Journal of Pakistan Association of Dermatologists Volume 13, Number 3 July-September, 2003 Editor Ijaz Hussain Associate Editors Farhana Muzaffar Zahida Rani Faria Asad Editorial Board Abdul Ghafoor Qamar Abdul Aziz Memon Ahsan Hameed Akhtar Waheed Khan Ali Khan Tareen Anjum Kanjee Arif Maan Ashfaq Ahmed Khan Atif Hasnain Kazmi Arfan-ul-Bari Anoop Kumar Badr S. Dhanani Farooq Soomro Ghulam Mujtaba Hasina Thawerani Iqbal Chowdhry Iqbal Tareen Iqbal Akhtar Khan Jameel A. Shaheen Jawaid Anwar Khadimullah Kakakhel Khalid Hussain Khalid Makhdoomi Khalid Hashmi Khawar Khurshid Liaqat Ali Khan Mansoor Dilnawaz Muhammad Jahangir Nasser Rashid Dar Nizamul Hussain Naeem Iqbal Naseema Kapadia Pervaiz Iqbal Raza Jaffery Raza Muhammad Khan S. M. Azam Bokhari S.M. Shamim Sabrina Suhail Pal Sajid Mushtaq Sharaf Ali Shah Shehab Afzal Beg Shahbaz Aman Simeen Ber Rahman Satish S. Savant Tahir Anees Tahir Jamil Ahmad Tahir Saeed Haroon Tariq Rashid Tariq Zaman Yasmeena Khan Zarnaz Wahid Zohra Zaidi Zubair Memon Publication Manager Mr. Omar Abdul Aziz JPAD, the official journal of Pakistan Association of Dermatologists is published quarterly, four issues per volume and one volume per year (ISSN 1560-9014). The journal is recognized by Pakistan Medical and Dental Council and is indexed in College of Physicians and Surgeons Pakistan MEDLIP; Ulrich’s International Periodical Directory, USA; ExtraMED, London; EMBASE/Excerpta Medica, The Netherlands; and Index Medicus, WHO Alexandria, Egypt. Subscription A complimentary copy of the journal is provided to all PAD members. Subscription rates per volume are Rs. 1000.00 for Pakistan, £80.00 for UK and $120.00 for US and rest of the world. Copyright 2003 Any material published in JPAD is copyright of Pakistan Association of Dermatologists. 2 Journal of Pakistan Association of Dermatologists Volume 13, Number 3 July-September, 2003 Contents Editorial Vitiligo. From Babechi to lasers. Zahida Rani 112 Original articles Autologous skin punch grafting in localized, fixed vitiligo Tahir Jamil Ahmad, Tariq Rashid, Zahida Rani, Tahir Saeed Haroon 114 An audit of dermatoses at Baqai Institute of Skin Diseases, Karachi Ijaz Ahmed, Mujeeb Ansari, Kashef Malick 117 Successful treatment of tinea capitis due to Microsporum canis with griseofulvin Shahbaz Aman, Ijaz Hussain, Tahir Saeed Haroon 123 Lichen planus and hepatitis C virus infection: An epidemiologic study Tameez-ud-deen, Shahzana Naqqash, Abdul Quddus Butt 127 Review articles Zinc: An overview and therapeutic uses in dermatology Arfan-ul-Bari, Simeen ber Rahman 130 Cockayne syndrome. An update. Farhana Muzaffar, Ijaz Hussain 135 Surgical Pearl Modifications in punch grafting Tahir Jamil Ahmad, Tariq Rashid, Zahida Rani 146 Case reports Acrodermatitis enteropathica in three siblings. Arfan-ul-Bari, Muhammad Abbas, Simeen ber Rahman 148 A family with xeroderma pigmentosum-Cockayne syndrome complex Ijaz Aman, Shahbaz Aman, Tahir Masood Ahmad 153 Quiz An erythematous plaque on the breast Faria Asad, Sabrina Suhail Pal 157 News 159 Information for authors Editorial Vitiligo. From Babechi to lasers. Zahida Rani Department of Dermatology, King Edward Medical College/Mayo Hospital, Lahore Vitiligo is an acquired depigmentary disorder which affects 1-3% of world population without any age, sex, or racial predilection. The disease has a great negative psychological impact, particularly, in coloured skin. The history of disease is as old as that of mankind. Treatment of vitiligo still remains challenging as it was in the past. Due to genetic predisposition, immune-mediated injury, or other unidentified toxins, melanocytes in the affected epidermis disappear whereas those in the hair follicles are spared. The treatment of vitiligo is based on the principle of repopulating the vitiliginous patches with active melanocytes. Photochemotherapy, in its crude form, was practiced for the treatment of vitiligo as early as 1500 to 1000 B.C. in India. Babechi (in Urdu) or Bavanchi/Bavachi (in Hindi), Psoralea corylifolia, is an indigenous plant of Indian subcontinent.1 Different parts of the plant especially seeds are rich in different psoralens. The seeds in powdered form (1-3g/day) or essential oil (oral as well as topical) have been the mainstay of treatment for leukoderma in the Eastern (Unani/ Ayurvedic) systems for centuries. The first modern use of light therapy in combination with purified topical and/or oral psoralens was by E1 Mofty in 1948.2 Later, in 1976, high intensity sources for UVA radiation were developed for the treatment of vitiligo. Even today when a number of other drugs (topical/oral steroids, levamisole, immunosuppressants) are available, the photo(chemo)therapy retains the pivotal role. The modern phototherapy aims at stimulation of adjacent melanocytes. Phototherapy comprises of topical and systemic photochemotherapy (PUVA) and narrowband UVB. In the conventional photochemotherapy, 8-methoxypsoralen is administered in a dose of 0.5mg/kg, followed by UVA irradiation at intervals of 2 to 3 times weekly. Treatment has to be continued for months to more than a year. Partial repigmentation is seen in 3040% of cases and complete repigmentation in fewer than 20% of patients.3 Systemic PUVA is associated with a number of acute and chronic hazards like increased risk of cutaneous malignancies. In topical PUVA, used for localized disease, 0.05%0.1% 8-methoxypsoralen is applied, followed by UVA radiation at intervals of 2-3 times weekly. Repigmentation is seen in about half of cases. Few researchers used other photosensitizers e.g. khellin (Ammi visnaga), phenylalanine, and melagenina with UVA or infrared light, as well. Narrowband UVB phototherapy with a spectrum of 311nm to 312nm and a peak emission of 311nm has recently been shown as effective as PUVA photochemotherapy. Njoo et al.4 demonstrated 75% repigmentation in 535 patients and stabilization of the disease in 80% of patients with only minimal side effects. However, UVB photherapy and 112 PUVA, both modalities require regular phototherapy sessions several times a week for up to a year. Based on the efficacy and safety of narrowband UVB therapy, Spencer et al.5 embarked on a study of targeted phototherapy using a single-wavelength 308nm UVB laser to treat focal areas of vitiligo. The 308nm excimer laser has the advantage of having increased precision and the ability to deliver higher energy to the target tissue in less time. In a pilot study, they treated 29 patches of vitiligo from 18 patients, using this laser with 120nanoseconds and 20Hz pulse, a 10x10mm spot size and a power output of 60mW. Lesions were treated 3 times a week for a maximum of 12 treatments. Some degree of repigmentation was noticed in 57% and 82% of treated patches after 6 and 12 treatments, respectively. The degree of repigmentation in 2-4 weeks achieved with laser therapy was much higher than that achieved with other available modes of vitiligo therapy. Further studies are required to determine the exact role of 308nm laser in vitiligo treatment. Similarly, a larger spot size will be required to make feasible the treatment of larger body areas. In case of localized, stable/fixed vitiligo various surgical techniques like autologous minigrafts, punch grafts, suction blister grafts, autologous thin thiersch grafts have been used. These procedures are associated with variable degree of scarring. The addition of PUVA therapy can expedite the process of repigmentation. Ahmad et al.6 (in this issue of JPAD) punch grafted 207 vitiliginous patches over different body sites in 40 patients and added topical PUVA, once the grafts were taken. They reported >75% repigmentation in >85% of patches after 6-12 months follow up. The focused (cutting) mode CO2 laser has also been used for punch grafting. Melanocyte transplants, using either autologous pure melanocyte culture or autologous melanocyte and keratinocytes co-cultures are another experimental approach to treat larger areas. However, the complexities of the technique and required equipment are the limiting factors. The story of treatment of vitiligo does not end here. Another area recently under experimentation is the use of various inflammatory mediators7 which will stimulate melanocyte migration proliferation e.g. receptor tyrosine kinase growth factor, tumour growth factor along with stem cell factor, leukotrienes especially LTC4, LTD4, and G-protein coupled with endothelin-1 insulin-like growth factor etc. These mediators are required for melanocyte proliferation, chemokinesis and haptaxis. If successful, these therapies will not require phototherapy. References 1. 2. 3. 4. 5. 6. Behl PN, Arora RB, Srivastava G, Malhotra SC, eds. Herbs useful in dermatological therapy, 1st edn. Delhi: CBS Publishers; 1993. El Mofty A. A preliminary clinical report on the treatment of leukoderma with Ammi majus linn. J Roy Egy Med Assoc 1948; 31: 651-5. Ortonne J. Psoralen therapy in vitiligo. Clin Dermatol 1989; 7: 120-35. Njoo MD, Bos JD, Westerhof W. Treatment of generalized vitiligo in children with narrow-band (TL-01) UVB radiation therapy. J Am Acad Dermatol 2000; 42: 245-53. Spencer JM, Nossa R, Ajmeri J. Treatment of vitiligo with the 308-nm excimer laser: A pilot study. J Am Acad Dermatolo 2002; 46: 727-31. Ahmad TJ, Rashid T, Rani Z, Haroon TS. Autologous skin punch grafting in localized, fixed vitiligo. J Pak Assoc Dermatol 2003; 13: 114-7. 113 7. Halder RM, Young CM. New and emerging therapies for vitiligo. Dermatol Clin 2000; 18: 79-88. 114 Original article Autologous skin punch grafting in localized, fixed vitiligo. Tahir Jamil Ahmad, *Tariq Rashid, Zahida Rani, Tahir Saeed Haroon Department of Dermatology, King Edward Medical College/Mayo Hospital, Lahore *Department of Dermatology, Allama Iqbal Medical College/Jinnah Hospital, Lahore Abstract Background A number of medical modalities including photo(chemo)therapy, topical and systemic steroids etc. are used in the treatment of vitiligo. Surgical treatment like punch grafting is recommended for localized, fixed disease. Objectives To assess the clinical efficacy and safety of autologous skin punch grafting in patients with localized, fixed vitiligo. Patients and methods 40 adult cases (26 females and 14 males) having 207 localized vitiligo patches, unresponsive to medical measures for more than a year were included in the study. After investigations, they were subjected to test grafting and later to complete grafting of involved areas. Donor grafts were taken from normal areas. Results More than 85% patches showed good to excellent response after three months of grafting and PUVA therapy. No alarming side effects were recorded. Conclusion Autologous skin punch grafting is a safe, effective and promising mode of treatment in cases of localized fixed vitiligo. Key words Autologous, punch graft, vitiligo. Introduction Vitiligo is an acquired achromic condition occurring in 1% to 2% of the general population affecting all races.1,2 When exposed areas are involved, it may have devastating aesthetic impact especially in dark skinned people.3 The medical treatment includes topical and systemic steroids, topical and/or systemic methoxalen and ultraviolet light in the A range, narrow band 311nm UVB, or natural sunlight.4-7 Repigmentation is best seen on face and neck (60-70%) and trunk and limbs (40-50%). Hands, feet and lips show even poorer results and segmental Address for Correspondence Dr. Tahir Jamil Ahmad 186 J, D.H.A., Phase 1, Lahore. Ph # 042-5726937 vitiligo may show no response to topical steroids and other modalities.8-13 There have been many reports of complete repigmentation of vitiligo after localized autologous minigrafting.6,7,13,15,16,17 We planned this clinical study to evaluate its efficacy and safety in our patients. Patients and methods Forty consecutive adult patients of vitiligo were enrolled from 1998 to 2002 at the department of dermatology, Mayo Hospital, Lahore. All had localized, nonprogressive disease at almost every part of the body for the last two to 20 years. All had already tried a number of modalities with no or minimum success. They were 115 investigated for bleeding disorders and chronic illnesses. Each patient was test punch grafted on one of the areas and outcome was recorded after regular follow up. All patients exhibiting satisfactory pigmentation were subjected to punch grafting on all the remaining sites. Disposable punches of 4 mm were used for both donor and recipient areas. Donor grafts were usually taken from inner side of upper arm, back of the ears and inner side of thighs. Areas operated were covered with surgical dressings for 48-72 hours. Any graft loss was replaced and dressings were removed after one week. Patients were started on PUVASOL or PUVA in the chamber. The resulting pigmentation and side effects were recorded during follow up for one year. Final assessment was made according to the five scale system from G0 to G4 as mentioned in Table 2. All the patients were photographed before, during and after treatment. Results Two hundred and seven patches of vitiligo were punch grafted in these forty patients (distribution given in Table 1). One hundred and seventy four patches showed G3 pigmentation or above in the range of excellent pigmentation. Figure 1 and 2 show almost 100% repigmentation. Rest of the patches showed variable pigmentation and three of them did not pigment at all despite repeated grafting. Table 2 gives break up description of the patches and their pigmentary response after following them up for 6 months to one year. Table 1 Vitiligo distribution (n =40) Area Male (n=14) Female (n=26) Face Neck Trunk 12 2 19 7 No. of vitiliginous patches (n=207) 48 20 2 3 1 7 2 3 14 12 7 13 12 12 28 26 15 20 31 19 Front Back Arms Hands Legs Feet Table 2 Results at 6 months - 1 year follow up Grade of repigmentation G4 G3 G2 G1 G0 Patches Result 105 69 21 9 3 Excellent Very good Good Satisfactory Poor G4 = > 75% repigmentation; G3 = 50-75% repigmentation, G2 = 25-50% repigmentation; G1 = up to 25% repigmentation; G0 = no repigmentation Figure 1 Autologus punch grafting on forehead Discussion Studies show 90% to 100% pigmentation after minigrafting.14,15,17 When we compare Figure 2 Complete repigmentation after six months 116 our results with these studies, almost similar response was obtained. Cobblestone appearance of the recipient areas is well known.14,15,17 We, too, had this problem earlier on but later, the use of thin donor grafts in recipient wells minimized it. However, no major complication was encountered throughout. Pigmentary improvement accomplished with minigrafting is not only due to melanin spread from the graft’s edges, but also to melanocyte recolonization of the epidermis within the achromic skin.7,19 Some of our cases did not respond after repeated grafting and PUVA exposure. The reason was not known but similar problem is well known.7, 15, 19 Conclusion Our results, when compared with those from abroad, are quite promising and we conclude that autologous skin punch grafting of fixed vitiligo is a safe and effective method of treatment of resistant cases in our patients. References 1. 2. 3. 4. 5. 6. Shah SA, Aftab S, Goplani S. Prevalence of vitiligo in skin clinic. J Pak Assoc Dermatol 1991; 1: 14-9. Najoo MD, Westerhof W, Bos JD, Bossuyt PMM. A systemic review of autologous transplantation methods in vitiligo. Arch Dermatol 1998; 134: 15439. Papadopolus L, Bor R, Legg C, Howk JLM. Impact of life events on the onset of vitiligo in adults. Preliminary evidence for psychological dimension in aetiology. Clin Exp Dermatol 1998; 23: 243-8. Halder RM, Young CM. New and emerging therapies for vitiligo. Dermatol Clin 2000; 18: 79-88. Qureshi AA, Qureshi AS, Shah SA. Vitiligo. J Pak Assoc Dermatol 1992; 2: 116. Boersma BR, Westerhof W, Bos JD. Repigmentation in vitiligo vulgaris by autologous minigrafting - results in 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. nineteen patients. J Am Acad Dermatol 1995; 33: 990-5. Grimes PE. Vitiligo: an overview of therapeutic approaches. Dermatol Clin 1993; 11: 325-38. Njoo MD, Spuls PI, Boss JD, Bossuyt PMM. Non surgical repigmentation therapies in vitiligo: meta-analysis of the literature. Arch Dermatol 1998; 134: 1532-40. Njoo MD, Bos JD, Westerhof W. Treatment of generalized vitiligo in children with narrow band (TL-01) UVB radiation therapy. J Am Acad Dermatol 2000; 42: 245-53. Parsricha JS, Khaitan BK. Oral minipulse therapy with betamethasone in vitiligo patients having extensive or fast spreading disease. Int J Dermatol 1993; 32: 753-7. Sahin S, Hindioglhu U, Karaduman A. PUVA treatment of vitiligo. A retrospective study of Turkish patients. Int J Dermatol 1999; 38: 542-5. Camacho F, Mazuecos J. Treatment of vitiligo with oral and topical phenylalanine: six years of experience. Arch Dermatol 1999; 135: 1514-21. Njoo MD, Westernhof W, Bos JD, Bossuyt PMM. The development of guidelines for the treatment of vitiligo. Arch Dermatol 1999; 135: 1514-21. Savant SS. Autologous miniature punch grafting in stable vitiligo. Ind J Dermatol Venereol Leprol 1992; 58: 310-4. Orentreich N, Selmanowitz VJ. Autograft repigmentation of leukoderma. Arch Dermatol 1972; 105: 734-6. Falabella R. Repigmentation of segmental vitiligo by autologous minigrafting. J Am Acad Dermatol 1983; 9: 514-21. Falabella R. Treatment of localized vitiligo by autologous minigrafting. Arch Dermatol 1988; 124: 1649-55. Billingham RE, Silvers WK. Studies on the migratory behavior of melanocytes in guinea pig skin. Int J Exp Med 1970; 131: 101-117. Drake LA, Dinehart SM, Farmer ER et al. Guidelines of care for vitiligo. J Am Acad Dermatol 1996; 35: 620-6. 117 Original article An audit of dermatoses at Baqai Institute of Skin Diseases, Karachi. Ijaz Ahmed, Mujeeb Ansari, Kashef Malick Baqai Institute of Skin Diseases, Baqai Medical University, Karachi Abstract Background Epidemiology offers one of the most powerful direct methods of evaluating skin diseases in human population. The study comprises an audit of the patients presenting in the outpatient department of Baqai Institute of Skin Diseases (BISD), during the calendar year 2002. Patients and methods A total of 13105 patients presented in the outpatient department during the said period. Their clinical diagnosis and results of relevant investigations were recorded. Results Patients belonged to all age groups and both sexes with 6684 (51%) females and 6421 (49%) males. The most common disease as a single entity was found to be scabies (15.4%). However, as a group, eczema accounted for 25% of the patients, followed by fungal infections (12.6%), acne (8.5%) and bacterial infections (6.4%). Other important diseases were melasma (4%), androgenetic alopecia (3.2%), diffuse alopecia (2.7%), urticaria (2.4%), psoriasis (2.1%), viral infections (1.7%), alopecia areata (1.5%), lichen planus (1.3%), and vitiligo (1.1%). Other less frequently reported diseases included drug eruptions, pediculosis, post inflammatory hypo- and hyperpigmentation, generalized pruritus, oral ulcers, miliaria, xanthelasma, milia, striae, palmoplantar keratoderma, leishmaniasis, leprosy, keloid and vasculitis. Some rare diseases were pityriasis rosea, angioedema, ichthyosis, canities, scleroderma, systemic lupus erythematosus and pemphigus. There were occasional case reports of porokeratosis of Mibelli, Bowen’s disease, rosacea, mastocytosis and histiocytosis. Conclusion Pattern of dermatoses at ‘BISD’ is much the same as in other cities of Pakistan with minor differences. Key words Epidemiology, skin diseases, hospital-based prevalence, frequency, Karachi, Pakistan. Introduction Epidemiology offers one of the most powerful direct methods of evaluating skin diseases in human population.1 For an epidemiological study, a large sample of population is required so that the nature and size of the health problems can be Address for Correspondence Dr. Ijaz Ahmad 36/2, Khayaban-e-Shujaat, D-H-A, Phase 5, Karachi. Ph # 021-584842, 021-5848454 adequately gauged. This in turn helps to establish their importance in a community. Not much epidemiological work has been done in this field in our country. Although, a few studies have been carried out at Karachi,2 Lahore,3 and Bahawalpur4 in the past but still there is a wide gap regarding the national data. Here we present an audit of dermatoses at ‘Baqai Institute of Skin Diseases’ (BISD), 118 affiliated with Baqai Medical University, Karachi. This institute covers not only the whole of Nazimabad, a thickly populated area, but also the rest of previously called district central of Karachi. Moreover, patients also present here from adjoining areas like Gulshan-e-Iqbal, New Karachi, Banaras Colony, Qasba Colony, Garden and Lasbela. In addition, patients coming from remote areas like Malir and Landhi and virtually the rest of Karachi present here. This study was aimed to determine the frequency of various skin diseases in patients presenting at BISD and to compare the results with previous data from our country.2-6 Patients and methods During the calendar year 2002, a proper record of all the OPD patients was maintained at BISD. After a clinical diagnosis, investigations, if required, were also carried out. These included blood for hematological and biochemical profile, urine examination and X-ray chest. Specific investigations included smears, swabs and scrapings for microscopy and culture from the lesional skin, radiological examination, serology, skin biopsy and rarely immunofluorescence. Results A total of 13105 patients attended the OPD, during the said period. Patients belonged to both sexes with 6684 (51%) females and 6421 (49%) males. Of the total patients 1956 (15%) were below 12 years of age. The minimum age of presentation was 7 days and maximum 96 years. Patients belonged to all ethnic groups. Table 1 enlists the hospital-based prevalence of different disease entities/groups in the descending order of frequency. Scabies as a single entity, with a frequency of 15.4% remained the most common skin disease. However, as a group of skin disorders, eczema topped the list with a combined frequency of 25%. This group included hand eczema (7.5%), seborrhoeic dermatitis (3.4%), lichen simplex chronicus (3%), atopic dermatitis (2.6%), pityriasis alba (2.3%), xerotic eczema (2.3%), allergic contact dermatitis (2%), photodermatitis (0.7%), pompholyx (0.7%), napkin dermatitis (0.4%) and asteototic eczema (0.1%) Fungal infections, as a group had a frequency of 12.6%. The break up in the descending order included, pityriasis versicolor (4.2%), tinea capitis (2.9%), tinea corporis (1.5%), onychomycosis (1.1%), chronic paronychia (0.7%), tinea cruris (0.7%), oral candidiasis (0.6%), tinea pedis (0.5%), tinea manuum (0.2%) and vaginal candidiasis (0.1%). Table 1 Hospital-based prevalence of different dermatoses (n=13105) Disease Eczemas Scabies Fungal infections Sebaceous gland diseases Hair follicle diseases Bacterial infections Pigmentary disorders Papulosquamous disorders Vascular disorders Viral infections Papular urticaria Intertrigo Drug eruptions Tumours/cysts Pediculosis Keratinization disorders Pruritus Oral ulcers Nevoid disorders Leishmaniasis Connective tissue disorders Mycobacterial infections Bullous disorders Psychocutaneous disorders Number 3282 2038 1640 1316 1029 840 809 465 362 224 147 105 90 69 68 64 55 51 31 31 27 26 18 14 % 25.0 15.4 12.6 10.1 8.0 6.4 6.2 3.5 2.8 1.7 1.1 0.8 0.7 0.5 0.5 0.5 0.4 0.4 0.2 0.2 0.2 0.2 0.1 0.1 119 Miscellaneous disorders 313 2.4 Table 2 Miscellaneous disorders (n=13105) Disease Burns Miliaria Xanthelasma Skin tags Striae Corns Keloids Ingrowing toenails Postherpetic neuralgia Pitted keratolysis Total Number 56 47 42 37 35 32 24 17 16 7 313 % 0.4 0.4 0.3 0.3 0.3 0.2 0.2 0.1 0.1 0.1 2.4 Frequency of sebaceous gland disorders was 10.1% and comprised acne (8.5%), dandruff (1.5%) and rosacea (0.1%). The disorders of hair follicles accounted for 8% of all the patients. The combined frequency of alopecia was 7.6% with a breakup of androgenetic alopecia (3.2%), telogen effluvium (2.7%), alopecia areata (1.5%) and drug-induced alopecia (0.2%). Hirsutism (0.16%) and canities (0.1%) were the other hair follicle diseases seen. Total frequency of bacterial infections was 6.4%. This group included folliculitis (1.8%), impetigo (1.5%), furunculosis (1.3%), ecthyma (1.1%), cellulitis (0.4%) and periporitis (0.3%). Frequency of disorders of pigmentation (6.2%) included melasma (4%), vitiligo (1.2%), postinflammatory hypopigmentation (0.5%) and postinflammatory hyperpigmentation (0.5%). Papulosquamous disorders i.e. psoriasis vulgaris (2.1%), lichen planus (1.3%) and pityriasis rosea (0.1%) had a combined frequency of 3.5%. The group of vascular disorders accounted for 2.8% of the patients and included urticaria (2.4%), vasculitis (0.2%), angioedema (0.1%) and Schamberg’s disease (0.1%). Viral infections (1.7%) included common warts (0.4%), molluscum contagiosum (0.4%), chicken pox (0.3%), verruca plana (0.2%), herpes simplex (0.2%), genital warts (0.1%) and herpes zoster (0.1%). Papular urticaria and intertrigo were reported in 1.1% and 0.8% patients, respectively. The combined frequency of drug eruptions (0.7%) included generalized drug eruption (0.6%) and fixed drug eruption (0.1%). The group of tumors and cysts included milia (0.2%), syringomas (0.1%), pyogenic granulomas (0.05%), mastocytosis (0.05%), histiocytosis (0.05%) and Bowen’s disease (0.05%). The frequency of pedicu1osis capitis was (0.5%). Frequency of disorders of keratinization (0.5%) had the following break up: palmoplantar keratoderma (0.2%), ichthyosis (0.2%), lichen spinolosus (0.04%), porokeratosis of Mibelli (0.03%) and lichen striatus (0.03%). Generalized pruritus (0.4%), oral ulcers (0.4%) and cutaneous leishmaniasis (0.2%) were a few other disorders seen. Nevoid disorders (0.3%) included 1entigines (0.1%), hemangiomas (0.1%) and adenoma sebaceum (0.1%). Connective tissue diseases (0.2%) included scleroderma (0.1%) and lupus erythematosus (0.1%). Leprosy (0.2%) and tuberculosis cutis (0.1%) were seen rarely. Amongst the bullous disorders, pemphigus vulgaris and bullous pemphigoid had a frequency of 0.05% each. Psychocutaneous disorders (0.1%) were again rarely reported. 120 Some other diseases included in the miscellaneous group are shown in Table 2. Discussion Karachi is the largest city of Pakistan, a thickly populated metropolis with a population around 15 millions. It is a city with executives working in offices as well as labourers working for long hours in the sunlight. The weather here is hot and humid throughout the year with winter season lasting a few days. Such weather could be responsible for different cutaneous infections. The population of Karachi is a mixed one, with people belonging to different ethnic groups and coming from different areas of our country. This factor accounts for diseases like leishmaniasis being transported from endemic areas. Lack of health education, poverty, illiteracy, poor hygiene and communal living are other contributory factors. Table 3 compares the hospital-based prevalence of different dermatoses in previous studies with that in the present one. Scabies as a single entity, with a frequency of 15.4% remained the most common skin disease in Karachi, as in other parts of Pakistan. In all the past studies, scabies topped the list.2-4 As a group of skin disorders, eczema topped the list with a combined frequency of 25%. Hand eczema (7.5%) was the most common, a diagnosis not mentioned as a distinct entity in any of the past studies.2-4 Seborrhoeic dermatitis (3.4%) had a frequency significantly lower than that reported in previous studies.2-4 Lichen simplex chronicus was the common type of eczema in our series with a frequency of 3%, not reported from Karachi in the past.2 However, this frequency is almost 3 times higher than that reported from Bahawalpur4 (1%) and Lahore3 (1%). The frequency of atopic dermatitis (2.6%) was almost double than that reported from Bahawalpur4 (1.2%). Muzzafar et al.5 reported a frequency of 13.3% at Children Hospital, Lahore. The frequency of pityriasis alba (2.4%) was 2.5 times higher than that reported from Bahawalpur4 and Karachi.2 A higher percentage of children in our series may account for this figure. Xerotic eczema (2.3%) had no comparable figures in the past studies.2-4 Allergic contact dermatitis seen in 2% of patients, had a frequency significantly lower than in Bahawalpur4 (4.8%). Nadeem et aI.6 reported contact dermatitis in 10% of patients, out of which 30-50% were allergy-related. No comparable figures were available for photodermatitis, pompholyx, napkin dermatitis and asteototic eczema.2-4 The prevalence of fungal infections, as a group, was 12.5%, in agreement to that seen in Karachi2 (12.6%) and Bahawlpur4 (10.7%). The hot and humid climate of Karachi may be responsible for this high prevalence. Acne vulgaris had a frequency of 8.5% in our series, much higher than that reported previously from Karachi2 (2.8%) and Lahore3 (1.6%) but similar to that reported from Bahawalpur4 (7%). Does it show a real increase in the occurrence of acne or patients have become more cosmeticconscious, needs to be determined. The disorders of hair accounted for 8% of all patients. Alopecia was seen in 7.6% patients with androgenetic alopecia (3.2%), telogen effluvium (2.7%), and alopecia areata (1.5%) as common causes. Hirsutism (0.2%) and canities (0.1%) were 121 Table 3 Comparison of prevalence rate of different disease in the present study with previous studies Disease Scabies Eczema Atopic Lichen simplex chronicus Contact dermatitis Fungal infections Bacterial infections Tuberculosis cutis Viral infections Acne Disorders of hyperpigmentation Vitiligo Urticaria Psoriasis Pityriasis rosea Fixed drug eruption Ichthyosis Lupus erythematosus Karachi 1985 [2] 22.4% Lahore 1961 [3] 9.6% Bahawalpur 2000 [4] 14.6% Present 2003 15.4% 12.6% 12.8% 0.7% 2.5% 2.8% 1.3% 3.1% 0.7% 0.2% 0.8% 0.7% 0.4% 1% 4.8% 17.5% 0.6% 0.7% 1.6% 1.2% 1.5% 2% 2% - 1.2% 1% 4.8% 10.7% 5.9% 0.4% 3.7% 7% 3.3% 1.6% 4.9% 1.8% 0.2% 0.6% 0.5% 0.6% 2.6% 3% 2% 12.5% 6.4% 0.1% 1.7% 8.5% 6.2% 1.2% 2.4% 2.1% 0.1% 0.1% 0.4% 0.1% rare. No comparable data were available for these conditions. The overall prevalence of bacterial infections (6.4%) was significantly lower than that previously reported from Karachi2 (12.8%) and Lahore3 (17.5%) but comparable to figure from Bahawalpur.4 The most common bacterial infection in this series was folliculitis as reported by Kanjee et al.7 in 2001 at Jinnah Postgraduate Medical Centre, Karachi. Folliculitis remains the most common bacterial infection in Karachi. Hot weather, poor hygiene, communal living leading to frequent physical contact and lack of proper and timely advice are a few factors accounting for a high frequency of bacterial infections. Among the disorders of pigmentation, melasma was the commonest, as reported all over the country.2-4 We found a frequency of 4%. It may be due to a higher percentage of female patients in our series. Vitiligo (1.2%) had a frequency similar to that from Bahawalpur4 (1.6%) and Lahore3 (1.5%). The prevalence of psoriasis vulgaris (2.1%) was higher than that from Karachi2 (0.7%), but similar to that from Lahore3 (2%) and Bahawalpur4 (1.8%). Pityriasis rosea had a comparable figure to that from Karachi2 (0.2%) and Bahawalpur4 (0.2%). In the group of vascular disorders urticaria (2.4%) was the major disorder. Its prevalence was significantly less than that from Bahawalpur4 (4.9%) but almost similar to that from Karachi2 (3.1%) and Lahore3 (2%). The combined frequency of viral infections (1.7%) was less than that seen in Bahawalpur4 (3.7%) and Karachi2 (2.5%) but higher than that from Lahore3 (0.7%). Cutaneous leishmaniasis is an endemic disease in various areas of Pakistan and of late there been an increase in case reports from different areas of Sindh.8-10 In the current series, the frequency of cutaneous leishmaniasis was 0.2%. All these patients presented from Gaddap town. Amongst mycobacterial infections, leprosy was seen in 0.2% patients. Karachi is one of the endemic area for leprosy and according to an estimate Karachi is believed to harbor around 20,000 infected 122 persons who will develop leprosy in the next 10-20 years.11 Tuberculosis cutis, (0.1%) was less frequent than that reported by all the compared studies; Karachi2 (0.7%), Lahore3 (0.6%), and Bahawalpur4 (0.4%). All the cases in our series suffered from lupus vulgaris, although Khan et al.12 reported scrofuloderma to be the most common type of tuberculosis cutis in Pakistan. For drug eruptions, tumours, the disorders of keratinization, bullous disorders, connective diseases, and psychocutaneous diseases, the prevalence rate was less than 1%, similar to that from other cities.2-4 Conclusion It can be concluded from the above study that the pattern of skin diseases is same in various cities of Pakistan with minor differences in frequency. Scabies being the most common disease necessitates a need for better health education, improved hygiene and better living standards. 7. Kanjee A, Yasmeena N, Siddiqi K. Effect and tolerability of cephradine in bacterial skin infections. J Pak Assoc of Dermatol 2002; 12: 18-20. 8. Mujtaba G, Khalid M. Cutaneous leishmaniasis in Multan, Pakistan. Int J Dermatol 1998; 37: 843-6. 9. Raja KM, Khan AA, Hameed A. Unusual clinical variants of cutaneous leishmaniasis in Pakistan. Br J Dermatol 1998; 139: 111-3. 10. Khan I, Khan MA. Managing cutaneous leishmaniasis from Peru to Pakistan. J Pak Assoc Dermatol 2000; 10: 5-15. 11. Jabeen S, Shaikh A, Sheikh AR. Psychological aspects of female leprosy patients. J Pak Assoc Dermatol 2000; 10:16-20. 12. Khan Y, lqbal P, Kumar A. Cutaneous tuberculosis: A study of 10 cases. J Pak Assoc Dermatol 200l; 11: 7-10. References 1. 2. 3. 4. 5. 6. Williams HC. Epidemiology of skin diseases. In: Champion RH, Burton JL, Burns DA, Breathnach SM, eds. Textbook of dermatology, 6th edn. Oxford: Blackwell Science; 1998. p.139-57. Haroon TS. Pattern of skin diseases in Karachi. J Pak Med Assoc 1985; 35: 73-8. Shabbir G. Dermatoses prevalent in Lahore. The Medicus 1961; 22: 33-42. Qamar AG, Malik RA. Skin diseases in Bahawalpur. J Pak Assoc Dermatol 2000; 10: 3-8. Muzzafar F, Hussain I, Rashid T. An audit of childhood eczema. J Pak Assoc Dermatol 2000; 10: 9-14. Nadeem M, Akber T, Haroon TS. Patch testing with European standard series, our experience at Mayo hospital Lahore. J Pak Assoc of Dermatol 2001; 11: 7-12. 123 Original article Successful treatment of tinea capitis with griseofulvin caused by Microsporum canis. Shahbaz Aman, Ijaz Hussain, Tahir Saeed Haroon Department of Dermatology, King Edward Medical College/Mayo Hospital, Lahore Abstract Background Griseofulvin is an antimycotic which has been used successfully as a treatment of tinea capitis caused by dermatophytes. Objective Our aim was to assess the efficacy of griseofulvin therapy in tinea capitis caused by zoophilic species, Microsporum canis. Patients and methods Nine mycologically confirmed cases of inflammatory and noninflammatory tinea capitis were enrolled in the study. Griseofulvin therapy was started 10mg/kg once daily at night with milk for 8 weeks and the patients were followed up to 8 weeks after the completion of therapy. Results Of 9 patients, 4 were males while 5 were female children. The age ranged from 6 to 12 years. The agminate folliculitis type was noted in five patients and grey patch variety was seen in four patients. Microsporum canis was the pathogen isolated in all cases. The patients were prescribed griseofulvin. Clinical cure was seen in 89% cases while mycological cure was seen in 100% patients at 16 weeks final evaluation (8 weeks after the completion of therapy). The adverse events were few, mild and reversible in nature. Conclusion Griseofulvin was found to be effective, well-tolerated and safe therapy for tinea capitis caused by Microsporum canis. Key words Tinea capitis, griseofulvin, Microsporum canis. Introduction Tinea capitis is a fungal infection of scalp, skin and hair characterized by erythema, scaling, pruritus and alopecia.1 Like other dermatophytoses, tinea capitis is also common in this part of the world. Clinical patterns of the disease include noninflammatory (grey patch and black dot) or inflammatory (kerion celsi, agminate folliculitis and favus) types2 caused by dermatophytes of both genera Trichophyton and Microsporum.3 Although grey patch variety is encountered most frequently but agminate Address for Correspondence Dr. Shahbaz Aman 2-C Hearn Road, Islampura Lahore. Ph# 042-7226054 folliculitis is not uncommon in our society.1,2,3 Tinea capitis caused by M. Canis is a difficult therapeutic problem which requires an adequate antimycotic therapy.4 Griseofulvin is a metabolic product of Penicillium griseofulvum, firstly described in 1939.5 It acts on microtubules and inhibits fungal mitosis.5 Absorption occurs primarily from the duodenum and jejunum while some quantity also absorbed from ileum, stomach and rectum.5 The peak plasma level occurs between 2 and 9 hours after administration and remains high for 10 to 20 hours. It is effective for the infections of skin, hair and nails caused by dermatophytes but not against Candida 124 spp.5 We report nine cases of tinea capitis due to M. canis and their successful treatment with griseofulvin therapy. Patients and Methods This was an open, clinical, pilot study. Nine children presented with clinically suspected tinea capitis at the mycology clinic of the Department of Dermatology, King Edward Medical College/Mayo Hospital, Lahore were included in the study after taking informed consent. A detailed history and meticulous clinical examination was recorded. The lesions were examined clinically and under Wood’s light for any fluorescence. To confirm the diagnosis, specimens from affected scalp area along with hair were taken. The specimens were examined under light microscope after treating with 25% potassium hydroxide and fluorescent microscopy was also done after using calcofluor white stain. For fungus culture, the specimens were inoculated on Sabouraud’s dextrose agar together with chloramphenicol and with or without cycloheximide. The cultures were incubated at 25-300C for 4 to 6 weeks and were examined twice weekly to confirm any negative growth. The positive cultures were identified by gross colonial morphology and microscopic characteristics after making teased mounts of a mature colony and stained with lactophenol cotton blue. The criteria for inclusion in the study were clinical and mycological evidence of dermatophytosis of the scalp. Those patients who had topical antifungal therapy within 2 weeks or oral antifungal agents within 4 weeks of entering the study were excluded from the study. Patients who had any concomitant topical or systemic treatment were also excluded from the study. Treatment was administered 10mg/kg once daily at night with milk. The therapeutic efficacy of the drug was determined by evaluation at every 2 weeks, end of treatment and at follow-up period by observing the clinical signs, symptoms and mycological examination. The clinical parameters were assessed according to a four-point scale ranging from (0=absent, 1=mild, 2=moderate, and 3=severe) for erythema, scaling (desqumation), edema, pustules, pruritus and hair loss. Hematological investigations performed for each patient before, during and if needed after the treatment were: hemoglobin, hematocrit, white cell count, bilirubin, serum glutamic oxaloacetic transaminase (SGOT), serum glutamate pyruvic transaminase (SGPT), lactate dehydrogenase (LDH), alkaline phosphatase, gamma glutamyl transferase, potassium, creatinine, uric acid, cholesterol and triglycerides. Results Of 9 patients, 4 were males while 5 were female children (Table 1). The age ranged from 6 to 12 years (mean age, 7.7+2.02 years). The agminate folliculitis variety was seen in 5 patients while grey patch variety was noted in four patients (Figure 1). Physical examination revealed scaling, erythema, pustules, pruritus and alopecia. There was a history of exposure to pet animals (dogs=3, cats=2) in our patients but there was no history of trauma, drug intake, application of medicament or other skin diseases like psoriasis or eczema. Wood’s light examination revealed green fluorescence in 4 cases. M. canis was the pathogen, isolated on fungal culture in all 9 patients. The upper surface of colony revealed whitish hue while yellow pigment was seen on reverse side (Figure 2). Teased mounts of a 125 Table 1 Demographic and clinical data of patients (n=9) Sr. No. Age (yrs) Sex Duration of Clinical disease variety (mo) 1. 7 M 4 G 2. 6 M 6 A 3. 10 F 2 A 4. 8 F 6 A 5. 12 M 3 G 6. 7 M 4 A 7. 6 F 5 G 8. 7 F 2 G 9. 6.5 F 3 A M=male, F=female; G=grey patch, A=agminate folliculitis mature colony stained with lactophenol Wood’s lamp examination Fungus culture + + + + - M. canis M. canis M. canis M. canis M. canis M. canis M. canis M. canis M. canis desquamation, pustules and pruritus was noted during the third week of treatment Figure 3 Spindle-shaped macroconidia (lactophenol cotton blue mount) Figure 1 Agminate folliculitis Figure 2 Colony of M. canis cotton blue, revealed macroconidia (Figure 3). spindle-shaped A reduction in the severity of erythema, and the improvement continued until the end of treatment and during the follow-up period. Hair loss was not improved at 8 weeks but some regrowth of hair was seen at 12 weeks (4 weeks after the completion of therapy) in the follow-up period and continued slowly at 16 weeks’ final evaluation (8 weeks after the end of therapy). Clinical cure was seen in 77.7% cases and mycological cure was noted in 88.8% patients at 8 weeks time while clinical cure was 89% and mycological cure was 100% at final evaluation. One patient developed mild headache while another complained of nausea after intake of griseofulvin which settled after the completion of medication. Griseofulvin treatment was well tolerated and the adverse events were of mild intensity and reversible nature. 126 Discussion Tinea capitis is a common pediatric scalp dermatophytosis.6,7 Topical therapy alone is ineffective and systemic antifungal agents are the mainstay of treatment.8,9 Griseofulvin, still ‘the gold standard therapy’ is being used in many countries due to its good efficacy, cost effectiveness and less number of hazards.9,10 The new antimycotic agents like terbinafine, itraconazole and fluconazole are effective alternatives but costly and beyond the reach of most patients in Pakistan. 2. M. canis is a zoophilic fungus which causes grey patch, kerion and agminate folliculitis type of tinea capitis1-3 and the history of animal exposure in four of our patients reflects animal host for this species. 6. 3. 4. 5. 7. 8. Our results showed clinical cure in 89% patients and mycological cure in 100% cases at final evaluation with griseofulvin therapy, comparable with the results of similar studies.10,11 The clinical parameters noted were improved except the hair loss because a longer period is required for hair regrowth.12-14 In our opinion griseofulvin which is the cheapest of systemic antifungals has shown good antimycotic and antiinflammatory response7 in this zoophilic infection similar to the studies which reveal that Microsporum scalp infections are better treated with griseofulvin rather than new antifungal drug like terbinafine, a better choice for Trichophyton scalp infections.6,15 In conclusion, the present study showed griseofulvin to be effective, well-tolerated and safe therapy for tinea capitis caused by M. canis in our scenario. References 1. 9. 10. 11. 12. 13. 14. 15. Hay RJ, Moore M. Mycology. In: Champion RH, Burton JL, Burns DA, Breathnach SM, eds. Textbook of dermatology, 6th edn. Oxford: Blackwell Science; 1998. p. 1277-1376. Martin AG, Kobayashi GS. Superficial fungal infection: dermatophytosis, tinea, nigra, piedra. In: Freedberg IM, Eisen AZ, Wolff K et al., eds. Dermatology in general medicine, 5th edn. New York: McGraw-Hill; 1999. p. 2373-88. Hussain I, Aman S, Haroon TS et al. Tinea capitis in Lahore, Pakistan. Int J Dermatol 1994; 33: 255-7. Aman S, Hussain I, Haroon TS. Tinea capitis: still no change in the etiological spectrum of disease in our scenario. J Pak Assoc Dermatol 2002; 12: 119-21. Koumantaki E, Georgalla S, Rallis E, Papadavid E. Doubled dose of oral terbinafine is required for Microsporum canis tinea capitis. Pediatr Dermatol 2001; 18: 60-2. Becker LE. Griseofulvin: symposium on superficial fungal infections. Dermatol Clin 1984; 2: 115-28. Higgins EM, Fuller LC, Smith CH. Guidelines for the management of tinea capitis. Br J Dermatol 2000; 143: 53-8. Bennett ML, Fleischer AB, Loveless JW, Feldman SR. Oral griseofulvin remains the treatment of choice for tinea capitis in children. Pediatr Dermatol 2000; 17: 3049. Lopez-Gomez S, Del Palacio A, Van Cutsem J et al. Itraconazole versus griseofulvin in the treatment of tinea capitis: a double-blind randomized study in children. Int J Dermatol 1994; 33: 7437. Elewski B. Treatment of tinea capitis beyond griseofulvin. J Am Acad Dermatol 1999; 40: S27-30. Rademaker M, Havill S. Griseofulvin and terbinafine in the treatment of tinea capitis in children. N Z Med J 1998; 111: 55-7. Haroon TS, Hussain I, Aman S et al. A randomized double-blind comparative study of terbinafine and griseofulvin in tinea capitis. J Dermatol Treat 1995; 6: 167-9. Dragos V, Lunder M. Lack of efficacy of 6-week treatment with oral terbinafine for tinea capitis due to Microsporum canis in children. Pediatr Dermatol 1997; 14: 468. Ormerod AD. What is new in therapy? Br J Dermatol 2001; 145: 691-95. Elewski B. Tinea capitis. Dermatol Clin 1996; 14: 23-31. 127 128 Original article Lichen planus and hepatitis C virus infection: An epidemiologic study Tameez-ud-deen, Shahzana Naqqash, Abdul Quddus Butt. Dermatology Department, Rawalpindi General Hospital, Rawalpindi Abstract Background Lichen planus is an immunologically mediated skin and mucous membrane disease, which has been described in patients with hepatitis C virus-related liver disease, with variable frequency. Objective The purpose of this study was to determine the association of lichen planus with hepatitis C virus related liver diseases. Methods We tested sera of 55 patients with lichen planus for HCV antibodies by means of a second generation enzyme linked immunosorbent assay. Serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were simultaneously determined in all the patients. During the same period, a group of 110 patients admitted to the Dermatology Department, RGH, Rawalpindi, served as a control. Results Of the 55 patients with lichen planus, 18 had HCV antibodies (prevalence 32.7%), of the 110 control patients 8 had HCV antibodies (prevalence 7.2%). There was significant difference between the two groups. The ALT was raised in 21 patients with lichen planus, and 15 of them also had an elevated AST level. In the control patients, the AST level was raised in 4 of the 110 patients, 3 also had an elevated ALT level. The number of patients with an abnormal transaminase level significantly differed in the two groups (38.1% in the lichen planus group, and 4% in the control group). Conclusion These results support a possible relationship between LP and chronic hepatitis C and the hypothesis that LP may be associated with chronic liver diseases as a result of a cytotoxic attack on the hepatocytes. Key words Lichen planus, hepatitis C virus Introduction Hepatitis C virus (HCV), identified in 1989, is an RNA virus that is a major cause of acute and chronic hepatitis. Both are asymptomatic in most patients, however, chronic hepatitis C is a slowly progressive disease and results in severe morbidity in 20% of infected individuals.1 Majority of transfusion associated cases of Address for Correspondence Dr. Shahzana Naqqash House No. 22, Ravi Road, Wah Cantt, Punjab, Pakistan. hepatitis are due to HCV,2 as blood donors are now screened for HCV antibodies, the risk of post-transfusion hepatitis is declining.3 Low level of sexual transmission is also possible.4 According to WHO about 170 million people i.e. 3% of the world’s population are estimated to be infected with HCV with prevalence of 0.5% to more than 10% in population samples around the world.5 Prevalence of HCV infection varies from 129 4% to 7% in various segments of Pakistan.6 Chronic hepatitis C is associated with a variety of disorders, particularly as regards dermatology. The most frequent of these are mixed cryoglobulinemia with leukocytoclastic vasculitis, porphyria cutanea tarda and lichen planus.1 In 1991 Mockni et al.7 described a patient in whom lichen planus (LP) developed during HCV-induced chronic hepatitis. Since then numerous cases of HCV-associated LP have been published, and association of chronic hepatitsis with lichen planus has been established, especially in Italian patients.8 LP is considered by certain authors as a possible marker of HCV infection. The prevalence of HCV infection in patients with LP varies considerably from one geographic area to another, ranging from 4% in northern France9 to 62% in Japan.10 On the other hand, studies from Great Britain have failed to reveal any association. Similarly another study from France by Cribier et al.11 found no difference with regard to HCV prevalence in patients with lichen planus and in patients with other dermatoses. However, Jubert et al.9 described six patients with lichen planus and chronic HCV infection. Rebora12 reported that prevalence of HCV antibodies was 14% in 87 patients with lichen planus. We describe the prevalence of HCV antibodies in a group of 55 patients in a case-controlled study. Patients and methods Between January, 2002 and February, 2003, 55 patients with lichen planus were diagnosed on the basis of usual clinical features and specific histologic findings. Patients suspected of drug-induced lichenoid eruption were not included. There were 22 women, 16-75 years of age (average 43), and 33 men aged 11-55 years (average 52.8). Of the 55 patients, 19 had erosive lichen planus of the mouth, while 3 had associated genital lesions. During the same period, a group of 110 patients presented to the dermatology department for various dermatological diseases excluding lichen planus served as control. The group included 60 females 780 years (average 37.5) of age, 40 males 12-60 years of age (average 51.5). Sera from all the patients were tested for HCV antibodies by means of secondgeneration enzyme-linked immunosorbent assay. The serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were simultaneously determined in all patients. The modified chi square test was used for statistical comparison of the two groups. Results The number of male patients with lichen planus was significantly higher than the control group. The age of male patients did not differ in the two groups, whereas the age of female patients with lichen planus was higher than in the control group. Of the 55 patients with lichen planus, 18 had HCV antibodies (prevalence 32.7%), of the 100 control patients 7 had HCV antibodies (prevalence 7%). There was significant difference between the two groups. The ALT was raised in 21 patients with lichen planus, and 15 of them also had an elevated AST level. In the control patients, the AST level was elevated in 4 of the 100 patients, 3 also had an elevated ALT level. The number of patients with an abnormal transaminase level significantly differed in 130 the two groups (38.1% in the lichen planus group, and 4% in the control group). Discussion A frequent occurrence of liver abnormalities has been reported in patients with lichen planus.13,14 Chronic active hepatitis especially due to hepatitis C virus is suspected to be a contributing factor. Significant association of erosive lichen planus with chronic hepatitis was demonstrated in a case controlled study.15 Recently this association between lichen planus and liver disease has been questioned. A study in 180 English patients with oral lichen planus failed to show any significant association with liver dysfunction.16 Similarly no difference was found with regard to HCV antibodies prevalence in patients with lichen planus and in patients with other dermatoses by Bernard et al.11 in 1992. The prevalence of HCV in patients with lichen planus varies considerably from one geographic area to another, ranging from 4% in France9 to 62% in Japan.10 In our study a strong association between lichen planus and HCV infection was revealed. The prevalence of HCV infection in our community ranges between 3-7%.6 In our patients with lichen planus the HCV prevalence of 32.7% cannot be a chance association. In patients with lichen planus HCV may be etiologically related, and these patients should have assessment of liver function for early detection and prevention of possible liver damage. References 1. 2. Bonkovsky, HL, Mehta S. Hepatitis C: a review and update. J Am Acad Dermatol 2001; 44: 150- . Vrielink H, Vander Poel CL, Reesnik HW et al. Look-back study of infectivity of 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. anti-HCV ELISA-positive blood components. Lancet 1995; 345: 95-6. Donahue JG, Alvaro M, Ness PM et al. The declining risk of post-transfusion hepatitis C virus infection. N Engl J Med 1992; 327: 369-73. Gabrielli C, Zannini A, Corradini R et al. Spread of hepatitis C virus among sexual partners HCVab positive intravenous drug users. J Infect Dis 1994; 29: 17-22. World Health Organization. Hepatitis C: global prevalence. Epidemiol Rep 1997; 45: 341-8. Umar M, Bushra HT, Shuaib A et al. Spectrum of chronic liver disease due to hepatitis C virus infection. J Coll Phys Surg Pak 2000; 10: 380-3. Mokni M, Rybojad M, Puppin D Jr et al. Lichen planus and hepatitis C virus. J Am Acad Dermatol 1991; 24: 792. Gruppo Italiano Sudi Epidermiologici in Dermatologia (GISED). Lichen planus and liver disease: a multicentre casecontrolled study. BMJ 1990; 300: 227-30. Jubert C, Pawlotsky JM, Pouget F et al. Lichen planus and hepatitis C virusrelated chronic active hepatitis. Arch Dermatol 1994; 130: 73-6. Nagao Y, Sata M, Tanikawa K et al. Lichen planus and hepatitis C virus in northern region of Japan. Eur J Clin Invest 1995; 25: 910-4. Cribier B, Garnier C, Laustriat D, Heid E. Lichen planus and hepatitis C virus infection: an epidemiologic study. J Am Acad Dermatol 1994; 31: 1070-2. Rebora A. Lichen planus and the liver. Int J Dermatol 1992; 3: 392-5. Doutre MS. Hepatitis C virus-related skin disease. Arch Dermatol 1999; 135: 14013. Tanei R, Watanabe K, Nishiyama S. Clinical and histopathologic analysis of the Relationship between lichen planus and chronic hepatitis C. J Dermatol 1995; 22: 316-23. Mignogna MD, Muzio LL, Favia G et al. Oral lichen planus and HCV infection: a clinical evaluation of 263 cases. Int J Dermatol 1998; 37: 575-8. El–Kabir M, Scully C, Porter S et al. Liver function in UK patients with oral lichen planus. Clin Exp Dermatol 1993; 18: 12-16. 131 Review article Zinc: An overview and therapeutic uses in dermatology Arfan-ul-Bari, *Simeen Ber Rehman PAF Hospital, Sargodha *Dermatology Department, Military Hospital, Rawalpindi Abstract Zinc is an essential component of various important enzymes in our body and its deficiency causes multi-enzyme defects and multisystemic disease. It ranks with biotin as a truly essential element in both cutaneous health and disease. Zinc deficiency may explain alopecia, ulcers, infections and a host of strange unexplainable skin changes. Introduction Zinc is an essential mineral that is found in almost every cell. It stimulates the activity of approximately 100 enzymes, which are substances that promote biochemical reactions in the body.l,2 It must be obtained from the diet since the body cannot make enough. Next to iron, it is the most abundant trace mineral in the body. It is stored primarily in muscles, but is also found in high concentrations in red and white blood cells, the retina of the eye, bones, skin, kidneys, liver, and pancreas. In men, the prostate gland stores high amounts of it. Zinc plays an important role in the immune system and is helpful in protecting against infection,3,4 is needed for wound healing,5 helps maintain the sense of taste and smell,6 and is needed for DNA synthesis.2 Zinc also supports normal growth and development during pregnancy, childhood, and adolescence.7,8 Zinc also has some antioxidant properties,9 which means that it helps protect cells in Address for Correspondence Squadron Leader Dr. Arfan-ul-Bari Consultant Dermatologist PAF Hospital, Sargodha. Ph# 051-561-33799, 5583688 Email: albariul@yahoo.com the body from the potential damage caused by free radicals. Free radicals are believed to contribute to the aging process. The typical daily intake of zinc in the Western diet is approximately 10 mg, two thirds of the recommended dietary allowance (RDA).2 Low zinc intake is often seen in the elderly, alcoholics, people with anorexia, and individuals on restrictive weight loss diets.2 Zinc deficiency can also be caused by diseases that interfere with the absorption of nutrients from food, such as irritable bowel disease, celiac disease, and chronic diarrhea.10,11 Some of the symptoms of zinc deficiency include loss of appetite, poor growth, weight loss, impaired taste or smell, poor wound healing, skin abnormalities (such as acne, atopic dermatitis and psoriasis), hair loss, lack of menstrual period, night blindness, hypogonadism and delayed sexual maturation, white spots on the fingernails and feelings of depression.2,10,12-14 The body absorbs 20% to 40% of the zinc present in food. Dietary fiber, particularly phytates, can interfere with the body's ability to absorb zinc. Zinc is best absorbed when taken with a meal that contains protein.15 The best sources of zinc are oysters (richest source), beef, liver, pumpkin 132 seeds, pecans, poultry, cheese (ricotta, Swiss, gouda), shrimp, crab, and other shellfish. Other good, though less easily absorbed sources of zinc include legumes (especially lima beans, black-eyed peas, pinto beans, soybeans, peanuts), whole grains, miso, tofu, brewer's yeast, cooked greens, mushrooms, green beans, tahini, and pumpkin and sunflower seeds.16-18 Zinc sulfate is the most frequently used supplement. This is the least expensive form, but it is the least easily absorbed and may cause stomach upset. Health care providers usually prescribe 220 mg zinc sulfate, which contains approximately 55 mg of elemental zinc.15 The more easily absorbed forms of zinc are zinc picolinate, zinc citrate, zinc acetate, zinc glycerate, and zinc monomethionine. If zinc sulfate causes stomach irritation, another form such as zinc citrate should be tried.15,19 Zinc should be taken with water or juice. However, if zinc causes stomach upset, it can be taken with meals. It should not be taken at the same time as iron or calcium supplements.20 A strong relationship exits between zinc and copper. Too much of one can cause a deficiency of the other. Long-term use of zinc (including zinc in a multivitamin) should be accompanied by copper. For every 15 mg of zinc include 1 mg of copper. Daily intakes of dietary zinc, according to the US RDA, are: infants and children up to 3 years: 2 - 3 mg (RDA); children 4 to 8 years: 5 mg (RDA); children 9 to 13 years: 8 mg (RDA); males 14 to 18 years: 11 mg (RDA); females 14 to 18 years: 9 mg (RDA); pregnant females 19 years and older: 11 mg (RDA); breastfeeding females: 12 -14 mg (RDA).2 Therapeutic range of elemental zinc in men is 30 to 60 mg daily and in women is 30 to 45 mg daily. Doses over the amounts listed should be limited to only a few months under the supervision of a healthcare professional. Research has shown that less than 50 mg a day is a safe amount to take over time, but researchers are not sure what happens if more is taken over a long period. Taking more than 150 mg per day may interfere with the body's ability to use other minerals.2,15 Common side effects of zinc include stomach upset, nausea, vomiting, and a metallic taste in the mouth. Other reported side effects of zinc toxicity are dizziness, headache, drowsiness, increased sweating, loss of muscle coordination, alcohol intolerance, hallucinations, and anemia.21 High doses of zinc may also lower HDL ("good") cholesterol and raise LDL ("bad") cholesterol. This may be due to a copper deficiency brought on by the long-term use of zinc.22 Zinc can have interactions with drugs like ACE inhibitors, quinolones, tetracycline, hormone replacement therapy (HRT), hydralazine, immunosuppressants, nonsteroidal anti-inflammatory drugs (NSAIDs) and penicillamine.23-27 Therapeutic uses in dermatology Infections Zinc is required for the development and activation of T-lymphocytes, a kind of white blood cell that helps fight infection.2 People who are zinc deficient tend to be more susceptible to a variety of infections. Zinc supplementation enhances immune system activity and protects against a range of infections including upper respiratory tract infections, skin and mucocutaneous infections.28-33 HIV / AIDS Zinc deficiency is common in people with HIV (even before symptoms appear) or AIDS. Zinc deficiency leads to increased susceptibility to opportunistic infections in people with AIDS. When studied, zinc supplementation has increased CD4 133 counts.34 Burns When skin is burned, a substantial percentage of micronutrients, such as copper, selenium, and zinc may be lost. This increases the risk for infection, slows the healing process, prolongs the hospital stay, and even increases the risk of death. Although it is unclear which micronutrients are most beneficial for people with burns, many experts suggest that a multivitamin containing zinc and other vital nutrients be included in the therapy to aid recovery.35 Acne There is some evidence that zinc supplementation (such as zinc gluconate) reduces acne inflammation. Studies to date have had certain limitations, however. Therefore, it is difficult to draw definite conclusions about how much zinc to use, what type of zinc is best, and the duration of treatment. Antibiotics such as erythromycin and tetracyclines are sometimes combined with zinc in topical preparations for inflammatory acne. It is unclear whether zinc enhances the effects of the antibiotics or simply serves as a mode of delivery for the antibiotics.36-41 Herpes simplex Topical preparations of zinc have shown benefit in relieving symptoms and preventing recurrences of oral herpes lesions (canker sores).42 Acrodermatitis enteropathica Zinc dramatically reverses the manifestations within hours to days in patients with acrodermatitis enteropathica (a skin disorder that is due to an inherited inability to absorb zinc properly; generally affects the limbs, mouth, or anus and may include hair loss and diarrhea.43-45 Skin wounds and ulcers Zinc supplements are often given to help heal skin ulcers or bed sores but they do not increase rates of wound healing when zinc levels are normal.2,46 Conclusion Zinc is a truly essential element required for a normal functioning healthy skin and it has a definite role in treating a variety of dermatological disorders. It pays to think zinc when looking at a strange dermatitis. Before ordering a plasma level determination, be sure that rubber stoppers are not used and specimen does not hemolyze because red cells and rubber stoppers are zinc rich. References 1. 2. 3. 4. 5. 6. 7. 8. 9. Sandstead HR. Understanding zinc: recent observations and interpretations. J Lab Clin Med 1994; 124: 322-7. Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academy Press, 2001. Solomons NW. Mild human zinc deficiency produces an imbalance between cell-mediated and humoral immunity. Nutr Rev 1998; 56: 27-8. Prasad AS. Zinc: an overview. Nutrition 1995; 11: 93-9. Heyneman CA. Zinc deficiency and taste disorders. Ann Pharmacother 1996; 30: 186-7. Prasad AS, Beck FW, Grabowski SM et al. Zinc deficiency: changes in cytokine production and T-cell subpopulations in patients with head and neck cancer and in noncancer subjects. Proc Soc Am Physicians 1997; 109: 68-77. Simmer K, Thompson RP. Zinc in the fetus and newborn. Acta Paediatr Scand Suppl 1985; 319: 158-63. Fabris N, Mocchegiani E. Zinc, human diseases and aging. Aging (Milano) 1995; 7: 77-93. Anderson RA, Roussel AM, Zouari N et al. Potential antioxidant effects of zinc 134 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. and chromium supplementation in people with type 2 diabetes mellitus. J Am CoIl Nutr 2001; 20: 212-8. Hambidge KM. Mild zinc deficiency in human subjects. In: Mills CF, ed. Zinc in human biology. New York: SpringerVerlag; 1989. p. 281-96. Naber TH, van den Hamer CJ, Baadenhuysen H, Jansen JB. The value of methods to determine zinc deficiency in patients with Crohn’s disease. Scand J Gastroenterol 1998; 33: 514-23. King JC, Keen CL. Zinc. In: Shils ME, Olson JA, Shike M, Ross AC, eds. Modern nutrition in health and disease, 9th edn. Baltimore: Williams & Wilkins; 1999. p. 223-39. Ploysangam A, Falciglia GA, Brehm BJ. Effect of marginal zinc deficiency on human growth and development. J Trop Pediatr 1997; 43: 192-8. Nishi Y. Zinc and growth. J Am Coll Nutr 1996; 15: 340-4. Gordon KF, Gordon RC, Passal DB. Zinc metabolism: basic, clinical, and behavioral aspects. J Pediatr 1981; 9: 341-9. Murray MT. The healing power of foods. Rocklin: CN Prima Publishing; 1993. US Department of Agriculture, Agricultural Research Service, 2001. United States Department of Agriculture Nutrient Database for Standard Reference, Release 14. Nutrient Data Laboratory Home Page, http://www.nal.usda.gov/fnic/foodcomp. Dietary Guidelines Advisory Committee, Agricultural Research Service, United States Department of Agriculture (USDA). HG Bulletin No. 232, 2000. Sandstrom B. Bioavailability of zinc. Eur J Clin Nutr 1997; 51 (Suppl 1): SI7-S19. Whittaker P. Iron and zinc interactions in humans. Am J Clin Nutr 1998; 68: 442S446S. Lewis MR, Kokan L. Zinc gluconate: acute ingestion. J Toxicol Clin Toxicol 1998; 33: 99-101. Hooper PL, Visconti L, Garry PI, Johnson GE. Zinc lowers high-density lipoprotein cholesterol levels. J Am Med Assoc 1980; 244: 1960-1. Brouwers JR. Drug interactions with quinolone antibacterials. Drug Saf 1992; 7: 268-81. Dendrinou-Samara C, Tsotsou G, Ekateriniadou E et al. Anti-inflammatory drugs interacting with Zn(II), Cd(II) and Pt(II) metal ions. J Inorg Biochem 1998; 71: 171-9. Golik A, Zaidenstein R, Dishi V et al. 26. 27. 28. 29. 30. 31. 32. Effects of captopril and enalapril on zinc metabolism in hypertensive patients. J Am Col1 Nutr 1998; 17: 75-8. Neuvonen PJ. Interactions with the absorption of tetracyclines. Drugs 1976; 11: 45-54. Otomo S, Sasajima M, Ohzeki M, Tanaka I. Effects of D-penicillamine on vitamin B6 and metal ions in rats [in Japanese]. Njppon Y Agurigaku Zsshi 1980; 76: 1-13. Fortes C, Forastiere F, Agabiti N et al. The effect of zinc and vitamin A supplementation on immune response in an older population. J Am Geriatr Soc 1998; 46: 19-26. Garland ML, Hagmeyer KO. The role of zinc lozenges in treatment of the common cold. Ann Pharmacother 1998; 32: 63-9. Girodon F, Lombard M, Galan P et al. Effect of micronutrient supplementation on infection in institutionalized elderly subjects: a controlled trial. Ann Nutr Metab 1997; 41: 98-107. Prasad AS, Beck FW, Kaplan J et al. Effect of zinc supplementation on incidence of infections and hospital admissions in sickle cell disease (SCD). Am J Hematol 1999; 61:194-202. Shankar AH, Prasad AS. Zinc and immune function: the biological basis of altered resistance to infection. Am J Clin Nutr 1998; 68: 447S-63S. 33. Black RE. Therapeutic and preventive effects of zinc on serious childhood infectious diseases in developing countries. Am J Clin Nutr 1998; 68: 476S79S. 34. Beck FW, Prasad AS, Kaplan J et al. Changes in cytokine production and T cell subpopulations in experimentally induced zinc-deficient humans. Am J Physiol 1997; 272: E1002-7. 35. De-Souza DA, Greene LJ. Pharmacological nutrition after burn injury. J Nutr 1998; 128: 797-803. 36. Dreno B, Amblard P, Agache P et al. Low doses of zinc gluconate for inflammatory acne. Acta Derm Venereol 1989; 69: 5413. 37. Dreno B, Trossaert M, Boiteau HL, Litoux P. Zinc salts effects on granulocyte zinc concentration and chemotaxis in acne patients. Acta Derm Venereol 1992; 73: 250-2. 38. Krowchuk DP. Treating acne. A practical guide. Med Clin North Am 2000; 84: 81128. 39. Meynadier 1. Efficacy and safety study of two zinc gluconate regimens in the treatment of inflammatory acne. Eur J 135 Dermatol 2000; 10: 269-73. 40. Papageorgiou PP, Chu AC. Chloroxylenol and zinc oxide containing cream (Nels cream®) vs. 5% benzoyl peroxide cream in the treatment of acne vulgaris. A double-blind, randomized, controlled trial. Clin Exp Dermatol 2000; 25: 16-20. 41. Toyoda M, Morohashi M. An overview of topical antibiotics for acne treatment. Dermatology 1998; 196: 130-4. 42. Godfrey HR, Godfrey NJ, Godfrey JC, Riley D. A randomized clinical trial on the treatment of oral herpes with topical zinc oxide/glycine. Altern Ther Health Med 2001; 7: 49-56. 43. Walravens FA, Hambidge KM, Neldner KH. Zinc metabolism in acrodermatitis enteropathica. J Pediatr 1978; 93: 71-3. 44. Der Kaloustian VM, Musallam SS, Sanjad SA et al. Oral treatment of acrodermatitis enteropathica with zinc sulfate. Am J Dis Child 1976; 130: 421-3. 45. Leupold D, Poley JR, Meigel WN. Zinc therapy in acrodermatitis enteropathica. Helv Paediatr Acta 1976; 31: 109-15. 46. Anderson I. Zinc as an aid to healing. Nurs Times 1995; 91: 68-70. 136 Review article Cockayne syndrome. An update. Farhana Muzaffar, *Ijaz Hussain Department of Pediatric Dermatology, Institute of Child Health/Children Hospital, Lahore * Department of Dermatology, King Edward Medical College/Mayo Hospital, Lahore Abstract Cockayne’s syndrome is a rare heterogeneous autosomal recessive disorder with poor genotype-phenotype correlation. The basic underlying abnormality in CS is defective transcription-coupled repair of DNA whereas the global genome repair pathway of nucleotide-excision repair is normal. Clinically the spectrum of CS spans from classical type (CS type 1, CKN1, CSA), a more severe form with symptoms present at birth (CS type 2, CSB, also known as cerebro-oculo-facial syndrome and Pena-Shokeir type II syndrome), a milder form (CS type 3), and xeroderma pigmentosum-Cockayne syndrome (XP-CS). However, CS type 1 and CS type 2 are the major phenotypes. The cardinal features of CS are growth failure, premature aging, and pigmentary retinal degeneration along with a number of nonspecific clinical findings. The definite diagnosis requires assay of DNA repair in skin fibroblasts or lymphoblasts. Prenatal diagnosis is also possible at 16-18 weeks of gestation. There is progressive downhill course with premature death before adulthood. Besides genetic counselling a multidisciplinary approach is required. Introduction Cockayne’s syndrome (CS); also called Neill-Dingwall syndrome, progeria-like syndrome and progeroid nanism; belongs to a group of inherited disorders with heterogeneous clinical features which have in vitro or in vivo cellular hypersensitivity to damage by certain physical or chemical agents. These diseases include xeroderma pigmentosum (XP), Cockayne syndrome, trichothiodystrophy (TTD), Bloom syndrome, Fanconi anemia, dyskeratosis congenita, basal cell nevus syndrome, ataxia-telangiectasia, and familial melanoma with dysplastic nevi.1 Clinically, the cutaneous, ocular, nervous, immune, Address for Correspondence Dr. Farhana Muzaffar Assistant Professor Department of Paediatric Dermatology Institute of Child Health/ Children Hospital Lahore hemopoietic, skeletal, or gastrointeinal systems are affected. Some are associated with increased incidence of neoplasia. There may be a progressive deterioration of body functions. The cellular hypersensitivity is helpful in the diagnosis, understanding the pathogenic mechanisms and devising therapeutic or prophylactic intervention. The molecular basis of the cellular hypersensitivity has been explored in some of these disorders. This review focuses on the clinical features and laboratory abnormalities of CS. History The syndrome was described first by Edward Alfred Cockayne, a British pediatrician in 1936.2 His patient had cachectic dwarfism, deafness, and pigmentary retinal degeneration with a characteristic “salt and pepper” appearance 137 of the retina. The skin had photosensitivity without the excessive pigmentary abnormalities seen in XP. There was marked loss of subcutaneous fat, resulting in a “wizened” appearance with typical “birdheaded” facies and prominent “Mickey Mouse” ears. Other ocular findings included cataracts and optic atrophy. Later, Catherine M. Neill and Mary M. Dingwall3 reported similar cases in 1950. Since then many cases have been recognized and published in the literature. A review published in 1992 described 140 cases reported in the literature.4 Prevalence The exact prevalence is not known as essentially all cases have been reported as single cases or family reports. The figure generally used for rare diseases is 1/100,000 but CS occurs even less frequently than this.5 The reported frequency in United States6 is less than 1/250,000. CS has been reported to be more common in isolated or inbred communities. CS affects all races without any sex predilection.6 As it is a genetic disorder the manifestations may be delayed until early childhood. Etiology CS is an autosomal recessive disorder. The basic defect is the slow transcriptioncoupled DNA repair whereas the global genome repair pathway of nucleotideexcision repair mechanism is intact.7 Complementation groups in CS [5,6,8] On the basis of underlying genetic, CS has two complementation groups, CS type 1 (CSA) and CS type 2 (CSB) due to defect in ERCC8 and ERCC6 genes, respectively. Table 1 The underlying molecular genetic defects in Cockayne’s syndrome [5] CKN1, CSA Gene CSA gene ERCC8 CS type CSB CSB gene ERCC6 Gene locus 5 MIM 216400 10q11 MIM 133540 Frequency 25% of cases 75% of cases Product Cockayne syndrome WD-repeat protein (CSA protein) 396 amino acids 44 kDa Excision repair protein ERCC6 (CSB protein) Point mutation Deletion ERCC8 Missense mutation Insertion deletion ERCC6 Types of mutation of 1349 acids 2, amino of ERCC=excision repair cross-complementig group, MIM=Mendelian inheritance in man Both ERCC8 and ERCC6 transcribe to two proteins CSA and CSB, respectively. Wild CSA and CSB proteins remove the stalled polymerase in such a way that the lesion becomes accessible to repair enzymes. The mutated proteins are deficient in their function. However, the genotype-phenotype relation is not absolute. The involved genes, their respective loci and product are shown in Table 1. Cellular and molecular genetic overlap in CS, XP, and TTD [8,9] CS, XP, and TTD share common etiology i.e. defective nucleotide excision repair (NER). It is a complex mechanism to repair DNA and hence to protect the genome against injury induced by numerous mutagenic and carcinogenic agents 138 steps involved are, a) recognition of DNA lesion, b) removal of the damaged oligonucleotide, c) gap filling by DNA synthesis, and d) ligation. NER further comprises of two pathways. One is the more rapid, transcription-coupled repair (TCR) of expressed genes, targeted to the transcribed strand. The other is slower, global genome repair (GGR) of DNA, which includes repair of the nontranscribed strand of expressed genes and the inactive chromatin. Figure 1 Model showing two pathways of NER i.e. global genome repair (left side) and transcription-coupled repair (right side) [10]. Figure 2 Suggested hypothesis of TFIIH dysfunction can lead to XP, CS and TTD [10]. e.g. photoproducts, chemical-produced adducts, intrastrand crosslinks etc. Different Figure 1 shows both pathways of NER. In GGR (left part), the complex XP-C/HR233B binds to DNA lesions and attracts XP-A, RPA (ssDNA binding protein) and then TFIIH (recognition of DNA lesion). XP-E protein facilitates the identification of lesions which are poorly recognized by XP-C/HR233B e.g. cyclobutane pyrimidine dimers. Demarcation of the lesions is carried out by XP-B and XP-D (two helicases) of TFIIH followed by sequential cleavage by two structure-specific nucleases XP-G (on 3’ side) and ERCC1-XP-F (on 5’ side) [removal of damaged oligonucleotides]. After removal of an oligonucleotide containing the lesion, DNA synthesis occurs using either polymerase δ or ε in the presence of PCNA and RF-C complexes as processitivity factors (gap filling by DNA synthesis). The final step is ligation of the newly synthesized DNA patch to parental strand by DNA ligase I.10 TCR differs from GGR in the initial step i.e. recognition of lesion only (right half). On damaged templates, RNA polymerase II is blocked by the lesion inducing signal for TCR. Proteins CSA, CSB, and possibly 139 XP-G and TFIIH displace the stalled RNA poly II from the lesion. Now the lesion becomes accessible for further repair in the same way as for GGR.10 Transcription and DNA repair are two closely associated processes. TFIIH is a complex of 9 proteins which has dual role in transcription and repair. It inhibits cell cycle and transcription but induces TCR, DNA repair, or apoptosis after genome damage. It is speculated that CS, XP, or TTD are the consequences of TFIIH dysfunction. Mutations in one of the two DNA repair genes in TFIIH may lead to three different human disorders: a) XP (the skin cancerprone syndrome), b) CS or TTD alone, and c) CS- or TTD-associated with XP in the same patient (Figure 2). It is hypothesized that some of DNA-repair deficient patients may also have transcription deficiency. The same gene defect can result in apparently identical cellular phenotypes related to DNA repair deficiency, yet give rise to completely different clinical features. Cellular hypersensitivity Like XP, cultured cells (fibroblasts or lymphocytes) from patients with CS are hypersensitive to UV-induced inhibition of growth and colony-forming ability.11 Host cell reactivation of UV-damaged adenovirus or plasmids is reduced, although to a lesser extent than in XP.12 Increased mutation frequency has been reported in circulating lymphocytes from two donors with CS.13 Chromosome abnormalities Chromosome karyotype and sister chromatid exchange frequency is usually normal in untreated cells but increase in sister chromatid exchanges and a delayed recovery Table 2 compares the laboratory characteristics and main clinical features in the three NER syndromes [10]. UV sensitivity Residual UDS TCR GGR Photosensitivity Skin cancer Progressive mental degeneration Neuronal loss Neurodysmyelination Thin facies Growth defect Hypogonadism Brittle hair and nails Ichthyosis XP +, ++ 5%50% ↓ except XP-C ↓ ++ ++ +/- CS + 1550% ↓ TTD + WT WT +a -b + ↓ +a -b + +/+/+/- + + + + + - + + + + + + + ↓ GGR=global genome repair, TCR=transcriptioncoupled repair, UDS=unscheduled DNA synthesis, WT=wild type (control level), +=present, ++=markedly present, +/-=sometimes present, ↓=reduced, a=patients with CS and TTD may have no photosensitivity, b=skin cancer may be present in XP/CS or XP/TTD overlap of chromosome damage is reported after UVR exposure.11,14,15 Pathophysiology Pathologic studies reveal diffuse and extensive demyelinating in the central and peripheral nervous systems. Patients demonstrate pericapillary calcifications in the cortex and basal ganglia at an early age.6 Severe neuronal loss in the cerebaral cortex and cerebellum also occurs. These changes correlate with the physiologic changes of skin. Clinical features [4,5,6] With elucidation of molecular genetic defects, it has been recognized that CS is not a single phenotype but it spans a spectrum 140 that comprises: CS type 1, the classical form; CS type 2, a more severe form with symptoms present at birth, also called connatal CS (previously called cerebrooculo-facial [COFS] syndrome and PenaShokeir type 2 syndrome; CS type 3, a milder form; and xeroderma-pigmentosumCockayne syndrome (XP-CS). CS type 1 and CS type 2 are the two well-accepted types. CS type 1 (classical, CNK1, CSA) Birth weight, length and head circumference are normal. However, within the first two years growth and development become abnormal. There is delayed psychomotor development, poor feeding, photosensitive rashes and cataract. By the time the disease becomes fully manifest, height, weight, and head circumference are far below the fifth percentile. The characteristic appearance of a child with CS is a cachectic dwarf with thinning of the skin and hair, sunken eyes, and a stooped standing posture (Figure 3). Different clinical signs and symptoms reported in CS are enlisted in Table 3. Progressive impairment of vision (due to cataracts and pigmentary retinopathy), sensorineural deafness, hypertension, joint Figure 3 A girl showing typical facies of CS with sunken eyes, beaked nose, large ears, and frecles over face. Table 3 Clinical signs/symptoms reported in Cockayne syndrome [4,5,6]. Neurologic Increased tone/spasticity Hyper- or hyporeflexia Abnormal gait or inability to walk, ataxia Incontinence Tremors Abnormal speech or absence of speech, seizures Weak cry/poor feeding Muscle atrophy Behavioral abnormality Seizures Dermatologic Photosensitivity (~75%) Malar rash Xerosis Mottled pigmentation and atrophic scars Loss of subcutaneous fat Premature aging Anhidrosis Thin, dry hair Ophthalmologic [16] Pigmentary retinal degeneration/retinitis pigmentosum (develops late) [~55%] Cataract (before 3 years)[36%] Miotic pupils Farsightedness Decreased or absent tears Strabismus Nystagmus Photophobia Narrowed retinal arterioles Microcornea Iris hypoplasia Microphthalmia. Optic atrophy Ears Sensorineural deafness (mild-moderate) [~66%] Dental Caries (~86%) Absent or hypoplastic teeth Delayed eruption of deciduous teeth Malocclusion Endocrinal Undescented testes Delayed/absent sexual maturation Infertility Musculoskeletal Skeletal dysplasia Relatively long limbs Contractures of hips, knees, ankles 141 Gastrointestinal Elevated liver function tests Hepatosplenomegaly Renal [17] Hypertension Decreased creatinine clearance Other Reduced immunity to infections contractures and ataxia lead to severe disability. However, CS is not associated with an increased incidence of neoplasia. Death typically occurs in the first or second decade as a result of pneumonia and other respiratory infections. The mean age of death is 12 years, but survival into third decade has been reported. CS type 2 (CSB) Also called ‘connatal’ CS, is the severe form of syndrome in which growth failure is evident at birth and little or no postnatal neurological development occurs. Congenital cataracts or other structural anomalies of the eye are reported in 30%. Patients have arthrogryposis or early contractures joints and spine (kyphosis, scoliosis). Patients typically die by the age of 7 years. This group overlaps clinically with two other genetic disorders named, the cerebro-oculo-facial syndrome (COFS) and Pena-Shokeir type II syndrome. A mutation in the ERCC6 gene has been reported in COFS. It is now recognized that patients previously labeled to have COFS or PenaShokeir type II syndrome, who have molecular or biochemical evidence of ERCC8 or ERCC6 mutations or characteristic DNA repair abnormalities, should be diagnosed as having Cockayne syndrome type 2. CS type 3 Before the discovery of molecular defects of CS, a few cases with some features of CS but with essentially normal growth and cognitive development, or late onset, were reported.18 These have been categorized as CS type 3. The molecular defect in DNA repair or protein complementation has not been documented. In a single case clinically resembling late-onset CS, an insertional deletion of chromosome 10q21.1 has been reported. Xeroderma pigmentosum–Cockayne syndrome complex The correlation between genotype, cellular phenotype, and clinical phenotype is not absolute. A number of patients with CS have been found to have, in addition, clinical features of XP. These features include freckling on sun-exposed skin and cutaneous neoplasms. Cells from these XP/CS patients have reduced DNA excision repair characteristic of XP. Clinically, these patients may be distinguished from XP patients with neurologic abnormalities by the presence of the CS features of pigmentary retinal degeneration, calcification of the basal ganglia, normalpressure hydrocephalus, and hyperreflexia. Cells from patients with this complex have been assigned to XP-B, -D, and -G, complementation groups. The De-SanctisCacchione19 variant of xeroderma pigmentosum includes some features of CS such as mental retardation, spasticity, short stature, and hypogonadism, but without skeletal dysplasia, the facial phenotype of CS, or CNS demyelination and calcifications. Diagnosis [4,5,6] The characteristic features of syndrome may not be evident and the diagnosis may be delayed for years. Poor psychomotor 142 development, emergence of a typical abnormality of CS e.g. blindness, deafness, or extreme photosensitivity make parents visit a physician. No consensus guidelines have been developed whether CS should be diagnosed exclusively on the basis of clinical criteria, cellular phenotype, genetic phenotype, or a combination of the three. The syndrome is diagnosed by clinical findings in classical cases and in nonclassical cases by assay of DNA repair in skin fibroblasts or lymphocytes. Such testing is available in a few clinical laboratories. Clinical Diagnosis Classical Cockayne syndrome (CS type 1) The suggested diagnostic criteria for CS1 are given in Table 4. CS type 1 is suspected in an older child when both major and three minor criteria are present or in an infant or toddler when both major and one minor criterion along with abnormalities of DNA repair are present. Connatal Cockayne syndrome (CS type 2) CS type 2 is suspected in infants with growth failure at birth with little postnatal increase in height, weight, or head circumference. 1. Little or no postnatal neurological development. 2. Congenital cataracts with other structural defects of the eye (microphthalmos, microcornea, iris hypoplasia). Laboratory findings [5,6] Molecular genetic testing includes the following test: UV survival curve test CS cells are abnormally sensitive to ultraviolet radiation. Typically half to one- Table 4: Suggested diagnostic criteria for CS type 1 [5] Major criteria 1. Height and weight below fifth percentile for age and sex. 2. Developmental delay (absence or delayed nervous system milestones e.g. ability to speak or walk) Minor criteria 1. Cutaneous photosensitivity with or without thin or dry skin or hair. 2. Sensorineural deafness. 3. Pigmentary retinopathy and/or cataract. 4. Dental caries. 5. A characteristic physical appearance of cachectic dwarfism with thinning of the skin and hair, sunken eyes, and a stooping posture, large for head size ears ‘Mickey-mouse ears,’ small chin with prominent, pointed ‘birdlike’ nose, decreased facial subcutaneous adipose tissue, microcephaly, an aged or wizened facial appearance. 6. Demyelinating peripheral neuropathy (~ 75%) diagnosed by electromyography, nerve conduction testing, and/or nerve biopsy. 7. Characteristic radiographic findings of thickening of the calvarium, sclerotic epiphyses, vertebral and pelvic abnormalities. fourth as much as UVR kills majority of CS cells (fibroblasts or lymphoblasts) as compared to normal cells. RNA synthesis inhibition assay This test assesses the transcription-coupled DNA repair. CS cells along with control (cells from a normal person) are exposed to UVR. RNA synthesis in CS cells is much lower than normal cells due to their inability to repair UVR-induced damage. Complementation group testing This test identifies whether a patient belongs to CSA or CSB, seen in 25% and 75% of patients, respectively. When fused together and exposed to UVR, cells from different 143 groups having different genetic defect will complement each other, showing enhanced DNA repair. Currently complement testing is more of research interest than of immediate value to patient. Such testing may be helpful, in future, to plan protein therapy or gene therapy that is defective in a patient. Mutation analysis This test is also of research interest. This detects the type of mutation and the mutated genes in a family. Many other tests may be helpful in the management. CT scan of brain shows characteristic brain structural abnormalities including calcium deposits in the basal ganglia and normal pressure hydrocephalus (ventricular enlargement without obstruction). Magnetic resonance imaging (MRI) of the brain shows atrophy and dysmyelination of the cerebrum and cerebellum. The electroencephalogram may be abnormal, and x-ray examination may show thickened skull and microcephaly. Other tests may show sensorineural deafness, neuropathica electromyogram, and slow motor nerve conduction velocity. Bone age is usually normal. Prenatal Diagnosis Prenatal diagnosis has been reported by analysis of ultraviolet light sensitivity and DNA repair in fetal cells obtained by amniocentesis at 16-18 weeks gestation. This test is still of research interest and not offered clinically.21 Differential diagnosis [5,6] The differential diagnosis of CS depends on the presenting features of the particular patient. Abnormalities that suggest alternative diagnoses are congenital anomalies of the face, limbs, heart, or viscera, recurrent infections other than otitis media or respiratory infections; metabolic or neurologic crises; hematologic abnormality e.g. anemia, leuopenia; or malignancy of any kind. Growth failure is a feature of many chromosomal, endocrine, metabolic, or gastrointestinal disorders including malnutrition. Syndromes with profound growth failure e.g. Brachmann-de Lange, Duboitz, Hallerman-Streiff, RubinsteinTaybi, Russel-Silver, Seckel, and Wiedemann-Rautenstrauch etc. can usually be excluded on the basis of physical appearance. In cases with photosensitivity or thinning of the skin and hair, the differential diagnosis includes xeroderma pigmentosum, Bloom syndrome, Rothmund-Thompson syndrome, and the premature aging syndromes e.g. progeria, Werner syndrome etc. Barring Pelizaeus-Merabacher disease, growth failure does not occur in most leukodystrophies. The presence of calcification on brain imaging might suggest congenital infections e.g. rubella or toxoplasmosis. Management [5,6] The management issues are, comprehensive baseline evaluation and then serial monitoring; symptomatic care; and genetic counseling. Baseline evaluation includes measurement of growth, development assessment, dental 144 evaluation, dermatologic assessment, ophthalmologic evaluation possibly including electroretinogram, audiologic evaluation including audiogram, brain MRI, CT scan, EMG to document the presence of demyelinating neuropathy, laboratory studies to assess renal and hepatic function, testing for diabetes mellitus or disorders of calcium metabolism, and skeletal radiographs to document the skeletal dysplasia. Patients should be followed up and yearly assessed for known potential complications e.g. hypertension, renal or hepatic dysfunction, declining vision and hearing. CS children, despite their many problems, are affectionate and cheerful. Nonetheless, they need more attention because of their physical and mental handicap. Families of children with CS are under great stress due to the need to provide extra attention, medical emergencies due to complications of CS, and financial burden. There is an educational, advocacy, and support 22 organization for helping patients with CS and their families: The Share and Care Cockayne Syndrome Network Box 552 Stanleytown, VA 24168Tel: 540-629-2369; FAX: 540-647-3728 E-mail: cockayne@kimbanet.com Symptomatic care should focus on an individualized education program, assistive devices, and safety in the home for developmental delay and gait disturbances. Regular physiotherapy may help prevent contractures and maintain ambulation. Feeding tube may be indicated, if feeding is unsatisfactory, to prevent malnutrition. Aggressive dental care, use of sunscreens and avoidance of excessive sun exposure are advisable. Specific problems may be evaluated and treated by appropriate specialists e.g. pediatricians, dermatologists, ophthalmologists, otolaryngologists, audiologists, clinical geneticists and rehabilitation therapists. These children may benefit from special education including sign language training, and from devices such as ankle and foot orthotics to assist walking, and hearing aids. From the dermatologist viewpoint, children with CS should avoid sun exposure though not such strict protection is required as in XP. Additional protection may be acquired by use of protective clothing and sunblocks with SPF ≥ 15. It is also important to provide the patient and family with information on the nature, inheritance, and other implications of the disease to help them make informed medical and personal decisions. The parents of an affected child are both obligate carriers of an abnormal gene. The sibs of a proband have a 25% chance of being affected, a 50% chance of being an ‘unaffected carrier’, and a 25% chance of being normal. As this is a very rare disorder, carriers can be counseled that their chance of meeting another in the general population is on the order of 1/5,000, and the chance of having an affected child is one-quarter of that i.e. 1/20,000. Carrier testing can only be performed by DNA analysis. Reproduction has not been reported in any individual with CS. Prognosis Patients with CS suffer a lot of morbidity including neurological, dermatological, ophthalmologic, dermatological, and otic complications. The average life span in CS is reported to be 12 years, though, the 145 severity of the genetic damage in the affected individual and the food intake are two important determinants. The oldest CS patient is reported to be of 30’s. They end up with premature death due to respiratory tract infection. Future prospects It is hoped that the understanding of genes, mutations and testing methodologies will improve in future. As medical genetics and bioengineering advances, gene therapy or treatment with their products remains another ray of hope for CS patients. DNA of patients (extracted from leukocytes) should be stored for future use. 9. 10. 11. 12. References 1. 2. 3. 4. 5. 6. 7. 8. Kraemer KH. Heritable diseases with increased sensitivity to cellular injury. In: Freedberg IM, Eisen AZ, Wolff K et al., eds. Dermatology in general medicine, 5th edn. New York: McGraw-Hill; 1999. p. 1848-62. Cockayne EA. Dwarfism with retinal atrophy and deafness. Arch Dis Child 1936; 11: 148. Neil C, Dingwall MM. A syndrome resembling progeria. A review of two cases. Arch Dis Child 1950; 11: 213-21. Nance MA, Berry SA, Cock S. Review of 140 cases. Am J Med 1992: 42: 68-84. Nance MA. Cockayne syndrome. Gene Reviews [serial online] 2000. Available from: URL: htt:www.geneclinics.org/servlet/access…/de tails/htm. Carter SM, Gross SJ. Cockayne syndrome. eMed J [serial online] 2002; 3(4): [11 screens]. Available from; URL: htt://www.emed.com/cgibin/foxweb.exe/screen. Venema J, Mullenders LHF, Natarajan AT et al. The genetic defect in Cockayne syndrome is associated with a defect in repair of UV-induced DNA damage in transcriptionally active DNA. Proc Natl Acad Sci USA 1990; 87: 4707-11. Cleaver JE, Thompson LH, Richardson AS, States JC. A summary of mutations in the 13. 14. 15. 16. 17. 18. UV-sensitive disorders: xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. Hum Mutat 1999; 14: 9-22. Le Page F, Kwoh EE, Aurutskaya A et al. Transcription-coupled base excision repair and mutation avoidance at 8-oxoguanine requirement for XPG, TFIIH, and CSB and implication for Cockayne syndrome. Cell 2000; 101: 159-71. Itin PH, Sarasin A, Pittelkow MR. Trichthiodystrophy: update on the sulfurdeficient brittle hair syndromes. J Am Acad Dermatol 2001; 44: 891-920. Marshall RR, Arlette CF, Harcourt SA, Broughton BA. Increased sensitivity of cell strains from Cockayne's syndrome to sisterchromatid-exchange induction and cell killing by UV light. Mutat Res 1980; 69: 107-12. Parris CN, Kraemer KH. Ultraviolet-induced mutations in Cockayne syndrome cells are primarily caused by cyclobutane dimmer photoproducts while repair of other photoproducts is normal. Proc Natl Acad Sci USA 1993; 90: 7260-9. Norris PG, Arlette CF, Cole J et al. Abnormal erythemal response and elevated T lymphocyte HRPT mutant frequency in Cockayne's syndrome. Br J Dermatol 1991; 124: 453-60. Seguin LR, Tarone RE, Liao KH, Robbins JH. Ultraviolet light-induced chromosomal aberrations in cultured cells from Cockayne syndrome and complementation group C xeroderma pigmentosum patients: lack of correlation with cancer susceptibility. Am J Hum Genet 1988; 42: 468-75. Price FM, Parshad R, Tarone RE, Sanford KK. Radiation-induced chromatid aberrations in Cockayne syndrome and xeroderma pigmentosum group C fibroblasts in relation to cancer predisposition. Cancer Genet Cytogenet 1991; 57: 1-10. Traboulsi EI, De Becker I, Maumenee IH. Ocular findings in Cockayne syndrome. Am J Ophthalmol 1992; 114: 579-83. Higginbottom MC, Griswold WR, Jones KL et al. The Cockayne syndrome: an evaluation of hypertension and studies of renal pathology. Pediatrics 1979; 64: 92934. Colella S, Nardo T, Mallery D et al. Alteration in the CSB gene in three Italian patients with severe form of CS but without 146 clinical photosensitivity. Hum Mol Genet 1999; 8: 935-41. 19. Czeizel AE, Marchalko M. Cockayne syndrome type III with high intelligence. Clin Genet 1995; 48: 331-3. 20. Colellia S, Nardo T, Botta E et al. Identical mutations in CSB gene associated with either CS or DeSanctis-Cacchione variant of xeroderma pigmentosum. Hum Mol Genet 2000; 9: 1171-5. 21. Cleaver JE, Volpe JP, Charles WC, Thomas GH. Prenatal diagnosis of xeroderma pigmentosum and Cockayne syndrome. Prenat Diagn 1994; 14: 921-8. 22. The share and care Cockayne syndrome network: http//members.aol.com/DBBusch/shareandc arehome.html 147 Surgical Pearl Modifications in punch grafting Tahir Jamil Ahmad, Tariq Rashid, Zahida Rani Department of Dermatology, King Edward Medical College/Mayo Hospital, Lahore Although autologous punch grafting can be performed on any body area1,2 but it may cause some appearance problems at certain sites. Two of such problems are mentioned with their solution. 1. Hairy areas like eyebrows pose special problems when they are involved in vitiligo. Traditional punch grafting of the area gives satisfactory pigmentation but at the same time leads to permanent and disfiguring patchy loss of hair. In such a situation wedge insertion is suggested without any loss of hair bearing area. An incision, 2mm deep is made along the shaved eyebrow (in the centre, preferably) and the wound allowed to gape. A wedge of pigmented skin is incised and placed with broad epithelial side facing outside and thin dermal portion going deep in the recipient area. The tissue is anchored with stay sutures. Rest of the story of pigmentation of skin and hair remains the same. Figure 1 Punches on hairy areas and micropockets Figure 2 Incision line for wedge 2. Thin skin like that on eyelids is also difficult for grafting3,4 with skin from relatively thick donor sites. We suggest micrografting in epidermal pockets at such places. Address for Correspondence Dr. Tahir Jamil Ahmad 186 J, D-H-A, Phase 1, Lahore. Ph # 042-5726937 148 Figure 3 & 4 Wide bore needles for micropocketing Figure 5 Macrografts Figure 6 Wedge graft positioned with stitches Figure 8 Complete repigmentation Donor punches of 1mm in size are taken and further cut into four pieces under magnification (since smaller biopsy punches are not available). Pockets are made at the dermoepidermal junction with the help of wide bore syringe needle at vitiliginous areas with opening at its top. Micrografts are placed in the pockets and bandage is applied over it for 48 hours. The graft take is excellent and pigmentation areola appears as at any other site with satisfactory repigmentation. References 1. 2. Figure 7 Micropocketing with grafts 3. 4. Falabella R. Treatment of localized vitiligo by autologous minigrafting. Arch Dermatol 1988; 124: 1649-55. Savant SS. Miniature punch grafting. In: Savant SS, Atal-Shah R, Gore D, eds. Textbook and atlas of dermatology cosmetology, 1st edn. Mumbai: ASCAD; 1998. p. 235-9. Savant SS. Autologous miniature punch grafting in stable vitiligo. Ind J Dermatol Venereol Leprol 1992; 58: 310-4. Orentreich DS, ed. Punch graft: principles and techniques of cutaneous surgery, Ist edn. New York: Mcgraw-Hill; 1996. p. 283-95. 149 Case report Acrodermatitis enteropathica in three siblings Arfan-ul-Bari, *Muhammad Abbas, *Simeen ber Rahman PAF Hospital, Sargodha. *Dermatology Department, Military Hospital, Rawalpindi Abstract Acrodermatitis enteropathica is an autosomal recessive disease due to a partial disorder of intestinal zinc uptake. Signs usually appear within the first months of life, with a characteristic cutaneous rash that is symmetrical, located around the body orifices, behind the ears, and on hands, feet, and head. We report three siblings with characteristic features of the disease and laboratory evidence of low serum zinc levels. Symptoms in all three patients reversed remarkably on supplementation of zinc. A brief history, clinical profile, pathophysiology and treatment of the disease have also been discussed in this article for better understanding of this disorder. Introduction Acrodermatitis enteropathica (AE) was first described in 1942 by Danbolt and Closs. The condition is now recognized as an inborn error of zinc metabolism that is inherited as an autosomal recessive disorder.1 Characteristic symptoms in infancy include periorificial (oral, anal, genital) and acral dermatitis, diarrhea, behavioral and mental changes, neurological disturbances, and secondary bacterial and fungal infections. In older children, failure to thrive, anorexia, alopecia, nail dystrophy, and repeated infections are more common. Zinc deficiency may be due to inadequate intake, malabsorption, excessive loss, or a combination of these factors. If treated early, most of the symptoms are reversible and usually leave no sequelae. The pathophysiology of AE is not fully understood.2-4 Untreated patients usually die within the first few years of life. They have severe growth retardation, dermatitis, Address for Correspondence Squadron Leader Dr. Arfan-ul-Bari Consultant Dermatologist PAF Hospital, Sargodha. Ph# 051-561-33799, 5583688 Email: albariul@yahoo.com alopecia, secondary bacterial and fungal infections, and neurological and 5,6 behavioral changes. No race or sex predilection has been reported. AE symptoms generally manifest when an infant is weaned from breastfeeding or earlier if the infant is formula fed.2-4 Fullterm breastfed infants can develop signs of zinc deficiency late in the course of lactation because some nursing mothers have low levels of zinc in their breast milk.7-9 AE-like symptoms have been described in older children and adults who are on prolonged parenteral nutrition without zinc supplementation.6,10 Erythematous to vesiculobullous or pustular lesions leading to dry, scaly, or eczematoid rash distributed around periorificial and acral areas of the body are characteristic of AE. The borders of affected areas are sharply demarcated and have an accentuation of craquelé like scale at the periphery. Paronychia may be present. Partial or total hair loss may be evident.2-4 Zinc deficiency causes all these clinical symptoms, which are easily and rapidly reversible with zinc 150 supplementation and therapy achieves a survival rate of 100%. In most patients with AE, plasma zinc concentrations are low (<50 μg/dl) but this is not diagnostic. Reference range zinc concentrations have been reported in patients with AE and low zinc concentrations may be seen in patients without AE.11 Plasma level range is 70–110 μg/dl. Leukocyte zinc level is very sensitive test for early minor changes, but is more expensive. Urinary zinc levels are highly unreliable depending upon body state of zinc. Normal value is 200–500 μg/24 hrs. Hair and saliva zinc levels are rarely needed. Production of serum alkaline phosphatase depends on zinc; therefore, a low level of alkaline phosphatase may support an AE diagnosis.12,13 Skin biopsy reveals nonspecific eczematous changes while intestinal mucosal biopsies show loss of villous architecture with increased cell infiltration in the lamina propria of patients with AE. These are not routinely done. Treatment is essentially with dietary or intravenous supplementation. Dietary supplementation with 2-3 times the recommended daily allowance, 3055mg/day of elemental zinc dramatically reverses the manifestations within hours to days. Improvement in mental status and diarrhea is seen within 24 hrs. Severely infected and erosive lesions show reversal within 1-2 weeks. A surge of hair growth may be detected within 3-4 weeks. Zinc compounds, which appear to be effective, include zinc complexes with sulfates, acetates, gluconate, chloride, and amino acid chelate.2-4,14,15 For most zinc deficient individuals a single capsule of 220mg zinc sulfate contains 55 mg of elemental zinc. In AE, zinc therapy is maintained throughout the patient's life span, although periods of remission have been reported. Exacerbation during pregnancy or the stress of disease may require an increase in therapy. In acquired zinc deficiency, treatment can be stopped after the precipitating cause has resolved. Zinccontaining foods include oysters, crab, meat products, human milk, dried beans, and lentils may also be encouraged. Oral diodoquine has also got a therapeutic role probably by enhancing the absorption of zinc.16 Case histories Three siblings with respective ages of 11, 8 and 3 years from a low socioeconomic group family belonging to Tehsil Gujar Khan, District Rawalpindi presented in Military Hospital, Rawalpindi with history of recurrent weeping and crusting lesions around the mouth and perineum along with loose motions off and on. The children were asymptomatic till the age of about 4 months. They started developing itchy weeping and crusted lesions over skin around mouth and perineum during period of weaning. Later similar lesions appeared on hands, feet and flexures of upper and lower limb (Figures 1). 151 Figure 1 Three affected children of a family showing skin involvement in acrodermatitis enteropathica Age (yrs) 11 All the three patients used to have episodic loose motions which were watery in consistency, 50–100 ml in volume, 3-4 times a day lasting for 3–7 days. They did not have jaundice, joint pains, or abdominal distension. Their parents did not have any history of blood transfusion, extramarital sexual contact or intravenous drug abuse. The three patients were among the six siblings born to consanguineous parents (Figure 2). They were all breast fed till the age of 1–1½ yrs and were vaccinated to the age. All three had history of delayed milestones development. On physical examination all were found to be fully conscious and well oriented. There was no pallor, jaundice, cyanosis, clubbing or lymphadenopathy. Weights and heights of all the patients were slightly below the normal lower limit relevant to their age. 8 7 6 4 Figure 2 Pedigree showing whole family. Filled circles and squares show diseased females and males. Systemic examination was unremarkable. Periorificial and perineal areas revealed eczematous, lichenified, and hyperpigmented lesions. Similar lesions were also seen in flexures of upper and lower limbs. Angular cheilitis was present. Hair were relatively sparse and thin. Mucous membranes and nails were found to be normal. Blood profile, urine 152 3 examination, liver function tests, serum total proteins and albumin were within normal limit. Serum zinc levels were 36.5μg/dl, 31.4μg/dl and 42.7μg/dl, respectively. Histopathology revealed hyperkeratosis, hypergranulosis and epidermal hyperplasia along with upper dermal perivascular mononuclear infiltrate (consistent with chronic eczematous changes). A diagnosis of acrodermatitis enteropathica was made and patients were treated with zinc sulfate 2 mg/kg/day. One week after start of treatment, skin lesions improved remarkably. On follow up visit after 1 month diarrhea had settled and there was a definite improvement in the general health of the patients. Discussion Acrodermatitis is an inherited disorder transmitted as an autosomal recessive trait and is caused by inability to absorb sufficient zinc from diet. In fact the term acrodermatitis is now being used to include all the patients with acral dermatitis due to zinc deficiency, hereditary or acquired in origin. In order to understand the disease, a brief overview of zinc metabolism remains essential. The adult body contains 2-3 gm of zinc, which exists almost totally in its oxidized (Zn+2) form and does not undergo further oxidation or reduction. Normally about 30% of daily intake is absorbed and 60– 70% of it gets bound to albumin and 10– 20% to α-2 microglobulins.12,13 Because oral or intravenous zinc supplementation in patients with AE improves their symptoms, a defect in zinc metabolism (especially in intestinal absorption or bioavailability of zinc in the intestinal lumen) is a possible pathological pathway. Grider and Mouat17 described differences in 2 novel proteins in the fibroblasts carrying the AE mutation. Wang18 has recently mapped the AE genetic locus to band 8q24.3. In infants with AE, an absence of a binding ligand may contribute to zinc malabsorption during weaning. Such a ligand has been identified in normal pancreatic secretions as well as in human milk.19 Other causes, such as high phytate concentrations found in cereals and soy milk, inhibit zinc absorption. Geophagia, also decreases zinc absorption.20 Periorificial and acral dermatitis can be observed with many other conditions, including biotin deficiency, atypical epidermolysis bullosa, generalized and local candidiasis, atopic dermatitis, abnormality of essential fatty acid metabolism, seborrheic dermatitis, and kwashiorkor. If differentiation becomes difficult on clinical grounds, therapeutic trial with zinc can be distinctive in such cases. Zinc can also have a role in other diarrhea-like illnesses and more often zinc deficiency occurs in association with other micronutrients deficiencies especially iron and copper and replacement therapy in such cases has proved very beneficial.15,21 Reduction in infant mortality was also noted by zinc replacement therapy in case of premature infants.24 Conclusion Acrodermatitis enteropathica remains one of the most intriguing disorders known to medical science. Seldom have so many physical signs and symptoms, been attributable to deficiency of one single element. All of these signs and symptoms are dramatically reversed by single dietary supplement of zinc. References 1. Danbolt N, Closs K. Arodermatitis enteropathica. Acta Derm Venereol 1942; 22: 17. 153 2. Portnoy B, Molokhia M. Acrodermatitis enteropathica treated by zinc. Br J Dermatol 1974; 91: 701-3 3. Wells BT, Winkelmann RD. Acrodermatitis enteropathica: report of six cases. Arch Dermatol 1961; 84: 40-52. 4. Stevenson JR, Fidone GS, Leland LS. Acrodermatitis enteropathica. Arch Dermatol 1964; 89: 224-8. 5. Moynahan EJ. Acrodermatitis enteropathica: a lethal inherited human zinc deficiency disorder (letter). Lancet 1974; 2(7877): 399-400. 6. Sivasubramanian KN, Henkin RI. Behavioral and dermatologic changes and low serum zinc and copper concentrations in two premature infants after parenteral alimentation. J Pediatr 1978; 93: 847-51. 7. Bilinski DL, Ehrenkranz RA, CooleyJacobs J. Symptomatic zinc deficiency in a breast-fed, premature infant. Arch Dermatol 1987; 123: 1221-4. 8. Kuramoto Y, Igarashi Y, Tagami H. Acquired zinc deficiency in breast-fed infants. Semin Dermatol 1991; 10: 309-12. 9. Piela Z, Szuber M, Mach B. Zinc deficiency in exclusively breast-fed infants. Cutis 1998; 61: 197-200. 10. Arakawa T, Tamura T, Igarashi Y. Zinc deficiency in two infants during total parenteral alimentation for diarrhea. Am J Clin Nutr 1976; 29: 197-204. 11. Garretts M, Molokhia M. Acrodermatitis enteropathica without hypozincemia. J Pediatr 1977; 91: 492-4. 12. Gordon EF, Gordon RC, Passal DB. Zinc metabolism: basic, clinical, and behavioral aspects. J Pediatr 1981; 99: 341-9. 13. Walravens PA, Hambidge KM, Neldner KH. Zinc metabolism in acrodermatitis enteropathica. J Pediatr 1978; 93: 71-3. 14. Leupold D, Poley JR, Meigel WN. Zinc therapy in acrodermatitis enteropathica. Helv Paediatr Acta 1976; 31: 109-15. 15. Bhutta ZA. The role of zinc in health and disease: relevance in child health in developing countries. J Pak Med Assoc 1997; 47: 68-73. 16. Dallaha CJ, Lorincz AL, Aarnik ON. Acrodermatitis enteropathica: review of the literature and report on a case successfully treated with diodoquin. JAMA 1953; 152: 509-12. 17. Grider A, Mouat MF. The acrodermatitis enteropathica mutation affects protein expression in human fibroblasts: analysis by two-dimensional gel electrophoresis. J Nutr 1998; 128: 1311-4. 18. Pugh EW, Griffen S. Homozygosity mapping places the acrodermatitis enteropathica gene on chromosomal region 8q24.3. Am J Hum Genet 2001; 68: 1055-60. 19. Lonnerdal B, Stanislowski AG, Hurley LS. Isolation of a low molecular weight zinc binding ligand from human milk. J Inorg Biochem 1980; 12: 71-8. 20. Prasad AS. Zinc: an overview. Nutrition 1995; 11 (Suppl 1): 93-9. 21. Bhutta ZA, Nizami SQ, Isani Z. Zinc supplementation in malnourished children with persistent diarrhea in Pakistan. Paediatrics 1999; 103: 42. 154 Case report A family with xeroderma pigmentosumCockayne syndrome complex. Ijaz Aman, *Shahbaz Aman, Tahir Massod Ahmad Department of Paediatric Medicine, King Edward Medical College/Mayo Hospital, Lahore. *Department of Dermatology, King Edward Medical College/Mayo Hospital, Lahore. Abstract Xeroderma pigmentosum-Cockayne syndrome complex is the coexistence of two genodermatoses, xeroderma pigmentosum (XP) and Cockayne syndrome (CS) in one patient. The patients of this syndrome present with photosensitivity, freckling on sunexposed skin, loss of subcutaneous fat from face, prominent ears, dwarfism, microcephaly, mental retardation or other neurological and eye abnormalities. Many similar cases with additional features have been reported in foreign literature. We describe 3 cases of this syndrome along with review of literature. Introduction Xeroderma pigmentosum-Cockayne syndrome complex is one of the genodermatoses including photosensitivity, freckling, ocular defects, disproportionately large hands, feet and ears, microcephaly, mental retardation and other neurological abnormalities.1,2 Photosensitivity with neurological abnormalities of variable severity can occur in various genodermatoses like xeroderma pigmentosum (XP) and its variants, Cockayne syndrome (CS), trichothiodystrophy and Hartnup disease.13 Other differential diagnoses include Bloom’s syndrome and progeria.1,2,3 In many of these the underlying molecular defects have been demonstrated. These include nucleotide excision repair defects, reduced unscheduled DNA synthesis and increased chromatid exchange.2-4 The diagnosis of this group of diseases in our part of the work is based on clinical features due to lack of facilities for genetic studies. We describe, for the first time, 3 Address for Correspondence Dr. Ijaz Aman 2-C, Hearn Road, Islampura Lahore. Ph#042-7226054 cases who have both the features of xeroderma pigmentosum and Cockayne syndrome. Case report Three brothers of ages 12, 7 and 2 years presented at the out-patient department of Paediatric Medicine, Mayo Hospital, Lahore in September 2001 with a history of photosensitivity and black-brown pigmented spots on face and other exposed parts with redness and soreness of eyes. The children were born to a consanguineous couple after an uneventful pregnancy and labour. They were normal at birth and the symptoms began at ages 9, 12 and 17 months, respectively. They developed black-brown pigmented spots and scaly lesions over their faces and back of hands after sun exposure. Their complexion gradually became dark and skin became dry. Two of them also had excessive lacrimation and redness of eyes. The symptoms used to exacerbate particularly during hot weather and febrile illnesses. They also developed anorexia, weight loss and thinning out of nose 155 weight loss and thinning out of nose. Figure 1 Dry scaly, freckling, atrophy involving face in a butterfly distribution, prominent ears and premature senile appearance. Figure 2 Long lower extremities with genu valgum. However, there was no complaint of seizures or hearing deficit in our patients. They remained underweight as compared to their peers. They attained normal motor milestones but cognitive functions were impaired and the eldest child was the student of class one. They had progressively increasing difficulty in walking with tremulous movements of hands especially when performing any task. Another sibling with similar skin lesion had died at the age of 11 months due to unknown reasons while other family members did not suffer from similar illness. Physical examination revealed three thin built, anxious looking boys with short stature. They had dry, scaly skin and freckling involving face in a butterfly distribution (Figure 1). They had pinched nose, atrophy of the facial skin, loss of subcutaneous fat and prematurely senile appearance. There were no vesiculobullous, eczematous or telangiectatic lesions seen in our patients. Similarly, there were no cutaneous lesions suggestive of malignant transformation. Heights of all three children were less than 5th percentile. Hands and feet were relatively large. Lower limbs were disproportionately long as compared to the trunk in the eldest child (Figure 2) while younger children were normal. Ears were relatively large while hair, nails and mucous membranes were normal. They also had carious teeth and skeletal abnormalities which included restriction of knee joint movements with lumbar lordosis and genu valgum (Figure 2). Neurological examination revealed broadbased gait and spasticity, pointing a defect in cerebellum. Other cerebellar signs included intention tremors, past pointing and incoordination. Deep tendon reflexes in the lower limbs were exaggerated with up going plantars. However, there was no nystagmus, choreoathetosis or ataxia in our patients. Photophobia was found in all 156 the three patients while keratitis was noted in one patient. Hearing was found to be normal. Psychiatric analysis showed lower IQ in all the three patients. Their mental age was assessed to be 6, 4 and 1 year, respectively on portage guide. Laboratory investigations showed no abnormality. EEG was also normal while CT scan of brain in eldest child showed foci of calcification at basal ganglia. Nucleotide excision repair, unscheduled DNA synthesis and complementation assay studies could not be performed due to unavailability. Discussion Cockayne syndrome, first described by a British pediatrician in 1936, is a rare autosomal recessive degenerative disease with cutaneous, ocular and neurological abnormalities.3 The syndrome has classical and non-classical types.4 One of the nonclassical variety has features of both XP and CS and a number of cases have been reported.4,5 The disease usually starts during the second year of life with slowly progressive neurological degeneration, intellectual impairment, deafness, peripheral neuropathy, normal pressure hydrocephalus and microcephaly.1 The cutaneous findings seen in our patients included photosensitivity with pigmentary abnormalities as seen in XP.1 A thin nose, large hands and feet with larger lower limbs as compared to trunk are conspicuous of CS.1-4 Ocular abnormalities included photophobia in all cases and keratitis in one child, the findings being present in both syndromes while the characteristic ‘salt and pepper’ appearance of retina, cataract and optic atrophy present in CS were not seen in our cases.4-6 We did not find any lesion suggestive of malignant change in our cases similar to CS in which there is no increase in the incidence of neoplasia.1,3 Hypereflexia in lower limbs of our cases is a useful diagnostic feature of CS rather than XP.2,5 Although our patients were mentally retarded and had photosensitivity, there were no hair and nail changes, ichthyosis or pellagra-like skin manifestations. Hence the diagnosis of trichothiodystrophy and Hartnup disease were not considered. Dwarfism and premature senile appearance are also features of progeria but photosensitivity, disproportionately large extremities, normal hair and demyelination are not present in cases of progeria. In Bloom’s syndrome, the erythema of face and hands is associated with growth retardation, but mental development is normal. Poor cognition, spasticity, incoordination and upper motor neuron signs in the lower limbs indicate central and peripheral demyelination, the signs of CS.5-6 Confirmation of the diagnosis by assay of DNA repair in skin fibroblasts, protein complementation studies and molecular genetic testing of the two genes (ERCC6, ERCC8) could not be done due to lack of facility. The final diagnosis of XP-CS complex could only be made on clinical background. They were prescribed topical sun screen lotions with advice to avoid sunlight. Currently, the patients are under observation with continued treatment. References 1. 2. Harper JI. Genetics and genodermatoses. In: Champion RH, Burton JL, Burns DA, Breathnach SM, eds. Textbook of dermatology, 6th edn. Oxford: Blackwell Science; 1998. p. 357-436. Kraemer KH. Heritable diseases with increased sensitivity to cellular injury. In: Freedberg IM, Eisen AZ, Wolff K et al., eds. Dermatology in general medicine, 5th 157 3. 4. 5. edn. New York: McGraw-Hill; 1999. p. 1848-62. Levy M, Hirschhorn K, Willner J. Disorders with photosensitivity. In: Pine JW, Mullen ML, eds. Genodermatoses: a full color clinical guide to genetic skin disorders, 6th edn. New York: JB Lippincott; 1996. p. 204-12. Nance MA. Cockayne syndrome. Gene Reviews, 2001; 1-13. http://www.geneclinics.org/servlet/access. Mallory S. Disorders with malignant potential. In: Pine JW, Mullen ML, eds. Genodermatoses: a full color clinical guide to genetic skin disorders, 6th edn.Le 6. 7. New York: JB Lippincott; 1996. p. 15068. Butterworth T, Ladda RL, eds. Clinical genodermatology. New York: Praeger Scientific; 1981. Kraemer KH, Scotto J. Xeroderma pigmentosum: cutaneous, ocular and neurologic abnormalities in 830 published cases. Arch Dermatol 1987; 123: 241-50. 158 Quiz An erythematous plaque on the breast Faria Asad, Sabrina Suhail Pal Department of Dermatology, King Edward Medical College/Mayo Hospital, Lahore Report of a case A 46-year-old woman presented with erythema and scaling of the nipple and areola of her right breast for the last one and a half years. It was associated with itching, mild burning and serous discharge. She applied various medicaments over the past years but there was only symptomatic relief. Physical examination revealed an illdefined, crusted, erythematous plaque involving the nipple and areola of right breast associated with mild retraction of the nipple. Breast examination did not reveal any palpable mass. Axillary lymph nodes were not enlarged. Her systemic examination and laboratory investigations were unremarkable. A biopsy was taken for histopathology (Figure 1 and 2). Figure 1 (Haematoxylin-eosin, original magnification x 40) What is your diagnosis? Figure 2 (Haematoxylin-eosin, original magnification x 400) Address for Correspondence Dr. Faria Asad, Department of Dermatology, Mayo Hospital, Lahore. 159 Diagnosis Paget’s disease of breast Microscopic findings and clinical course Section of the biopsy specimen showed infiltration of the acanthotic epidermis with numerous Paget cells lying singly and in groups. These were large, rounded cells that contained a large nucleus and ample cytoplasm. The cytoplasm of these cells stained much lighter than that of adjacent squamous cells which were compressed between them. There was no invasion of the dermis by Paget cells. Chronic inflammatory cells were present in the upper dermis. Discussion Paget’s disease of breast occurs almost exclusively in women, but a few instances of its occurrence in male breast have been described.1 It is a rare disorder of nippleareola complex that is often associated with an underlying in situ or invasive carcinoma.2 It is characterized by progressive, eczematoid changes with persistent soreness or itching. Due to its seemingly benign appearance, diagnosis is often delayed. There are two main theories regarding the histogenesis of the disease: the epidermotropic and the in situ transformation. The first suggests that Paget cells are ductal cells that have migrated from an underlying carcinoma of breast parenchyma to the epidermis of the nipple. The second postulates that nipple keratinocytes undergo transformation into malignant cells independent from any pathology within the breast parenchyma.3 In 50% of the cases, a palpable mass is evident and it usually represents an infiltrating carcinoma with involved axillary lymph nodes. In the absence of a mass, the prognosis is invariably better as it reflects a non-invasive tumor. The standard treatment is mastectomy. Although in our patient, no palpable mass or lymphadenopathy was present, yet a biopsy was imperative. For long-standing unilateral breast eczema which is not responsive to medicaments a skin biopsy to confirm or rule out Paget’s disease. References 1. 2. 3. Satiani B, Powell RW, Mathews WH. Paget’s disease of male breast. Arch Surg 1977; 12: 587-92. Sakorafas GH, Blanchard DK, Sarr MG. Paget’s disease of the breast: a clinical perspective. Langenbecks Arch Sur 2001; 386: 444-50. Lev-Schelouch D, Sperba F, Gat A. Paget’s disease of the breast. Harefuah 2003; 142: 433-7. 160 News 2004 National events 2003 September 26-28, 2003 10th Annual Conference of Dermatology - Bhurban, Pakistan. For further information contact: Dr. Riaz A. Sheikh, 10-F, PIMS Campus, G/8-3, Islamabad - 4400 Pakistan. Tel: +92 51 9261203, 0300 9505421 E-mail: derma_2003@yahoo.com, or riaz_a_sheikh@yahoo.com 2004 December 9-12, 2004 Silver Jubilee Conference of Pakistan Association of Dermatologists, Karachi. Organizing Chairman: Dr. Khurshid H. Alvi, K.V. SITE Hospital, Karachi. Tel: +92 21 7789666 Fax: +92 21 7789677 E-mail: info@pad.org.pk, badr@pad.org.pk May 19-22 IX ISD International Congress on Dermatology, Beijing, China Contact: International Congress Secretariat Tel: +86 10 6524 9989 ext 1606 Fax: + 86 10 6512 3754 E-mail: icd2004@chinamed.com.cn November 17-21 13th Congress of the European Academy of Dermatology and Venereology Contact: Torello M. Lotti, Florence, Italy E-mail: president@eadv2004.org or info@eadv2004.org February 6-11 American Academy of Dermatology 62nd Annual Meeting, Washington, DC For more information contact: American Academy of Dermatology, 930 E Woodfield Rd, Schaumberg, IL 60173/847-330-0230; fax 847-330-1090. E-mail: rescalante@aad.org 2005 International events 2003 October 15-18 12th Congress of the European Academy of Dermatology and Venereology Mario Lecha, Barcelona, Spain E-mail: congresos@atlantaviayes.es www.eadv.org October 12-15 European Academy of Dermatology and Venereology Congress (EADV) London, UK Contact: Marilyn Benham Tel: 020 7383 0266 E-mail: eadv@bad.org.uk www.eadv.org November 9-12 14th Congress of Aesthetic Medicine Las Vegas, Nevada, USA Tel: 604 681-5226 Fax: 604 681-2503 E-mail: congresos@venuewest.com www.venuewest.com/aestheicmedicine2003 161 Information for Authors Manuscripts The JPAD agrees to accept manuscripts prepared in accordance with the “Uniform Requirements for Manuscript Submission to the Biomedical Journals” approved by the International Committee of Medical Journals Editors. Three copies of all material for publication should be sent to Dr. Ijaz Hussain, Editor, JPAD, Department of Dermatology, Mayo Hospital, Lahore, e-mail: dderma@paknet4.ptc.pk dr_ijazhussain@yahoo.com Manuscripts should be printed on one side of paper only, with a 2.5 cm margin on either side, be double spaced, and bear the title of the paper, name and address of each author, together with the name of the hospital, laboratory or institution where the work has been carried out. The name and full address of corresponding author should be given on the first page. Pages should be numbered. Authors should keep a copy of the manuscript. In addition to the hard copy, an exact copy of the manuscript, containing all parts of the paper, must be submitted on high-density disk. The editor reserves the right to make corrections, both literary and technical, to the papers. Papers received are supposed to have been submitted exclusively to the Journal of Pakistan Association of Dermatologists and all authors must give a signed consent to publication in a letter sent with the manuscript. Authorship implies a significant contribution. In case of clinical trials, the names of pharmaceutical sponsors should be mentioned. Types of articles JPAD welcomes original and review articles, case reports, quizzes, items of correspondence etc. addressing any aspect of dermatology. The original article should be of about 2000 words, with no more than 6 tables or illustrations. Letters should not normally exceed 400 words and have more than 10 references. Parts of the paper The manuscript should be prepared as below. Title: In addition to the full title of the paper, a short version not more than 50 characters, for a running head, be provided. Author(s) details: Name(s) of the author(s) should be given as initial(s) followed by surnames, and should be clearly linked to the respective addresses by the use of symbols e.g. , †,‡ etc. Abstract: All articles other than correspondence should have an abstract. The original articles should have a structured abstract comprising of 4 subheadings: background, methods, results and conclusions. Keywords 5 should be provided to aid indexing. Main text: The main text should appear in the following sequence: introduction, methods, results, discussion, acknowledgments, references, tables and legends for illustrations. Each section should begin on a new page. Generic names of the drugs should be used. Full names with abbreviations must be used given with the first mention, thereafter the abbreviation will be used. Abbreviations should be used for unwieldy names or where the names occur frequently. For all quantitative measurements the International System of Units (SI) should be used. References Only papers closely relevant to the author’s work should be referred to. References should be in the Vancouver style i.e. references should be written as unbracketed superscript numbers in the order in which they appear in the text e.g. ‘our previous reports1 and that of Cohen et al.2…..’. At the end of the article, references should give the name(s) and initials of author(s). If there are more than four authors, include the first three authors followed by et al., title of paper, title of the journal abbreviated in the standard manner (as published in the Index Medicus), year of publication, volume number, and first and final numbers of the article, e.g. Grattan C, Powell S, Humphreys F. Management and diagnostic guidelines for urticaria and angiooedema. Br J Dermatol 2001; 144: 708-14. References to books should give the name(s) followed by initials of author(s) or editor(s), chapter (if relevant), book title, edition, place, publisher, year, and pages referred to e.g. Friedman WF, Child JS. Congenital heart disease in the adult. In: Fauci AS, Braunwald E, Isselbacher KJ et al., editors. Harrison’s principles of internal medicine. 14th edn. New York: McGraw-Hill; 1998. p. 1300-9. Tables There should be as few tables as possible and these should include only essential data. These should be printed on separate sheets and should be given Arabic numbers. No horizontal or vertical rules should be used. Avoid wordy, over-full tables. Legends should be provided. Illustrations Three sets of illustrations should be sent with each manuscript. Illustrations should be referred to in the text as ‘Figures’ and be given Arabic numbers. Each figure should be marked on the back with the name of the author(s), the title of the paper and the reference number used in the text. Orientation of the illustration should be indicated by marking the top with arrow. Photographs should be unmarked glossy prints. Diagrams should be on separate sheets and a legend should be provided for each illustration. Proofs Page proofs will be sent, without the original manuscript, to the corresponding author for proof correction and should be returned to the editor within three days. Major alterations from the text cannot be accepted. Any alterations should be marked, preferably in red. 162