The lipomatous hyperplasia usually affects the thoracic region and abdominal wall and may go undetected at birth if the tumor is small. However, these masses demonstrate massive, asymmetric, progressive, contiguous growth through adolescence and adulthood, often extending across the midline and sometimes even reaching the buttocks. They occasionally infiltrate the mediastinum, paraspinal space, pleura, and retroperitoneum.
All patients with CLOVES syndrome have slow-flow (capillary, lymphatic, or venous) malformations that are typically located adjacent to or overlying the lipomatous masses. Those with phlebectasias or extensive complex vascular malformations are at greater risk for pulmonary embolism. Rarely, individuals have a fast-flow (arteriovenous) malformation. However, these tend to affect the spinal and paravertebral region, thereby potentially damaging the spinal cord. Other spinal abnormalities include tethered cord and neural tube defects such as spina bifida.
The characteristic linear epidermal nevus tends to grow and become more verrucous until adolescence, at which time the lesion usually stabilizes.
The most common musculoskeletal abnormalities affect the hands and feet. They include acral gigantism, cubital deviation of the hand, macrodactyly, polydactyly, an unusually wide gap between the first and second toe (sandal gap toe), and syndactyly. Additional features involving the extremities include patellar dislocation, patellar chondromalacia, leg-length discrepancy, and rarely, hip dysplasia. Abnormalities of the axial skeleton include pectus excavatum, vertebral anomalies, and scoliosis.
The kidney is also affected in CLOVES syndrome. Renal anomalies include agenesis, hydroureteronephrosis, hypoplasia, renal cysts, and Wilms tumor. Less commonly, splenic lesions may be present. Neural abnormalities include dysgenesis of the corpus callosum, hemimegalencephaly, seizures, syringomyelia, and polymicrogyria.
While genetic in nature, the disease is not inherited in a typical Mendelian manner. It arises from a postzygotic mosaic activating mutation in the PIK3CA gene on chromosome 3q26. The protein encoded by this gene is a catalytic subunit of PI3K, an upstream activator of the Akt-mTOR cell-signaling pathway. Therefore, the resultant PI3K overactivity leads to the cellular proliferation responsible for the clinical findings of CLOVES syndrome.
Q87.89 – Other specified congenital malformation syndromes, not elsewhere classified
719475006 – Congenital lipomatous overgrowth, vascular malformation, epidermal nevi, skeletal anomaly syndrome
Differential Diagnosis & Pitfalls
- Beckwith-Wiedemann syndrome
- Dysplastic megalencephaly (DMEG)
- Hemihyperplasia-multiple lipomatosis syndrome (HHML)
- Fibroadipose overgrowth (FAO)
- Klippel-Trenaunay syndrome (KTS)
- Megalencephaly-capillary malformation (MCAP) overgrowth
- Nonsyndromic hemihyperplasia
- Parkes-Weber syndrome
- Proteus syndrome – collagenomas or elastomas, acquired rather than congenital lipomatous masses
- PTEN hamartoma tumor syndrome
- Sotos syndrome