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

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.

Figure 1.. Gross Clinical Appearance of Connective Tissue Nevi in Tuberous Sclerosis Complex

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.

Figure 2.. Distribution of Connective Tissue Nevi in Tuberous Sclerosis Complex

A, Composite of 100 lesions that were mapped from photographs. Grey represents lesions on the posterior surface; blue represents lesions on anterior surface. B, Number and corresponding percentages of tuberous sclerosis complex (TSC)-related connective tissue nevi found on various regions of the posterior trunk based on photographs or clinical records. The total lesion count was 120, including 2 lesions on the anterior trunk and 4 lesions on the thighs for which percentages are not shown.

Figure 3.. Histological Appearance of Shagreen Patch

A, Hematoxylin-eosin stain shows thickened, disorganized collagen bundles in the reticular dermis (original magnification ×40). B, Elastin stain shows little elastin in connective tissue nevi (original magnification ×40).

Figure 4.. Immunoblot Analysis of Skin Tumor and Control Fibroblasts From Patients With TSC

Patients are indicated as P numbers. Immunoblotting is shown for TSC2, TSC1, pS6, S6, and β-actin. 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.