Update on Vascular Malformation Overgrowth Syndromes€¦ · · 2017-07-25©2015 MFMER | slide-1 Megha M. Tollefson, MD Associate Professor of Dermatology and Pediatrics July 27,

©2015 MFMER | slide-1

Megha M. Tollefson, MD Associate Professor of Dermatology and Pediatrics

July 27, 2017

Update on Vascular Malformation

Overgrowth Syndromes


Disclosures

• None


Vascular Malformation Overgrowth Syndromes


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


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


KTS

Pain

Cellulitis

Superficial

thrombophlebitis

DVT/PE

Bleeding

Lymphedema

Varicosities

Limb length

discrepancy

Challenge:

How to predict

who will get

what


Can we predict which patient may have more problems?

• Stain is either blotchy and widespread or geographic

JAAD 2004;51:391-8.


JAAD 2004;51:391-8.


Geographic vs “blotchy”

Geographic Blotchy

JAAD 2004;51:391-8.


Geographic vs blotchy

• Geographic stains more likely to be associated with

• Lymphatic malformations

• Leg length discrepancy

• Cellulitis

• Pain

• Recurrent bleeding and blebs


• Skin-related complications are common, affecting 3 out every 5 patients.

• Presence of LM was significantly correlated with likelihood of having a cutaneous complication.


• 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


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


©2011

MFMER |

slide-14 Sapp et al. Am J Med Gen 2007: 2944-2958.


CLOVE Syndrome

• Often previous diagnosis of Proteus syndrome or KTS

• Better prognosis than Proteus

©2011

MFMER |



CLOVE Syndrome- Ballooning overgrowth

©2011

MFMER |



©2011

MFMER |

slide-17

Sapp et al. Am J Med Gen 2007: 2944-2958.


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.


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.


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.


©2011

MFMER |

slide-21 Lee et al. JAAD 2013;69:589-94.


©2011

MFMER |

slide-22 Rucker Wright et al.. Arch Derm 2009;145(3):287-293.


Megalencephaly-Capillary Malformation

• Previous names

• Macrocephaly- CMTC

• Macrocephaly- capillary malformation

• Overgrowth present in 92%

©2011

MFMER |

slide-23


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.


©2011

MFMER |

slide-25 Martinez-Glez et al. Am J Med Gen 2010:3101-3106.


Genetic developments

©2011

MFMER |

slide-26


©2011

MFMER |

slide-27


©2011

MFMER |

slide-28


©2011

MFMER |

slide-29


• PIK3CA

• Lymphatic malformation (16/17)

• Klippel Trenaunay (19/21)

• CLOVE (31/33)

©2011

MFMER |

slide-30


GNAQ and GNA11


PROS: PIK3CA-Related Overgrowth Spectrum






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?


PIK3CA

New ISSVA Classification

• Expert group consensus

• Regrouping

• More detail

• Many new genes added in

• www.issva.org


©2011

MFMER |

slide-37

PI3K

PTEN

AKT1

mTOR

Cell growth and proliferation

Cell membrane

CLOVE

MCAP

KTS, HH-ML

SOLAMEN

BRRS

Proteus

DCMO?


More to Come

• Multi-center Genotype-Phenotype Correlation of Vascular Overgrowth Syndromes

©2011

MFMER |

slide-38


Commercial Genetic Testing

• Insurance company lack of coverage

©2011

MFMER |

slide-39


What’s new in treatment?





Topical Use


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.






• PDL + rapamycin superior

• Best photographic image score

• Lowest # vessels on histology @ 12 weeks

• **systemic absorption (0.45 ng/mL to 3.39 ng/mL)



Ivars and Redondo. JAMA Derm 2017.


Management Approach


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


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


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


Can the cellulitis be prevented?

• Good skin care

• Wash daily

• Bleach baths

• ~ once/week

• Compression

• Treat any athlete’s foot

• ?Topical sirolimus


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


Compression Therapy


33 yo M with recurrent folliculitis, cellulitis


13 yo F basketball player with recurrent knee swelling


Leg length discrepancy

• Epiphysiodesis if leg length discrepancy > 2cm

• Shoe lifts


Joint Involvement



18 yo M s/p sclerotherapy

©2011

MFMER |

slide-61


33 yo F with increasing infections, cutaneous lesions


12 yo F


Sirolimus


GI bleeding and recurrent infections


9 yo F with chronic leakage


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


Bone Health Questions

• Known overgrowth syndrome

• Bone mineral density

• DEXA

• Xtreme CT

• Mobility

• Serum endocrine factors

©2011

MFMER |

slide-68


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.


Tumor Risk

©2011

MFMER |

slide-70


Tumor Risk

• Embryonal tumor risk higher in generalized overgrowth disorders

• Benign tumor risk higher in some partial overgrowth syndromes

©2011

MFMER |

slide-71


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


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


Thank you!

Documents

Update on Vascular Malformation Overgrowth Syndromes€¦ · · 2017-07-25©2015 MFMER | slide-1 Megha M. Tollefson, MD Associate Professor of Dermatology and Pediatrics July 27,