Postzygotic mutations in the GNAQ/GNA11 genes, which encode the G-protein nucleotide binding protein alpha subunits, have been identified in patients with phakomatosis pigmentovascularis (PPV). However, little is known about the Chinese population. To identify pathogenic mutations in pediatric patients with PPV within the Chinese population. We performed whole-exome sequencing (WES) using skin lesion tissues from pediatric patients diagnosed with PPV. Additionally, ultradeep-targeted sequencing was conducted to validate the somatic mutations. A genotype-phenotype correlation was analyzed by integrating data from previous reports with the findings of the present study. Thirteen patients were enrolled, all diagnosed with the cesioflammea type of PPV, except for one patient with an unclassifiable type. We identified somatic GNA11 c.547C>T (p.R183C) variant in seven patients and GNAQ c.548G>A (p.R183Q) in four patients, with low allelic fractions ranging from 2.1% to 8.6% through ultradeep sequencing. Besides, a GNAQ c.548G>A (p.R183Q) variant was detected through targeted sequencing in one of two patients who did not exhibit detectable variants via WES. The genotype-phenotype correlation analysis, involving 15 patients with a GNA11 variant and 10 with a GNAQ variant, revealed that facial capillary malformation (87% vs. 50%, P = 0.075) and ocular melanocytosis (80% vs. 40%, P = 0.087) appeared to be more frequent in patients with GNA11 mutation compared to those with GNAQ mutations. All four patients diagnosed with cesiomarmorata type or overlapping cesioflammea and cesiomarmorata type PPV carried the GNA11 variant. Our study demonstrated that the majority of PPV patients in the Chinese population carried a postzygotic variant of GNAQ/GNA11, thus further confirming the pathogenic role of GNAQ/GNA11 mosaicism in the development of PPV cesioflammea type.

Phakomatosis pigmentovascularis (PPV) is a family of rare congenital diseases where vascular malformation coexists with melanocytic, dermal, or ocular lesions. The cesiomarmorata type is even rarer, and most such cases are reported with unilateral occurrence. We present an atypical case of a patient with bilateral phakomatosis cesiomarmorata, bilateral ocular melanocytosis, and bilateral glaucoma. No malformation to resist aqueous drainage was identified. Long-term management of intraocular pressure (IOP) using topical antiglaucoma medication was successful. This case report refines the clinical presentation of phakomatosis cesiomarmorata and may help diagnose and treat future cases.

Phacomatosis pigmentovascularis is a term encompassing a group of disorders characterized by the coexistence of a segmental pigmented nevus of melanocytic origin and segmental capillary nevus. Over the past decades, confusion over the names and definitions of phacomatosis spilorosea, phacomatosis melanorosea, and their defining nevi, as well as of unclassifiable phacomatosis pigmentovascularis cases, has led to several misplaced diagnoses in published cases. A systematic and critical review of the worldwide literature on phacomatosis spilorosea and phacomatosis melanorosea was carried out. This study yielded 18 definite instances of phacomatosis spilorosea and 14 of phacomatosis melanorosea, with one and six previously unrecognized cases, respectively. Phacomatosis spilorosea predominantly involves the musculoskeletal system and can be complicated by neurological manifestations. Phacomatosis melanorosea is sometimes associated with ancillary cutaneous lesions, displays a relevant association with vascular malformations of the brain, and in general appears to be a less severe syndrome. Established phacomatosis pigmentovascularis variants now include phacomatosis cesioflammea, phacomatosis cesiomarmorata, phacomatosis spilorosea, phacomatosis melanorosea, phacomatosis cesioflammeomarmorata, and phacomatosis melanocesioflammea.

Phacomatosis pigmentovascularis (PPV) comprises a family of rare conditions that feature vascular abnormalities and melanocytic lesions that can be solely cutaneous or multisystem in nature. Recently published work has demonstrated that both vascular and melanocytic abnormalities in PPV of the cesioflammea and cesiomarmorata subtypes can result from identical somatic mosaic activating mutations in the genes GNAQ and GNA11. Here, we present three new cases of PPV with features of the cesioflammea and/or cesiomarmorata subtypes and mosaic mutations in GNAQ or GNA11. To better understand the risk of potentially occult complications faced by such patients we additionally reviewed 176 cases published in the literature. We report the frequency of clinical findings, their patterns of co-occurrence as well as published recommendations for surveillance after diagnosis. Features assessed include: capillary malformation; dermal and ocular melanocytosis; glaucoma; limb asymmetry; venous malformations; and central nervous system (CNS) anomalies, such as ventriculomegaly and calcifications. We found that ocular findings are common in patients with phacomatosis cesioflammea and cesiomarmorata. Facial vascular involvement correlates with a higher risk of seizures (p = .0066). Our genetic results confirm the role of mosaic somatic mutations in GNAQ and GNA11 in phacomatosis cesioflammea and cesiomarmorata. Their clinical and molecular findings place these conditions on a clinical spectrum encompassing other GNAQ and GNA11 related disorders and inform recommendations for their management.

Phacomatosis pigmentovascularis is a rare group of syndromes characterized by the co-existence of a vascular nevus and a pigmentary nevus with or without extracutaneous systemic involvement. The existing classifications of phacomatosis pigmentovascularis are based on phenotypic characteristics. We report four new cases of phacomatosis pigmentovascularis, three with phacomatosis cesioflammea demonstrating phenotypic variability, and one with phacomatosis cesiomarmorata. Extracutaneous manifestations were observed in three patients (75%) that included central nervous system involvement in three, bilateral congenital glaucoma in two, and cardiovascular system involvement in one. The molecular basis of phacomatosis pigmentovascularis is yet to be elucidated. Whether the various subtypes of phacomatosis pigmentovascularis are separate molecular entities or phenotypic variants of the same disease needs to be settled.