Connective Tissue Nevi in Tuberous Sclerosis Complex Reach Beyond the Classic Lower-Back Patch
Patients with tuberous sclerosis complex often carry cutaneous clues that are easy to miss when they do not fit the textbook image. In this cohort, connective tissue nevi were common, variable in size, and distributed across more than one anatomic region, including the central back, upper back, buttocks, and thighs. The familiar shagreen patch remained the best-known phenotype, but it was not the only one clinicians need to recognize.
Among 104 adults with TSC examined at the National Institutes of Health over a 15-year period, 58 patients had at least one connective tissue nevus on the trunk or thighs. The median age was 42 years, with a range from 19 to 70 years, and the cohort was overwhelmingly female because it was enriched for pulmonary lymphangioleiomyomatosis. Even with that demographic skew, the dermatologic message was straightforward: the skin lesions of TSC do not confine themselves to the lower back.
One sentence matters here. A connective tissue nevus can be the only visible dermatologic clue to a systemic genetic disorder.
Lesion Burden Was Common, But the Pattern Was Heterogeneous
Of the 58 patients with trunk or thigh involvement, 28 had a solitary lesion and 30 had two or more. That split is clinically important because a single lesion can be dismissed as a benign curiosity, while multiple lesions may more readily trigger a broader syndromic search. Across 55 patients, 120 lesions were classified by size and anatomic location, creating a more detailed map of the cutaneous expression of TSC than the classic “shagreen patch on the lower back” description allows.
Size varied enough to change bedside recognition. Forty-six lesions were collagenomas, accounting for 38% of the total. Small shagreen patches made up 39 lesions, or 32%; medium shagreen patches accounted for 21 lesions, or 18%; and large shagreen patches comprised 14 lesions, or 12%. Lesions smaller than 1 cm were labeled collagenomas, while shagreen patches were divided into small, medium, and large categories based on diameter. This size-based scheme is useful because it captures a spectrum of disease expression rather than forcing every lesion into a single classic pattern.
The distribution across the back was similarly broad. Eleven lesions, or 9%, were on the upper back. Thirty-five lesions, or 29%, were on the middle back. Sixty-one lesions, or 51%, were on the lower back. Thirteen lesions, or 11%, were found at other locations. Even though the lower back remained the most frequent site, nearly half of the lesions were outside that region or situated above it. For dermatologists, neurologists, and geneticists evaluating a patient for TSC, that means inspection must extend well beyond the lumbosacral area.
Histology Confirmed a Fibrotic Pattern With Reduced Elastic Tissue
The pathology findings were consistent across examined shagreen patches. All 26 histopathologically analyzed lesions showed coarse collagen fibers, and 24 of 26 lesions stained with Miller elastic stain demonstrated decreased elastic fibers. This microscopic profile fits the clinical impression of connective tissue nevi: an abnormal dermal connective tissue architecture rather than a purely inflammatory or melanocytic process.
At the tissue level, the loss of elastic fibers matters because it helps explain why these lesions feel and look different from surrounding skin. Shagreen patches often present as thickened, pebbled, or leathery plaques. Coarse collagen and reduced elastic fibers provide a structural basis for that altered texture. In practical terms, a lesion that may appear subtle on casual inspection can become more apparent on palpation, especially when the clinician is thinking about TSC rather than searching only for pigmentary changes.
Cellular Signaling Findings Pointed to mTOR Pathway Activation
Fibroblasts grown from shagreen patches expressed higher levels of phosphorylated ribosomal protein S6 than paired fibroblasts from normal-appearing skin. Phosphorylated S6 is a downstream marker of mTOR pathway activity, and its elevation reinforces the biologic link between TSC and aberrant cellular growth signaling. In a disease driven by pathogenic changes in TSC-related growth control, the skin lesions are not just structural abnormalities; they also reflect altered intracellular signaling.
That cellular signal gives the dermatologic findings mechanistic weight. The same pathway that contributes to multisystem manifestations in TSC appears to be active in the fibroblasts populating these lesions. For clinicians, the implication is not that skin biopsy is required for every patient, but that the skin findings are biologically credible markers of the underlying disorder rather than incidental collagenous variations.
Diagnostic Recognition Depends on Looking for the Atypical Presentation
The clinical value of this study lies in its restraint. It does not argue that shagreen patches are rare. It shows that their appearance is broader than the classic lower-back plaque described in teaching files and board review material. Small collagenomas, central back lesions, upper-back plaques, and lesions on the buttocks or thighs all belong within the cutaneous spectrum of TSC-related connective tissue nevi.
This matters most when diagnosis is uncertain. A patient with subtle lesions may not have the dramatic facial angiofibromas or seizures that usually prompt suspicion of TSC. In those cases, recognizing a faint plaque on the upper back or a small collagenoma on the thigh can be the difference between a missed diagnosis and a genetic workup that uncovers renal, pulmonary, neurologic, or cardiac involvement.
The cohort design also shapes interpretation. Because the sample was enriched for women with pulmonary lymphangioleiomyomatosis, it does not represent a perfectly balanced TSC population. Still, the lesion morphology, size distribution, and histology are concrete observations from a defined clinical series, and they support a broader dermatologic exam strategy in patients with suspected or known TSC.
Bedside Implications for Dermatology and TSC Evaluation
For clinicians, the practical lesson is to inspect the entire trunk and proximal lower extremities, not only the lower back. A connective tissue nevus smaller than 1 cm may be classified as a collagenoma, while larger plaques may represent one of several shagreen patch subtypes. In either form, the lesion can carry diagnostic weight far beyond its size.
Recognition of these variable presentations can alter the path to diagnosis in patients whose skin findings are subtle, scattered, or atypically placed. The histology provides the expected connective tissue signature, and the elevated phosphorylated S6 in lesional fibroblasts ties the cutaneous phenotype back to the disease biology. For a disorder as protean as TSC, the skin still offers one of the most accessible windows into the diagnosis—but only if the examination looks beyond the classic lower back plaque.