Raised limb bands developing in infancy.
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Amniotic Band Syndrome↗
Biomedical subjects
A S Paller
Publications and source records attributed to A S Paller.
A colorimetric bead-binding assay for detection of intermolecular interactions.
We have developed a new technique that rapidly and reproducibly allows direct visualization of molecular interactions, including receptor-ligand binding. The technique can be easily applied to examine binding between proteins and glycoproteins, or proteins and glycolipids, including gangliosides. In this novel bead-binding assay, the suspected 'ligand' molecule is bound to 0.2- or 1.0- micro m colored FluoSphere beads. These coated beads are then mixed directly with 150- micro m Sepharose or 50- to 75- micro m agarose beads coated with the second 'target' molecule. Binding between molecules is easily detected by immunofluoresence microscopy as colored rosettes or aggregations formed by clustering of the smaller fluorescent beads around the larger non-fluorescent bead. The validity of this technique for glycolipid binding to protein was verified through demonstration of the known interaction between the beta subunit of cholera toxin with ganglioside GM1. The bead-binding technique facilitated the novel observations of interaction between ganglioside GT1b with the alpha5 subunit of alpha5beta1 integrin and the interaction of GM3 with the epidermal growth factor receptor. A modification of this technique, in which the coated beads are bound to protein fixed on plates, allows a quantifiable colorimetric assay of interaction. This versatile and rapid technique will have widespread applications for in vitro systems and may also be useful for in vivo analysis of binding to cell surface receptor molecules.
Animals↗
Inhibition of integrin-linked kinase/protein kinase B/Akt signaling: mechanism for ganglioside-induced apoptosis.
Ganglioside GT1b inhibits keratinocyte attachment to and migration on a fibronectin matrix by binding to alpha(5)beta(1) and preventing alpha(5)beta(1) interaction with fibronectin. The role of gangliosides in triggering keratinocyte apoptosis, however, is unknown. Addition of GT1b to keratinocyte-derived SCC12 cells, grown in serum-free medium but exposed to fibronectin, suppressed Bad phosphorylation, activated caspase-9, and inhibited cyclin D and E expression, resulting in cell cycle arrest at G(1) phase and initiation of apoptosis. The mechanism of GT1b activation of caspase-9 involved inhibition of beta(1) integrin serine/threonine phosphorylation and decreased phosphorylation of both integrin-linked kinase and protein kinase B/Akt at its Ser-473 site, leading to cytochrome c release from mitochondria. Consistently, blockade of GT1b function with anti-GT1b antibody specifically activated the Ser-473 site of Akt, markedly suppressing apoptosis. The ganglioside-induced inhibition of Akt phosphorylation was GT1b-specific and was not observed when cells were treated with other keratinocyte gangliosides, including GD3. These studies suggest that the modulation of keratinocyte cell cycle and survival by GT1b is mediated by its direct interaction with alpha(5)beta(1) and resultant inhibition of the integrin/integrin-linked kinase/protein kinase B/Akt signaling pathway.
Apoptosis↗
Expanding our concepts of mosaic disorders of skin.
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Adult↗
Langerhans cell histiocytosis presenting in the neonatal period: a retrospective case series.
OBJECTIVES: To describe the morphologic characteristics of skin lesions, extent of extracutaneous disease, and outcomes in patients with neonatal presentation of Langerhans cell histiocytosis (LCH), and to examine clinical predictors of disease prognosis. DESIGN: Retrospective validation cohort study. Maximum duration of follow-up was 10 years. SETTING: A tertiary care children's hospital in Chicago, Ill. PATIENTS: Nineteen children with cutaneous findings in the first 4 weeks of life and subsequently diagnosed with LCH based on compatible tissue histologic analysis, confirmed by electron microscopy and/or immunohistochemical analysis. MAIN OUTCOME MEASURE: Cutaneous lesion morphologic characteristics, extracutaneous manifestations, treatments, and outcomes were tabulated and compared. RESULTS: The most common initial skin lesion was erythematous, often crusted, vesiculopustules. Skin lesion morphologic traits did not correlate with extent of extracutaneous disease. One third of patients had disease limited to the skin and/or mucous membranes. All of these patients are alive and well, and 1 has developed diabetes insipidus. Twelve of the 19 patients had multisystem disease, and 2 died of disease. The results of a multiorgan workup performed at the time of diagnosis were predictive of which patients in this cohort manifested multisystem disease. The overall incidence of diabetes insipidus was 21%. CONCLUSIONS: Vesiculopustular lesions are common in congenital/neonatal LCH, but the morphologic characteristics of lesions are not helpful in predicting the extent of disease. A multiorgan evaluation at the time of diagnosis may be predictive of the probability of multisystem involvement with LCH.
Female↗
Ganglioside modulates ligand binding to the epidermal growth factor receptor.
Whereas previous investigations have shown that pharmacologic addition of gangliosides inhibits keratinocyte proliferation by downregulating epidermal growth factor receptor phosphorylation, the underlying biochemical basis and physiologic relevance are unknown. Using Scatchard and displacement plots, we have shown that supplemental purified gangliosides decrease the binding of (125)I-labeled epidermal growth factor to keratinocyte-derived SCC12 cells. Conversely, SCC12 cells transfected with sialidase and thus depleted of gangliosides show increased ligand binding to the epidermal growth factor receptor, which is consistent with their increased proliferation in response to epidermal growth factor and transforming growth factor-alpha, and increased phosphorylation of the epidermal growth factor receptor, and downstream signal transduction pathway components. The mechanism of the altered binding appears to involve primarily decreased numbers of available receptors within the intact membrane, but not altered receptor protein expression. These studies provide evidence that the effect of gangliosides on keratinocyte proliferation results, at least in part, from the direct binding of ganglioside to the receptor and disruption of the receptor-ligand interaction. Manipulation of membrane ganglioside content may be a powerful new means to alter epidermal growth factor receptor-dependent cell proliferation.
DNA, Complementary↗
A novel KIT mutation results in piebaldism with progressive depigmentation.
Piebaldism is an autosomal dominant disorder of melanocyte development characterized by white skin (leukoderma) and white hair (poliosis). In general, piebaldism has been distinguished from vitiligo by the presence of lesions from birth, the hyperpigmented macules of depigmented and normal skin, and the static course. We hypothesized that an 8-year-old girl and her mother who had unusual piebaldism of a progressive nature would have a novel mutation of the KIT gene, the gene that is altered in patients with piebaldism, or of the MITF (microphthalmia activating transcription factor) gene, which would be expected to cause type II Waardenburg syndrome, but is associated with a phenotype of progressive depigmentation in mice. Genomic DNA was extracted from the blood of affected and unaffected family members, and the KIT and MITF genes were sequenced. Genetic analysis of genomic DNA from both the mother and daughter with progressive piebaldism revealed a novel Val620Ala (1859T>C) mutation in the KIT gene, which was not detected in family members without progressive piebaldism or in 52 normal control individuals. This KIT mutation affects the intracellular tyrosine kinase domain and thus predicts a severe phenotype, as was the case in this family. Although other KIT mutations in the vicinity of codon 620 lead to the standard phenotype of static piebaldism, the Val620Ala mutation is novel and may result in a previously undescribed phenotype with melanocyte instability, leading to progressive loss of pigmentation as well as the progressive appearance of the hyperpigmented macules.
Adult↗
Aquagenic palmoplantar keratoderma.
Aquagenic palmoplantar keratoderma is an acquired condition characterized by burning and edema limited to the hands after brief immersion in water. The 3 patients described possess a striking similarity to those with transient reactive papulotranslucent acrokeratoderma. All 3 patients manifested the "hand-in-the-bucket" sign, having presented to a physician with a hand immersed in a bucket of water to more promptly demonstrate the physical findings. Aluminum chloride hexahydrate represents a potentially valuable therapeutic option for this unusual condition.
Adolescent↗
Ongoing blistering in a boy with congenital erosive and vesicular dermatosis healing with reticulated supple scarring.
Congenital erosive and vesicular dermatosis healing with reticulated supple scarring is a rare entity presenting in the newborn with crusted erosions and vesicles that heal relatively rapidly, forming unique reticulated scars. A 9-year-old boy presented with a diagnosis of junctional epidermolysis bullosa, but displayed this characteristic scarring pattern and very mild ongoing blistering. In addition, he had severe chronic conjunctivitis due to cicatricial alopecia of the eyelashes and lacrimal duct obstruction. He had no evidence of enamel defects or other features of junctional epidermolysis bullosa. Ultrastructural analysis of his skin biopsy specimens showed a normal dermoepidermal junction. This characteristic scarring disorder may be associated with mild ongoing blistering and must be distinguished from other congenital blistering disorders.
Blister↗
Use of nonsteroidal topical immunomodulators for the treatment of atopic dermatitis in the pediatric population.
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Adjuvants, Immunologic↗
Epidermal growth factor receptor glycosylation is required for ganglioside GM3 binding and GM3-mediated suppression [correction of suppresion] of activation.
Gangliosides are able to bind to the epidermal growth factor receptor and inhibit its activation, but the mechanism of this inhibition is unknown. To address the role of receptor carbohydrates in facilitating interaction with gangliosides, we examined the ability of GM3 to bind the deglycosylated receptor and inhibit its autophosphorylation. Flow cytometry studies demonstrated that deglycosylation of the receptor did not affect its ability to be transported to the cell membrane. In contrast with the native (fully glycosylated) receptor, GM3 did not coimmunoprecipitate with the deglycosylated receptor. Using a novel colorimetric bead binding assay, GM3 was shown to bind well to the immunoprecipitated native receptor but not at all to the deglycosylated receptor. Finally, the addition of GM3 to cells with deglycosylated epidermal growth factor receptors did not result in significant further inhibition of autophosphorylation of the receptor, despite a 10-fold decrease in phosphorylation of the native epidermal growth factor receptor by 200 microM GM3. These studies suggest that ganglioside affects epidermal growth factor receptor activity through a direct interaction that requires receptor glycosylation, and contribute to our understanding of the role of gangliosides in cell membrane function.
Cell Line↗
Full-thickness surgical excision for the treatment of inflammatory linear verrucous epidermal nevus.
Inflammatory linear verrucous epidermal nevus (ILVEN) is a benign cutaneous hamartoma characterized by intensely erythematous, pruritic, inflammatory papules that occur as linear bands along the lines of Blaschko. Because of its chronic and unremitting symptomatology, patients with ILVEN seek medical treatment for relief of discomfort as well as concerns regarding cosmetic appearance. Reported therapeutic approaches include topical agents, dermabrasion, cryotherapy, laser therapy, and partial-thickness excision. Unfortunately, no one therapy has been successful consistently. Medical management is often unsatisfactory, because improvement tends to be temporary. Surgical modalities have met with better success in relief of symptoms but at the risk of marked scarring and a high rate of recurrence. Furthermore, the occurrence of extensive ILVEN or localization to certain anatomic regions has been considered previously a relative contraindication to excision. The authors report 4 patients with extensive ILVEN treated successfully with full-thickness surgical excision. Our report underscores the effectiveness of this surgical modality for the definitive treatment of ILVEN.
Adult↗
Kwashiorkor in the United States: fad diets, perceived and true milk allergy, and nutritional ignorance.
BACKGROUND: Kwashiorkor is the edematous form of protein-energy malnutrition. It is associated with extreme poverty in developing countries and with chronic malabsorptive conditions such as cystic fibrosis in developed countries. Rare cases of kwashiorkor in affluent countries unrelated to chronic illness have been reported. We present 12 cases of kwashiorkor unrelated to chronic illness seen over 9 years by pediatric dermatologists throughout the United States, and discuss common causative themes in this easily preventable condition. OBSERVATIONS: Twelve children were diagnosed as having kwashiorkor in 7 tertiary referral centers throughout the United States. The diagnoses were based on the characteristic rash and the overall clinical presentation. The rash consisted of an erosive, crusting, desquamating dermatitis sometimes with classic "pasted-on" scale-the so-called flaky paint sign. Most cases were due to nutritional ignorance, perceived milk intolerance, or food faddism. Half of the cases were the result of a deliberate deviation to a protein-deficient diet because of a perceived intolerance of formula or milk. Financial and social stresses were a factor in only 2 cases, and in both cases social chaos was more of a factor than an absolute lack of financial resources. Misleading dietary histories and the presence of edema masking growth failure obscured the clinical picture in some cases. CONCLUSIONS: Physicians should consider the diagnosis of kwashiorkor in children with perceived milk allergies resulting in frequent dietary manipulations, in children following fad or unorthodox diets, or in children living in homes with significant social chaos. The presence of edema and "flaky paint" dermatitis should prompt a careful dietary investigation.
Diet Fads↗
Primary generalized and localized hypertrichosis in children.
OBJECTIVE: To review the causes, presentation, and therapy of primary generalized and localized symmetrical hypertrichosis in children. DESIGN: Retrospective medical record review. SETTING: Academic specialty referral clinic for pediatric dermatological disorders. PATIENTS: Case series of 11 prepubertal male and female patients who had idiopathic hypertrichosis between July 1, 1990, and November 30, 1999. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Clinical distribution of increased hair growth and types of hair removal methods used. RESULTS: Seven girls and 4 boys, ranging in age from 4 months to 11 years, were evaluated. Four patients showed generalized hypertrichosis. The other 7 patients had localized symmetrical hypertrichosis, representing the subsets of hypertrichosis cubiti, anterior cervical hypertrichosis, posterior cervical hypertrichosis, and faun tail deformity. All patients with generalized hypertrichosis manifested the condition at birth; the age of onset in children with localized symmetrical primary hypertrichosis ranged from birth to 4 years. One girl with generalized hypertrichosis had gingival hyperplasia and the girl with faun tail deformity had bony diastematomyelia with spina bifida occulta. The medical histories and physical examination findings of all of the children were otherwise unremarkable. All patients were referred for diagnostic and therapeutic considerations. CONCLUSIONS: Primary hypertrichotic conditions, whether localized or generalized, are rare in pediatric patients and of unknown origin. Although otherwise benign, these disorders may result in cosmetic disfigurement and psychosocial trauma for patients and families. Patients and their families should be adequately advised of the available treatment methods for both temporary and permanent hair removal.
Child↗
Carbohydrate-carbohydrate binding of ganglioside to integrin alpha(5) modulates alpha(5)beta(1) function.
Gangliosides GT1b and GD3, components of keratinocyte membranes, inhibit keratinocyte adhesion to fibronectin. Although ganglioside sialylation is known to be important, the mechanism of inhibition is unknown. Using purified insect recombinant alpha(5) and beta(1) proteins and alpha(5)beta(1) integrin from lysed keratinocyte-derived SCC12 cells, we have shown that GT1b and GD3 inhibit the binding of alpha(5)beta(1) to fibronectin. Co-immunoprecipitation of GT1b and alpha(5)beta(1) from SCC12 cells and direct binding of GT1b and GD3 to affinity-purified alpha(5)beta(1) from SCC12 cells and insect recombinant alpha(5)beta(1), particularly the alpha(5) subunit, further suggest interaction between ganglioside and alpha(5)beta(1). The carbohydrate moieties of integrin appear to be critical since gangliosides are unable to bind deglycosylated forms of alpha(5)beta(1) from SCC12 and insect cells or poorly glycosylated recombinant alpha(5)beta(1) from Escherichia coli cells. The GT1b-alpha(5)beta(1) interaction is inhibited by concanavalin A, suggesting that GT1b binds to mannose structures in alpha(5)beta(1). The preferential binding of GT1b to high mannose rather than reduced mannose ovalbumin further implicates the binding of GT1b to mannose structures. These data provide evidence that highly sialylated gangliosides regulate alpha(5)beta(1)-mediated adhesion of epithelial cells to fibronectin through carbohydrate-carbohydrate interactions between GT1b and the alpha(5) subunit of alpha(5)beta(1) integrin.
Cell Adhesion↗
Itraconazole pulse therapy for dermatophyte onychomycosis in children.
BACKGROUND: Onychomycosis, or fungal infection of the nail, can occur in prepubertal children. However, its diagnosis is often missed or the condition is inappropriately treated with topical medication. Griseofulvin has been the therapy of choice, but even long-term treatment is associated with a poor cure rate and high rate of relapse. Trials with adult patients have shown that itraconazole pulse therapy for onychomycosis requires a shorter duration of total therapy than griseofulvin treatment and is rarely associated with adverse reactions, suggesting that it may be the treatment of choice for pediatric patients with onychomycosis. DESIGN: We retrospectively reviewed the courses of prepubertal patients with dermatophyte onychomycosis who initiated treatment with itraconazole pulse therapy between January 1995 and June 1998. SETTING: Urban and suburban pediatric dermatology clinics of a children's hospital. PATIENTS: Seventeen prepubertal patients met the enrollment and follow-up criteria. These included fungal infection of the nail(s), documented by fungal culture and/or positive potassium hydroxide mounts of nail scrapings; at least 1 follow-up visit; and contact by telephone or clinic visit within 2 months prior to compilation of data. In 59% of patients, a relative living at the home had onychomycosis at the time of diagnosis. INTERVENTION: Patients were treated with daily to twice-daily pulses of itraconazole, administered for 1 week of each of 3 to 5 months. MAIN OUTCOME MEASURES: Clinical cure after itraconazole therapy in patients with documented onychomycosis and clinical and mycologic relapse after initial cure. Fungal cultures were not repeated if clinical cure was noted. RESULTS: All but 1 patient responded fully to therapy, showing improvement within a few months and subsequently clearance (94% clinical cure rate). No patients experienced any clinical adverse reactions. No relapses occurred after clinical cure during a follow-up period of 1 to 4.25 years after initiation of therapy. CONCLUSIONS: Itraconazole pulse therapy is effective and safe for the treatment of onychomycosis in children. The relapse rate in pediatric patients is lower than in adults, although the high frequency of onychomycosis in non-pediatric family members suggests that the recurrence risk is increased if other family members are not treated concomitantly.
Adolescent↗
Dermatologic clues to inherited disease.
Genetic diseases often have cutaneous manifestations, which can be the first or most prominent signs of the underlying problem. Recognition of these dermatologic clues allows prompt diagnosis and intervention. In this article, the authors have attempted to outline several important examples of genodermatoses.
Child↗
Responses to anti-angiogenic therapies.
Vascular tumors occur in approximately 10% of infants, and range from small cherry-red lesions to large, life-threatening tumors. Although the majority of these tumors involute after several years, there are few therapeutic options and their use is limited by the risk of side-effects. The recent increase in understanding of angiogenesis has led to investigations of new antiangiogenic treatment options using models of vascular tumors in mice. These studies have demonstrated the success of a variety of antiangiogenic approaches, including systemic administration of the antiangiogenic proteins AGM-1470 and angiostatin or of the matrix metalloproteinase inhibitor batimastat, and gene gun therapy with interleukin-12. Although these trials provide further evidence of the role of angiogenesis in the enlargement of these vascular tumors, their potential utility and safety await future trials in patients.
Angiogenesis Inhibitors↗