Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 78
Filter
Add more filters

Country/Region as subject
Publication year range
1.
Am J Hum Genet ; 110(6): 979-988, 2023 06 01.
Article in English | MEDLINE | ID: mdl-37141891

ABSTRACT

Tuberous sclerosis complex (TSC) is a neurogenetic disorder due to loss-of-function TSC1 or TSC2 variants, characterized by tumors affecting multiple organs, including skin, brain, heart, lung, and kidney. Mosaicism for TSC1 or TSC2 variants occurs in 10%-15% of individuals diagnosed with TSC. Here, we report comprehensive characterization of TSC mosaicism by using massively parallel sequencing (MPS) of 330 TSC samples from a variety of tissues and fluids from a cohort of 95 individuals with mosaic TSC. TSC1 variants in individuals with mosaic TSC are much less common (9%) than in germline TSC overall (26%) (p < 0.0001). The mosaic variant allele frequency (VAF) is significantly higher in TSC1 than in TSC2, in both blood and saliva (median VAF: TSC1, 4.91%; TSC2, 1.93%; p = 0.036) and facial angiofibromas (median VAF: TSC1, 7.7%; TSC2 3.7%; p = 0.004), while the number of TSC clinical features in individuals with TSC1 and TSC2 mosaicism was similar. The distribution of mosaic variants across TSC1 and TSC2 is similar to that for pathogenic germline variants in general TSC. The systemic mosaic variant was not present in blood in 14 of 76 (18%) individuals with TSC, highlighting the value of analysis of multiple samples from each individual. A detailed comparison revealed that nearly all TSC clinical features are less common in individuals with mosaic versus germline TSC. A large number of previously unreported TSC1 and TSC2 variants, including intronic and large rearrangements (n = 11), were also identified.


Subject(s)
Tuberous Sclerosis , Tumor Suppressor Proteins , Humans , Tumor Suppressor Proteins/genetics , Tuberous Sclerosis/genetics , Tuberous Sclerosis/pathology , Tuberous Sclerosis Complex 2 Protein/genetics , Mutation , Tuberous Sclerosis Complex 1 Protein/genetics , Phenotype
2.
Am J Hum Genet ; 104(3): 484-491, 2019 03 07.
Article in English | MEDLINE | ID: mdl-30803705

ABSTRACT

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.


Subject(s)
Aminopyridines/pharmacology , Imidazoles/pharmacology , Nevus/prevention & control , Pain/prevention & control , Proteus Syndrome/drug therapy , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Adolescent , Adult , Aminopyridines/pharmacokinetics , Child , Female , Humans , Imidazoles/pharmacokinetics , Male , Maximum Tolerated Dose , Middle Aged , Phosphorylation , Pilot Projects , Prognosis , Proteus Syndrome/metabolism , Proteus Syndrome/pathology , Tissue Distribution , Young Adult
3.
Am J Med Genet A ; 188(9): 2766-2771, 2022 09.
Article in English | MEDLINE | ID: mdl-35441778

ABSTRACT

Proteus syndrome (PS) is a rare segmental overgrowth disorder caused by a mosaic activating variant in AKT1. The features of PS are often not present at birth but develop during the first few years of life. We describe a 55-year-old female, whose first symptom of overgrowth, a cerebriform connective tissue nevus, occurred at 19 years of age. We report the identification of the AKT1 c.49G > A p.(Glu17Lys) variant in this progressive lesion, the bony overgrowth, and recurrence after surgical intervention. In the sixth decade of life, this individual developed intraductal papillomas within her right breast which were confirmed to contain the same activating AKT1 variant as the connective tissue nevus. While similar neoplasms have been described in an individual with Proteus syndrome, none has been evaluated for the presence of the AKT1 variant. The tumor also contained two likely pathogenic variants in PIK3R1, c.1392_1403dupTAGATTATATGA p.(Asp464_Tyr467dup) and c.1728_1730delGAG p.(Arg577del). The finding of additional genetic variation putatively affecting the PI3K/AKT pathway in the neoplastic tissue may provide preliminary evidence of a molecular mechanism for tumorigenesis in PS. The late onset of symptoms and molecular characterization of the breast tumor expand the clinical spectrum of this rare disorder.


Subject(s)
Breast Neoplasms , Nevus , Papilloma, Intraductal , Proteus Syndrome , Breast Neoplasms/genetics , Female , Humans , Infant, Newborn , Middle Aged , Nevus/diagnosis , Nevus/genetics , Nevus/pathology , Phosphatidylinositol 3-Kinases , Proteus Syndrome/diagnosis , Proteus Syndrome/genetics , Proteus Syndrome/pathology , Proto-Oncogene Proteins c-akt/genetics
4.
Am J Hum Genet ; 103(6): 976-983, 2018 12 06.
Article in English | MEDLINE | ID: mdl-30449416

ABSTRACT

We have investigated a distinct disorder with progressive corneal neovascularization, keloid formation, chronic skin ulcers, wasting of subcutaneous tissue, flexion contractures of the fingers, and acro-osteolysis. In six affected individuals from four families, we found one of two recurrent variants in discoidin domain receptor tyrosine kinase 2 (DDR2): c.1829T>C (p.Leu610Pro) or c.2219A>G (p.Tyr740Cys). DDR2 encodes a collagen-responsive receptor tyrosine kinase that regulates connective-tissue formation. In three of the families, affected individuals comprise singleton adult individuals, and parental samples were not available for verification of the de novo occurrence of the DDR2 variants. In the fourth family, a mother and two of her children were affected, and the c.2219A>G missense variant was proven to be de novo in the mother. Phosphorylation of DDR2 was increased in fibroblasts from affected individuals, suggesting reduced receptor autoinhibition and ligand-independent kinase activation. Evidence for activation of other growth-regulatory signaling pathways was not found. Finally, we found that the protein kinase inhibitor dasatinib prevented DDR2 autophosphorylation in fibroblasts, suggesting an approach to treatment. We propose this progressive, fibrotic condition should be designated as Warburg-Cinotti syndrome.


Subject(s)
Connective Tissue Diseases/genetics , Discoidin Domain Receptor 2/genetics , Adult , Amino Acid Sequence , Child , Child, Preschool , Collagen/genetics , Connective Tissue Diseases/drug therapy , Female , Fibroblasts/drug effects , Humans , Middle Aged , Protein Kinase Inhibitors/therapeutic use , Receptor Protein-Tyrosine Kinases/genetics , Sequence Alignment , Signal Transduction/drug effects , Signal Transduction/genetics
5.
Histopathology ; 79(4): 619-628, 2021 Oct.
Article in English | MEDLINE | ID: mdl-33882161

ABSTRACT

AIMS: Fibrous cephalic plaques (FCPs) in individuals with tuberous sclerosis complex (TSC) may be excised for cosmetic reasons or biopsied to confirm lesion identification and TSC diagnosis. The aim of this study was to determine the range of histopathological features of FCPs. METHODS AND RESULTS: A retrospective analysis was conducted on 119 adults with TSC. Twenty-one lesions from 16 individuals were evaluated by a dermatopathologist. Additionally, we assessed whether lesion colour or histology varied by anatomical location. Seventy-six lesions were observed in 36 of 119 individuals. Erythematous lesions were more commonly found on the forehead, face or neck than on the scalp (odds ratio = 12.6, P = 0.0001). Thickened and disorganised collagen fibre bundles were present in 95% (20/21) of lesions. Perifollicular fibrosis was observed in 95% (20/21) of lesions, enhanced vascularity was observed in 52% (11/21) of lesions, and features of fibrofolliculoma were observed in 43% (9/21) of lesions. Other abnormalities included features similar to trichofolliculoma, follicular-derived, infundibular-type cysts, and abnormally arranged primitive hair follicles. CONCLUSIONS: FCPs in TSC show thickened bundles of collagen, and hamartomatous changes involving hair follicles. Recognition of these histopathological features may raise the possibility of unsuspected TSC or confirm FCP identification.


Subject(s)
Skin Diseases/pathology , Tuberous Sclerosis/pathology , Adult , Female , Fibrosis/etiology , Fibrosis/pathology , Head , Humans , Male , Middle Aged , Retrospective Studies , Skin Diseases/etiology , Tuberous Sclerosis/complications
6.
J Am Acad Dermatol ; 84(2): 415-424, 2021 Feb.
Article in English | MEDLINE | ID: mdl-32035943

ABSTRACT

BACKGROUND: Proteus syndrome is an overgrowth disorder caused by a mosaic activating AKT1 variant. Hair abnormalities in Proteus syndrome have rarely been reported, and frequencies of such findings have not been elucidated. OBJECTIVE: To define the types and frequencies of hair findings in individuals with Proteus syndrome. METHODS: A cross-sectional study was conducted of individuals with clinical features of Proteus syndrome and a confirmed pathogenic variant in AKT1 evaluated between November 1996 and June 2019 at the National Institutes of Health Clinical Center. Medical records were reviewed for patterning, density, and color of hair on the body and scalp. RESULTS: Of 45 individuals evaluated, 29 (64%) had asymmetric hypertrichosis on the body. This included unilateral blaschkoid hypertrichotic patches overlying normal skin or epidermal nevi in 16 (36%), unilateral nonblaschkoid hypertrichotic patches in 11 (24%), and unilateral limb hypertrichosis in 10 (22%). Diffuse, scattered, or patchy changes in scalp hair density or color were present in 11 individuals (24%). LIMITATIONS: The retrospective, observational design, and limited longitudinal follow-up. CONCLUSIONS: Asymmetric variations in hair distribution, thickness, length, and color contribute to the overall mosaic appearance of the skin in Proteus syndrome, an observation that provides novel insights into the role of phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) signaling in skin appendage development.


Subject(s)
Hypertrichosis/epidemiology , Mosaicism , Proteus Syndrome/complications , Proto-Oncogene Proteins c-akt/genetics , Adolescent , Adult , Child , Child, Preschool , Cross-Sectional Studies , DNA Mutational Analysis , Female , Hair Follicle/growth & development , Hair Follicle/pathology , Humans , Hypertrichosis/genetics , Hypertrichosis/pathology , Male , Mutation , Phosphatidylinositol 3-Kinases/metabolism , Prevalence , Proteus Syndrome/diagnosis , Proteus Syndrome/genetics , Proto-Oncogene Proteins c-akt/metabolism , Retrospective Studies , Signal Transduction/genetics , Young Adult
7.
Pediatr Dermatol ; 38(4): 794-799, 2021 Jul.
Article in English | MEDLINE | ID: mdl-34105192

ABSTRACT

BACKGROUND/OBJECTIVE: Proteus syndrome, caused by a mosaic activating AKT1 variant, typically presents in toddlers with progressive, asymmetric overgrowth of the skin and bones. We aimed to define the spectrum of dermatologic disease in individuals with genetically confirmed Proteus syndrome. METHODS: We conducted a retrospective review of records from dermatologic examinations of individuals evaluated at the NIH with a molecular diagnosis of Proteus syndrome. The types, prevalence, and localization of dermatologic findings were assessed. RESULTS: Fifty-one individuals (29 males, 22 females, mean age: 9 years) with clinical features of Proteus syndrome had the mosaic c.49G>A, p.Glu17Lys AKT1 variant. Fifty (98%) had at least one cutaneous feature constituting current clinical diagnostic criteria, including vascular malformations in 42 (82%), epidermal nevus in 41 (80%), volar cerebriform connective tissue nevi in 34 (67%), and adipose dysregulation in 30 (59%). Forty-nine (96%) had at least one dermatologic finding not included within the diagnostic criteria, including confluent volar skin-colored to hypopigmented papules or nodules (n = 33, 65%), papules or nodules on the digits or face (n = 27, 53%), and nonlinear epidermal nevi (n = 15, 29%). Other frequently observed features include nail changes (n = 28, 55%), hyperpigmented macules (n = 27, 53%), patchy dermal hypoplasia (n = 18, 35%), gingival/oral mucosal overgrowth (n = 17, 33%), hypopigmented macules (n = 16, 31%), dental enamel changes (n = 9, 18%), acrochordons (n = 6, 12%), and lingual overgrowth (n = 4, 8%). CONCLUSIONS: The range of mucocutaneous features occurring in Proteus syndrome is broader than previously considered. These observations may assist in earlier diagnosis and management and provide novel insights regarding the pathogenesis of the condition.


Subject(s)
Nevus , Proteus Syndrome , Skin Neoplasms , Vascular Malformations , Child , Female , Humans , Male , Nevus/diagnosis , Nevus/epidemiology , Nevus/genetics , Proteus Syndrome/diagnosis , Proteus Syndrome/genetics , Retrospective Studies , Skin Neoplasms/diagnosis , Skin Neoplasms/epidemiology , Skin Neoplasms/genetics
8.
Proc Natl Acad Sci U S A ; 115(5): E944-E953, 2018 01 30.
Article in English | MEDLINE | ID: mdl-29339522

ABSTRACT

Lymphangioleiomyomatosis (LAM), a rare disease of women, is associated with cystic lung destruction resulting from the proliferation of abnormal smooth muscle-like LAM cells with mutations in the tuberous sclerosis complex (TSC) genes TSC1 and/or TSC2 The mutant genes and encoded proteins are responsible for activation of the mechanistic target of rapamycin (mTOR), which is inhibited by sirolimus (rapamycin), a drug used to treat LAM. Patients who have LAM may also be treated with bronchodilators for asthma-like symptoms due to LAM. We observed stabilization of forced expiratory volume in 1 s over time in patients receiving sirolimus and long-acting beta-agonists with short-acting rescue inhalers compared with patients receiving only sirolimus. Because beta-agonists increase cAMP and PKA activity, we investigated effects of PKA activation on the mTOR pathway. Human skin TSC2+/- fibroblasts or LAM lung cells incubated short-term with isoproterenol (beta-agonist) showed a sirolimus-independent increase in phosphorylation of S6, a downstream effector of the mTOR pathway, and increased cell growth. Cells incubated long-term with isoproterenol, which may lead to beta-adrenergic receptor desensitization, did not show increased S6 phosphorylation. Inhibition of PKA blocked the isoproterenol effect on S6 phosphorylation. Thus, activation of PKA by beta-agonists increased phospho-S6 independent of mTOR, an effect abrogated by beta-agonist-driven receptor desensitization. In agreement, retrospective clinical data from patients with LAM suggested that a combination of bronchodilators in conjunction with sirolimus may be preferable to sirolimus alone for stabilization of pulmonary function.


Subject(s)
Adrenergic beta-Agonists/pharmacology , Lymphangioleiomyomatosis/drug therapy , Lymphangioleiomyomatosis/metabolism , Tumor Suppressor Proteins/genetics , Adult , Aged , Bronchodilator Agents/pharmacology , Catalytic Domain , Cell Proliferation/drug effects , Cyclic AMP/metabolism , Cyclic AMP-Dependent Protein Kinases/metabolism , Disease Progression , Female , Fibroblasts/cytology , Fibroblasts/metabolism , Humans , Isoproterenol/pharmacology , Middle Aged , Multivariate Analysis , Phosphorylation , Respiratory Function Tests , Retrospective Studies , Signal Transduction/drug effects , Sirolimus/pharmacology , Skin/metabolism , TOR Serine-Threonine Kinases/metabolism , Tuberous Sclerosis Complex 1 Protein , Tuberous Sclerosis Complex 2 Protein , Tumor Suppressor Proteins/metabolism
9.
Genet Med ; 21(11): 2594-2604, 2019 11.
Article in English | MEDLINE | ID: mdl-31114024

ABSTRACT

PURPOSE: To determine if mosaic tuberous sclerosis complex (TSC) can be stratified into subtypes that correspond with prognosis and extent of disease. METHODS: Next-generation sequencing of skin tumor and other samples was used to identify patients with mosaic pathogenic variants in TSC1 or TSC2. Extent of disease, onset age, and family history of TSC were determined through retrospective analysis of patient records. RESULTS: The median number of disease findings and age at penetrance differed between mosaic patients with asymmetrically distributed facial angiofibromas (4 findings, 24 years, n = 7), mosaic patients with bilaterally symmetric facial angiofibromas (8 findings, 10 years, n = 12), and germline TSC patients (10 findings, 4 years, n = 29). Cutaneous and internal organ involvement positively correlated in mosaic (R = 0.62, p = 0.005), but not germline (R = -0.24, p = 0.24) TSC. Variant allele fraction (VAF) in the blood (range: 0-19%) positively correlated with the number of major features (R = 0.55, p = 0.028). Five had a TSC2 variant identified in the skin that was below detection in the blood. One of 12 children from a mosaic parent had TSC. CONCLUSION: The phenotype of mosaic TSC ranged from mild to indistinguishable from germline disease. Patients with mosaicism and asymmetric facial angiofibromas exhibited fewer findings, later onset, and lower VAF in the blood.


Subject(s)
Tuberous Sclerosis/classification , Tuberous Sclerosis/genetics , Adult , Female , High-Throughput Nucleotide Sequencing/methods , Humans , Male , Middle Aged , Mosaicism , Mutation/genetics , Phenotype , Retrospective Studies , Skin Neoplasms/genetics , Tuberous Sclerosis Complex 1 Protein/genetics , Tuberous Sclerosis Complex 2 Protein/genetics , Tumor Suppressor Proteins/genetics
10.
Genet Med ; 21(5): 1189-1198, 2019 05.
Article in English | MEDLINE | ID: mdl-30270358

ABSTRACT

PURPOSE: PIK3CA-related overgrowth spectrum (PROS) encompasses a range of debilitating conditions defined by asymmetric overgrowth caused by mosaic activating PIK3CA variants. PIK3CA encodes the p110α catalytic subunit of phosphatidylinositol-3-kinase (PI3K), a critical transducer of growth factor signaling. As mTOR mediates the growth-promoting actions of PI3K, we hypothesized that the mTOR inhibitor sirolimus would slow pathological overgrowth. METHODS: Thirty-nine participants with PROS and progressive overgrowth were enrolled into open-label studies across three centers, and results were pooled. For the primary outcome, tissue volumes at affected and unaffected sites were measured by dual energy X-ray absorptiometry during 26 weeks of untreated run-in and 26 weeks of sirolimus therapy. RESULTS: Thirty participants completed the study. Sirolimus led to a change in mean percentage total tissue volume of -7.2% (SD 16.0, p = 0.04) at affected sites, but not at unaffected sites (+1.7%, SD 11.5, p = 0.48) (n = 23 evaluable). Twenty-eight of 39 (72%) participants had ≥1 adverse event related to sirolimus of which 37% were grade 3 or 4 in severity and 7/39 (18%) participants were withdrawn consequently. CONCLUSION: This study suggests that low-dose sirolimus can modestly reduce overgrowth, but cautions that the side-effect profile is significant, mandating individualized risk-benefit evaluations for sirolimus treatment in PROS.


Subject(s)
Class I Phosphatidylinositol 3-Kinases/metabolism , Growth Disorders/drug therapy , Sirolimus/pharmacology , Abnormalities, Multiple/drug therapy , Abnormalities, Multiple/genetics , Adolescent , Adult , Aged , Child , Child, Preschool , Class I Phosphatidylinositol 3-Kinases/genetics , Female , Growth Disorders/genetics , Humans , Male , Middle Aged , Mutation , Phenotype , Phosphatidylinositol 3-Kinases/genetics , Sirolimus/metabolism , Sirolimus/therapeutic use , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolism
11.
Am J Respir Cell Mol Biol ; 58(6): 678-683, 2018 06.
Article in English | MEDLINE | ID: mdl-29406787

ABSTRACT

Lymphangioleiomyomatosis (LAM) is a multisystem disease of women, affecting lungs, kidneys, and lymphatics. It is caused by the proliferation of abnormal smooth muscle-like LAM cells, with mutations and loss of heterozygosity in the TSC1 or, more frequently, TSC2 genes. Isolated pulmonary LAM cells have been difficult to maintain in culture, and most studies of LAM lung cells involve mixtures of TSC2 wild-type and TSC2-null cells. A clonal population of LAM lung cells has not been established, making analysis of the cells challenging. Cell lines have been established from angiomyolipomas, a common manifestation of LAM, and from tumors from patients with TSC. Circulating LAM cells have also been isolated from blood and other body fluids. LAM cells may also be identified in clusters apparently derived from lymphatic vessels. Genetics, patterns of antigen expression, and signaling pathways have been studied in LAM lung tissue and in LAM cell models, although rarely all in the same study. We show here that LAM cells manifest differences in these characteristics, depending on the source investigated, suggesting further studies.


Subject(s)
Lung Neoplasms/pathology , Lymphangioleiomyomatosis/pathology , Female , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/genetics , Lymphangioleiomyomatosis/genetics , Mutation , Skin/pathology , Tumor Cells, Cultured
13.
J Am Acad Dermatol ; 78(4): 717-724, 2018 04.
Article in English | MEDLINE | ID: mdl-29258863

ABSTRACT

BACKGROUND: Fibrous cephalic plaques (FCPs) stereotypically develop on the forehead of patients with tuberous sclerosis complex (TSC). They constitute a major feature for TSC diagnosis and may present before other TSC-related cutaneous hamartomas. OBJECTIVE: To describe the clinical characteristics of FCPs in TSC. METHODS: A total of 113 patients with TSC were enrolled in an observational cohort study. Retrospective analysis of medical records and skin photography was performed. FCPs were categorized by anatomic location and size. RESULTS: FCPs were observed in 36% of patients (41 of 113). Of 62 total lesions, 58% were 1 to less than 5 cm, 13% were 5 cm or larger, and 29% were of unknown size mostly because of prior excision. The distribution of lesions was 39% on the forehead, 27% on the face (nonforehead), 3% on the neck, and 31% on the scalp. Fourteen patients had similar lesions less than 1 cm in diameter. Histopathologically, FCPs displayed dermal collagenosis, decreased elastic fibers, and features of angiofibromas or fibrofolliculomas. LIMITATIONS: Men were under-represented because the cohort was enriched for patients with TSC with lymphangioleiomyomatosis, which occurs in adult women. CONCLUSION: Two-fifths of FCPs presented on the forehead, with most of the remainder in other locations on the face and scalp. Better recognition of these lesions may lead to earlier diagnosis of TSC.


Subject(s)
Facial Dermatoses/etiology , Scalp Dermatoses/etiology , Skin Neoplasms/complications , Tuberous Sclerosis/complications , Adolescent , Child , Child, Preschool , Facial Dermatoses/pathology , Female , Humans , Infant , Male , Retrospective Studies , Scalp Dermatoses/pathology
14.
J Am Acad Dermatol ; 78(4): 725-732, 2018 04.
Article in English | MEDLINE | ID: mdl-29042227

ABSTRACT

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.


Subject(s)
Foot Diseases/etiology , Foot Diseases/pathology , Nevus/etiology , Nevus/pathology , Proteus Syndrome/complications , Skin Neoplasms/etiology , Skin Neoplasms/pathology , Adolescent , Adult , Child , Child, Preschool , Female , Humans , Infant , Male , Middle Aged , Retrospective Studies , Young Adult
17.
Am J Med Genet C Semin Med Genet ; 172(4): 402-421, 2016 12.
Article in English | MEDLINE | ID: mdl-27860216

ABSTRACT

The phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR signaling pathway plays an essential role in regulation of normal cell growth, metabolism, and survival. Somatic activating mutations in the PI3K/AKT/mTOR pathway are among the most common mutations identified in cancer, and have been shown to cause a spectrum of overgrowth syndromes including PIK3CA-Related Overgrowth Spectrum, Proteus syndrome, and brain overgrowth conditions. Clinical findings in these disorders may be isolated or multiple, including sporadic or mosaic overgrowth (adipose, skeletal, muscle, brain, vascular, or lymphatic), and skin abnormalities (including epidermal nevi, hyper-, and hypopigmented lesions), and have the potential risk of tumorigenesis. Key negative regulators of the PI3K-AKT signaling pathway include PTEN and TSC1/TSC2 and germline loss-of function mutations of these genes are established to cause PTEN Hamartoma Tumor Syndrome and Tuberous Sclerosis Complex. Mosaic forms of these conditions lead to increased activation of PI3K and mTOR at affected sites and there is phenotypic overlap between these conditions. All are associated with significant morbidity with limited options for treatment other than symptomatic therapies and surgeries. As dysregulation of the PI3K/AKT/mTOR pathway has been implicated in cancer, several small molecule inhibitors targeting different components of the PI3K/AKT/mTOR signaling pathway are under clinical investigation. The development of these therapies brings closer the prospect of targeting treatment for somatic PI3K/AKT/mTOR-related overgrowth syndromes. This review describes the clinical findings, gene function and pathogenesis of these mosaic overgrowth syndromes, and presents existing and future treatment strategies to reduce or prevent associated complications of these disorders. © 2016 Wiley Periodicals, Inc.


Subject(s)
Growth Disorders/therapy , Signal Transduction/genetics , Growth Disorders/complications , Growth Disorders/genetics , Growth Disorders/prevention & control , Humans , Mutation , Phosphatidylinositol 3-Kinase/metabolism , Proto-Oncogene Proteins c-akt/metabolism , TOR Serine-Threonine Kinases/metabolism
18.
Hum Mol Genet ; 23(8): 2023-9, 2014 Apr 15.
Article in English | MEDLINE | ID: mdl-24271014

ABSTRACT

Tuberous sclerosis complex (TSC) is characterized by the formation of tumors in multiple organs and is caused by germline mutation in one of two tumor suppressor genes, TSC1 and TSC2. As for other tumor suppressor gene syndromes, the mechanism of somatic second-hit events in TSC tumors is unknown. We grew fibroblast-like cells from 29 TSC skin tumors from 22 TSC subjects and identified germline and second-hit mutations in TSC1/TSC2 using next-generation sequencing. Eighteen of 22 (82%) subjects had a mutation identified, and 8 of the 18 (44%) subjects were mosaic with mutant allele frequencies of 0 to 19% in normal tissue DNA. Multiple tumors were available from four patients, and in each case, second-hit mutations in TSC2 were distinct indicating they arose independently. Most remarkably, 7 (50%) of the 14 somatic point mutations were CC>TT ultraviolet 'signature' mutations, never seen as a TSC germline mutation. These occurred exclusively in facial angiofibroma tumors from sun-exposed sites. These results implicate UV-induced DNA damage as a cause of second-hit mutations and development of TSC facial angiofibromas and suggest that measures to limit UV exposure in TSC children and adults should reduce the frequency and severity of these lesions.


Subject(s)
Angiofibroma/etiology , Facial Neoplasms/etiology , Mutation/genetics , Skin Neoplasms/etiology , Sunlight/adverse effects , Tuberous Sclerosis/genetics , Tumor Suppressor Proteins/genetics , Adolescent , Adult , Angiofibroma/pathology , Blotting, Western , Child , Child, Preschool , Facial Neoplasms/pathology , Female , Fibroblasts/pathology , Follow-Up Studies , High-Throughput Nucleotide Sequencing , Humans , Middle Aged , Prognosis , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Skin Neoplasms/pathology , Tuberous Sclerosis/complications , Tuberous Sclerosis/pathology , Tuberous Sclerosis Complex 1 Protein , Tuberous Sclerosis Complex 2 Protein , Young Adult
20.
J Am Acad Dermatol ; 73(5): 802-8, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26365597

ABSTRACT

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.


Subject(s)
Antibiotics, Antineoplastic/administration & dosage , Sirolimus/administration & dosage , Skin Neoplasms/drug therapy , Tuberous Sclerosis/drug therapy , Acne Vulgaris/chemically induced , Administration, Oral , Adult , Antibiotics, Antineoplastic/adverse effects , Drug Administration Schedule , Female , Humans , Middle Aged , Oral Ulcer/chemically induced , Retrospective Studies , Ribosomal Protein S6/analysis , Sirolimus/adverse effects , Treatment Outcome
SELECTION OF CITATIONS
SEARCH DETAIL