Neera Nathan

Mosaic Disorders of the PI3K/PTEN/AKT/TSC/mTORC1 Signaling Pathway

Somatic mutations in genes of the PI3K/PTEN/AKT/TSC/mTORC1 signaling pathway cause segmental overgrowth, hamartomas, and malignant tumors. Mosaicism for activating mutations in AKT1 or PIK3CA cause Proteus syndrome and PIK3CA-Related Overgrowth Spectrum, respectively. Postzygotic mutations in PTEN or TSC1/TSC2 cause mosaic forms of PTEN hamartoma tumor syndrome or tuberous sclerosis complex, respectively. Distinct features observed in these mosaic conditions in part reflect differences in embryological timing or tissue type harboring the mutant cells. Deep sequencing of affected tissue is useful for diagnosis. Drugs targeting mTORC1 or other points along this signaling pathway are in clinical trials to treat these disorders.

Improvement of tuberous sclerosis complex (TSC) skin tumors during long-term treatment with oral sirolimus

BACKGROUND Oral mechanistic target of rapamycin inhibitors have been shown to reduce visceral tumor volume in patients with tuberous sclerosis complex (TSC). OBJECTIVE We sought to evaluate the cutaneous response to oral sirolimus in patients with TSC and an indication for systemic treatment, including long-term effects. METHODS A retrospective analysis of 14 adult patients with TSC prescribed sirolimus to treat lymphangioleiomyomatosis was performed. Serial photographs of angiofibromas, shagreen patches, and ungual fibromas taken before, during, and after the treatment period were blinded, then assessed using the Physician Global Assessment of Clinical Condition (PGA). Microscopic and molecular studies were performed on skin tumors harvested before and during treatment. RESULTS Sirolimus significantly improved angiofibromas (median treatment duration 12 months; median PGA score 4.5 [range 1.5-5]; Wilcoxon signed rank test, P = .018) and shagreen patches (median treatment duration 10 months; median PGA score 4.5 [range 3.5-5]; Wilcoxon signed rank test, P = .039), whereas ungual fibromas improved in some patients (median treatment duration 6.5 months; median PGA score 4.66 [range 2.75-5]; Wilcoxon signed rank test, P = .109). Clinical, immunohistochemical, or molecular evidence of resistance was not observed (range 5-64 months of treatment). LIMITATIONS This was a retrospective analysis limited to adult women with lymphangioleiomyomatosis. CONCLUSION Oral sirolimus is an effective long-term therapy for TSC skin tumors, particularly angiofibromas, in patients for whom systemic treatment is indicated.

A diagnostic and management algorithm for individuals with an isolated skin finding suggestive of tuberous sclerosis complex

DEAR EDITOR, Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous syndrome caused by mutations in TSC1 or TSC2, leading to development of hamartomas in the brain, kidneys, heart, lungs, eyes and skin. A diagnostic evaluation for TSC includes (i) family history; (ii) skin, dental and eye examination; (iii) functional and imaging studies of internal organs depending on patient age and presentation; and (iv) consideration of genetic testing. The decision to pursue a complete evaluation for TSC is readily made for those presenting early in life with multiple complications of the disease. This decision may be more difficult in those who manifest only one skin finding of TSC. In such instances, additional considerations enter the decision-making process, such as concern for causing unnecessary anxiety in the patient or his/her family, possible health risks and the financial costs of screening individuals with a seemingly low diagnostic yield, or the potential for misidentification or misattribution of skin lesions that pose little or no problem to the patient. Our goal was to identify situations that should increase suspicion for TSC and others where extensive TSC-related work-up may not be warranted. We evaluated the earliest cutaneous manifestations in a cohort of 115 adults with TSC. Based on these patients and our experience evaluating 13 additional patients screened for TSC, we propose a new algorithm that refines the evaluation of those presenting with one skin finding suggestive for TSC. A retrospective review of medical records from patients recruited for studies of TSC and lymphangioleiomyomatosis (LAM) at the National Institutes of Health Clinical Center in Bethesda, MD, U.S.A., from 1998 to 2015, was performed. This cohort was enriched for patients diagnosed with TSC in adulthood, frequently after complications arising from renal angiomyolipomas or LAM. Others were referred to our institution for TSC screening and underwent full TSC diagnostic evaluation. Written informed consent was obtained according to protocols 00-H-0051, 95-H-0186 and/or 82-H-0032, which were approved by the National Heart, Lung and Blood Institute’s institutional review board. Individuals were diagnosed based on clinical criteria, and they met updated criteria that outline a definite diagnosis of TSC as two or more major features or one major feature plus two or more minor features. Individuals with only one major feature, or two or more minor features, were considered as having ‘possible’ TSC. Skin findings that satisfy major features are hypomelanotic macules (≥ 3, at least 5 mm in diameter), angiofibromas (≥ 3) or fibrous cephalic plaque, shagreen patch and ungual fibromas (≥ 2). Of 115 adults with TSC, 68 (59%) provided a history of manifesting only one cutaneous major feature of TSC for at least 1 year before onset of any other skin features. During this diagnostic opportunity window, 28 had only hypomelanotic macules, 21 angiofibromas (which were misdiagnosed in seven patients), 14 fibrous cephalic plaque, four shagreen patch and one ungual fibromas. Thirty-five patients (51%) eventually developed AMLs and 46 (68%) LAM. Median age of manifestation of first cutaneous major feature was 1 year (range 0–20). At the time of manifestation, TSC diagnosis was confirmed in seven of 68 (10%) patients. Median age of definite TSC diagnosis was 26 years (range 1–63). Lesion-specific details are presented in Table 1. Thirteen additional adults were referred to dermatology to evaluate skin findings suggestive of TSC, including facial papules in eight, skin-coloured plaques on the head or trunk in three and localized hypopigmentation in two. Histopathological analysis excluded TSC in eight cases. Biopsy showed angiofibromas in one patient; however, adult onset increased suspicion for Birt–Hogg–Dub e

Tsc2 disruption in mesenchymal progenitors results in tumors with vascular anomalies overexpressing Lgals3

Increased mTORC1 signaling from TSC1/TSC2 inactivation is found in cancer and causes tuberous sclerosis complex (TSC). The role of mesenchymal-derived cells in TSC tumorigenesis was investigated through disruption of Tsc2 in craniofacial and limb bud mesenchymal progenitors. Tsc2cKOPrrx1-cre mice had shortened lifespans and extensive hamartomas containing abnormal tortuous, dilated vessels prominent in the forelimbs. Abnormalities were blocked by the mTORC1 inhibitor sirolimus. A Tsc2/mTORC1 expression signature identified in Tsc2-deficient fibroblasts was also increased in bladder cancers with TSC1/TSC2 mutations in the TCGA database. Signature component Lgals3 encoding galectin-3 was increased in Tsc2-deficient cells and serum of Tsc2cKOPrrx1-cre mice. Galectin-3 was increased in TSC-related skin tumors, angiomyolipomas, and lymphangioleiomyomatosis with serum levels in patients with lymphangioleiomyomatosis correlating with impaired lung function and angiomyolipoma presence. Our results demonstrate Tsc2-deficient mesenchymal progenitors cause aberrant morphogenic signals, and identify an expression signature including Lgals3 relevant for human disease of TSC1/TSC2 inactivation and mTORC1 hyperactivity. DOI: http://dx.doi.org/10.7554/eLife.23202.001

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

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.

Nipple Angiofibromas with Loss of TSC2 Are Associated with Tuberous Sclerosis Complex

Nevertheless, our ability to identify meaningful differences between these two populations suggests that this is a reasonable cutpoint. One hypothesis for the increasing incidence rates of early-onset BCC has been increased awareness and skin surveillance. However, lesion size has not decreased over time, as might be anticipated if earlier detection were the underlying cause of increased incidence (Christenson et al., 2005). Our results likewise suggest that early-onset BCC is associated with aggressive histologic characteristics, as opposed to a less aggressive phenotype that might be expected if surveillance bias were operating. Although additional studies are needed, these results suggest there may be underlying biological differences between earlyand late-onset BCC.

Pathogenetic insights from quantification of the cerebriform connective tissue nevus in Proteus syndrome

Background: The plantar cerebriform connective tissue nevus (CCTN) is the most common and problematic cutaneous manifestation of Proteus syndrome. Objective: To gain insights into CCTN pathogenesis and natural history. Methods: The size and location of plantar CCTN was measured on 152 images from 22 individuals with Proteus syndrome by 2 independent, blinded reviewers. Average measures of plantar CCTN were transformed into a linear mixed model to estimate proportionate change in size with age. Results: Median patient age was 6.9 years at study onset. The intraclass correlation coefficient between 2 blinded reviewers was 0.946 for CCTN single measures. The CCTN relative area increased with age in children (n = 18, P < .0001) by 5.6% per year. Confluent papules and nodules extending beyond the boundaries of CCTNs were gradually replaced by typical CCTN over time. The location of CCTN in different individuals overlapped near the ball of the foot. A positive relationship between CCTN growth rate and AKT1 mutant allele frequency was observed (0.62, P = .10, n = 8). Limitations: This was a retrospective review using photographs. Conclusion: CCTN growth is affected by age and extent of the CCTN precursor lesion. Monitoring of CCTN size might prove useful for evaluating drug response in the treatment of Proteus syndrome.