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Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

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Table 3.

Selected Syndromic PIK3CA-Related Overgrowth Phenotypes

Phenotype 1Types of OvergrowthMalformations/Abnormalities
Cutaneous & vascularMusculoskeletalVisceralNeurologic
CLOVES (See Figure 1.)
  • Asymmetric
  • Congenital lipomatous overgrowth of limb or on trunk
  • Hand &/or foot
  • Plantar-palmar overgrowth
  • Typically lymphatic low flow in areas of overgrowth
  • Linear EN
  • Morbid paraspinal high-flow lesions & phlebectasia
  • Scoliosis
  • Spina bifida
  • Pectus deformities
  • Sandal-gap toes
  • Splayed feet & toes
  • Macro-, poly-, & syndactyly
  • Chondromalacia patellae
  • Dislocated knees
  • Renal agenesis/ hypoplasia
  • Splenic lesions
  • Wilms tumor
  • HMEG
  • Seizures
CLAPOPartial/generalized of soft tissues & bone
  • Lower-lip capillary malformation w/o progression
  • Lymphatic malformation of face/neck & upper body
FH or FAO
  • Segmental & progressive overgrowth of subcutaneous & visceral fibroadipose tissue
  • Occasional skeletal overgrowth
  • Disproportionate linear overgrowth
  • Vascular malformation
  • EN
  • Progressive skeletal overgrowth (preserved architecture)
  • Polydactyly
  • Lipomatous infiltration of muscle
  • Testicular or epididymal cysts & hydrocele
  • Non-spleen/ thymus visceral overgrowth
HHML
  • Asymmetric overgrowth of a body part or body segment
  • Overgrowth may be static or mildly progressive.
Multiple lipomas
KTSBone &/or soft tissue overgrowth in a unilateral limb
  • Low-flow venous or lymphatic malformations
  • Port-wine nevus (capillary malformations)
Digital enlargement
MCAP or M-CM (See Figures 2, 3.)
  • Megalencephaly & HMEG 2
  • Generalized overgrowth (macrosomia)
Cutaneous vascular malformations, esp cutis marmorata & capillary malformations of the face
  • Cutaneous syndactyly & postaxial polydactyly or polysyndactyly
  • Subcutaneous lipomas
Wilms tumor (rare)
  • Hypotonia
  • Seizures
  • Autistic features
  • Mild-to-severe ID
  • Behavioral problems
  • Meningioma-assoc symptoms (rare)
MPPH 3Brain overgrowth 4
  • Syndactyly
  • Depressed nasal bridge
  • DD
  • ID
  • Hypotonia
  • Seizures
  • Medulloblastoma-assoc clinical features (very rare)

CLAPO = capillary malformation of the lower lip, lymphatic malformation of the face and neck, asymmetry and partial/generalized overgrowth; CLOVES = congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal and spinal; DD = developmental delay; EN = epidermal nevi; FH or FAO = fibroadipose hyperplasia or overgrowth; HHML = hemihyperplasia multiple lipomatosis; HMEG = hemimegalencephaly; ID = intellectual disability; KTS = Klippel-Trenaunay syndrome; MCAP or M-CM = megalencephaly-capillary malformation; MPPH = megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome

1.

Most common findings; see text for more information.

2.

May also include cortical dysplasia, polymicrogyria, Arnold-Chiari malformation, and ventriculomegaly

3.

Individuals with this phenotype may also display dysmorphic features including prominent forehead, widely spaced eyes, downslanted palpebral fissures, low-set ears, preauricular pits, anteverted nares, and a high and narrow palate.

4.

May include megalencephaly, hydrocephalus, and polymicrogyria

From: PIK3CA-Related Overgrowth Spectrum

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