©2015 MFMER | slide-1
Megha M. Tollefson, MD Associate Professor of Dermatology and Pediatrics
July 27, 2017
Update on Vascular Malformation
Overgrowth Syndromes
©2015 MFMER | slide-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-4
©2015 MFMER | slide-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-5
©2015 MFMER | slide-6
KTS
Pain
Cellulitis
Superficial
thrombophlebitis
DVT/PE
Bleeding
Lymphedema
Varicosities
Limb length
discrepancy
Challenge:
How to predict
who will get
what
©2015 MFMER | slide-7
Can we predict which patient may have more problems?
• Stain is either blotchy and widespread or geographic
JAAD 2004;51:391-8.
©2015 MFMER | slide-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-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.
©2015 MFMER | slide-12
• Cellulitis, ulceration, capillary malformation complications
Skin complications
in 69%
• Superficial thrombophlebitis DVT/PE
Heme complications
in 39%
• Limb length discrepancy, scoliosis, bone health
Orthopedic complications
in 64%
• Bleeding Genitourinary complications
in 9%
410 patients
Lymphatic malformation
Foot involvement
Buttock, perineum, genitalia
involvement
©2015 MFMER | slide-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-13
©2015 MFMER | slide-15
CLOVE Syndrome
• Often previous diagnosis of Proteus syndrome or KTS
• Better prognosis than Proteus
©2011
MFMER |
slide-15 Sapp et al. Am J Med Gen 2007: 2944-2958.
©2015 MFMER | slide-16
CLOVE Syndrome- Ballooning overgrowth
©2011
MFMER |
slide-16 Sapp et al. Am J Med Gen 2007: 2944-2958.
©2015 MFMER | slide-18
CLOVE Syndrome
• Normal bony architecture
• Severe scoliosis
• Splayed toes
©2011
MFMER |
slide-18 Sapp et al. Am J Med Gen 2007: 2944-2958., Gucev et al Am J Med Gen 2008:2688-2690.
©2015 MFMER | slide-19
CLOVE Syndrome- Dysregulated adipose tissue
• Lipomas
• Regional lipohypoplasia
©2011
MFMER |
slide-19 Sapp et al. Am J Med Gen 2007: 2944-2958., Gucev et al Am J Med Gen 2008:2688-2690.
©2015 MFMER | slide-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% ©2011
MFMER |
slide-20 Lee et al. JAAD 2013;69:589-94.
©2015 MFMER | slide-23
Megalencephaly-Capillary Malformation
• Previous names
• Macrocephaly- CMTC
• Macrocephaly- capillary malformation
• Overgrowth present in 92%
©2011
MFMER |
slide-23
©2015 MFMER | slide-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
©2011
MFMER |
slide-24 Martinez-Glez et al. Am J Med Gen 2010:3101-3106.
©2015 MFMER | slide-30
• PIK3CA
• Lymphatic malformation (16/17)
• Klippel Trenaunay (19/21)
• CLOVE (31/33)
©2011
MFMER |
slide-30
©2015 MFMER | slide-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-36
PIK3CA
New ISSVA Classification
• Expert group consensus
• Regrouping
• More detail
• Many new genes added in
• www.issva.org
©2015 MFMER | slide-37
©2011
MFMER |
slide-37
PI3K
PTEN
AKT1
mTOR
Cell growth and proliferation
Cell membrane
CLOVE
MCAP
KTS, HH-ML
SOLAMEN
BRRS
Proteus
DCMO?
©2015 MFMER | slide-38
More to Come
• Multi-center Genotype-Phenotype Correlation of Vascular Overgrowth Syndromes
©2011
MFMER |
slide-38
©2015 MFMER | slide-39
Commercial Genetic Testing
• Insurance company lack of coverage
©2011
MFMER |
slide-39
©2015 MFMER | slide-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;72:151-8.
©2015 MFMER | slide-47
Topical Rapamycin for PWS in SWS
• PDL + rapamycin superior
• Best photographic image score
• Lowest # vessels on histology @ 12 weeks
• **systemic absorption (0.45 ng/mL to 3.39 ng/mL)
Marques et al. JAAD 2015;72:151-8.
©2015 MFMER | slide-50
KTS
Pain
Cellulitis
Superficial
thrombophlebitis
DVT/PE
Bleeding
Lymphedema
Varicosities
Limb length
discrepancy
Diagnostic Radiology
Interventional Radiology
Orthopedic Surgery
Physical Medicine
Lymphedema PT
Urology
Gastroenterology
Hematology
Genetics
Pain Clinic
General Surgery
Plastic Surgery
ENT
©2015 MFMER | slide-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-51
©2015 MFMER | slide-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-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-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-58
Leg length discrepancy
• Epiphysiodesis if leg length discrepancy > 2cm
• Shoe lifts
©2015 MFMER | slide-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-68
Bone Health Questions
• Known overgrowth syndrome
• Bone mineral density
• DEXA
• Xtreme CT
• Mobility
• Serum endocrine factors
©2011
MFMER |
slide-68
©2015 MFMER | slide-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
• www.k-t.org
©2011
MFMER |
slide-69
Oduber et al. JPRAS 20010;63:603-609.
©2015 MFMER | slide-71
Tumor Risk
• Embryonal tumor risk higher in generalized overgrowth disorders
• Benign tumor risk higher in some partial overgrowth syndromes
©2011
MFMER |
slide-71
©2015 MFMER | slide-72
Suggested Screening
©2011
MFMER |
slide-72
Syndrome Malignancy Screening
Beckwith-
Wiedemann
Embryonal
tumors~8%
Abdominal US q3 months
SOLAMEN Breast, thyroid,
endometrial
Cowden/PTEN hamargoma screening (next
slide)
PTEN
Hamartoma/
BRR
Breast, thyroid,
endometrial
Cowden/PTEN hamartoma screening (next
slide)
KTS None None
HHML Embryonal
tumors?
Abdominal US q3-6 months until age 8?
Proteus Mostly benign
tumors
Abdominal US q3-6 months until age 20
CLOVE Unknown Unknown
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
©2015 MFMER | slide-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