Sofia Magina

Mechanisms regulating melanogenesis

Skin pigmentation is an important human phenotypic trait whose regulation, in spite of recent advances, has not yet been fully understood. The pigment melanin is produced in melanosomes by melanocytes in a complex process called melanogenesis. The melanocyte interacts with endocrine, immune, inflammatory and central nervous systems, and its activity is also regulated by extrinsic factors such as ultraviolet radiation and drugs. We have carried out a review of the current understanding of intrinsic and extrinsic factors regulating skin pigmentation, the melanogenesis stages and related gene defects. We focused on melanocyte-keratinocyte interaction, activation of melanocortin type 1 receptor (MC1-R) by peptides (melanocyte-stimulating hormone and adrenocorticotropic hormone) resulting from proopiomelanocortin (POMC) cleavage, and mechanisms of ultraviolet-induced skin pigmentation. The identification and comprehension of the melanogenesis mechanism facilitate the understanding of the pathogenesis of pigmentation disorders and the development of potential therapeutic options.

Dermatological and Ophthalmological Sequels in Toxic Epidermal Necrolysis

Background: Toxic epidermal necrolysis (TEN) is a rare, drug-induced disease characterized by epidermal detachment and mucosal involvement. After an acute period, potentially disabling cutaneous and ocular sequels may appear. Although long-term complications are not rare, only few outcome studies are published. Objective: To evaluate the incidence of dermatological and ophthalmological sequels following TEN, to describe its clinical aspects and correlation with acute involvement. Patients and Methods: Eight patients surviving to TEN were submitted to dermatological and ophthalmological observation ranging from 0.5 to 8 years after hospitalization. Cutaneous and ocular involvement, during the acute phase, was retrospectively analysed. Results: Dermatological sequels were observed in 6 patients (75%) corresponding to those with more extensive skin involvement in the acute phase. The most frequent complications were cutaneous dyschromia (62.5%) and nail dystrophies (37.5%). Six patients (75%) had ocular complications with tarsal conjunctiva keratinization in 5 (62.5%) and keratoconjunctivitis sicca in 4 of them (50%). Trichiasis, corneal neovascularization and symblepharon were observed in 1 case. There was no correlation between the severity of acute ocular involvement and long-term complications. Conclusion: Following TEN, most patients have dermatological and ophthalmological sequels that persist for several years.

A case of toxic epidermal necrolysis treated with intravenous immunoglobulin

q 2000 British Association of Dermatologists, British Journal of Dermatology, 142, 177±199 response to IFN began to be appreciable within the third and fourth week of treatment in all patients, similar to that seen with daily injections. Overall, there was a striking 50% or more regression of the IHs within 8 months of treatment, a result comparable to that of other authors who used the higher dose regime (Fig. 1a±d). It is also noteworthy that an earlier onset of treatment resulted in a more rapid and evident reduction of IHs (patients 3±5). In none of our patients did regrowth of IHs follow withdrawal of the drug; instead, lesion involution continued. Side-effects were a mild febrile reaction in the first weeks of therapy in three patients and a modest transient increase of transaminases in the second and third month in only one patient. In no case did treatment have to be discontinued and no long-term sequelae have been noted during follow up over at least 2 years. In particular, spastic diplegia was not observed, either in the present study or in the 11 patients reported in the previous study. IHs are benign vascular tumours occurring in 1±2% of infants. Their frequency is higher in girls, with a sex ratio ranging from 5 : 1 to 2 : 1. IHs undergo a proliferative phase, from birth to 6±20 months, and then an involutional phase beginning at 6 months to 1 year and continuing for the next 5±7 years. A small proportion of IHs are complicated by the obstruction of important structures such as the periorbital region, nose, lips, airways and perianal region. These problematic, alarming or complex IHs require treatment. The classical therapy for IHs consists of systemic corticosteroids, but subcutaneous IFN is a valid alternative therapy; IHs are among the first established indications for antiangiogenic therapy in humans. A recent study provided evidence of high levels of positive angiogenic factors but absence of the endogenous inhibitor, IFN, in the proliferative tissue of IHs. IFN is usually given at high doses, beginning with an initial dose of 1 million U/m per day. If tolerated, the dose is increased to 2±3 million U/m per day and then maintained at this level for many months. In a previous paper we provided evidence indicating that lower doses are equally effective. The following schedule was suggested: 1 million U/m per day three times a week for 2 weeks, then increased to 3 million U/m per day three times a week for the duration of the treatment. This schedule was as effective as a dose of 3 million U/m per day for a similar time. In particular, we obtained results comparable to those of Ezekowitz et al. and Ohlms et al. The present study provides evidence that further reduction of the IFN dose did not diminish the efficacy of the treatment, i.e. the speed of reduction in size of IHs proceeded at the same rate as with a dose of 3 million U/m per day. This is noteworthy because the cost of treatment is reduced by 60% and IFN side-effects are alleviated. In conclusion we believe that IFN, at the low doses we suggested, should be considered the first-line agent for treatment of IHs, as the recommended systemic corticosteroid schedule not only achieves lower response rates but induces T-cell suppression and growth retardation, side-effects that limit corticosteroid use in the infant population. Acknowledgments

Tuberculosis in anti-TNF-α treated patients remains a problem in countries with an intermediate incidence: Analysis of 25 patients matched with a control population

BACKGROUND AND AIMS An increased incidence of tuberculosis (TB) in patients under anti-TNF-α therapy has been reported, but outcome compared with TB in the general population are unknown. METHODS Patients who had active tuberculosis while taking anti-TNF-α drugs were studied and compared with a control group of community-acquired TB matched for sex, age and data of TB. RESULTS Twenty-five cases of TB were reported from a cohort of 765 patients under anti-TNF-α from 2001 to 2012. The incidence of TB per 100,000 patient-years was estimated to be 1337, 792 and 405 respectively for those on infliximab, adalimumab and etanercept. Twelve patients had inflammatory bowel disease, ten had rheumatologic diseases and three had psoriasis. From the 17 patients screened for latent TB before anti-TNF-α, three were treated with isoniazid. TB was diagnosed 1-108 months after starting anti-TNF-α, being the median time six, seven and 89 months respectively for those on infliximab, adalimumab and etanercept. Sixty per cent of the cases had extra-pulmonary TB. No deaths occurred in the case groups, while two died in control TB patients. Patients on anti-TNF-α drugs had more frequent extra-pulmonary TB, fever on presentation, higher mean C-reactive protein and lower positive rate of acid-fast bacilli. CONCLUSIONS TB may still occur in those with negative testing, some of them probably representing new infections instead of reactivations. Three out of 25 patients had TB in spite of previously treated LTB, although, the outcome of TB was not worse than in the general population.

Cutaneous alternariosis by Alternaria chartarum in a renal transplanted patient.

Sir, Langerhans cell histiocytosis (LCH) includes a spectrum of disorders with overlapping clinical features, i.e. Letterer±Siwe disease, Hand±SchuÈ ller±Christian syndrome, eosinophilic granuloma and congenital self-healing reticulohistiocytosis. The typical cutaneous findings comprise seborrhoeic dermatitis-like lesions, reddish-brown purpuric papules and nodules, oozing erosions, and ulcerations. A child with LCH is described, who presented with an uncommon pattern of pustular lesions on the forehead, hands, feet and genital region, following an atypical clinical course. One week after birth, a 14-month-old girl developed multiple, sharply demarcated itchy pustules on the forehead, together with red papules, and pustules partly covered with haemorrhagic crusts, which were predominantly on the soles of the feet (Fig. 1a). Some pustules occurred on the hands and in the genital and gluteal region. No lymphadenopathy was detectable. During topical treatment with lotio zinci (lotion with zinc oxide, talcum, glycerol and distilled water) the cutaneous lesions regressed slowly, but new lesions developed during the following months. After 5 months, an ulcer developed in the maxillary region. There was no specific family history of skin diseases. A skin biopsy of a pustule from the gluteal region revealed a dense upper dermal infiltrate of large histiocytes with a reniform nucleus, and intraepidermal collections of histiocytic cells (Fig. 1b). Immunohistochemical stains were positive for CD1 and for S-100 antigen. Electron microscopy revealed intracytoplasmic Birbeck granules within the histiocytic cells, thus confirming the diagnosis of LCH. Bacteriological and mycological examinations from skin lesions were negative. Full blood count, liver and kidney function were normal. Scintiscanning and radiography showed distinct involvement of the maxilla. Abdominal sonography was normal. Based on the occurrence of new cutaneous lesions and the subsequent involvement of the osseous part of the maxilla, chemotherapy was initiated with oral prednisolone 40 mg m daily for 4 weeks; then reduction of dose, vinblastine 0 ́2 mg kg once weekly for 6 weeks, then once monthly; and 6-mercaptopurine 50 mg m daily. Cutaneous lesions on the scalp, hands and feet, and the osseous lesion of the maxilla healed during the chemotherapy, which was performed for 1 years. In 1955, Lichtenstein summarized the three entities Letterer±Siwe disease, Hand±SchuÈ ller±Christian disease and eosinophilic granuloma under the term histiocytosis X. The cause of histiocytosis X (LCH) is unknown, but it is believed to be a proliferative process of Langerhans cells. Lesional histiocytes in the child described here were positive for S-100 antigen and CD1, as well as for intracytoplasmic Birbeck granules. The skin lesions did not clear completely

Keratitis-Ichthyosis-Deafness Syndrome Caused by GJB2 Maternal Mosaicism

TO THE EDITOR Keratitis, ichthyosis, and deafness (KID) syndrome (OMIM #148210) is a rare autosomal disorder associating vascularizing keratitis with hyperkeratotic skin lesions and profound hearing loss. It is caused by dominant mutations in the gene GJB2 (OMIM *121011) encoding connexin-26 or, more rarely, in GJB6 (OMIM *604418) encoding connexin-30 (Jan et al, 2004). Connexin-26 is a protein of gap junctions in epithelia, notably of the corneal limbus, the epidermis, sweat glands and ducts, hair follicles, and the cochlea. Most cases are sporadic and arise from a recurrent missense mutation, c.148G4A (p.Asp50Asn) (Richard, 2005). We report a

Restrictive dermopathy—a lethal congenital laminopathy. Case report and review of the literature

Restrictive dermopathy (RD) is a rare, fatal, and genetically heterogeneous laminopathy with a predominant autosomal recessive heredity pattern. The phenotype can be caused by mutations in either LMNA (primary laminopathy) or ZMPSTE24 (secondary laminopathy) genes but mostly by homozygous or compound heterozygous ZMPSTE24 mutations. Clinicopathologic findings are unique, allowing a specific diagnosis in most cases. We describe a premature newborn girl of non-consanguineous parents who presented a rigid, translucent and tightly adherent skin, dysmorphic facies, multiple joint contractures and radiological abnormalities. The overall clinical, radiological, histological, and ultrastructural features were typical of restrictive dermopathy. Molecular genetic analysis revealed a homozygous ZMPSTE24 mutation (c.1085_1086insT). Parents and sister were heterozygous asymptomatic carriers. We conclude that RD is a relatively easy and consistent clinical and pathological diagnosis. Despite recent advances in our understanding of RD, the pathogenetic mechanisms of the disease are not entirely clarified. Recognition of RD and molecular genetic diagnosis are important to define the prognosis of an affected child and for recommending genetic counseling to affected families. However, the outcome for a live born patient in the neonatal period is always fatal.

Anti-TNF-alpha induced psoriasiform eruptions with severe scalp involvement and alopecia: report of five cases and review of the literature.

We describe 5 cases of anti-tumor necrosis factor-alpha (anti-TNF-α) induced psoriasiform eruptions with severe scalp involvement inducing inflammatory alopecia and review the literature on this subject. All our 5 patients were provided topical therapy, with good results in only 1 case. The remaining 4 were provided systemic therapy (methotrexate ± cyclosporine): 3 concomitantly suspended the anti-TNF-α treatment (2 are currently clear/almost clear but 1 has so far only observed mild improvement) and 1 switched anti-TNF-α (recurrent flare-ups of the disease continue). So far, no patient has developed scarring alopecia. To our knowledge, a total of 15 cases of anti-TNF-α induced psoriatic alopecia have been described. Anti-TNF-α was discontinued in 9 of the 15 patients and systemic therapy was provided to 9 of the 15 patients. Nonetheless, 2 patients developed scarring alopecia. We conclude that in anti-TNF-α induced psoriasiform eruptions some patients may respond to topical treatment, however in cases of severe scalp involvement anti-TNF-α suspension and systemic treatment should be considered in order to avoid scarring alopecia.

Infliximab in Psoriasis and Psoriatic Arthritis

Psoriasis is a chronic inflammatory disorder of the skin and joints. Although rarely life threatening, psoriasis can significantly impair quality of life (QOL) and cause considerable physical and psychological distress. Between 6 and 42% of patients with psoriasis develop psoriatic arthritis, which is characterized by stiffness, pain, swelling and tenderness of the joints. Nail psoriasis is highly prevalent in both plaque-type psoriasis and psoriatic arthritis and is found in approximately 50% of patients with psoriasis and in 80% of patients with psoriatic arthritis. Infliximab, a chimeric human-murine monoclonal antibody directed against tumour necrosis factor α, is approved in the USA and EU for the treatment of plaque psoriasis and psoriatic arthritis at a recommended dosage of 5 mg/kg administered by intravenous infusion at 0,2 and 6 weeks, then every 8 weeks thereafter. The EXPRESS and EXPRESS II trials demonstrated that infliximab is efficacious as induction and maintenance therapy in the treatment of moderate to severe plaque psoriasis and also improved health-related QOL. Infliximab is also efficacious in the treatment of psoriatic arthritis, as shown in the IMPACT and IMPACT II studies. Infliximab is generally well tolerated, with a similar adverse event profile in both psoriasis and psoriatic arthritis. The use of infliximab in three case reports is presented. The patients are similar to those normally seen by clinicians, and include a male patient with plaque psoriasis and a history of severe psoriatic arthritis who was corticosteroid dependent and in whom other systemic treatments were not effective or were not able to be used. This patient showed a rapid response to infliximab with no skin lesions or arthritis after 7 weeks’ treatment. Infliximab was also safe and effective in the treatment of a female patient with plaque and nail psoriasis and a history of psoriatic arthritis. Importantly, this case report supports the efficacy of infliximab in psoriatic nail disease in the context of severe skin and joint involvement. Case 3 describes a young male patient with moderate plaque-type psoriasis associated with severe nail involvement and early signs of psoriatic arthritis. Treatment with infliximab improved nail psoriasis and appears to be an effective biological treatment for nail psoriasis. Importantly, ultrasound was able to diagnose joint involvement, as seen from the proliferative synovitis in the distal interphalangeal joint and mild enthesitis, despite there being no clinical evidence of psoriatic arthritis. This case report highlights the importance of early screening. If such abnormalities are detected early on in the course of psoriasis, clinicians may be able to predict which patients are more likely to develop psoriatic arthritis, and therefore offer effective and long-term treatment that may reduce the disability and impairment of daily activities that can be associated with psoriatic arthritis.

Efficacy and safety of propranolol in the treatment of parotid hemangioma

A 2-month-old female patient presented an extensive bilateral parotid hemangioma (PH) focally ulcerated. Additionally, hepatic ultrasonography revealed a hemangioendothelioma located at right lobe. She was treated with oral prednisolone (3 mg/kg/day) during 10 months with clinical improvement of PH, despite failure to thrive and arterial hypertension. However, regrowth of the lesion occurred after discontinuation of oral steroid. Propranolol hydrochloride (2 mg/kg/day divided into two doses) was then started and maintained for 16 months, with marked involution of the hemangioma and with no systemic side effects during treatment course. Curiously, also the liver hemangioendothelioma completely resolved after starting propranolol. PH is a threatening cervicofacial segmental hemangioma that frequently proliferates after the year of age and needs long-term treatment. On the other hand, hepatic hemangioendotheliomas may be associated with cutaneous hemangiomas in some patients and their natural history is similar to these, although patients may die of associated conditions. As for other infantile hemangiomas, propranolol proved to be an effective, safe, and well-tolerated treatment for PH. Its role in liver hemangiomas and hemangioendotheliomas should also be taken into account.