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.

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Dr Adotama and Mr Tinker had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Adotama, Glass, Allen.

Capillary malformation-arteriovenous malformation (CM-AVM) syndrome, due to inactivating mutations in RASA1 in 68% of cases, is characterized by the development of cutaneous capillary malformations and arteriovenous malformations or fistulas; no known genetic etiology has been identified in patients with CM-AVM syndrome without RASA1 mutations. We present the case of a child with RASA1-negative CM-AVM syndrome with a de novo missense mutation in EPHB4, a transmembrane tyrosine kinase receptor essential for vasculogenesis. Inactivating the mutation in EPHB4 has been shown to upregulate the mitogen-activated protein kinase pathway and the mammalian target of rapamycin complex 1, possibly contributing to the development of vascular malformations.

IMPORTANCEUlceration is a common complication of infantile hemangioma (IH), which leads to substantial morbidity. Ulceration in IH has not been systematically studied since the advent of β-blocker therapy for IH. OBJECTIVESTo examine treatment interventions used for ulceration in IH and identify clinical prognostic indicators of healing time. DESIGN, SETTING, AND PARTICIPANTS A retrospective, multicenter cohort study was conducted on 436 consecutive patients with a clinical diagnosis of ulcerated IH and available clinical photographs. Patients receiving care at tertiary referral centers evaluated between 2012 and 2016 were included; statistical and data analysis were performed from February 7 to April 27, 2020. EXPOSURES Clinical characteristics, treatment interventions, course, complications, and resource use were analyzed. Treatment interventions for ulceration in IH included local (wound care, topical), systemic (β-blocker, corticosteroids), and procedural (pulsed-dye laser). MAIN OUTCOMES AND MEASURES The primary end point was time to complete or nearly complete ulceration healing. Clinical characteristics were analyzed to determine the responses to most common interventions and prognostic factors for healing of ulceration. RESULTSOf the 436 patients included in the study, 327 were girls (75.0%); median age at ulceration was 13.7 weeks (interquartile range, 8.86-21.30 weeks). The median heal time was 4.79 weeks (95% CI, 3.71-5.86 weeks) with wound care alone, 5.14 weeks (95% CI, 4.57-6.00 weeks) with timolol, 6.36 weeks (95% CI, 5.57-8.00 weeks) with a systemic β-blocker, and 7.71 weeks (95% CI, 6.71-10.14 weeks) with multimodal therapy. After adjusting for IH size, a dose of propranolol less than or equal to 1 mg/kg/d was associated with shorter healing time compared with higher propranolol doses (hazard ratio, 2.04; 95% CI, 1.11 to 3.73; P = .02). Size of the IH was identified as a significant prognostic factor for healing time in multivariable analysis. Increasing size of IH portends a proportionately longer time to heal of the ulceration.CONCLUSIONS AND RELEVANCE Despite the use of β-blockers, this cohort study found that a subset of patients with IH ulceration continued to experience prolonged IH healing times. Larger IH size appears to be a poor prognostic factor for time to heal. For patients requiring systemic therapy, initiation of propranolol at lower doses (Յ1 mg/kg/d) should be considered.

Posttransplant lymphoproliferative disorder (PTLD) is a known complication of solid organ transplantation. The majority are B cell in origin and related to Epstein-Barr virus infection. T-cell PTLD is much less common; most are Epstein-Barr virus negative and have a worse prognosis. Primary cutaneous Tcell lymphoma (CTCL) as a presentation of PTLD is rare. CTCL has a less favorable prognosis in transplant patients compared with that in immunecompetent patients. Herein, we report a case of a 13-year-old boy who developed folliculotropic mycosis fungoides, a rare subtype of CTCL, subsequent to renal transplantation. To our knowledge, this is the first report of this type of PTLD in a pediatric patient.

The qualitative grading of acne is important for routine clinical care and clinical trials, and although many useful systems exist, no single acne global grading system has had universal acceptance. In addition, many current instruments focus primarily on evaluating primary lesions (eg, comedones, papules, and nodules) or exclusively on signs of secondary change (eg, postinflammatory hyperpigmentation, scarring).OBJECTIVES To develop and validate an acne global grading system that provides a comprehensive evaluation of primary lesions and secondary changes due to acne. DESIGN, SETTING, AND PARTICIPANTSThis diagnostic study created a multidimensional acne severity feature space by analyzing decision patterns of pediatric dermatologists evaluating acne. Modeling acne severity patterns based on visual image features was then performed to reduce dimensionality of the feature space to a novel 2-dimensional grading system, in which severity levels are functions of multidimensional acne cues. The system was validated by 6 clinicians on a new set of images. All images used in this study were taken from a retrospective, longitudinal data set of 150 patients diagnosed with acne, ranging across the entire pediatric population (aged 0-21 years), excluding images with any disagreement on their diagnosis, and selected to adequately span the range of acne types encountered in the clinic.

IMPORTANCEPatients 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 PARTICIPANTSThis 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 RELEVANCEExcessive 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.