The Classification of Capillary Malformations

The classification of capillary malformations

Dubrovnik 3 May 2019

Rudolf Happle Department of Dermatology University of Freiburg Germany

Background::

The unsuitable classification of the International Society for the Study of Vascular Anomalies (ISSVA) The unsuitable classification of the ISSVA

Capillary malformation Capillary malformation Capillary malformation

Capillary malformation Capillary malformation

Vascular Anomalies Classification: Recommendations From the International Society for the Study of Vascular Anomalies Wassef M et al and ISSVA Board and Scientific Committee: Pediatrics 2015

Klippel-Trenaunay syndrome: CM + VM +/− LM + limb overgrowth Parkes-Weber syndrome: CM + AVF + limb overgrowth Servelle-Martorell syndrome: limb VM + bone undergrowth Sturge-Weber syndrome: facial + leptomeningeal CM + ocular anomalies +/− bone and/or soft tissue overgrowth Limb CM + congenital nonprogressive limb hypertrophy Maffucci syndrome: VM +/− spindle cell hemangioma + enchondroma Macrocephaly-CM (M-CM)/megalencephaly-CM-polymicrogyria (MCAP) Microcephaly-CM (MICCAP) CLOVES syndrome: LM + VM + CM +/− AVM + lipomatous overgrowth Proteus syndrome: CM, VM and/or LM + asymmetric somatic overgrowth Bannayan-Riley-Ruvalcaba syndrome: AVM + VM + macrocephaly, lipomatous overgrowth Approved in Amsterdam, May 2018

For pediatric dermatologists, this classification is useless!

http://www.issva.org/classification All of these capillary nevi may occur without any extracutaneous abnormality! Nevus flammeus Nevus roseus Rhodoid nevus

Nevus vascularis mixtus Segmental angioma serpiginosum

1 Nevus flammeus 1 Nevus flammeus

GNAQ Shirley MD et al: N Engl J Med 2013

Nevus flammeus and Sturge-Weber syndrome are G-protein disorders

G proteins control the cellular signal transduction

Do facial nevi flammei reflect the trigeminal innervation?

No! Do facial nevi flammei reflect the trigeminal innervation?

Authors who still believe Authors who argue in this concept against the concept

Most authors of chapters Alexander GL: Handbook of in textbooks Clinical Neurology 1972 Happle R: Exp Dermatol 2006

Happle R: Mosaicism in Human Skin 2014

Dutkiewicz AS et al: J Am Acad Dermatol 2015 Apparently, nevus flammeus is arranged in a flag-like (checkerboard) pattern

Tomi Ungerer (1931-2019)

Torchia D et al: Vissers W et al: Int J Dermatol 2013 Eur J Dermatol 2003

Epilepsy surgery in Sturge-Weber syndrome Epilepsy surgery in Sturge-Weber syndrome: Lobotomy of a posterior quadrant is preferable to lobectomy

8/10 patients became free from seizures

Postoperative MRI

Line of disconnection:

Scheme of disconnection Sugano H et al: Epilepsia 2014 Thomas SG et al: Int J Pediatr 2012 Hemispherotomy is preferable to hemispherectomy

Axial scan one year after hemispherotomy

Giordano F et al: Childs Nerv Syst 2015

Liu X et al: SpringerPlus 2016 De Palma L et al: Epilepsy Behav 2019

Port-wine nevus of the Proteus type

AKT1

Thanks to Dr. Sigrid Tinschert, Berlin, Germany 2 3

Port-wine nevus Port-wine nevus of the Proteus type of the CLOVES type

AKT1 PIK3CA

Thanks to Gucev ZS et al: Dr. Sigrid Tinschert, Am J Med Genet part A Berlin, Germany 2008

4 Nevus roseus Nevus flammeus versus Nevus roseus

Thanks to the late Dr. Urs W. Schnyder, Zurich

Happle R: Eur J Dermatol 2005 Phacomatosis spilorosea: Macular nevus spilus combined with a nevus roseus (and never with a nevus flammeus!)

Jordaan HF, Happle R: Happle R: Fink C et al: Br J Dermatol 2008 J Eur Acad Dermatol Venereol J Eur Acad Dermatol Venereol 2015 2016 Phacomatosis cesioflammea Phacomatosis spilorosea

GNAQ PTPN11* GNA11

* Will be presented tomorrow Thomas AC et al: by Dr. Satyamaanasa Polubothu J Invest Dermatol 2016 at 8:30 hrs in Elafiti Hall II !

5 6

Cutis marmorata Reticular capillary telangiectatica congenita nevus

Cause is unknown, so far Postzygotic PIK3CA mutation Rivière JB et al: Nat Genet 2012

PROS (PIK3CA-Related Overgrowth Spectrum) Reticular capillary nevus- megalencephaly syndrome („M-CAP“)

Megalencephaly Polymicrogyria Ventriculomegaly

Mirzaa GM et al: Am J Med Genet 2012 Reticular capillary nevus

Gonzalez ME et al: Lee MS et al: Pediatr Dermatol 2009 J Am Acad Dermatol 2013

7 8 9

Nevus Nevus vascularis Angiokeratoma anemicus mixtus circumscriptum

? ?

Hamm H, Happle R: Hautarzt 1986

10 Rhodoid nevus

RASA1 (Eerola et al. 2003) EPHB4 (Yu et al. 2017; Amyere M et al. 2017)

Thanks to Dr. Regina Fölster-Holst, Thanks to Dr. Antonio Torrelo, Thanks to Kiel, Germany Madrid, Spain Dr. Cornelia Seitz, Göttingen, Germany 10 Rhodoid nevus

RASA1 (Eerola et al. 2003) EPHB4 (Yu et al. 2017; Amyere M et al. 2017)

Thanks to Dr. Regina Fölster-Holst, Thanks to Dr. Antonio Torrelo, Kiel, Germany Madrid, Spain

In this autosomal dominant trait, AVM is a type 2

segmental manifestation that occurs rather rarely. Gandon C et al: Hence, „CM-AVM“ is a misleading term. Pediatr Dermatol 2016

11 12 Segmental angioma serpiginosum Midfacial port-wine stain of the PROS type

? Chen WC et al: Dermatology 2006 Krämer D et al: Int J Dermatol 2016

13 14 15 Unilateral punctate Unilateral nevoid Carter-Mirzaa macules telangiectasia telangiectasia, patchy type

STAMPB Grimaldi M et al: ? McDonell LM et al: Nat Genet 2013 ? Acta Derm Venereol 2001

Capillary non-nevi Capillary non-nevi

16 17 18 Autosomal dominant Teleangiectasia Fabry disease angiokeratoma corporis diffusum haemorrhagica hereditaria

ENG; GLA ? HHT2; ALK1 Zampetti A et al: Calzavara-Pinton PG et al: Bedford J et al: Br J Dermatol 2012 Arch Dermatol 1995 N Z Med J 2013

Hereditary angioma serpiginosum

Marriott PT et al: Br J Dermatol 1975 ?

Capillary non-nevi

20 Salmon patch

„Unna‘s nevus“ „Nevus simplex“ „Median nevus flammeus“

Juern AM et al: J Am Acad Dermatol 2010

20 different capillary malformations

Capillary nevi

• Naevus flammeus • Carter-Mirzaa macules • Port-wine nevus of the Proteus type • Unilateral punctate telangiectasia • Port-wine nevus of the CLOVES type • Unilateral nevoid telangiectasia, patchy type (PROS) • Nevus roseus • Cutis marmorata telangiectatica • Reticular capillary nevus (PROS) Capillary non-nevi • Nevus anemicus • Salmon patch • Nevus vascularis mixtus • Rendu-Osler disease • Angiokeratoma circumscriptum • Fabry disease • Rhodoid nevus • Autosomal dominant angiokeratoma • Segmental angioma serpiginosum corporis diffusum • Hereditary angioma serpiginosum • Midfacial port-wine patch (PROS) 20 different capillary malformations

Capillary nevi

Different capillary nevi:

Rhodoid nevus

Nevus flammeus Nevus roseus

„Capillary malformation“ Nevus vascularis Nevus anemicus mixtus is an

Port-wine nevus asylum ignorantiae of the CLOVES type Reticular Happle R: J Eur Acad Dermatol Venereol 2015 capillary nevus

Port-wine nevus Cutis marmorata Angiokeratoma Segmental angioma telangiectatica congenita of the Proteus type circumscriptum serpiginosum

Thank you!