Multicenter Study of Long-Term Outcomes and Quality of Life in PHACE Syndrome after Age 10.

OBJECTIVE: To characterize long-term outcomes of PHACE syndrome. STUDY DESIGN: Multicenter study with cross-sectional interviews and chart review of individuals with definite PHACE syndrome ≥10 years of age. Data from charts were collected across multiple PHACE-related topics. Data not available in charts were collected from patients directly. Likert scales were used to assess the impact of specific findings. Patient-Reported Outcomes Measurement Information System (PROMIS) scales were used to assess quality of life domains. RESULTS: A total of 104/153 (68%) individuals contacted participated in the study at a median of 14 years of age (range 10-77 years). There were infantile hemangioma (IH) residua in 94.1%. Approximately one-half had received laser treatment for residual IH, and the majority (89.5%) of participants were satisfied or very satisfied with the appearance. Neurocognitive manifestations were common including headaches/migraines (72.1%), participant-reported learning differences (45.1%), and need for individualized education plans (39.4%). Cerebrovascular arteriopathy was present in 91.3%, with progression identified in 20/68 (29.4%) of those with available follow-up imaging reports. Among these, 6/68 (8.8%) developed moyamoya vasculopathy or progressive stenoocclusion, leading to isolated circulation at or above the level of the circle of Willis. Despite the prevalence of cerebrovascular arteriopathy, the proportion of those with ischemic stroke was low (2/104; 1.9%). PROMIS global health scores were lower than population norms by at least 1 SD. CONCLUSIONS: PHACE syndrome is associated with long-term, mild to severe morbidities including IH residua, headaches, learning differences, and progressive arteriopathy. Primary and specialty follow-up care is critical for PHACE patients into adulthood.

Immunohistochemical Expression of Lymphatic Endothelial Markers in Blue Rubber Bleb Nevus Syndrome.

INTRODUCTION: Blue rubber bleb nevus syndrome (BRBNS) is an uncommon vascular anomaly characterized by multifocal cutaneous, visceral, and other soft tissue or solid organ venous malformations. We observed that BRBNS lesions express immunohistochemical markers of lymphatic differentiation. METHODS: BRBNS histopathologic specimens assessed at our institution during the past 27 years were reviewed. Slides from 19 BRBNS lesions were selected from 14 patients (9 cutaneous, 9 gastrointestinal, and 1 hepatic). We recorded the involved anatomical compartments and presence/absence of thrombi or vascular smooth muscle. Immunohistochemical endothelial expression of PROX1 (nuclear) and D2-40 (membranous/cytoplasmic) was evaluated semi-quantitatively. RESULTS: Endothelial PROX1 immunopositivity was noted in all specimens; the majority (89.5%) demonstrated staining in more than 10% of cells. D2-40 immunopositivity was present in one-third (33%) of cutaneous lesions and only 1 gastrointestinal lesion. CONCLUSION: Endothelial cells in BRBNS almost always express 1 or more immunohistochemical markers of lymphatic differentiation.

Next generation sequencing aids diagnosis and management in a case of encephalocraniocutaneous lipomatosis.

Encephalocraniocutaneous lipomatosis (ECCL) is a rare neurocutaneous disorder caused by somatic FGFR1 and KRAS variants. It shares significant phenotypic overlap with several closely related disorders caused by mutations in the RAS-MAPK pathway (mosaic RASopathies). We report a diagnostically challenging case of ECCL in which next-generation sequencing of affected tissue identified a pathologic FGFR1 p.K656E variant, thereby establishing a molecular diagnosis. Patients with FGFR1-associated ECCL carry a risk of developing malignant brain tumors; thus, genetic testing of patients with suspected ECCL has important management implications.

Non-vascular intracranial lesions in three children with PHACE association.

PHACE (posterior fossa malformations, hemangiomas, arterial anomalies, cardiac anomalies, eye anomalies) association has many recognized clinical features. A link between PHACE and non-vascular intracranial lesions has not been well-described. We report three pediatric patients with PHACE and non-vascular intracranial lesions.

Metopic ridge presenting to pediatric dermatology and vascular anomalies clinics.

Metopic ridge (MeR) is a midline osseous forehead prominence resulting from physiologic closure of the underlying metopic suture. This mass-like ridge can be mistaken for serious conditions such as a craniosynostosis or vascular anomaly, prompting concern and workup. We reviewed patients presenting for a forehead mass to Vascular Anomalies and Dermatology clinics and diagnosed with MeR to increase familiarity with this finding and to encourage MeR in the differential diagnosis of pediatric midline forehead masses.

Paraneoplastic pemphigus associated with Castleman disease: A multicenter case series.

INTRODUCTION: Paraneoplastic pemphigus (PNP) is a rare, often fatal, autoimmune blistering disease of the skin and mucous membranes. In children, PNP is frequently associated with Castleman disease (CD). This series describes five cases of PNP associated with CD. METHODS: Data were collected retrospectively from the medical records of patients with a diagnosis of PNP and CD from January 2013 to June 2022. Patients ≤22 years old with clinical and immunopathologic evidence of PNP were included; CD was diagnosed histopathologically. RESULTS: Two children, two adolescents, and one young adult (two males, three females) were included. The average age at disease presentation was 11.8 years (range: 7-22 years). Oral (n = 5) and anogenital (n = 3) mucositis were common. Four patients had "unicentric" CD (UCD); one patient had "multicentric" CD (MCD). Castleman tumors were in the retroperitoneum (n = 4) or axilla (n = 1). One patient had myasthenia gravis without thymoma. Three patients had bronchiolitis obliterans (BO). Three patients had complete resection of their CD; two had partial resection. Three patients remain alive with a median follow-up of 13 months (range: 12 months to 13 years); two are clinically stable with resolution of mucocutaneous lesions; one has persistent BO requiring ongoing ventilatory support. Patients who remain alive had UCD with complete resection; all deceased patients had partial resection and BO. CONCLUSION: Most patients had UCD, and the retroperitoneum was the most common location. Patients with MCD, incomplete resection, and BO died; patients with UCD and complete resection remain alive, even in the setting of BO. Consideration of PNP is critical when pediatric patients present with mucositis as PNP may be clinically indistinguishable from more common causes of mucositis.

Spectrum of lymphatic anomalies in patients with RASA1-related CM-AVM.

BACKGROUND: Capillary malformation-arteriovenous malformation (CM-AVM) is characterized by multifocal fast-flow capillary malformations, sometimes with arteriovenous malformations/fistulas, skeletal/soft tissue overgrowth, telangiectasias, or Bier spots. Lymphatic abnormalities are infrequently reported. We describe seven patients with CM-AVM and lymphatic anomalies. METHODS: Following IRB approval, we identified patients with CM-AVM and lymphatic anomalies seen at the Vascular Anomalies Center at Boston Children's Hospital from 2003 to 2023. We retrospectively reviewed records for clinical, genetic, laboratory, and imaging findings. RESULTS: We found seven patients with CM-AVM and lymphatic abnormalities. Five patients were diagnosed prenatally: four with pleural effusions (including one suspected chylothorax) and one with ascites. Pleural effusions resolved after neonatal drainage in three patients and fetal thoracentesis in the fourth; however, fluid rapidly reaccumulated in this fetus causing hydrops. Ascites resolved after neonatal paracentesis, recurred at 2 months, and spontaneously resolved at 5 years; magnetic resonance lymphangiography for recurrence at age 19 years suggested a central conducting lymphatic anomaly (CCLA), and at age 20 years a right spermatic cord/scrotal lymphatic malformation (LM) was detected. Chylous pericardial effusion presented in a sixth patient at 2 months and disappeared after pericardiocentesis. A seventh patient was diagnosed with a left lower extremity LM at 16 months. Six patients underwent genetic testing, and all had RASA1 mutation. RASA1 variant was novel in three patients (c.1495delinsCTACC, c.434_451delinsA, c.2648del), previously reported in two (c.2603+1G>A, c.475_476del), and unavailable in another. Median follow-up age was 5.8 years (4 months-20 years). CONCLUSION: CM-AVM may be associated with lymphatic anomalies, including pericardial/pleural effusions, ascites, CCLA, and LM.

Classification of lower extremity venous malformations and risk of knee involvement: A retrospective cohort study.

BACKGROUND: Venous malformation (VM) is the most common vascular anomaly in the lower extremity. VMs can be classified as focal, multifocal, or diffuse types. Intraarticular VM (IA-VM) of the knee portends morbidity. Association of the lower extremity VM type with IA-VM is not well defined. OBJECTIVE: To classify a large cohort of lower extremity, nonsyndromic VMs by type and determine associations with IA-VM. METHODS: Retrospective cohort study. RESULTS: We assessed 156 patients with nonsyndromic, lower extremity VM; 71 (46%) were focal and 85 (54%) were diffuse type VM, and 97 (62%) were IA-VM. Of diffuse VMs, 26 (31%) were Bockenheimer and 59 (69%) were localized subtypes. Pure VM had a significantly elevated risk of IA-VM (relative risk [RR], 2.34; 95% confidence interval [CI], 1.42-3.89). IA-VM was more common in diffuse (73%) versus focal (49%) types. Risk of IA-VM in diffuse type VM was significantly elevated (RR, 1.48; 95% CI, 1.13-1.94). One hundred percent of diffuse Bockenheimer type VM had IA-VM, and this subtype had the highest risk (RR, 1.83; 95% CI, 1.56-2.14) of IA-VM. LIMITATIONS: Retrospective, single-institution study. CONCLUSIONS: Intraarticular involvement of the knee should be considered in all lower extremity VMs. Pure VM and the Bockenheimer diffuse VM subtype had the highest risk of IA-VM.

Verrucous Venous Malformation-Subcutaneous Variant.

BACKGROUND: Verrucous venous malformation (VVM), previously called "verrucous hemangioma," typically involves the dermis and the subcutaneous fat. We have encountered patients with VVM confined to the hypodermis. MATERIALS AND METHODS: During a nearly 20-year period, 13 patients, aged 2-17 years, presented with a subcutaneous mass in the limb without clinically obvious epidermal alterations. Consequently, operative excisions did not include the skin. RESULTS: Histopathologically, the specimens were composed of blood-filled channels with morphologic characteristics of capillaries and veins that infiltrated adipose tissue. Aggregates often formed nodules with variable fibrosis and a component of large and radially oriented vessels. A diagnosis of VVM was supported by endothelial immunopositivity for GLUT-1 (25%-75% immunopositive channels in 16/16 specimens); D2-40 (1%-25% channels in 14/15 specimens); and Prox-1 (1%-50% of channels in 14/16 specimens). A MAP3K3 mutation was identified by droplet digital PCR in 3 of the 6 specimens. CONCLUSIONS: Diagnosis of VVM in this uncommon location is challenging because of absence of epidermal changes and lack of dermal involvement. Imaging is not pathognomonic, and mimickers are many. Appropriate immunohistochemical stains and molecular analysis contribute to the correct diagnosis.

Congenital Disseminated Pyogenic Granuloma: Characterization of an Aggressive Multisystemic Disorder.

OBJECTIVE: To describe the clinical, radiologic, and histopathologic features of "congenital disseminated pyogenic granuloma" involving various organs with high morbidity related to cerebral hemorrhagic involvement. STUDY DESIGN: We searched the database of the Vascular Anomalies Center at Boston Children's Hospital from 1999 to 2019 for patients diagnosed as having multiple vascular lesions, visceral vascular tumors, congenital hemangiomatosis, multiple pyogenic granulomas, or multiple vascular lesions without a definite diagnosis. A retrospective review of the medical records, photographs, histopathologic, and imaging studies was performed. Only patients with imaging studies and histopathologic diagnosis of pyogenic granuloma were included. RESULTS: Eight children (5 male, 3 female) had congenital multifocal cutaneous vascular tumors. Lesions also were found in the brain (n = 7), liver (n = 4), spleen (n = 3), muscles (n = 4), bone (n = 3), retroperitoneum (n = 3), and intestine/mesentery (n = 2). Less commonly affected were the spinal cord, lungs, kidneys, pancreas, and adrenal gland (n = 1 each). The mean follow-up period was 21.8 months. The cerebral and visceral lesions were hemorrhagic with severe neurologic sequelae. The histopathologic diagnosis was pyogenic granuloma with prominent areas of hemorrhage and necrosis. The endothelial cells had enlarged nuclei, pale cytoplasm and were immunopositive for CD31 and negative for D2-40 and glucose transporter 1. CONCLUSIONS: Congenital disseminated pyogenic granuloma is a distinct multisystemic aggressive disorder that primarily affects the skin, brain, visceral organs, and musculoskeletal system. Differentiation of this entity from other multiple cutaneous vascular lesions is critical because of possible cerebral hemorrhagic involvement.

Diffuse capillary malformation with overgrowth contains somatic PIK3CA variants.

Diffuse capillary malformation with overgrowth (DCMO) is a clinical diagnosis describing patients with multiple, extensive capillary malformations (CMs) associated with overgrowth and foot anomalies. The purpose of the study was to identify somatic variants in DCMO. Skin containing CM and overgrown subcutaneous adipose tissue was collected from patients with DCMO. Exons from 447 cancer-related genes were sequenced using OncoPanel. Variant-specific droplet digital PCR (ddPCR) independently confirmed the variants and determined variant allele frequencies (VAF). One subject contained a somatic PIK3CA p.G106V variant. A second patient had a PIK3CA p.D350G variant. VAF was 27% to 29% in skin and 16% to 28% in subcutaneous adipose. Variants were enriched in endothelial cells (VAF 50%-51%) compared to nonendothelial cells (1%-8%). DCMO is associated with somatic PIK3CA variants and should be considered on the PIK3CA-related overgrowth spectrum (PROS). Variants are present in both skin and subcutaneous adipose and are enriched in endothelial cells.

Pediatric facial pyoderma gangrenosum preceding the diagnosis of inflammatory bowel disease.

We describe two adolescent patients with pyoderma gangrenosum (PG) involving the face. Subsequent gastrointestinal evaluation revealed microscopic bowel inflammation suggestive of inflammatory bowel disease. While PG is rarely localized to the face, this brief report reveals two cases of pediatric facial PG and suggests a correlation between facial PG and microscopic colitis.

Clinical and radiological characteristics of patients with retroperitoneal infantile hemangiomas.

BACKGROUND: Infantile hemangiomas (IHs) are the most common tumors of infancy. The objective was to identify clinical and radiological patterns in patients with retroperitoneal IHs. METHODS: We reviewed patients from our Vascular Anomalies Center database with IHs and abdominal imaging presenting from 1999 to 2017 to identify retroperitoneal involvement. RESULTS: Eleven patients (10 females, one male) with retroperitoneal IHs were found. Cutaneous IHs were present in eight patients (five segmental (45%), three multifocal (27%)) and absent in 1 (9%). Segmental hemangiomas involved the face in 2/5 (40%) and lower body in 3/5 (60%). The most common symptoms were dyspnea (n = 4), hematochezia (n = 3), and/or ulceration (n = 2). Three patients were asymptomatic. Involved retroperitoneal organs included the duodenum (n = 4), pancreas (n = 3), and adrenal glands (n = 1). Non-retroperitoneal organ involvement included the liver (n = 5), non-duodenal small intestine (n = 4), and large intestine (n = 3). Perivascular retroperitoneal hemangiomas were seen in 6/11 patients (55%), most commonly surrounding the aorta (n = 5), iliac vessels (n = 2), and/or inferior vena cava (n = 2). Three of 11 patients (27%) had LUMBAR based on a segmental, sacral hemangioma with tethered cord or anorectal malformation. Follow-up information was available in 6/11 patients (55%): 5 symptomatically improved with treatment (propranolol, corticosteroids, and/or vincristine), while one succumbed from extensive hepatic involvement. CONCLUSION: Retroperitoneal IHs are rare and tend to involve organs or surround vessels. Associated cutaneous IHs, if present, lack anatomical predilection and may be segmental or multifocal.

Pediatric leukemia cutis: A case series.

BACKGROUND: Pediatric leukemia cutis (LC) is often difficult to diagnose due to similarity in appearance to other dermatologic diseases. Several case reports and smaller case series have been published in the medical literature, but studies on larger cohorts of children with LC are lacking. OBJECTIVE: This study aimed to better characterize the clinical features, course, and prognosis of LC in the pediatric population. METHODS: We performed a retrospective case series of 31 patients diagnosed with LC at Boston Children's Hospital and the Children's Hospital of Philadelphia. RESULTS: The number and morphology of LC lesions varied among patients, with the head and lower extremities being the most common sites of involvement. Leukemia cutis presented concomitantly with systemic leukemia in the majority of cases. Most cases of LC arose during initial leukemia episodes, rather than with relapsed leukemia. Acute myeloid leukemia was the subtype most frequently associated with LC, followed by acute lymphoblastic leukemia. Diagnosis altered treatment timing and therapeutic decisions. CONCLUSION: Children most often present concomitantly with LC and systemic leukemia. Since the morphology and distribution of LC varies, physicians must maintain a high index of suspicion for this diagnosis, as the presence of LC may change the management of systemic leukemia.

Internal venous anomalies in patients with a genital venous malformation.

BACKGROUND: Cutaneous venous malformation (VM) can be associated with internal vascular anomalies. Our objective was to investigate the frequency of internal vascular anomalies in patients with an isolated genital venous malformation to assess the utility of screening for internal findings. METHODS: We retrospectively reviewed our Vascular Anomalies Center database for patients with a focal genital venous malformation presenting between 1999 and 2016. Abdominal and pelvic imaging reports were reviewed for internal vascular anomalies. Endoscopy reports were also reviewed when available. RESULTS: A focal genital venous malformation was found in 22 patients (14 female, 8 male). Ten (45%) had a venous malformation of at least one internal structure, most commonly the pelvic floor (n = 6), colon (n = 5), urethra (n = 4), and/or bladder (n = 3). Eight experienced hematuria, hematochezia, and/or rectorrhagia secondary to their internal venous malformation. In patients with internal venous malformations, the mean age of symptom presentation was 7.3 years (range 1-22 years). Two patients had malformed inferior mesenteric and portal veins visible using ultrasonography and magnetic resonance imaging. They required surgical intervention to prevent thrombosis and decrease urogenital and gastrointestinal bleeding. CONCLUSION: Nearly half of our patients with a focal genital venous malformation had internal venous anomalies. Physicians should suspect urogenital or gastrointestinal venous malformations in patients with a focal genital venous malformation, especially if they develop hematuria, hematochezia, or rectorrhagia. Significant mesenteric venous trunk anomalies can also occur. Because these require surgical intervention, early recognition is important. We recommend that all patients with a focal genital venous malformation undergo abdominal and pelvic ultrasound to evaluate for internal venous anomalies.

Holmes heart and tetralogy of Fallot in association with PHACE.

PHACE is an association between large infantile hemangiomas and brain, arterial, cardiac, and/or ocular abnormalities. Aortic or subclavian aberrations are the most common cardiovascular anomalies in PHACE, whereas complex congenital heart disease is rare. We report a case of Holmes heart and three cases of tetralogy of Fallot in PHACE association.

Herpes zoster at the vaccination site in immunized healthy children.

In this case series, we report seven immunized healthy children without underlying immunodeficiency who presented with herpes zoster that correlated with varicella-zoster vaccination site. The morphology of the lesions included erythematous papules, pseudovesicles, and plaques, with associated pain in two and pruritus in three patients; systemic symptoms ranged from none to low-grade fevers, upper respiratory symptoms, and joint pain. These cases highlight the clinical, diagnostic, and therapeutic implications of herpes zoster in vaccinated children.

Clinical Trial of the Protein Farnesylation Inhibitors Lonafarnib, Pravastatin, and Zoledronic Acid in Children With Hutchinson-Gilford Progeria Syndrome.

BACKGROUND: Hutchinson-Gilford progeria syndrome is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in LMNA yielding the farnesylated aberrant protein progerin. Without progerin-specific treatment, death occurs at an average age of 14.6 years from an accelerated atherosclerosis. A previous single-arm clinical trial demonstrated that the protein farnesyltransferase inhibitor lonafarnib ameliorates some aspects of cardiovascular and bone disease. This present trial sought to further improve disease by additionally inhibiting progerin prenylation. METHODS: Thirty-seven participants with Hutchinson-Gilford progeria syndrome received pravastatin, zoledronic acid, and lonafarnib. This combination therapy was evaluated, in addition to descriptive comparisons with the prior lonafarnib monotherapy trial. RESULTS: No participants withdrew because of side effects. Primary outcome success was predefined by improved per-patient rate of weight gain or carotid artery echodensity; 71.0% of participants succeeded (P<0.0001). Key cardiovascular and skeletal secondary variables were predefined. Secondary improvements included increased areal (P=0.001) and volumetric (P<0.001-0.006) bone mineral density and 1.5- to 1.8-fold increases in radial bone structure (P<0.001). Median carotid artery wall echodensity and carotid-femoral pulse wave velocity demonstrated no significant changes. Percentages of participants with carotid (5% to 50%; P=0.001) and femoral (0% to 12%; P=0.13) artery plaques and extraskeletal calcifications (34.4% to 65.6%; P=0.006) increased. Other than increased bone mineral density, no improvement rates exceeded those of the prior lonafarnib monotherapy treatment trial. CONCLUSIONS: Comparisons with lonafarnib monotherapy treatment reveal additional bone mineral density benefit but likely no added cardiovascular benefit with the addition of pravastatin and zoledronic acid. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00879034 and NCT00916747.

A somatic GNA11 mutation is associated with extremity capillary malformation and overgrowth.

BACKGROUND: Capillary malformation is a cutaneous vascular anomaly that is present at birth, darkens over time, and can cause overgrowth of tissues beneath the stain. The lesion is caused by a somatic activating mutation in GNAQ. In a previous study, we were unable to identify a GNAQ mutation in patients with a capillary malformation involving an overgrown lower extremity. We hypothesized that mutations in GNA11 or GNA14, genes closely related to GNAQ, also may cause capillary malformations. METHODS: Human capillary malformation tissue obtained from 8 patients that had tested negative for GNAQ mutations were studied. Lesions involved an extremity (n = 7) or trunk (n = 1). Droplet digital PCR (ddPCR) was used to detect GNA11 or GNA14 mutant cells (p.Arg183) in the specimens. Single molecule molecular inversion probe sequencing (smMIP-seq) was performed to search for other mutations in GNA11. Mutations were validated by subcloning and sequencing amplimers. RESULTS: We found a somatic GNA11 missense mutation (c.547C > T; p.Arg183Cys) in 3 patients with a diffuse capillary malformation of an extremity. Mutant allelic frequencies ranged from 0.3 to 5.0%. GNA11 or GNA14 mutations were not found in 5 affected tissues or in unaffected tissues (white blood cell DNA). CONCULSIONS: GNA11 mutations are associated with extremity capillary malformations causing overgrowth. Pharmacotherapy that affects GNA11 signaling may prevent the progression of capillary malformations.