Phakomatosis spilorosea

Phakomatosis spilorosea is considered a variant of phakomatosis pigmentovascularis (phakomatosis pigmentovascularis type III a/b). Phakomatosis pigmentovascularis is a diagnosis that denotes the coexistence of pigmentary and vascular hamartomas of certain types accompanied by variable multisystem involvement, including CNS disease, asymmetric growth and a predisposition to malignancy.

Somatic mutations have been detected in the PTPN11 gene (Polubothu S et al. 2019; Polubothu S et al. 2023). The enzyme vencoded by this gene belongs to an enzyme family consisting of signaling molecules that regulate a variety of cellular processes including cell growth, cell differentiation and oncogenic transformation.

Ubiquitous; the distribution pattern describes both hemiplegic and bilateral localizations.

Phakomatosis spilorosea is characterized by a bright red vascular malformation of the skin (nevus roseus - bright red vascular nevus) in combination with an ipsi- or contralaterally located pigmentary nevus (e.g. nevus spilus). The syndrome can occur in isolation but can also be associated with asymmetry of the extremities, unilateral lymphedema, epileptic seizures and scoliosis. A naevus anaemicus is not associated with this syndrome.

A review study (Torchia D 2021)

showed the following characteristics and frequencies in phacomatosis spilorosea:

• In 83.3 %, the two characteristic nevi were completely or predominantly ipsilateral.
• ipsilateral soft tissue and skeletal abnormalities were detectable in 72.2
• neurological manifestations were detectable in 27.8
• Additional cutaneous lesions occurred mostly in PMR (35.7 % of cases)
• No extracutaneous abnormalities were detected in 22.2% of cases.

At the molecular genetic level, it was found that the same mutation could be detected in both the pigmentary and vascular hamartomas of this syndrome in the same individual. However, the mutation was not detectable in the blood. It could be shown that the same variants can cause either the pigmentary or the vascular phenotype alone. Apparently, the PTPN11 mutation in the pigmentary lesions leads to an increased tendency to develop malignancy. In vitro modeling of the missense variants confirms an overactivation of the downstream MAPK pathway and a widespread disruption of angiogenesis of human endothelial cells. Importantly, patients with PTPN11 mosaicism theoretically carry the risk of inheriting the variant as a germline RASopathy (Polubothu S et al. 2023).

1. Abdolrahimzadeh S et al. (2021) Ocular manifestations in phakomatosis pigmentovascularis: Current concepts on pathogenesis, diagnosis, and management. Surv Ophthalmol 66:482-492
2. Arnold AW et al. (2012) Phacomatosis melanorosea without extracutaneous features: an unusual type of phacomatosis pigmentovascularis. Eur J Dermatol 22:473-475.
3. Happle R (2005) Phacomatosis pigmentovascularis revisited and reclassified. Arch Dermatol. 141:385-388.
4. Polubothu S et al. (2019) Phacomatosis pigmentovascularis spilorosea and speckled lentiginous naevus syndrome are caused by mosaic mutations in gene PTPN11. Pediatr Dermatol 36:S7
5. Polubothu S et al. (2023) PTPN11 Mosaicism Causes a Spectrum of Pigmentary and Vascular Neurocutaneous Disorders and Predisposes to Melanoma. J Invest Dermatol 143:1042-1051.e3.
6. Thomas AC et al. (2016) Mosaic activating mutations in GNA11 and GNAQ are associated with phacomatosis pigmentovascularis and extensive dermal melanocytosis. J Invest Dermatol 136:770-778.
7. Torchia D (2021) Phacomatosis spilorosea versus phacomatosis melanorosea: a critical reappraisal of the worldwide literature with updated classification of phacomatosis pigmentovascularis. Acta Dermatovenerol Alp Pannonica Adriat 30:27-30.
8. Torchia D, Happle R. Papular nevus spilus syndrome: old and new aspects of a mosaic RASopathy. Eur J Dermatol. 2019 Feb 1;29(1):2-5.