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Eulalia Baselga-Enfermedades raras de la piel
The document discusses various vascular malformations and overgrowth syndromes such as capillary malformations, proteus syndrome, Klippel-Trenaunay syndrome, and others, highlighting their classifications, associated genetic mutations, and clinical implications. It emphasizes the role of somatic mutations in the PI3K-AKT pathway in these conditions, which can lead to significant variations in presentation and severity. Additionally, it covers diagnostic challenges and potential treatments, including pharmacological options targeting these pathways.
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Eulalia Baselga-Enfermedades raras de la piel
- 1. Capillary malformations and overgrowth EulaliaBaselga Barcelona, Spain
- 4. –Capillary – Venous – Lymphatic –Arteriovenous – Combination (CV, CVL) Vascular Malform. Classification (ISSVA, 1996) Tumors • Infantile Hemangioma • Other vascular tumors
- 6. Nevus simplex /Salmon patch
- 7. “Solid” capillary malfper se
- 8. “Solid” capillary malfper se
- 9. Non- Random distribution/Non-random risk of association glaucoma/leptomeningeal angiomatosis
- 10. What causes SturgeWeber Sd? “It has been hypothesized that somatic mosaic mutations disrupting vascular development cause both the Sturge–Weber syndrome and port-wine stains, and the severity and extent of presentation are determined by the developmental time point at which the mutations occurred.” Comi A Happle R (1987)
- 11. • Somatic activatingmutation in GNAQ in CR 9 – In affected skin and brain tissue SWS (9pt) – In affected skin of nonsyndromic PWS – Not detected in normal skin or brain from normal controls 2013 May 23 368(21):1971-9.
- 12. Capillary malformation /PWS ??? Happle’s Definition 'Nevi are visible, circumscribed, long-lasting lesions of the skin or the neighboring mucosa, reflecting genetic mosaicism “. GNAQ mutation Nevus flammeus/ Nevus vascularis
- 13. “Reticulated” , “blotchy” cm
- 14. “RASA-1 Type” Capillarymalformations/Pre AVM
- 16.
- 17. Telangiectasia Spider Benign hereditary oressential Nevoid telangiectasia
- 18. Rendu-Osler ( Hereditaryhemorrhagic T)
- 21. Also referred as“KTS”….
- 22.
- 23.
- 25. •Megalencephaly • Digit abnormalities •Reticulated check board CM • Progressive, less distortive • Lipomatous masses • Epidermal nevus • Scoliosis/spinal AVM • Growth Highly distortive •Cerebriform soles •Combined CLM •Venous Anomalies •Less progressive growth •Risk thromboembolisim KTS Proteus MCAPCLOVES DCMO Type 2 Cowden ; PTHS
- 26. “true or polar”KTS • Geographic CM/CLM • Progressive limb overgrowth • Underlying venous anomalies • Risk of Thromboembolism
- 27. Diffuse capillary malformationwith overgrowth (DCMO) Lee et al. JAAD 2013;69:589-94
- 28. Diffuse capillary malformationwith overgrowth (DCMO) Lee et al. JAAD 2013;69:589-94
- 29. Diffuse capillary malformationwith overgrowth (DCMO) Lee et al. JAAD 2013;69:589-94/ Limb CM + Congenital non progressive limb hypertrophy ( ISSVA 2014) • All reticulated or a combination of reticulated/ solid PWS • Proportionate soft tissue overgrowth – mainly leg discrepancy – some true hemihypertrophy ( those with very extensive CM) • Digital abnormalities: – Sandal gap – Cutaneous Syndactily – Macrodactily
- 30.
- 31. Courtesy of AnaMartin, MD Megalencephaly CM syndrome
- 32. MCAP Macrocephaly-Capillary MalformationSd • Reticulate capillary malformation – Facial lesion – Mosaic pattern • Hypotonia • Doughy skin • Progressive macrocephaly • Assymetric overgrowth • Digit abnormalities • Sporadic occurrence • Lack of familial transmission
- 33.
- 35. Cerebriform soles inProteus syndrome
- 36. Proteus syndrome N EnglJ Med. 2011 August 18
- 37. Cloves Syndrome Congenital LipomatousOvergrowth with Vascular, Epidermal and Skeletal/Spinal Abnormalities Kyle C. Kurek et al. 2012
- 39. What is yourdiagnosis: a. Cloves b. Proteus c. KTS d. DCMO e. Proteus-like syndrome
- 41. Baselga E, Lopez-GutierrezJC, Martin A, Redondo P. Atlas Clínico
- 42. •Megalencephaly • Digit abnormalities • Reticulated checkboard CM • Progressive, less distortive • Lipomatous masses • Epidermal nevus • Scoliosis/spinal AVM • Growth Highly distortive •Cerebreform soles •Combined CLM •Venous Anomalies •Less progressive growth •Risk thromboemb olisim KTS Proteus MCAPCLOVES DCMO Type 2 Cowden ; PTHS
- 43. Vascular overgrowth syndromes Vascular malformations Digital abnormalities Overgrowth: Fat, Musle, Bone,CNS Epidermal Nevus Cancer risk Sporadic Mosaic distribution Progressive Growth
- 44. Happle 1986 Proteussyndrome represented a dominant lethal gene surviving by somatic mosaicism.
- 45. Lindhurst et al.A mosaic Activating mutation in AKT1 in Proteus Syndrome. N Eng J Med 2011 Youssefian L, JID 2015
- 46. Maria Garzon, MDBeth Drolet, MD Spectrum
- 47.
- 48. MCAP (Lindhurst etal, 2011) • Somatic/postzygotic mosaicism – Not found in DNA extracted from blood – Found only in affected tissue • Activating mutations • Three core components of the phosphatidylinositol 3-kinase (PI3K)- AKT pathway – AKT3- – PIK3R2 – PIK3CA
- 49. Mosaic overgrowth withfibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA. Lindhurst et al Nature Genetics 2012 Somatic gain-of function mutations in PIK3CA in patients with macrodactIly Rios et al Hum Molecular Genetics 2013 De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes Riviere et al Nature Genetics 2012 A Mosaic Activating Mutation in AKT1 Associated with the Proteus Syndrome Lindhurst et al N Engl J Med 2011 De Novo somatic mutations in components of PI3K-AKT3-mTOR pathway cause hemimegalencephaly Lee et al Nature Genetics 2012 Somatic Mosaic Activating Mutations in PIK3CA Cause CLOVES SyndromeAm J Hum Gen 2012 Kurek et al Pik3Ca Related Overgrow Spectrum
- 50. P PIP 2 **AK T PIP 3 mTOR P P P P P P PP *PTEN PDK P mTOR 1 PIK3K mTOR 2 P ik3Ca Related O vergrow S pectrum PTEN- hamartoma Tumor -PROTEUS LIKE (SOLAMEN) -COWDEN -BRR -PROTEUS -MCAP -KT - HHML/FAH -CLOVES
- 52. WHY so manyclinical differences • Tissue distribution of the mutation is different • The level of the mutation is different • The class of mutations
- 53. Courtesy of DrDrolet CLOVE spectrum-high level of PIK3CA mutant cells
- 54. CLOVE spectrum-low levelof PIK3CA mutant cells
- 55. • Deep NGSmethods for PIK3 CA mutation • 241 DNA samples from 181 individual with brain and body overgrowth Mirzaa G et al. JCI Insight. 2016 Jun 16;1(9). pii: e87623.
- 57.
- 58. • 29 differentmutations ( 41 with literature review) – 27 recurrent mutations: • 3 hot spot mutations (p.Glu542Lys, p.Glu545Lys, and p.His1047Arg) highly recurrent • 2 “ non hot spot “p.Glu726Lys and p.Gly914Arg – Most Gain of Function Mutation – Oncogenic mutations described in COSMIC
- 60. 3 main gropus(clinical/molecular) • Broad mutational spectrum • More tan 20 milder GOF mutations MCAP •Hot spot Mutations of cancerCLOVES, dysplastic megalencephaly • most often hotspot mutationsIntermediate Phenotypes
- 61. MCAP CLOVES • Headand brain overgrowth presenting sign • Faint reticulated capillary malformation • Body overgroth minimal • Lipomas rare • Lymphatic malformation rare • Head and brain normal • Capillary stain darker, well demarcated • Overgrowth segmental, severe, progressive • Epidermal nevus • Lipomas common • Lymphatic malformation common
- 62. Is genetic testingthe answer ?
- 63. Is genetic testingthe answer ? • Diagnosis of somatic mosaicism may be difficult due to sampling of erroneus tissue • Various mutation in any given gene • Various levels of postzygotic mutations • More widespread the skin larger number of cells with mutation • Various distribution of said mutations
- 64. Vascular Lesions &Overgrowth General Approach • Most cases overgrowth is already present at birth • Follow-up and prognosis depends on degree of involvement • Screening should be dictated by affected areas and signs
- 66. Physical exam Lenghtdiscrepancies Head circunference Digital abnormalities Scoliosis Varicosities Check for epidermal nevus Check for cerebriform soles
- 67. What to Worry/ What to screen • Lenght abnormalitiesLower limb • Cranial MRI: • Megalencephaly; ventriculomegaly, Megalencephaly progressive macrocephaly • D- dimers/ fibrinogen • Consider prophylactic heparin at risk Large venous malform Intravascular coagulopathy Pulmonary embolism • Plain RX if scoliosis • Basal Whole body MRI if truncal overgrowth Spinal involvement: lipomas, NF, spinal AVMs, tethered • Renal ultrasound evey 3 monts until 8 years of ageCancer risk
- 68. General Approach CM +overgrowth • Limb lengths • Renal ultrasound • Prognosis is good
- 69. CM+ Leg discrepancy+ Syndactily Limb lengths/ RX at 1 y.o Renal ultrasound Prognosis is good
- 70. General approach: reticulatedCM & overgrowth Limb lengths/ RX at 1 y.o Renal ultrasound Check macrocephaly DCMO: good prognosis MCAP: prognosis more variable, Head MRI
- 71. Geographic CM +Overgrowth Limb lengths Chack varicosities Check D-dimers/ fibrinogen Prognosis depends on venous anomalies
- 72. CM + Hemihipertrophy+ digitalabnormalities • Limb lengths • Look for epidermal nevus • Serial head circumference • Consider screening MRI (Cranial/ spinal) • Renal ultrasound • Follow yearly
- 73. PIK3CA mutations • Drivescancers ( oncogenic mutation) • Somatic mosaicism responsable for developmental/overgrowth disorders And….
- 74. Big brother knowsbest… PIK3CA Sprr2f-Cre - No lymphatic markers - Elevated D- dimers - Human EC transduced, aberrant vessel formation
- 75.
- 76. 61% of casesTIE2 mutations
- 78. The Evolving Landscapeof Genomic Alterations in VM March 30, 2016 Vol 8: 332 MSK-IMPACT assay ( 341 cancer-related genes)
- 80. Rapamycin for thetreatment of Venous malformation PIK3 inhibitors
- 81. 1 2 3 0 50 100 150 200 250 300 350 400 VMvolume(%) Vehicle FreeBYL719 Soluble BYL719 WeekPre-treatment VM can be treated topically using specific formulations of PI3K inhibitors
- 82. • In vitro,Pt fibroblast showed overactivation of PI3K/AKT/mTOR pathway was abrogated by pharmacological inhibition of PI3K • Growth factor-independent proliferation of Pt’s fibroblast was decreased by the pharmacological blockade of PI3K
- 83. Summary • Vascular lesionsoften associated with overgrowth • De-novo, postzygotic mutations in PIK3-AKT pathway mutations • Each patient is unique, • Variation dictated by; – Gene mutated, functional impairment , level of mutated cells, distribution of mutated cells • New treatment – PI3K/AKT/mTOR inhibitors
- 84. Thanks to Manypeople