Update on Vascular Malformation Overgrowth Syndromes
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1 Update on Vascular Malformation Overgrowth Syndromes Megha M. Tollefson, MD Associate Professor of Dermatology and Pediatrics July 27, MFMER slide-1
2 Disclosures None 2015 MFMER slide-2
3 Vascular Malformation Overgrowth Syndromes 2015 MFMER slide-3
4 Klippel-Trenaunay Syndrome (KTS) Described in 1900 by Klippel and Trenaunay Parkes-Weber in 1907 Etiology unknown until recently Persistent embryologic lateral marginal vein in up to 72% PIK3CA 2011 MFMER slide MFMER slide-4
5 KTS Triad Capillary malformation Overgrowth May be present at birth Venous varicosities or complex venolymphatic malformation Usually isolated to one extremity May not be fully evident at birth Spectrum of severity 2011 MFMER slide MFMER slide-5
6 Pain Limb length discrepa ncy Cellulitis Varicosities KTS Superfici al thrombop hlebitis Lymphedema Bleeding DVT/PE Challenge: How to predict who will get what 2015 MFMER slide-6
7 Can we predict which patient may have more problems? Stain is either blotchy and widespread or geographic JAAD 2004;51: MFMER slide-7
8 JAAD 2004;51: MFMER slide-8
9 Geographic vs blotchy Geographic Blotchy JAAD 2004;51: MFMER slide-9
10 Geographic vs blotchy Geographic stains more likely to be associated with Lymphatic malformations Leg length discrepancy Cellulitis Pain Recurrent bleeding and blebs 2015 MFMER slide-10
11 Skin-related complications are common, affecting 3 out every 5 patients. Presence of LM was significantly correlated with likelihood of having a cutaneous complication MFMER slide-11
12 410 patients Skin complications in 69% Cellulitis, ulceration, capillary malformation complications Buttock, perineum, genitalia involvement Foot involvement Lymphatic malformation Heme complications in 39% Orthopedic complications in 64% Superficial thrombophlebitis DVT/PE Limb length discrepancy, scoliosis, bone health Genitourinary complications in 9% Bleeding 2015 MFMER slide-12
13 CLOVE Syndrome- Common features Congenital Lipomatosis, Overgrowth, Vascular Malformations, Epidermal Nevi Linear epidermal nevus Lipomas Vascular malformations Broad feet, splaying of digits Scoliosis 2011 MFMER slide MFMER slide-13
14 Sapp et al. Am J Med Gen 2007: MFMER slide MFMER slide-14
15 CLOVE Syndrome Often previous diagnosis of Proteus syndrome or KTS Better prognosis than Proteus Sapp et al. Am J Med Gen 2007: MFMER slide MFMER slide-15
16 CLOVE Syndrome- Ballooning overgrowth Sapp et al. Am J Med Gen 2007: MFMER slide MFMER slide-16
17 Sapp et al. Am J Med Gen 2007: MFMER slide MFMER slide-17
18 CLOVE Syndrome Normal bony architecture Severe scoliosis Splayed toes Sapp et al. Am J Med Gen 2007: , Gucev et al Am J Med Gen 2008: MFMER slide MFMER slide-18
19 CLOVE Syndrome- Dysregulated adipose tissue Lipomas Regional lipohypoplasia Sapp et al. Am J Med Gen 2007: , Gucev et al Am J Med Gen 2008: MFMER slide MFMER slide-19
20 Diffuse capillary malformation with overgrowth (DCMO) Capillary malformation May lighten with time Soft tissue and/or bony overgrowth Leg length discrepancy in 55% 1 extremity most common True HH in 11% More diffuse staining No further progression but may not be apparent at birth No tumors in 73 patients Digital anomalies in 30% Lee et al. JAAD 2013;69: MFMER slide MFMER slide-20
21 Lee et al. JAAD 2013;69: MFMER slide MFMER slide-21
22 Rucker Wright et al.. Arch Derm 2009;145(3): MFMER slide MFMER slide-22
23 Megalencephaly-Capillary Malformation Previous names Macrocephaly- CMTC Macrocephaly- capillary malformation Overgrowth present in 92% 2011 MFMER slide MFMER slide-23
24 Megalencephaly-capillary malformation Macrocephaly/megalencephaly (>95%) Cortical brain malformations Developmental delay (85%) Cutaneous capillary malformations Reticulate/confluent PWS ~60% also present on lip, philtrum, or glabella May fade Syndactyly Wilms in 2/112 Martinez-Glez et al. Am J Med Gen 2010: MFMER slide MFMER slide-24
25 Martinez-Glez et al. Am J Med Gen 2010: MFMER slide MFMER slide-25
26 Genetic developments 2011 MFMER slide MFMER slide-26
27 2011 MFMER slide MFMER slide-27
28 2011 MFMER slide MFMER slide-28
29 2011 MFMER slide MFMER slide-29
30 PIK3CA Lymphatic malformation (16/17) Klippel Trenaunay (19/21) CLOVE (31/33) 2011 MFMER slide MFMER slide-30
31 GNAQ and GNA MFMER slide-31
32 PROS: PIK3CA-Related Overgrowth Spectrum 2015 MFMER slide-32
33 PROS: PIK3CA-Related Overgrowth Spectrum 2015 MFMER slide-33
34 PROS: PIK3CA-Related Overgrowth Spectrum 2015 MFMER slide-34
35 PROS Clinical Features Overgrowth Lower extremities most common Asymmetric, disproportionate, progressive Dysregulation of adipose tissue Vascular malformations Syndactyly Genitourinary abnormalities Macrocephaly Challenge: need for tumor surveillance? 2015 MFMER slide-35
36 New ISSVA Classification Expert group consensus Regrouping More detail Many new genes added in PIK3CA 2015 MFMER slide-36
37 Cell membrane CLOVE MCAP KTS, HH-ML PI3K SOLAMEN BRRS PTEN Proteus AKT1 mtor DCMO? Cell growth and proliferation 2011 MFMER slide MFMER slide-37
38 More to Come Multi-center Genotype- Phenotype Correlation of Vascular Overgrowth Syndromes 2011 MFMER slide MFMER slide-38
39 Commercial Genetic Testing Insurance company lack of coverage 2011 MFMER slide MFMER slide-39
40 What s new in treatment? 2015 MFMER slide-40
41 2015 MFMER slide-41
42 2015 MFMER slide-42
43 2015 MFMER slide-43
44 Topical Use 2015 MFMER slide-44
45 Topical Rapamycin for PWS in SWS Phase 2, RCT, double-blind, intra-individual trial 23 adult patients with SWS and facial PWS Interventions in each patient Placebo PDL + placebo Rapamycin PDL + rapamycin Clinical and histologic responses Marques et al. JAAD 2015;72: MFMER slide-45
46 Topical Rapamycin for PWS in SWS Marques et al. JAAD 2015;72: MFMER slide-46
47 Topical Rapamycin for PWS in SWS PDL + rapamycin superior Best photographic image score Lowest # vessels on 12 weeks **systemic absorption (0.45 ng/ml to 3.39 ng/ml) Marques et al. JAAD 2015;72: MFMER slide-47
48 Ivars and Redondo. JAMA Derm MFMER slide-48
49 Management Approach 2015 MFMER slide-49
50 Diagnostic Radiology Interventional Radiology Orthopedic Surgery Physical Medicine Lymphedema PT Urology Gastroenterology Hematology Genetics Pain Clinic General Surgery Plastic Surgery ENT Varicosities Limb length discrepa ncy Pain KTS Cellulitis Superfici al thrombop hlebitis Lymphedema DVT/PE Bleeding 2015 MFMER slide-50
51 Varicosities 80% symptom improvement with sclerotherapy Removal of symptomatic varicosities If functioning deep venous system 50% recurrence Challenge- Marginal vein ablation? 2011 MFMER slide MFMER slide-51
52 Cellulitis Fluid pools, especially in affected legs Leads to impaired skin integrity Drainage of blebs and cutaneous lymphatic malformations Can result in cellulitis of the skin Redness Warmth Pain 2015 MFMER slide-52
53 Can the cellulitis be prevented? Good skin care Wash daily Bleach baths ~ once/week Compression Treat any athlete s foot?topical sirolimus 2015 MFMER slide-53
54 Compression Pearls Proper fit Proper coverage Ensure areas do not cut in to malformations Thin foam Medical type lamb s wool Mistake is more commonly too much pressure, not too little pressure 2015 MFMER slide-54
55 Compression Therapy 2015 MFMER slide-55
56 33 yo M with recurrent folliculitis, cellulitis 2015 MFMER slide-56
57 13 yo F basketball player with recurrent knee swelling 2015 MFMER slide-57
58 Leg length discrepancy Epiphysiodesis if leg length discrepancy > 2cm Shoe lifts 2015 MFMER slide-58
59 Joint Involvement 2015 MFMER slide-59
60 2015 MFMER slide-60
61 18 yo M s/p sclerotherapy 2011 MFMER slide MFMER slide-61
62 33 yo F with increasing infections, cutaneous lesions 2015 MFMER slide-62
63 12 yo F 2015 MFMER slide-63
64 Sirolimus 2015 MFMER slide-64
65 GI bleeding and recurrent infections 2015 MFMER slide-65
66 9 yo F with chronic leakage 2015 MFMER slide-66
67 Challenges with sirolimus How long to leave patients on it? Long-term side effects Adjuvant use in surgery More directed treatments? One size does not fit all Risk of systemic absorption in topical use 2015 MFMER slide-67
68 Bone Health Questions Known overgrowth syndrome Bone mineral density DEXA Xtreme CT Mobility Serum endocrine factors 2011 MFMER slide MFMER slide-68
69 Quality of Life in KTS 78 Dutch Patients QoL lower than general Dutch population Also lower than other chronic medical conditions Worse in those with Pulmonary embolism Gait disturbance Adult males Oduber et al. JPRAS 20010;63: MFMER slide MFMER slide-69
70 Tumor Risk 2011 MFMER slide MFMER slide-70
71 Tumor Risk Embryonal tumor risk higher in generalized overgrowth disorders Benign tumor risk higher in some partial overgrowth syndromes 2011 MFMER slide MFMER slide-71
72 Suggested Screening Syndrome Malignancy Screening Beckwith- Wiedemann SOLAMEN PTEN Hamartoma/ BRR Embryonal tumors~8% Breast, thyroid, endometrial Breast, thyroid, endometrial KTS None None HHML Proteus Embryonal tumors? Mostly benign tumors CLOVE Unknown Unknown Abdominal US q3 months Cowden/PTEN hamargoma screening (next slide) Cowden/PTEN hamartoma screening (next slide) Abdominal US q3-6 months until age 8? Abdominal US q3-6 months until age 20 M-CM Wilms sl increase Abdominal US q3-6 months until age 8 DCMO Embryonal tumors if true HH Abdominal US q3-6 months until age 8 if total hemihypertrophy 2011 MFMER slide MFMER slide-72
73 Summary Exciting time for vascular anomalies, especially overgrowth syndromes Updated classification starting to reflect genetic findings New systemic treatments for malformations Still many unanswered questions 2015 MFMER slide-73
74 Thank you! 2015 MFMER slide-74
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