Pediatric cutaneous T-cell neoplasm and mimics with gamma-delta expression: Not always aggressive.

Pediatric cutaneous T-cell lymphoma with γδ immunophenotype is extremely rare. Only a few cases of γδ T-cell neoplasm have been reported in the literature, and therefore little is known whether γδ T-cell neoplasms in children are distinct from their adult counterparts with respect to the clinicopathological presentation, behavior, and prognosis. In this study, we demonstrate three unique pediatric cutaneous T-cell neoplasm and mimics with increased γδ T cells. All cases showed an indolent clinical course.

Severe reactive infectious mucocutaneous eruption mimicking drug-induced epidermal necrolysis triggered by norovirus.

Reactive infectious mucocutaneous eruption (RIME) is an eruptive mucositis with varying degrees of cutaneous involvement presumed to be due to an immunologic response to various infectious pathogens. Most reported cases occur after a prodromal upper respiratory illness. We present a patient with a particularly severe case mimicking drug-induced epidermal necrolysis found to be triggered by asymptomatic norovirus infection, a virus not previously reported in association with RIME.

Myeloid sarcoma in a newborn: A rare manifestation of congenital acute myeloid leukemia.

Cutaneous myeloid sarcoma is rarely present prior to the diagnosis of congenital acute myeloid leukemia (AML); the former is typically diagnosed with or after the leukemia. We report a 2-day-old male born with multiple cutaneous red to violaceous nodules. Histopathologic and immunohistochemistry findings from a skin nodule were suspicious for myeloid sarcoma. Bone marrow biopsy was initially negative for aberrant blasts; however, at age 4 months, AML with a KMT2A gene rearrangement was identified via bone marrow biopsy.

A widespread blistering eruption: diffuse cutaneous mastocytosis.

Diffuse cutaneous mastocytosis with bullous formation is a rare childhood disease. We report a 5-month-old male who presented with a 3-week history of cutaneous bullae and pruritus. On examination, he had erythema of the cheeks bilaterally and diffuse slightly hyperpigmented, indurated skin on his trunk and abdomen. There were tense vesicles, bullae, and erosions linearly arranged on his trunk and extremities. Both the laboratory and imaging workup were normal. Subsequently, a punch biopsy of a vesicle on the abdomen was obtained and findings confirmed a diagnosis of diffuse cutaneous mastocytosis. An EpiPen(r) was prescribed due to the slightly increased anaphylaxis risk compared to other forms of mastocytosis. There are many purported triggers of diffuse cutaneous mastocytosis and there is currently no known cure which makes management of this disease challenging. This case highlights a rare condition for which official treatment guidelines do not exist. A prompt dermatologic diagnosis is necessary to ensure proper workup and regulation is in place.

Numerous Angiomatous Lesions in an Infant.

A 3-month-old infant presented with bright red macules, papules, and plaques that appeared at birth and grew in size and number. What is your diagnosis?

Facial cleft presenting as a congenital facial papule.

Tessier number 3 craniofacial clefts are a rare congenital deformity of the oronasoocular region with variable severity, most often with serious impacts on appearance and function due to involvement of the bone and soft tissue. However, they can occasionally manifest mildly as a skin-colored congenital facial papule present with subtle anatomic anomalies and signs of deeper involvement, such as crusting and oozing. Recognizing that a congenital facial papule, including non-midline lesions, may be the presenting sign of an underlying developmental anomaly is important to avoid missing the diagnosis of a more extensive underlying congenital defect. We present a rare case of a forme fruste variant of a Tessier number 3 craniofacial cleft to raise awareness of its presentation and advise initial management in hopes of improving outcomes.

Congenital Pigmentary Anomalies in the Newborn.

Congenital pigmentary anomalies may be evident at birth or soon after, with some birthmarks becoming apparent later in infancy or early childhood. It is important to recognize various pigmentary anomalies in the neonate, most of which are benign but a subset of which are associated with cutaneous morbidity or systemic ramifications and require further evaluation. This review will focus on pigmentary mosaicism, congenital melanocytic nevi, nevus spilus, dermal melanocytosis, and pigmentary anomalies associated with neurofibromatosis type 1 (café au lait spots, freckling, plexiform neurofibromas, nevus anemicus), tuberous sclerosis (hypomelanotic macules), and incontinentia pigmenti.

Use of psoralen therapies obtained abroad in two children with Vitiligo.

We describe two American-born children with vitiligo, each of whom travelled to their family's ancestral home (India and Ethiopia), where their skin conditions were treated with PUVAsol, which involves the use of topical or oral psoralens followed by exposure to natural sunlight. Both children experienced modest repigmentation and were subsequently seen in our dermatology clinics. PUVAsol may be an attractive treatment option for some families, but there are potentially serious side effects including phototoxicity and cutaneous malignancy. Dermatologists should be aware of the existence of this treatment modality as well as its complications.

Treatment of benign cephalic histiocytosis with topical 1% rapamycin ointment.

We report a pediatric case of extensive, progressive benign cephalic histiocytosis (BCH) involving the face, trunk, and extremities with response of facial lesions to treatment with topical 1% rapamycin. A split-face model was used to demonstrate improvement on the treated side versus the untreated side. After physician and parental perception of effectiveness, based in part on photodocumentation, subsequently both cheeks were treated with continued improvement.

Common Neonatal Skin Lesions: Melanocytic Nevi, Pigment Alterations, and Nonmelanocytic Nevi.

Birthmarks are common in the healthy population and are generally harmless. Certain presentations, however, raise concern for associated syndromes or potential complications. It is important for pediatricians to be familiar with both harmless and potentially concerning birthmarks. This article discusses congenital melanocytic nevi, café-au-lait macules, hypomelanotic macules, nevus depigmentosus, nevus anemicus, epidermal nevi, and nevus sebaceous, including potential syndromes and complications. [Pediatr Ann. 2019;48(1):e23-e29.].

Segmental storiform collagenomas: Expanding the spectrum of PTEN hamartoma tumor syndrome in children.

A 4-year-old girl with autism spectrum disorder and congenital heart disease presented to dermatology clinic for evaluation of skin growths present since infancy. Physical examination was significant for macrocephaly and agminated skin-colored to pink papulonodules in a segmental distribution on the right lower back and buttocks, biopsy of which showed storiform collagenomas (sclerotic fibromas). Genetic testing revealed a pathogenic missense mutation in the PTEN gene, and a diagnosis of PTEN hamartoma tumor syndrome was made. The segmental nature of her storiform collagenomas is unique, to our knowledge, and may be explained by a postzygotic second-hit PTEN mutation, contributing to the growing spectrum of clinical findings associated with PTEN hamartoma tumor syndrome.

Identification of small molecules that inhibit the interaction of TEM8 with anthrax protective antigen using a FRET assay.

Tumor marker endothelial 8 (TEM8) is a receptor for the protective antigen (PA) component of anthrax toxin. TEM8 is upregulated on endothelial cells lining the blood vessels within tumors, compared with normal blood vessels. A number of studies have demonstrated a pivotal role for TEM8 in developmental and tumor angiogenesis. We have also shown that targeting the anthrax receptors with a mutated form of PA inhibits angiogenesis and tumor formation in vivo. Here we describe the development and testing of a high-throughput fluorescence resonance energy transfer assay to identify molecules that strongly inhibit the interaction of PA and TEM8. The assay we describe is sensitive and robust, with a Z' value of 0.8. A preliminary screen of 2310 known bioactive library compounds identified ebselen and thimerosal as inhibitors of the TEM8-PA interaction. These molecules each contain a cysteine-reactive transition metal, and complementary studies indicate that their inhibition of interaction is due to modification of a cysteine residue in the TEM8 extracellular domain. This is the first demonstration of a high-throughput screening assay that identifies inhibitors of TEM8, with potential application for antianthrax and antiangiogenic diseases.

1,2,3,4,6-Penta-O-galloyl-ß-D-glucopyranose inhibits angiogenesis via inhibition of capillary morphogenesis gene 2.

Capillary morphogenesis gene 2 (CMG2) is a transmembrane extracellular matrix binding protein that is also an anthrax toxin receptor. We have shown that high-affinity CMG2 binders can inhibit angiogenesis and tumor growth. We recently described a high-throughput FRET assay to identify CMG2 inhibitors. We now report the serendipitous discovery that PGG (1,2,3,4,6-penta-O-galloyl-ß-D-glucopyranose) is a CMG2 inhibitor with antiangiogenic activity. PGG is a gallotannin produced by a variety of medicinal plants that exhibits a wide variety of antitumor and other activities. We find that PGG inhibits CMG2 with a submicromolar IC50 and it also inhibits the migration of human dermal microvascular endothelial cells at similar concentrations in vitro. Finally, oral or intraperitoneal administration of PGG inhibits angiogenesis in the mouse corneal micropocket assay in vivo. Together, these results suggest that a portion of the in vivo antitumor activity of PGG may be the result of antiangiogenic activity mediated by inhibition of CMG2.

Phenolic compounds as antiangiogenic CMG2 inhibitors from Costa Rican endophytic fungi.

Targeting and inhibiting CMG2 (Capillary Morphogenesis Gene protein 2) represents a new strategy for therapeutic agents for cancer and retinal diseases due to CMG2's role in blood vessel growth (angiogenesis). A high throughput FRET (Förster Resonance Energy Transfer) assay was developed for the identification of CMG2 inhibitors as anti-angiogenetic agents. Bioassay-guided separation led to the isolation and identification of two new compounds (1 and 2) from CR252M, an endophytic fungus Coccomyces proteae collected from a Costa Rican rainforest, and one known compound (3) from CR1207B (Aurapex penicillata). Secondary in vitro assays indicated anti-angiogenic activity. Compound 3 inhibited the endothelial cell migration at 52 µM, but did not show any endothelial cell antiproliferative effect at 156 µM. The structure of the two new compounds, A (1) and B (2), were elucidated on the basis of extensive spectroscopic analysis, including 1D and 2D NMR experiments.

A FRET-based high throughput screening assay to identify inhibitors of anthrax protective antigen binding to capillary morphogenesis gene 2 protein.

Anti-angiogenic therapies are effective for the treatment of cancer, a variety of ocular diseases, and have potential benefits in cardiovascular disease, arthritis, and psoriasis. We have previously shown that anthrax protective antigen (PA), a non-pathogenic component of anthrax toxin, is an inhibitor of angiogenesis, apparently as a result of interaction with the cell surface receptors capillary morphogenesis gene 2 (CMG2) protein and tumor endothelial marker 8 (TEM8). Hence, molecules that bind the anthrax toxin receptors may be effective to slow or halt pathological vascular growth. Here we describe development and testing of an effective homogeneous steady-state fluorescence resonance energy transfer (FRET) high throughput screening assay designed to identify molecules that inhibit binding of PA to CMG2. Molecules identified in the screen can serve as potential lead compounds for the development of anti-angiogenic and anti-anthrax therapies. The assay to screen for inhibitors of this protein-protein interaction is sensitive and robust, with observed Z' values as high as 0.92. Preliminary screens conducted with a library of known bioactive compounds identified tannic acid and cisplatin as inhibitors of the PA-CMG2 interaction. We have confirmed that tannic acid both binds CMG2 and has anti-endothelial properties. In contrast, cisplatin appears to inhibit PA-CMG2 interaction by binding both PA and CMG2, and observed cisplatin anti-angiogenic effects are not mediated by interaction with CMG2. This work represents the first reported high throughput screening assay targeting CMG2 to identify possible inhibitors of both angiogenesis and anthrax intoxication.