Table 3.

Genes of Interest in the Differential Diagnosis of TEK-Related Venous Malformations

GeneDisorderMOIPhenotypeComment
GLMN Glomuvenous malformations (OMIM 138000)AD 1, 2Similar to VMCM:
  • Inherited
  • Multifocal
  • Small cutaneous venous-like lesions
  • Most lesions located on extremities
Unlike VMCM:
  • Not usually seen on mucous membranes
  • Cobblestone appearance
  • Deeper purple in color than VMCM
  • Painful on palpation
  • Less invasive than sporadic VM
PIK3CA PIK3CA-related vascular malformations (See PIK3CA-Related Overgrowth Spectrum.)Mosaic (not known to be inherited) 3
  • GoF of PIK3CA in 20% of isolated VM
  • PIK3CA-mutated VM do not typically extend to cutaneous surface.
A pathogenic variant in PIK3CA is observed in various PIK3CA-related overgrowth syndromes, in which combined vascular malformations are assoc w/hypertrophy of soft tissues & often involve the skeleton.
KRIT1 (CCM1)
CCM2
CCM3		Cerebral cavernous malformation (CCM) (OMIM 116860)Sporadic
or AD (20% of CCM) 4
  • 9% of persons w/CCM have cutaneous vascular malformations, incl nodular cutaneous VM
  • Single or multiple nodules, typically all over body
  • Most lesions are not present at birth, & new lesions may emerge into adulthood.
  • Size ranges from 1 mm to <5 cm.
  • CCM affects up to 0.5% of population.
  • Vascular lesions typically arise in central nervous system.
  • CCM usually manifests between age 20-30 years, but clinical manifestations can occur at any age.
MAP3K3 Verrucous VM (VVM)Mosaic (not known to be inherited) 5
  • VVM present at birth or early during infancy.
  • Most commonly affecting lower limbs
  • Well-circumscribed purple & hyperkeratotic linear plaques
  • Size ranges from 2 to 20 cm.
Very similar lesions, called hyperkeratotic cutaneous capillary-venous malformations (HCCVM), can occur in CCM, mostly in CCM1.

GoF = gain of function; VM = venous malformations; VMCM = multiple cutaneous and mucosal venous malformations

1.

Inheritance is autosomal dominant, although the pathophysiologic mechanism is recessive at the cellular level (i.e., disease caused by presence of a germline pathogenic variant on one allele and an acquired somatic pathogenic variant on the other allele), most frequently due to an acquired uniparental isodisomy [Brouillard et al 2002, Amyere et al 2013].

2.
3.
4.
5.

From: TEK-Related Venous Malformations

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