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Biomedical subjects

Seth J Orlow

Publications and source records attributed to Seth J Orlow.

At least 19 recordsLinked to original sources
PubMed2006

Eccrine angiomatous hamartoma.

A 7-year-old girl presented with asymptomatic bruise-like hairy nodules on her right lower leg since 8 months of age. Histopathology demonstrated an increased number of blood vessels and eccrine glands, thicker collagen bundles, and a terminal hair follicle in catagen phase. The patient was diagnosed with multiple eccrine pilar angiomatous nevi, an unusual variant of eccrine angiomatous hamartomas. The natural course of eccrine angiomatous hamartomas is typically slow growth and benign behavior. Simple excision is usually curative and is reserved for painful or cosmetically disfiguring lesions. Our patient's nevus is large and multifocal, making excision more challenging.

Child↗
PubMed2006

Patient perspectives on the management of atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is increasingly common, with a point prevalence of more than 30% in some countries, and is characterized by visible skin lesions and intense itching. OBJECTIVE: The International Study of Life with Atopic Eczema (ISOLATE) is the first large-scale study to assess the effect of AD on the lives of patients and society, how patients and caregivers manage the condition, and how well patients and caregivers currently believe that AD is controlled. METHODS: Two thousand two patients (>13 years) and caregivers of children (2-13 years) with moderate-to-severe AD randomly selected from 8 countries underwent standardized telephone interviews using questions developed in collaboration with national eczema patient groups and physicians. RESULTS: During each year, patients spend, on average, 1 of 3 days in flare. The majority of patients receive prescription topical corticosteroids to treat flares; however, 49% of respondents are concerned about using these agents. On average, patients and caregivers delay initiating treatment for 7 days after onset of a flare. Only 24% of patients and caregivers feel confident they can manage AD flares adequately. Seventy-five percent of caregivers and patients feel that being able to effectively control AD would be the single most important improvement to their or their child's quality of life. The avoidable secondary economic cost of AD is estimated at 2 billion Euro per year across the European Union. CONCLUSION: ISOLATE highlights the need to improve patients' control of AD to reduce the significant effect this condition has on the patient and society. CLINICAL IMPLICATIONS: ISOLATE shows that patients with AD are untreated for half the time they are in flare, and thus there is an urgent need for physicians to ensure that the patients are educated and confident in using medication as prescribed to gain disease control.

Adolescent↗
PubMed2006

Mucocutaneous neuromas: an underrecognized manifestation of PTEN hamartoma-tumor syndrome.

BACKGROUND: The spectrum of clinical findings associated with PTEN tumor suppressor gene germline mutations, referred to as PTEN hamartoma-tumor syndrome (PHTS), includes Cowden and Bannayan-Riley-Ruvalcaba syndromes. Although the skin is the ectodermal structure most often affected by these autosomal dominant genodermatoses, abnormalities of neural tissues are frequently observed. OBSERVATIONS: We describe a 5-year-old boy with macrocephaly, prominent corneal nerves, and progressive development of multiple painful, dome-shaped, translucent pink to skin-colored papules on the vermilion portion of the upper lip, fingers, palms, and shins. Histologic evaluation demonstrated dermal proliferation of well-demarcated nerve bundles associated with abundant mucin and surrounded by a distinct perineural sheath, findings diagnostic of a nonencapsulated neuroma. Genetic analysis revealed a novel heterozygous germline nonsense mutation in PTEN, predicted to result in a truncated PTEN protein. To our knowledge, this represents the first report of multiple neuromas as the sole mucocutaneous manifestation of PHTS. CONCLUSIONS: This article highlights neuromas as a cutaneous sign of PHTS, drawing attention to manifestations of PHTS in neural tissues of the skin, eye, gastrointestinal tract, and brain. Along with multiple endocrine neoplasia type 2B, PHTS should be considered in the differential diagnosis of multiple mucocutaneous neuromas, particularly those involving extrafacial sites.

Child, Preschool↗
PubMed2006

Phacomatosis pigmentokeratotica associated with hemihypertrophy and a rhabdomyosarcoma of the abdominal wall.

Phacomatosis pigmentokeratotica (PPK) represents a specific "twin nevus" syndrome in which a speckled lentiginous nevus (SLN) is associated with an organoid nevus with sebaceous differentiation. A boy with a large nevus sebaceus on the left face and upper part of the trunk, a giant segmental SLN extending from the abdomen to the feet bilaterally, and right hemihypertrophy developed an embryonal rhabdomyosarcoma of the right abdominal wall at age 6 months. A variety of musculoskeletal, neurologic, and ocular anomalies have been observed in patients with PPK, reflecting the individual manifestations of both SLN and Schimmelpenning syndromes. This report adds hemihypertrophy to the spectrum of extracutaneous manifestations of PPK and, to our knowledge, represents the first observation of a rhabdomyosarcoma arising in contiguity with an SLN in a patient with PPK. The development of a rhabdomyosarcoma in our patient likely reflects both increased propensity for growth (as evidenced by the hemihypertrophy) and the pluripotent nature of neural-crest derived cells within the field defect that underlies an SLN.

Abdominal Wall↗
PubMed2006

Ehlers-Danlos syndrome type VIII: periodontitis, easy bruising, marfanoid habitus, and distinctive facies.

An 11-year-old boy had a history of easy bruising and poorly healing wounds since infancy and severe, early-onset periodontitis. He also exhibited mild hypermobility of the small joints of the hands, long limbs with striking arachnodactyly, and a triangular face with delicate features. Analysis of type I and type III collagens revealed no abnormalities. These findings were consistent with a diagnosis of Ehlers-Danlos syndrome type VIII (EDS-VIII), an autosomal dominant connective tissue disorder that was recently mapped to chromosome 12q13. We draw attention to the clinical features that typify EDS-VIII, including extensive pretibial bruising, a marfanoid body habitus, and characteristic facies, as well as childhood onset of progressive periodontal disease.

Age of Onset↗
PubMed2006

Mutations in the desmoglein 4 gene underlie localized autosomal recessive hypotrichosis with monilethrix hairs and congenital scalp erosions.

Localized autosomal recessive hypotrichosis (LAH) is a recently defined disorder characterized by fragile, short, sparse hairs on the scalp, trunk, and extremities. Mutations in desmoglein 4 (DSG4), a novel member of the desmosomal cadherin family that is expressed in the hair follicle as well as the suprabasal epidermis, have been found to underlie LAH. Thus far, the allelic series includes a recurrent intragenic deletion identified in affected Pakastani kindreds and a missense mutation detected in an Iraqi family. We report three siblings of Iraqi and Iranian origin with LAH that presented with congenital scalp erosions and monilethrix-like hairs, features that have not been previously described in this disorder. Follicular hyperkeratotic papules and marked pruritus were also prominent clinical findings. Novel compound heterozygous DSG4 mutations, including a splice-site mutation and a missense mutation that disrupts a conserved calcium-binding site in the extracellular (EC)2-EC3 interface, were found to underlie the disease in this family. These observations broaden the phenotypic and genotypic spectrum of LAH, further illustrating the consequences of DSG4 dysfunction on epidermal and hair shaft integrity.

Amino Acid Sequence↗
PubMed2005

Juvenile amyopathic dermatomyositis.

A 3-year-old girl presented with a 6-month history of multiple, light-pink, flat-topped papules over the dorsal aspects of the metacarpophalangeal and interphalangeal joints of the hands and feet. Nailfold telangiectases, ragged cuticles, and a heliotrope color of the upper eyelids were also evident, but there was no clinical evidence of muscle weakness and levels of muscle enzymes were normal. A biopsy specimen from one of the papules showed a vacuolar interface dermatitis consistent with a diagnosis of dermatomyositis. This report draws attention to juvenile amyopathic dermatomyositis, which is an uncommon subtype of dermatomyositis with an excellent prognosis.

Child, Preschool↗
PubMed2005

X-linked recessive ichthyosis.

A 13-year-old boy presented with a lifelong history of tightly-adherent, brown, polygonal scales that covered the extensor surfaces of the extremities, lateral aspects of the trunk, and neck. The clinical presentation and the history of a similar skin condition in the patient's male maternal relatives helped establish the diagnosis of X-linked recessive ichthyosis (XLI). Systemic manifestations of the steroid sulfatase (STS) deficiency underlying XLI include cryptorchidism, asymptomatic corneal opacities, and maternal failure to progress during labor. Most cases of XLI are caused by deletions of the STS gene, and contiguous gene syndromes may occur when the deletions extend to neighboring genes on the distal short arm of the X chromosome.

Adolescent↗
PubMed2005

Pityriasis rubra pilaris, type IV.

A 4-year-old girl presented with a 3-year history of demarcated, salmon-pink, hyperkeratotic plaques, which were symmetrically distributed on the elbows, knees, ankles, and dorsal aspects of the hands and feet. A diffuse, orange-pink palmoplantar keratoderma was also evident. Clinical and histologic findings were consistent with a diagnosis of pityriasis rubra pilaris (PRP), type IV (circumscribed juvenile). Type IV PRP develops in prepubertal children, is typically localized to the distal aspects of the extremities, and has an unpredictable course. Although ultraviolet (UV) radiation can potentially exacerbate PRP, our patient has improved with broad-band UVB phototherapy.

Age of Onset↗
PubMed2005

Heterologous expression of tyrosinase recapitulates the misprocessing and mistrafficking in oculocutaneous albinism type 2: effects of altering intracellular pH and pink-eyed dilution gene expression.

The processing and trafficking of tyrosinase, a melanosomal protein essential for pigmentation, was investigated in a human epithelial 293 cell line that stably expresses the protein. The effects of the pink-eyed dilution (p) gene product, in which mutations result in oculocutaneous albinism type 2 (OCA2), on the processing and trafficking of tyrosinase in this cell line were studied. The majority of tyrosinase was retained in the endoplasmic reticulum-Golgi intermediate compartment and the early Golgi compartment in the 293 cells expressing the protein. Coexpression of p could partially correct the mistrafficking of tyrosinase in 293 cells. Tyrosinase was targeted to the late endosomal and lysosomal compartments after treatment of the cells with compounds that correct the tyrosinase mistrafficking in albino melanocytes, most likely through altering intracellular pH, while the substrate tyrosine had no effect on the processing of tyrosinase. Remarkably, this heterologous expression system recapitulates the defective processing and mistrafficking of tyrosinase observed in OCA2 albino melanocytes and certain amelanotic melanoma cells. Coexpression of other melanosomal proteins in this heterologous system may further aid our understanding of the details of normal and pathologic processing of melanosomal proteins.

Albinism, Oculocutaneous↗
PubMed2005

Ocular albinism 1 protein: trafficking and function when expressed in Saccharomyces cerevisiae.

The ocular albinism 1 (Oa1) protein is believed to be involved in the biogenesis of melanosomes, but its cellular localization is controversial and its function is unknown. Based upon sequence homology, it has been predicted that Oa1 belongs to the G protein coupled receptor (GPCR) superfamily. We used the yeast Saccharomyces cerevisiae as a genetically amenable system to study the localization and function of Oa1. Sucrose gradient and immunofluorescence studies revealed that when expressed in yeast, Oa1 localizes to the prevacuolar compartment, the functional equivalent of the mammalian late endosome. Oa1 behaved as G protein coupled receptor in a yeast-based GPCR signalling assay. Extracts of cultured melanocytes, and, in particular, a particulate fraction from cultured melanocytes, stimulated Oa1-mediated GPCR signalling.

Cells, Cultured↗
PubMed2005

Identification of the F1F0 mitochondrial ATPase as a target for modulating skin pigmentation by screening a tagged triazine library in zebrafish.

A triazine-based combinatorial library of small molecules was screened in zebrafish to identify compounds that produced interesting phenotypes. One compound (of 1536 screened) induced a dramatic increase in the pigmentation of early stage zebrafish embryos. This compound, PPA, was also found to increase pigmentation in cultured mammalian melanocytes. The cellular target was identified as the mitochondrial F1F0-ATP synthase (ATPase) by affinity chromatography. Oligomycin, a small molecule known to inhibit the mitochondrial ATPase, competed with PPA for its cellular target in melanocytes. In addition, PPA was shown to alter the membrane potential of mitochondria, consistent with inhibition of the mitochondrial ATPase. Thus, PPA has been successfully used as a chemical probe in a forward chemical genetic approach to establish a link between the phenotype and the protein. The results attest to the power of screening small molecule libraries in zebrafish as a means of identifying mammalian targets and suggest the mitochondrial ATPase as a target for modulating pigmentation in both melanocytes and melanoma cells.

Amino Acid Sequence↗
PubMed2005

Dissection of melanogenesis with small molecules identifies prohibitin as a regulator.

Bioactive compounds can be used to selectively modulate gene function. We utilized a chemical genetic approach to dissect the mammalian pigmentation pathway and identify protein regulators. We screened a tagged library of 1170 small molecules in a cell-based assay and discovered a class of pigment-enhancing chemicals. From this class we characterized the small molecule melanogenin. Using melanogenin bound to an affinity matrix and amino acid sequencing, we identified the mitochondrial protein, prohibitin, as an intracellular binding target. Studies employing siRNA demonstrate that prohibitin is required for melanogenin to exert its propigmentary effects and reveal an unsuspected functional role for this protein in melanin induction. This represents a mechanism by which propigmentary signals are transduced and ultimately provides a potential target for the treatment of pigmentary disorders.

Amino Acid Sequence↗
PubMed2005

Degradation of tyrosinase induced by phenylthiourea occurs following Golgi maturation.

Tyrosinase, the rate-limiting enzyme of melanin synthesis, is a di-copper metalloprotein that catalyzes the conversion of L-tyrosine to L-DOPAquinone. Phenylthiourea (PTU) is a well-known inhibitor of tyrosinase and melanin synthesis and is known to interact with sweet potato catechol oxidase, an enzyme possessing copper binding domain homology to tyrosinase. While PTU is frequently used to induce hypopigmentation in biological systems, little is known about its effects on tyrosinase and other melanogenic proteins. We have found that PTU induces degradation of tyrosinase but not of other melanogenic proteins including the tyrosinase-related metalloproteins tyrosinase-related protein (Tyrp)1 and Tyrp2. Using pulse-chase analysis coupled with glycosidase digestion, we observed that tyrosinase degradation occurs following complete maturation of the protein and that degradation was reversed by cysteine protease inhibitor E64 but not proteasome inhibitor N-acetyl-L-leucinyl-L-leucinyl-L-norleucinal. We conclude that PTU specifically induces tyrosinse degradation following Golgi maturation. Our data suggest that in addition to well-known ER-directed quality control, tyrosinase is also subject to post-Golgi quality control.

Animals↗
PubMed2005

Triazine-based tyrosinase inhibitors identified by chemical genetic screening.

As most of the available depigmenting agents exhibit only modest activity and some exhibit toxicities that lead to adverse side effects after long-term usage, there remains a need for novel depigmenting agents. Chemical genetic screening was performed on cultured melanocytes to identify novel depigmenting compounds. By screening a tagged-triazine library, we identified four compounds, TGH11, TGD10, TGD39 and TGJ29, as potent pigmentation inhibitors with IC50 values in the range of 10 microM. These newly identified depigmenting compounds were found to function as reversible inhibitors of tyrosinase, the key enzyme involved in melanin synthesis. Tyrosinase was further confirmed as the cellular target of these compounds by affinity chromatography. Kinetic data suggest that all four compounds act as competitive inhibitors of tyrosinase, most likely competing with L-3,4-dihydroxyphenylalanine (L-DOPA) for binding to the DOPA-binding site of the enzyme. No effect on levels of tyrosinase protein, processing or trafficking was observed upon treatment of melanocytes with these compounds. Cytotoxicity was not observed with these compounds at concentrations up to 20 muM. Our data suggest that TGH11, TGD10, TGD39 and TGJ29 are novel potent tyrosinase inhibitors with potential beneficial effects in the treatment of cutaneous hyperpigmentation.

Animals↗
PubMed2005

Efficacy and safety of oral retinoids in psoriasis.

With the advent of new biological agents, interest in the treatment of psoriasis has been renewed. Vitamin A and its derivatives (retinoids) have been used successfully in the treatment of psoriasis for over 30 years. In this paper, data on the efficacy and safety of oral retinoids for the treatment of various forms of psoriasis is reviewed. Studies have shown that retinoids are particularly effective in the treatment of pustular and palmoplantar psoriasis. When used in conjunction with ultraviolet therapy, retinoids appear to have a synergistic effect and can be used safely as long-term maintenance therapy. The most common side effects of oral retinoids are usually modest, treatable or reversible, and predominantly affect the liver, musculoskeletal and neurological systems. Potential teratogenicity remains the primary concern with use in women. Oral retinoids appear to be well tolerated in paediatric and HIV-infected patients.

Abnormalities, Drug-Induced↗