complaining of left side pain. Shagreen patches represent areas of skin affected by fibromatous infiltration. Sometimes numerous small macules may be present in TSC (especially on the arms and legs).  These may resemble confetti, and are a minor criterion for diagnosis.  L, Kannu A retrospective analysis of patient medical records and skin photography was performed; 104 adult patients with TSC were enrolled in an observational cohort study that was enriched for those with pulmonary lymphangioleiomyomatosis, and was therefore composed mostly of women (99 women, 5 men). Li © 2020 American Medical Association. Others have not observed significant differences in frequencies of shagreen patches in men vs women,28 but it is possible that the patterns of lesion size and distribution in women may not be generalizable to men. Please read our, Biosample Repository and Natural History Database. Routine hematoxylin-eosin staining revealed thickened, disorganized collagen bundles in the reticular dermis consistent with the diagnosis of connective tissue nevus in all 26 samples (Figure 3A). Rapidly growing collagenomas in multiple endocrine neoplasia type I. Nathan Awareness of the clinical appearance, location, and pathological composition of these and other TSC skin lesions is necessary to enable prompt disease identification and initiation of management. Patients were evaluated for the presence or absence of connective tissue nevi and queried regarding the age of onset of lesion(s). sign up for alerts, and more, to access your subscriptions, sign up for alerts, and more, to download free article PDFs, sign up for alerts, customize your interests, and more, to make a comment, download free article PDFs, sign up for alerts and more, Archives of Neurology & Psychiatry (1919-1959), Subscribe to the JAMA Dermatology journal, FDA Approval and Regulation of Pharmaceuticals, 1983-2018, Global Burden of Skin Diseases, 1990-2017, Health Care Spending in the US and Other High-Income Countries, Life Expectancy and Mortality Rates in the United States, 1959-2017, Medical Marketing in the United States, 1997-2016, Practices to Foster Physician Presence and Connection With Patients in the Clinical Encounter, US Burden of Cardiovascular Disease, 1990-2016, US Burden of Neurological Disease, 1990-2017, Waste in the US Health Care System: Estimated Costs and Potential for Savings, Register for email alerts with links to free full-text articles. Although there is no limit to the number of treatments that can be performed, generally speaking, if no noticeable improvement is apparent after two treatments, one has to reassess either (1) the nature of the lesion that is being treated; (2) the choice of laser; or (3) the laser setting used. Phone: 1-800-419-4041 Patients with tuberous sclerosis complex (TSC) frequently develop collagenous connective tissue nevi.  T, Katayama  et al. Tubers. Forty-six patients (79%) had either 1 lesion (28 patients) or 2 lesions (18 patients).  R, Roberto Their main medical significance is as a major feature for the diagnosis of TSC. It is not clear why skin at one body region is more susceptible to formation of a TSC connective tissue nevus than others, but it may reflect embryonic origins. The support they need is the support you can give. Shagreen patches are oval-shaped and nevoid, skin-colored or occasionally pigmented, smooth or crinkled, The word shagreen refers to a type of roughened untanned leather. doi:10.1001/jamadermatol.2017.0298. © 2020 American Medical Association.  The shagreen patch usually does not cause problems, but if it does it can be treated by surgical excision. Easily misdiagnosed. Angiofibroma. A shagreen patch (arrows) is an irregularly shaped, irregularly thickened, slightly elevated soft skin-colored patch, usually on the lower back, made up of excess fibrous tissue.  Y, Darling Nipple angiofibromas with loss of TSC2 are associated with tuberous sclerosis complex.  Sometimes hypomelanotic macules become less obvious in adulthood, and may even disappear.  A.  Tuberous sclerosis: a survey of 97 cases. This website uses cookies to improve your user experience. Flesh-colored plaques of variable size are primarily located in the lumbosacral area. Synonym(s): shagreen patch It can be single or multiple. Shagreen patches were characterized as small (1 to <4 cm), medium (4 to <8 cm), and large (≥8 cm).  TN, Moss  M, Burke This type of laser is designed to destroy blood vessels with low risk of scarring.  et al. Get free access to newly published articles. The limbus is typically spared. To help improve diagnostic accuracy, the current study was undertaken to describe the spectra of locations and sizes of connective tissue nevi in patients with TSC. Shagreen patches consist of lesions on the nape of the neck and lower back with an orange peel-like texture. Li Sometimes the shagreen patch is located elsewhere on the back or on the buttocks or upper thighs. All 26 shagreen patches that were analyzed histopathologically had coarse collagen fibers and 24 of 26 stained with Miller elastic stain had decreased elastic fibers. The prototypical lesion is a large shagreen patch located on the lower back, but some patients only manifest small collagenomas or have lesions elsewhere on the body.  AM, Turner  EW, Wataya-Kaneda Study concept and design: Bongiorno, Moss, Darling. Main Outcome and Measures  Fifty-eight patients (56%) had a connective tissue nevus. Sun exposure causes somatic second-hit mutations and angiofibroma development in tuberous sclerosis complex.  If these fibromas are large they can be surgically removed. Recognition of these variable presentations can be important for TSC diagnosis. Administrative, technical, or material support: Bongiorno, Wang, Lee, Moss. Question  Some people say they look like orange peel.  AT, Roach The ability to recognize these variable presentations can be important for the diagnosis of TSC. Hypomelanotic macules are not specific have been reported in 78% of patients, frequently Table 1 Diagnostic criteria for tuberous sclerosis complex Roach et al. These usually appear later in life, ages 20-50.  F, Wang The surface of a shagreen patch is often described as having the texture of an orange peel.  E, Dionyssopoulos Giannikou All patients included were examined at the National Institutes of Health (NIH) in Bethesda, Maryland, from 1998 to 2013.  M, Logan There are cosmetics available to cover hypomelanotic macules and facial angiofibromas. Whole exome sequencing identifies TSC1/TSC2 biallelic loss as the primary and sufficient driver event for renal angiomyolipoma development.  HC, Nijmeh Either plastic surgeons or dermatologists generally perform laser surgery. Wataya-Kaneda Overall, 120 lesions from 55 patients were classified by size; 46 lesions (38%) were collagenomas; 39 lesions (32%) were small shagreen patches; 21 lesions (18%), medium shagreen patches; and 14 lesions (12%), large shagreen patches. Our website uses cookies to enhance your experience. Critical revision of the manuscript for important intellectual content: All authors. Immunoblot Analysis of Skin Tumor and Control Fibroblasts From Patients With TSC, Table. Website:, Linda Seidel It consists of a slightly elevated, flesh-colored plaque of variable size, usually on the lower part of the trunk. Conclusions and Relevance  Anatomic location was mapped if the connective tissue nevus could be localized based on the presence of at least 2 position-defining landmarks (ie, gluteal crease, axillary crease, midline). Phone:  1-800-662-8011  SJ, Spiegel Darling 20 This flesh-colored, leathery plaque on the lumbosacral area is highly characteristic of the tuberous sclerosis complex. Lymphangioleiomyomatosis. Patients with tuberous sclerosis complex (TSC) frequently develop collagenous connective tissue nevi. On immunoblot analysis, fibroblasts grown from shagreen patches expressed higher levels of phosphorylated ribosomal protein S6 than paired fibroblasts from normal-appearing skin. Fewer than 3 hypomelanotic macules do not count towards making a diagnosis because one or two hypomelanotic macules are common in the general population, occurring in about 5% of children.  JP. Most people with TSC have hypomelanotic macules (hypo, meaning less than normal; melanotic, referring to the pigment of skin).  These may be present at birth, increase during early childhood and usually persist throughout life. Most people with tuberous sclerosis complex (TSC) have changes in their skin.  There may be light colored spots, called hypomelanotic macules, and bumps on the skin of several different types (angiofibromas, cephalic fibrous plaques, shagreen patches, and ungual fibromas).  In combination, these skin features are found only in TSC, and they are often used to diagnose TSC, especially in young patients. New developments in the genetics and pathogenesis of tumours in tuberous sclerosis complex.  However, these drugs have the potential for serious side effects, so they would not usually be used for treating only the skin. Immunoblotting is shown for TSC2, TSC1, pS6, S6, and β-actin. Tuberous sclerosis complex–related connective tissue nevi are not limited to the lower back, and occasionally present on the central or upper back, buttocks, or thighs. Shagreen patches were located dorsally and rarely ventrally. Regulation of mTORC1 by PI3K signaling. Angiofibromas may begin in early childhood as flat red “spots” on the face, or a diffuse redness of the cheeks.  The redness is due to increased blood vessels in the skin.  They later become elevated due to increased amounts of fibrous tissue.  Fibrous tissue is similar to what is found in a scar. This treatment has not been officially approved by the food and drug administration (FDA), therefore is only available at a special compounding pharmacy when prescribed by dermatologists. A new treatment using topical rapamycin cream has also shown to be effective in a recent case report (Wataya-Kaneda M et al., 2012). There is typically minimal postoperative pain when the face is treated with liberal application of topical emollient ointments. A total of 120 lesions were classified as 46 collagenomas, 39 small shagreen patches, 21 medium shagreen patches and 14 large shagreen patches. A shagreen patch is a subepidermal collagenous connective tissue nevus, also known as a collagenoma, associated with tuberous sclerosis. The following are a few of the cosmetic lines that can be contacted for more information: Clinique Gingival fibromas may be surgically removed by dermatologists, dentists or oral surgeons.  LC. Tuberous sclerosis complex is caused by germline mutation in 1 of 2 tumor suppressor genes, TSC1 or TSC2.10 The formation of tumors in TSC is driven by a somatic second-hit mutation of the wild-type allele.11,12 These inactivating mutations in either of the tumor suppressor genes lead to aberrant activation of mechanistic target of rapamycin complex 1 (mTORC1), causing downstream kinase activation and phosphorylation of ribosomal protein S6 (phospho-S6).13 While angiofibromas, ungual fibromas, and fibrous cephalic plaques have been shown to develop secondary to a second-hit mechanism in tumor fibroblast–like cells,14-16 molecular alterations in the shagreen patch have not yet been studied. Shagreen patches on the back were mostly firm whereas those on the thighs (Figure 1D) were soft and had less distinct margins. These precise patients, i.e., patients with a forme fruste of tuberous sclerosis, are more likely to have pulmonary involvement … AF indicates angiofibroma cells; C, control fibroblasts; FCP, fibrous cephalic plaque cells; PF, periungual fibroma cells; pS6, phospho-S6 (Ser-235/236); S6, ribosomal protein S6; SP, shagreen patch cells.  MC, Steinberg  N, Tyburczy Ungual fibromas can be removed by surgical excision.  This may be combined with CO2 laser removal to maximize effectiveness while limiting scarring and damage to the nail. Shagreen patch: flesh-colored papule in the lumbosacral region with an orange-peel appearance; Skin hamartomas; Ungual fibromas: flesh-colored papules that grow under (subungual) or around the nails (periungual) Small benign tumors.  S, Takeuchi A, Multiple collagenomas on the lower back; B, a small shagreen patch on the mid back; C, a shagreen patch composed of 2 medium-sized lesions on the lower back; and D, a large shagreen patch on the left posterior thigh. This sign is seen in approximately 20% of cases, often in the lower back.  ME, Hamieh Additional Contributions: We thank Claire Hong, BS, who assisted with figure creation and review of manuscript as part of her role as a student intern at the Uniformed Services University of the Health Sciences.  et al. Curatolo Ash-leaf spots. Tuberous sclerosis complex–related connective tissue nevi have various presentations, and their recognition is important for timely diagnosis. SEGA. Abdominal computed tomography showed multiple fat containing lesions in different, regions including right bladder wall, lower pole of left kidney, and right kidney. For a complete list, visit Visualizing the lateral somitic frontier in the Prx1Cre transgenic mouse. Papakonstantinou  JA,  Some people have TSC skin changes that are hardly noticeable.  Others may have growth on the skin that causes pain or bleeds easily. Genes.  D, Indelman Presence outside of the lower back may hinder recognition as a TSC manifestation. Acquisition, analysis, or interpretation of data: Bongiorno, Nathan, Oyerinde, Wang, Lee, Brown, Darling.  ME, Wang During infancy or in people with very fair skin, hypomelanotic macules are only visible with the use of a Wood’s lamp.  This is a special ultraviolet light that makes macules stand out against the surrounding normal skin. The shagreen patch is an area of thickened, elevated pebbly skin (like an orange peel) usually found on the lower back.  Others develop later in childhood or even in adulthood.  Most people with TSC eventually have at least one skin feature, and many will have several ( Darling et al., 2010; Northrup et al., 2013).  Currently, there is no way to predict how many TSC skin features will develop during childhood, but they tend to remain stable during adulthood. Some TSC skin features may appear at birth. Ungual fibromas may recur. NIH R01AR062080); the Sulzberger Dermatological Research and Education Endowment; the Intramural Research Program of the NIH; the National Heart, Lung, and Blood Institute; and the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH; generous contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation; the American Association for Dental Research; the Colgate-Palmolive Company; Genentech; and other private donors.

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