Clinical Characteristics of Connective Tissue Nevi in Tuberous Sclerosis Complex With Special Emphasis on Shagreen Patches | Congenital Defects | JAMA Dermatology | JAMA Network
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1.
Roach  ES.  Applying the lessons of tuberous sclerosis: the 2015 Hower Award lecture.  Pediatr Neurol. 2016;63:6-22.PubMedGoogle ScholarCrossref
2.
Darling  TN, Moss  J, Mausner  M. Dermatologic Manifestations of Tuberous Sclerosis Complex. In: Kwiatkowski DJ, Whittemore VH, Thiele EA, eds.  Tuberous Sclerosis Complex: Genes, Clinical Features, and Therapeutics. Weinheim, Germany: WILEY-VCH Verlag GmbH & Co. KGaA;2010:285-309.
3.
Northrup  H, Krueger  DA; International Tuberous Sclerosis Complex Consensus Group.  Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference.  Pediatr Neurol. 2013;49(4):243-254.PubMedGoogle ScholarCrossref
4.
Teng  JM, Cowen  EW, Wataya-Kaneda  M,  et al.  Dermatologic and dental aspects of the 2012 International Tuberous Sclerosis Complex consensus statements.  JAMA Dermatol. 2014;150(10):1095-1101.PubMedGoogle ScholarCrossref
5.
Hunt  A.  Tuberous sclerosis: a survey of 97 cases. II: physical findings.  Dev Med Child Neurol. 1983;25(3):350-352.PubMedGoogle ScholarCrossref
6.
Webb  DW, Clarke  A, Fryer  A, Osborne  JP.  The cutaneous features of tuberous sclerosis: a population study.  Br J Dermatol. 1996;135(1):1-5.PubMedGoogle ScholarCrossref
7.
Jóźwiak  S, Schwartz  RA, Janniger  CK, Michałowicz  R, Chmielik  J.  Skin lesions in children with tuberous sclerosis complex: their prevalence, natural course, and diagnostic significance.  Int J Dermatol. 1998;37(12):911-917.PubMedGoogle ScholarCrossref
8.
Józwiak  S, Schwartz  RA, Janniger  CK, Bielicka-Cymerman  J.  Usefulness of diagnostic criteria of tuberous sclerosis complex in pediatric patients.  J Child Neurol. 2000;15(10):652-659.PubMedGoogle ScholarCrossref
9.
Wataya-Kaneda  M, Tanaka  M, Hamasaki  T, Katayama  I.  Trends in the prevalence of tuberous sclerosis complex manifestations: an epidemiological study of 166 Japanese patients.  PLoS One. 2013;8(5):e63910.PubMedGoogle ScholarCrossref
10.
Curatolo  P, Moavero  R, Roberto  D, Graziola  F.  Genotype/phenotype correlations in tuberous sclerosis complex.  Semin Pediatr Neurol. 2015;22(4):259-273.PubMedGoogle ScholarCrossref
11.
Giannikou  K, Malinowska  IA, Pugh  TJ,  et al.  Whole exome sequencing identifies TSC1/TSC2 biallelic loss as the primary and sufficient driver event for renal angiomyolipoma development.  PLoS Genet. 2016;12(8):e1006242.PubMedGoogle ScholarCrossref
12.
Lam  HC, Nijmeh  JS, Henske  EP.  New developments in the genetics and pathogenesis of tumours in tuberous sclerosis complex.  J Pathol. 2017;241(2):219-255.PubMedGoogle ScholarCrossref
13.
Dibble  CC, Cantley  LC.  Regulation of mTORC1 by PI3K signaling.  Trends Cell Biol. 2015;25(9):545-555.PubMedGoogle ScholarCrossref
14.
Li  S, Takeuchi  F, Wang  JA,  et al.  Mesenchymal-epithelial interactions involving epiregulin in tuberous sclerosis complex hamartomas.  Proc Natl Acad Sci U S A. 2008;105(9):3539-3544.PubMedGoogle ScholarCrossref
15.
Li  S, Thangapazham  RL, Wang  JA,  et al.  Human TSC2-null fibroblast-like cells induce hair follicle neogenesis and hamartoma morphogenesis.  Nat Commun. 2011;2:235.PubMedGoogle ScholarCrossref
16.
Tyburczy  ME, Wang  JA, Li  S,  et al.  Sun exposure causes somatic second-hit mutations and angiofibroma development in tuberous sclerosis complex.  Hum Mol Genet. 2014;23(8):2023-2029.PubMedGoogle ScholarCrossref
17.
McCuaig  CC, Vera  C, Kokta  V,  et al.  Connective tissue nevi in children: institutional experience and review.  J Am Acad Dermatol. 2012;67(5):890-897.PubMedGoogle ScholarCrossref
18.
Pope  V, Dupuis  L, Kannu  P,  et al.  Buschke-Ollendorff syndrome: a novel case series and systematic review.  Br J Dermatol. 2016;174(4):723-729.PubMedGoogle ScholarCrossref
19.
Burger  B, Hershkovitz  D, Indelman  M,  et al.  Buschke-Ollendorff syndrome in a three-generation family: influence of a novel LEMD3 mutation to tropoelastin expression.  Eur J Dermatol. 2010;20(6):693-697.PubMedGoogle Scholar
20.
Xia  Y, Darling  TN.  Rapidly growing collagenomas in multiple endocrine neoplasia type I.  J Am Acad Dermatol. 2007;56(5):877-880.PubMedGoogle ScholarCrossref
21.
Darling  TN, Skarulis  MC, Steinberg  SM, Marx  SJ, Spiegel  AM, Turner  M.  Multiple facial angiofibromas and collagenomas in patients with multiple endocrine neoplasia type 1.  Arch Dermatol. 1997;133(7):853-857.PubMedGoogle ScholarCrossref
22.
Nathan  N, Burke  K, Moss  J, Darling  TN.  A diagnostic and management algorithm for individuals with an isolated skin finding suggestive of tuberous sclerosis complex.  Br J Dermatol. 2017;176(1):220-223.PubMedGoogle ScholarCrossref
23.
Durland  JL, Sferlazzo  M, Logan  M, Burke  AC.  Visualizing the lateral somitic frontier in the Prx1Cre transgenic mouse.  J Anat. 2008;212(5):590-602.PubMedGoogle ScholarCrossref
24.
Gąsior-Głogowska  M, Komorowska  M, Hanuza  J,  et al.  FT-Raman spectroscopic study of human skin subjected to uniaxial stress.  J Mech Behav Biomed Mater. 2013;18:240-252.PubMedGoogle ScholarCrossref
25.
Papakonstantinou  E, Dionyssopoulos  A, Aletras  AJ, Pesintzaki  C, Minas  A, Karakiulakis  G.  Expression of matrix metalloproteinases and their endogenous tissue inhibitors in skin lesions from patients with tuberous sclerosis.  J Am Acad Dermatol. 2004;51(4):526-533.PubMedGoogle ScholarCrossref
26.
Nathan  N, Tyburczy  ME, Hamieh  L,  et al.  Nipple angiofibromas with loss of TSC2 are associated with tuberous sclerosis complex.  J Invest Dermatol. 2016;136(2):535-538.PubMedGoogle ScholarCrossref
27.
Nathan  N, Wang  JA, Li  S,  et al.  Improvement of tuberous sclerosis complex (TSC) skin tumors during long-term treatment with oral sirolimus.  J Am Acad Dermatol. 2015;73(5):802-808.PubMedGoogle ScholarCrossref
28.
Au  KS, Williams  AT, Roach  ES,  et al.  Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States.  Genet Med. 2007;9(2):88-100.PubMedGoogle ScholarCrossref
Original Investigation
July 2017

Clinical Characteristics of Connective Tissue Nevi in Tuberous Sclerosis Complex With Special Emphasis on Shagreen Patches

Author Affiliations
  • 1Department of Dermatology, Uniformed Services University of the Health Sciences, Bethesda, Maryland
  • 2Naval Health Clinic, Pearl Harbor, Hawaii
  • 3Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
  • 4Department of Medicine, Case Western Reserve University at MetroHealth Medical Center, Cleveland, Ohio
  • 5Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
  • 6Lister Hill National Center for Biomedical Communications, US National Library of Medicine, Bethesda, Maryland
JAMA Dermatol. 2017;153(7):660-665. doi:10.1001/jamadermatol.2017.0298
Key Points

Question  What are the clinical characteristics of connective tissue nevi in patients with tuberous sclerosis complex (TSC)?

Findings  In this retrospective analysis of patient medical records and clinical photography of 104 adult patients with TSC, more than half of patients with TSC had at least 1 connective tissue nevus, and 51% of all nevi appeared on the lower back, while the other 49% were distributed throughout the upper and middle back, buttocks, and thighs.

Meaning  Tuberous sclerosis complex–related connective tissue nevi have various presentations, and their recognition is important for timely diagnosis.

Abstract

Importance  Patients with tuberous sclerosis complex (TSC) frequently develop collagenous connective tissue nevi. 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. The ability to recognize these variable presentations can be important for the diagnosis of TSC.

Objective  To describe the clinical characteristics of connective tissue nevi on the trunk and extremities of patients with tuberous sclerosis complex.

Design, Setting, and Participants  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). All patients included were examined at the National Institutes of Health (NIH) in Bethesda, Maryland, from 1998 to 2013. Connective tissue nevi were categorized per anatomic location and size. Lesions less than 1 cm in diameter were termed collagenomas. Shagreen patches were characterized as small (1 to <4 cm), medium (4 to <8 cm), and large (≥8 cm).

Main Outcome and Measures  Frequency, anatomic location, size, and histological appearance of connective tissue nevi in patients with TSC.

Results  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. 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. The distribution of lesions was 9% (n = 11), upper back; 29% (n = 35), middle back; 51% (n = 61), lower back; and 11% (n = 13), other locations. 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. On immunoblot analysis, fibroblasts grown from shagreen patches expressed higher levels of phosphorylated ribosomal protein S6 than paired fibroblasts from normal-appearing skin.

Conclusions and Relevance  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. Elastic fibers are typically decreased. Recognition of these variable presentations can be important for TSC diagnosis.

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