Vascular Anomalies + HHTs

Vascular anomaly presence

• characterized by endothelial proliferation. Vascular malformations are structural errors with no proliferation, and they don’t regress.

• Most of these conditions are caused by somatic (mosaic) variants, with a few germline exceptions. Somatic cases are usually sporadic with low recurrence risk, and testing often needs affected tissue because blood can be negative.

Infantile Hemangiomas

• absent at birth but then proliferates

• GLUT-1 positive

• Large segmental IH should prompt PHACES workup

GLUT1 Role in Proliferation of Hemangiomas

• Diagnostic immunohistochemical marker for infantile hemangiomas

PHACES

• Posterior fossa anomalies,

• Hemangioma, Arterial anomalies,

• Cardiac defects,

• Eye anomalies,

• Sternal defects/Supraumbilical raphe.

• It is diagnosed by a large facial/head hemangioma plus major or minor criteria.

Congenital hemangiomas (RICH/NICH)

fully formed at birth and GLUT-1 negative.

They are caused by somatic GNAQ/GNA11 variants.

Port wine stain

usually sporadic.

A PWS in the V1 (ophthalmic) distribution raises concern for Sturge-Weber.

Sturge-Weber

• facial capillary malformation

• leptomeningeal malformation

• refractory seizures

• glaucoma/buphthalmos

• developmental delay

  • It is caused by a somatic GNAQ variant

Capillary Malformation-Arteriovenous Malformation (CM-AVM)

• multifocal small CMs with fast-flow lesions.

• AD caused by RASA1 (CM-AVM1) or EPHB4 (CM-AVM2).

• Consider it in patients with multifocal CMs, and screen for fast-flow CNS lesions.

MCAP (macrocephaly-capillary malformation)

• macrocephaly

• multiple CMs

• brain anomalies such as Chiari-like findings

  • It is caused by somatic PIK3CA and is part of PIK3CA-Related Overgrowth Spectrum.

Venous malformations

• Most common vascular malformation

• Risk of localized intravascular coagulopathy (elevated D-dimer, phleboliths)

  • Usually found on the head, neck, extremities, trunk

• They are caused by somatic TEK (TIE2) or PIK3CA variants.

Blue rubber bleb nevus syndrome:

• multiple bluish nodules

• often with GI involvement

• Caused by somatic TEK.

• Typically with a double variant in cis.

Glomuvenous malformation

• Autosomal dominant, caused by GLMN loss of function.

• It is hyperkeratotic, cobblestone-like, and painful

• It has reduced penetrance and variable expressivity, explained by a second somatic hit (acquired uniparental disomy of 1p).

Lymphatic malformations

microcystic, macrocystic, or combined, and often associated with overgrowth syndromes.

PROS (PIK3CA-Related Overgrowth Spectrum)

• A spectrum of segmental overgrowth conditions that includes CLOVES, MCAP, KTS, and macrodactyly

• It is caused by somatic PIK3CA variants.

• Targeted therapy (alpelisib, sirolimus) is an option.

CLOVES

• Congenital

• Lipomatous

• Overgrowth

• Vascular malformations

• Epidermal nevi

• Skeletal anomalies.

  • AKT1/PIK3CA associated

Klippel-Trenaunay

• Triad of:

  • port wine stain

  • Varicosities (with a persistent lateral marginal vein)

  • Limb overgrowth

• It also falls under PROS.

Proteus syndrome

• Progressive

  • asymmetric overgrowth that is minimal at birth

  • It is caused by somatic AKT1 c.49G>A (p.Glu17Lys)

  • It carries a DVT risk and is distinct from PROS.

PTEN Hamartoma Tumor Syndrome (Cowden, Bannayan-Riley-Ruvalcaba):

• Autosomal dominant germline PTEN loss of function.

• Features include macrocephaly, trichilemmomas, lipomas, penile freckling, GI polyps, and vascular anomalies.

• It carries increased risk of breast, thyroid, and endometrial cancers (also colorectal, renal, and melanoma).

  • AD, PTEN GL variants

Hereditary hemorrhagic telangiectasia (HHT)

• Autosomal dominant, about 1 in 5,000, with age-related penetrance.

• Diagnosed by the Curaçao criteria:

  • recurrent epistaxis

  • mucocutaneous telangiectasias

  • visceral (inside organs) arteriovenous malformation (AVMs)

  • first-degree relative w/ HHTs

    • Definite requires 3 or more criteria.

HHT Molecular Testing Consideration

• Curacao criteria is age dependent, so kids young enough might not manifest symptoms yet

• Targeted familial variant testing in families with an identified variant can be valuable for inclusion and exclusion of screening.

HHT Genes

• ENG (HHT1, pulmonary and cerebral AVMs) 44%

• ACVRL1 (HHT2, liver AVMs) 52%

• SMAD4 (HHT with juvenile polyposis, increased risk for colorectal cancer) 1%

• GDF2/BMP9 (HHT-like phenotype) very rare

HHT Treatments and Complications

• Pulmonary AVMs can lead to stroke, hypoxemia.

• Pregnancy AVMs may lead to rupture, screening prior to conception needed

• Hepatic AVMs cause high output heart failure, secondary pulmonary hypertension

• Cerebral AVMs: seizures or hemorrhage