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Vascular anomalies are variably associated with overgrowth, skeletal anomalies, and abnormalities of the brain, leptomeninges, and eye. We assembled a 16-institution network to determine the range of genetic variants associated with a spectrum of vascular anomalies with overgrowth, ranging from mild to severe. Because of the overlap between cancer-associated variants and previously described somatic variants in vascular overgrowth syndromes, we employed tumor genetic profiling via high-depth next-generation sequencing using a panel to assay affected tissue from a diverse cohort of subjects with vascular anomalies with overgrowth. Seventy-five percent (43/57) harbored pathogenic or likely pathogenic variants in 10 genes. We identified two genes (mTOR, PIK3R1) and several variants previously described in the setting of cancer but that, to our knowledge, have not been described in vascular malformations. All were identified at low variant allele frequency consistent with somatic mosaic etiology. By leveraging somatic variant detection technology typically applied to cancer in a cohort inclusive of broad phenotypic severity, we demonstrated that most vascular anomalies with overgrowth harbor postzygotic gain-of-function mutations in oncogenes. Furthermore, continued interrogation of oncogenes in benign developmental disorders could provide insight into fundamental mechanisms regulating cell growth.

PHACE syndrome is the association of segmental facial hemangiomas with congenital arterial, brain, cardiac, and ocular anomalies. Structural brain malformations affect 41-52% of PHACE patients and can be associated with focal neurologic deficits, developmental delays, and/or intellectual disability. To better characterize the spectrum of structural brain and other intracranial anomalies in PHACE syndrome, MRI scans of the head/neck were retrospectively reviewed in 55 patients from the PHACE Syndrome International Clinical Registry and Genetic Repository. All registry patients with a diagnosis of definite PHACE syndrome who had MRI scans of satisfactory quality were included. Of 55 patients, 34 (62%) demonstrated ≥1 non-vascular intracranial anomaly; structural brain malformations were present in 19 (35%). There was no difference in the prevalence of brain anomalies between genders. Brain anomalies were more likely in patients with S1 and/or S2 distribution of facial hemangioma. The most common structural brain defects were cerebellar hypoplasia (25%) and fourth ventricle abnormalities (13%). Dandy-Walker complex and malformations of cortical development were present in 9% and 7%, respectively. Extra-axial findings such as pituitary anomalies (18%) and intracranial hemangiomas (18%) were also observed. Six patients (11%) had anomalies of the globes or optic nerve/chiasm detectable on MRI. Brain malformations comprise a diverse group of structural developmental anomalies that are common in patients with PHACE syndrome. Along with brain malformations, numerous abnormalities of the pituitary, meninges, and globes were observed, highlighting the need for careful radiologic assessment of these structures in the neuroimaging workup for PHACE syndrome.

Vascular anomalies present both a diagnostic and therapeutic challenge to physicians. Identification of these lesions is difficult due to their immense phenotypic variability, and naming conventions for vascular anomalies have historically been inconsistent. Terms such as “hemangioma” are informative when used correctly, but can cause confusion and miscommunication if applied indiscriminately to all vascular anomalies. Accuracy in classification is essential, as both disease course and therapeutic options differ greatly depending on the particular vascular anomaly present. In order for clinicians to properly diagnose and treat patients with these diseases, a unified nomenclature must be employed. This section provides an update on the current classification of vascular anomalies, with clinical descriptions of the most commonly encountered lesions, and clarifies the ambiguous nomenclature present in the existing literature.

IMPORTANCE: Patients with somatic overgrowth commonly require surgical intervention to preserve function and improve cosmesis. To our knowledge no observation of scarring outcomes in this population has been published to date. OBJECTIVE: To observe the frequency of abnormal scarring in patients with somatic overgrowth and sequencing-verified mutations in the PIK3CA gene. DESIGN, SETTING, AND PARTICIPANTS: This retrospective study evaluated scarring outcomes in patients with PIK3CA-related overgrowth. Samples of affected tissue were sequenced between July 2015 and October 2016. Medical records from multiple large academic tertiary care centers were reviewed for surgical history and scar descriptions, and clinical photographs were assessed by 2 surgeons (J.N.J. and D.M.K.) to confirm abnormal scarring. Analysis of medical records and photographs was performed between April 2017 and June 2017 by a multidisciplinary team from dermatology, plastic surgery, orthopedic surgery, radiology, and genetics departments. All patients considered for the study were diagnosed with somatic overgrowth and previously had affected tissue sent for next-generation sequencing. Those with pathogenic PIK3CA variants and 1 or more prior surgical procedures were reviewed. MAIN OUTCOMES AND MEASURES: Presence of excessive scarring in patients with PIK3CA overgrowth. RESULTS: A total of 57 patients with segmental overgrowth syndromes were sequenced. Of the 57 patients, 25 (44%) had pathogenic or likely pathogenic variants in PIK3CA. Of those with pathogenic PIK3CA variants, 6 (24%) had past surgical procedures, all with preoperative and postoperative photographs. Of 6 patients with PIK3CA-related overgrowth and a history of 1 or more surgical procedure, 4 (67%) developed excessive scarring. The cohort with abnormal scarring comprised 3 females and 1 male, with a median age of 8.5 years. All abnormal scarring occurred in affected overgrowth tissue. Three of the 4 patients developed the excessive scarring after debulking procedures for overgrowth and/or vascular malformations of the upper or lower extremity. CONCLUSIONS AND RELEVANCE: Excessive scarring occurred frequently in patients with PIK3CA-related overgrowth syndromes. The risk of abnormal scarring should therefore be discussed preoperatively. Given the activating nature of these PIK3CA variants, we suggest that the excessive scarring may be owing in part to up-regulation of the PI3K-Akt-mTOR pathway. Additional studies are needed to assess scarring outcomes in patients with other types of overgrowth.

Segmental infantile hemangiomas (IH) can be associated with congenital anomalies in a regional distribution. PHACE refers to large cervicofacial segmental IH in association with congenital anomalies of the aortic arch and medium-sized arteries of the head and neck, as well as structural anomalies of the posterior fossa and eye. A subset of PHACE patients have arterial anomalies that progress to moyamoya vasculopathy (MMV). MMV is defined as stenosis of the supraclinoid segment of the internal carotid arteries and/or their major branches, with subsequent development of a compensatory collateral vessel network. We describe a patient with MMV and segmental IH on the back and lower body who meets diagnostic criteria for PHACE based on a posterior segment eye anomaly and cerebral arterial anomalies. Whole exome sequencing demonstrated two inherited heterozygous variants in RNF213. Variants in RNF213 are associated with increased susceptibility to MMV. Our findings suggest that RNF213 variants may play a role in the development of MMV in patients with hemangioma syndromes associated with congenital cerebral arterial anomalies.

The cause of PHACE syndrome is unknown. In a study of 218 patients, we examined potential prenatal risk factors for PHACE syndrome. Rates of pre-eclampsia and placenta previa in affected individuals were significantly greater than in the general population. No significant risk factor differences were detected between male and female subjects.