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Thomas N. Darling - One of the best experts on this subject based on the ideXlab platform.
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Molecular heterogeneity of the cerebriform Connective Tissue Nevus in mosaic overgrowth syndromes.
Molecular Case Studies, 2019Co-Authors: Kim M. Keppler-noreuil, Marjorie J. Lindhurst, Julie C Sapp, Thomas N. Darling, Jasmine Burton-akright, Jasmine J Shwetar, Leslie G BieseckerAbstract:The clinical diagnostic criteria for Proteus syndrome were defined before the discovery of the AKT1 c.49G>A; p.(Glu17Lys) causal variant and used a combination of general and specific phenotypic attributes that could be combined to make a clinical diagnosis. The most heavily weighted specific criterion was the cerebriform Connective Tissue Nevus (CCTN). Here, we describe two individuals with Connective Tissue nevi (CTNs) and some general attributes of Proteus syndrome who were found to have mosaic PIK3CA variants. CTNs on the soles of individuals with PIK3CA-related overgrowth typically exhibit thickening of the soft Tissues with at most a wrinkled surface, but these two patients had firm plaques with ridges and furrows characteristic of CCTNs, which was histologically confirmed in one. These data show that CCTNs are not specific to Proteus syndrome and that clinicians should be cautious in diagnosing individuals with Proteus syndrome based on the CCTN alone. Rather, a complete evaluation should include careful assessment of other attributes of the diagnostic criteria and, whenever possible, genetic analysis of affected Tissue.
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pharmacodynamic study of miransertib in individuals with proteus syndrome
American Journal of Human Genetics, 2019Co-Authors: Kim M Kepplernoreuil, Marjorie J. Lindhurst, Julie C Sapp, Jasmine Burtonakright, Eva Dombi, Ashlyn Gruber, Paul Jarosinski, Mohammadhadi Bagheri, Thomas N. Darling, Staci MartinAbstract:Proteus syndrome is a life-threatening segmental overgrowth syndrome caused by a mosaic gain-of-function AKT1 variant. There are no effective treatments for Proteus syndrome. Miransertib is an AKT1 inhibitor that, prior to this study, has been evaluated only in adult oncology trials. We designed a non-randomized, phase 0/1 pilot study of miransertib in adults and children with Proteus syndrome to identify an appropriate dosage starting point for a future efficacy trial using a pharmacodynamic endpoint. The primary endpoint was a 50% reduction in the Tissue levels of AKT phosphorylation from biopsies in affected individuals. We also evaluated secondary efficacy endpoints. We found that a dose of 5 mg/m2/day (1/7 the typical dose used in oncology) led to a 50% reduction in phosphorylated AKT (pAKT) in affected Tissues from five of six individuals. This dose was well tolerated. Two of the six efficacy endpoints (secondary objectives) suggested that this agent may be efficacious. We observed a decrease in a cerebriform Connective Tissue Nevus and a reduction in pain in children. We conclude that 5 mg/m2/day of miransertib is an appropriate starting point for future efficacy trials and that this agent shows promise of therapeutic efficacy in children with Proteus syndrome.
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Pathogenetic insights from quantification of the cerebriform Connective Tissue Nevus in Proteus syndrome
Journal of the American Academy of Dermatology, 2018Co-Authors: Neera Nathan, Marjorie J. Lindhurst, Leslie G Biesecker, Rachna Patel, Molly M. Crenshaw, Cara H. Olsen, Kim M. Keppler-noreuil, Thomas N. DarlingAbstract: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 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.
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Clinical Characteristics of Connective Tissue Nevi in Tuberous Sclerosis Complex With Special Emphasis on Shagreen Patches
JAMA Dermatology, 2017Co-Authors: Michelle A. Bongiorno, Neera Nathan, Oyetewa Oyerinde, Ji-an Wang, Chyi-chia Richard Lee, G. Thomas Brown, Joel Moss, Thomas N. DarlingAbstract: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 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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progressive overgrowth of the cerebriform Connective Tissue Nevus in patients with proteus syndrome
Journal of The American Academy of Dermatology, 2010Co-Authors: Thomas M Beachkofsky, Julie C Sapp, Leslie G Biesecker, Thomas N. DarlingAbstract:Background Proteus syndrome is a rare overgrowth disorder that almost always affects the skin. Objective Our purpose was to evaluate progression of skin lesions in patients with Proteus syndrome. Methods Skin findings were documented in 36 patients with Proteus syndrome. Progression of skin lesions in 16 of these patients was assessed by comparing photographs obtained on repeated visits for an average total duration of 53 months. Results The skin lesion most characteristic of Proteus syndrome, the cerebriform Connective Tissue Nevus, showed progression in 13 children but not in 3 adults. The cerebriform Connective Tissue Nevus progressed by expansion into previously uninvolved skin, increased thickness, and development of new lesions. Lipomas increased in size, number, or both in 8 of 10 children with lipomas. In contrast, epidermal nevi and vascular malformations generally did not spread or increase in number. Limitations Only 3 adults with Proteus syndrome were evaluated longitudinally. Conclusion The cerebriform Connective Tissue Nevus in Proteus syndrome grows throughout childhood but tends to remain stable in adulthood.
Christopher D M Fletcher - One of the best experts on this subject based on the ideXlab platform.
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Plexiform Myofibroblastoma: Clinicopathologic Analysis of 36 Cases of a Distinctive Benign Tumor of Soft Tissue Affecting Mainly Children and Young Adults.
The American journal of surgical pathology, 2020Co-Authors: David J. Papke, Alyaa Al-ibraheemi, Christopher D M FletcherAbstract:The spectrum of benign superficial fibroblastic/myofibroblastic tumors continues to expand and includes entities such as plexiform fibrohistiocytic tumor, dermatomyofibroma and fibroblastic Connective Tissue Nevus. Here, we describe a seemingly distinctive group of lesions which we have labeled "plexiform myofibroblastoma" (PM). PM is a rare superficial mesenchymal tumor of fibroblastic/myofibroblastic lineage that predominantly occurs in children and young adults. Thirty-six cases from the consultation archives of one of the authors have been studied to characterize the clinicopathologic characteristics of PM. 19 patients (53%) were female and 17 were male, with age at presentation ranging from congenital (2 cases) to 50 years of age (median: 9.5 y). Three patients had multiple lesions. Males tended to develop tumors during childhood (median: 2 y; range: congenital-37 y), while in females the age distribution was relatively uniform from childhood through adulthood (median age: 25 y; range: 4 mo to 50 y). Most tumors occurred in truncal locations (25/40), including the back (11), anterolateral chest wall (4), axilla (4), abdominal wall (4), perineum (1) and suprapubic region (1). Other tumor sites were the neck (10/40), occiput (2), lower extremity (2) and breast (1). The average greatest dimension was 2.7±1.7 cm (range: 0.6 to 8 cm). Three male patients, 2 of whom were brothers, presented between 6 months and 1 year of age with multiple lesions variably involving the back, occiput and axillae; these lesions spontaneously regressed after being present for about 2 years, with no evidence of recurrence at a mean follow-up of 11.4±3.2 years. Histologically, PM was composed of plexiform fascicles of fibroblastic/myofibroblastic spindle cells that ramify through the subcutis and reticular dermis. The bland neoplastic cells had indistinct cell borders, palely eosinophilic cytoplasm and ovoid or tapered nuclei. There was no histiocytoid component in any case, and no cases contained osteoclast-like giant cells. Twelve of thirty-four (35%) reviewed cases showed at least focal keloidal hyalinization, 6/34 (18%) contained somewhat fasciitis-like areas and 6/34 (18%) contained focal myxoid stroma. Immunohistochemical studies were positive for SMA (27/32 cases), desmin (9/21) and CD34 (13/24) and negative for β-catenin (0/14) and S-100 (0/22). EMA was weakly positive in 2/15 cases. An FGFR2 M535L tyrosine kinase domain variant of unknown significance was detected in 1/7 sequenced cases, and no somatic alterations, copy number alterations or gene fusions were detected in the other 6. Clinical follow-up data were available for 16/36 patients (44%; median duration: 5.5 y). Although most excisions had positive margins (11/16), only 1 patient developed a local recurrence 4 years after initial excision. No tumors metastasized. PM is a benign tumor with characteristic histology, epidemiology and anatomic site distribution. Because PM rarely recurs, a watchful waiting approach would be reasonable for lesions excised with positive margins.
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fibroblastic Connective Tissue Nevus a rare cutaneous lesion analyzed in a series of 25 cases
The American Journal of Surgical Pathology, 2012Co-Authors: Sebastien De Feraudy, Christopher D M FletcherAbstract:Fibroblastic Connective Tissue Nevus (FCTN) represents a rare and distinct benign cutaneous mesenchymal lesion of fibroblastic/myofibroblastic lineage, which broadens the spectrum of lesions presently recognized as Connective Tissue Nevus. A series of 25 cases of FCTN has been analyzed to further ch
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Fibroblastic Connective Tissue Nevus: a rare cutaneous lesion analyzed in a series of 25 cases
The American Journal of Surgical Pathology, 2012Co-Authors: Sebastien De Feraudy, Christopher D M FletcherAbstract:Fibroblastic Connective Tissue Nevus (FCTN) represents a rare and distinct benign cutaneous mesenchymal lesion of fibroblastic/myofibroblastic lineage, which broadens the spectrum of lesions presently recognized as Connective Tissue Nevus. A series of 25 cases of FCTN has been analyzed to further characterize the clinicopathologic spectrum and immunohistochemical features of this entity. Sixteen patients were female (64%) and 9 were male (36%), with age at presentation ranging from 1.5 months to 58 years (median, 10 y). Most patients presented with a solitary, slowly growing, painless plaque-like or nodular skin lesion. Eleven cases (44%) arose on the trunk, 9 (36%) on the head and neck, and 5 (20%) on the limbs. The lesion was present for a median duration of 11.5 months (mean, 13.2 mo). Grossly, the lesions were tan-brown to tan-white, smooth, and firm. Their size ranged from 0.3 to 2.0 cm in greatest dimension (mean size, 0.67 cm; median, 0.6 cm). All tumors showed poor circumscription and were situated primarily in the reticular deep dermis, extending into the superficial subcutis in 13 cases (52%). The lesion was associated with papillomatous epidermis in 17 cases (70%) and the presence of adipose Tissue in the reticular dermis in 14 cases (60.9%). All tumors were composed of a proliferation of bland intradermal fibroblastic/myofibroblastic cells with indistinct palely eosinophilic cytoplasm and tapering nuclei, with no significant cytologic atypia or pleomorphism, arranged in short-intersecting fascicles and entrapping appendages. No mitoses were identified. Immunostains showed positivity for CD34 in 20 of 23 cases (87%) and weak focal positivity for smooth muscle actin in 9 of 19 cases (47%). No case stained positively for desmin or S100 protein. Clinical follow-up was obtained for 14 patients (median duration, 4 y). No tumor recurred locally, even when surgical excision was incomplete. No lesion metastasized. FCTN occurs most commonly as a plaque on the trunk and head/neck of children, involves deep dermis and superficial subcutis, and stains mainly for CD34. FCTN most likely represents a localized developmental dermal anomaly; it is entirely benign and should not be confused with dermatofibrosarcoma protuberans or other neoplasms such as dermatomyofibroma.
Michael M Cohen - One of the best experts on this subject based on the ideXlab platform.
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proteus syndrome review molecular clinical and pathologic features
Clinical Genetics, 2014Co-Authors: Michael M CohenAbstract:Proteus syndrome is caused by an activating AKT1 mutation (c.49G>A, p.Glu17Lys). Many variable features are possible in this mosaic disorder, including: (i) disproportionate, asymmetric, and distorting overgrowth; (ii) bone abnormalities different from those observed in other disorders; (iii) a characteristic cerebriform Connective Tissue Nevus made up of highly collagenized Connective Tissue; (iv) epidermal nevi in early life, consisting of acanthosis and hyperkeratosis; (v) vascular malformations of the capillary, venous, or lymphatic types; (vi) dysregulated adipose Tissue including lipomas, lipohypoplasia, fatty overgrowth, and localized fat deposits; (vii) other unusual features, including bullous lung alterations; specific neoplasms; a facial phenotype associated with intellectual disability and/or seizures, and/or brain malformations; and (viii) deep vein thrombosis, resulting in premature death. Concluding remarks address diagnostic criteria, natural history, management, psychosocial issues, and differential diagnosis.
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proteus syndrome clinical evidence for somatic mosaicism and selective review
American Journal of Medical Genetics, 1993Co-Authors: Michael M CohenAbstract:I report 2 unusual cases of Proteus syndrome that support the concept of somatic mosaicism. In one patient, a huge Connective Tissue Nevus covered the chest and abdomen and hyperostoses of the calvaria were observed. In the other patient, linear verrucous epidermal nevi, epibulbar dermoids, and hyperostoses were found. No enlargement of the limbs or digits occurred and the plantar surfaces of the feet were normal. Selective aspects of Proteus syndrome not previously reviewed are also presented including: uncommon neoplasms; pulmonary and renal abnormalities; brain malformations; facial phenotype associated with seizures and severe mental deficiency; and types of abnormal growth in the craniofacial skeleton. © 1993 Wiley-Liss, Inc.
Julie C Sapp - One of the best experts on this subject based on the ideXlab platform.
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Molecular heterogeneity of the cerebriform Connective Tissue Nevus in mosaic overgrowth syndromes.
Molecular Case Studies, 2019Co-Authors: Kim M. Keppler-noreuil, Marjorie J. Lindhurst, Julie C Sapp, Thomas N. Darling, Jasmine Burton-akright, Jasmine J Shwetar, Leslie G BieseckerAbstract:The clinical diagnostic criteria for Proteus syndrome were defined before the discovery of the AKT1 c.49G>A; p.(Glu17Lys) causal variant and used a combination of general and specific phenotypic attributes that could be combined to make a clinical diagnosis. The most heavily weighted specific criterion was the cerebriform Connective Tissue Nevus (CCTN). Here, we describe two individuals with Connective Tissue nevi (CTNs) and some general attributes of Proteus syndrome who were found to have mosaic PIK3CA variants. CTNs on the soles of individuals with PIK3CA-related overgrowth typically exhibit thickening of the soft Tissues with at most a wrinkled surface, but these two patients had firm plaques with ridges and furrows characteristic of CCTNs, which was histologically confirmed in one. These data show that CCTNs are not specific to Proteus syndrome and that clinicians should be cautious in diagnosing individuals with Proteus syndrome based on the CCTN alone. Rather, a complete evaluation should include careful assessment of other attributes of the diagnostic criteria and, whenever possible, genetic analysis of affected Tissue.
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pharmacodynamic study of miransertib in individuals with proteus syndrome
American Journal of Human Genetics, 2019Co-Authors: Kim M Kepplernoreuil, Marjorie J. Lindhurst, Julie C Sapp, Jasmine Burtonakright, Eva Dombi, Ashlyn Gruber, Paul Jarosinski, Mohammadhadi Bagheri, Thomas N. Darling, Staci MartinAbstract:Proteus syndrome is a life-threatening segmental overgrowth syndrome caused by a mosaic gain-of-function AKT1 variant. There are no effective treatments for Proteus syndrome. Miransertib is an AKT1 inhibitor that, prior to this study, has been evaluated only in adult oncology trials. We designed a non-randomized, phase 0/1 pilot study of miransertib in adults and children with Proteus syndrome to identify an appropriate dosage starting point for a future efficacy trial using a pharmacodynamic endpoint. The primary endpoint was a 50% reduction in the Tissue levels of AKT phosphorylation from biopsies in affected individuals. We also evaluated secondary efficacy endpoints. We found that a dose of 5 mg/m2/day (1/7 the typical dose used in oncology) led to a 50% reduction in phosphorylated AKT (pAKT) in affected Tissues from five of six individuals. This dose was well tolerated. Two of the six efficacy endpoints (secondary objectives) suggested that this agent may be efficacious. We observed a decrease in a cerebriform Connective Tissue Nevus and a reduction in pain in children. We conclude that 5 mg/m2/day of miransertib is an appropriate starting point for future efficacy trials and that this agent shows promise of therapeutic efficacy in children with Proteus syndrome.
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progressive overgrowth of the cerebriform Connective Tissue Nevus in patients with proteus syndrome
Journal of The American Academy of Dermatology, 2010Co-Authors: Thomas M Beachkofsky, Julie C Sapp, Leslie G Biesecker, Thomas N. DarlingAbstract:Background Proteus syndrome is a rare overgrowth disorder that almost always affects the skin. Objective Our purpose was to evaluate progression of skin lesions in patients with Proteus syndrome. Methods Skin findings were documented in 36 patients with Proteus syndrome. Progression of skin lesions in 16 of these patients was assessed by comparing photographs obtained on repeated visits for an average total duration of 53 months. Results The skin lesion most characteristic of Proteus syndrome, the cerebriform Connective Tissue Nevus, showed progression in 13 children but not in 3 adults. The cerebriform Connective Tissue Nevus progressed by expansion into previously uninvolved skin, increased thickness, and development of new lesions. Lipomas increased in size, number, or both in 8 of 10 children with lipomas. In contrast, epidermal nevi and vascular malformations generally did not spread or increase in number. Limitations Only 3 adults with Proteus syndrome were evaluated longitudinally. Conclusion The cerebriform Connective Tissue Nevus in Proteus syndrome grows throughout childhood but tends to remain stable in adulthood.
Douglas G Rogers - One of the best experts on this subject based on the ideXlab platform.
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Genital Tract Tumors in Proteus Syndrome: Report of a Case of Bilateral Paraovarian Endometrioid Cystic Tumors of Borderline Malignancy and Review of the Literature
Modern Pathology, 2002Co-Authors: Rajeeva R Raju, William R Hart, David K Magnuson, Janet R Reid, Douglas G RogersAbstract:Proteus syndrome is a rare, sporadic disorder that causes postnatal overgrowth of multiple Tissues in a mosaic pattern. Characteristic manifestations include: overgrowth and hypertrophy of limbs and digits, Connective Tissue Nevus, epidermal Nevus and hyperostoses. Various benign and malignant tumors and hamartomas may complicate the clinical course of patients with the syndrome. Commonly encountered tumors include hemangiomas, lymphangiomas and lipomas. Tumors of the genital tract occur less often. Bilateral ovarian cystadenomas are regarded as having diagnostic value in Proteus syndrome when occurring within the first two decades of life. We describe a 3-year-old girl with Proteus syndrome who developed bilateral paraovarian villoglandular endometrioid cystadenomatous tumors of borderline malignancy (low malignant potential) of the broad ligament. Desmoplastic tumor implants, presumably noninvasive, were present in biopsies from the pelvic floor, cul-de-sac and omentum. This is the first recognized example of a cystic borderline epithelial tumor of the female genital tract and the first paraovarian tumor reported in a patient with Proteus syndrome. Previously reported tumors and cystic lesions involving the female genital tract and the male genital tract in patients with Proteus syndrome are reviewed. We suspect that specific testicular and paratesticular tumors may prove to have the same diagnostic value in Proteus syndrome as do bilateral cystic ovarian and paraovarian tumors.