Severe epidermolysis bullosa/Kindler syndrome-like phenotype of an autoinflammatory syndrome in a child.

A 5-year-old boy presented with generalized cutaneous erosions, severe scarring, depigmentation and contractures affecting major joints. The lesions had initially affected his ears, nose, feet, and the genital and ocular mucosa, leading to significant depigmentation, scarring, contractures and mutilation. The whole of the trunk and limbs were involved at the time of presentation, with the exception of some islands of spared skin on the proximal thighs, legs, nipples and external genitalia. Electron microscopy revealed a split in the sublamina densa with the absence of anchoring fibrils, suggestive of dystrophic epidermolysis bullosa (EB). Immunofluorescence antigen mapping demonstrated a broad reticulate pattern of staining with collagen IV, VII, and laminin 332 in the floor of the blister, suggestive of Kindler syndrome. Next-generation sequencing revealed a de novo heterozygous missense mutation (a variant of unknown significance) in exon 22 of the phospholipase-C gamma 2 gene (PLCG2), which resulted in a substitution of serine by asparagine at codon 798 (p.Asp798Ser), a result that was validated using Sanger sequencing. The child was diagnosed with PLCG2-associated antibody deficiency and immune dysregulation (PLAID)/autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation (APLAID) syndrome. The cutaneous and corneal erosions, inflammation and scarring of this magnitude, and the eventual result of death have not been described previously for the PLAID/APLAID spectrum previously. In conclusion, this was an unusual acquired autoinflammatory severe EB-like disease that may be associated with de novo PLCG2 mutation.

Use of cyproterone acetate/ethinylestradiol in polycystic ovary syndrome: rationale and practical aspects.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is a common, heterogeneous disorder characterised by hyperandrogenic skin symptoms, irregular menstruation and subfertility, increased risk of endometrial malignancy, and increased risk of preventable diseases associated with metabolic syndrome. Cyproterone acetate (CPA) 2 mg, combined with ethinylestradiol (EE) 35 µg, is indicated for the treatment of moderate to severe acne related to androgen-sensitivity (with or without seborrhea) and/or hirsutism, in women of reproductive age. OBJECTIVES: To review the present knowledge about PCOS and summarize the role of CPA/EE in the care of patients suffering from this condition for the practitioner. METHODS: Experts with clinical interest and experience in treating symptoms of androgen excess performed a non-systematic review to provide updated information regarding the use of CPA/EE in patients with PCOS. RESULTS: Polycystic ovary-related hyperandrogenic skin symptoms are effectively treated by CPA/EE, reducing not only the symptoms but also their negative impact on quality of life and mental health. Proven additional benefits for these patients include the treatment of menstrual irregularities and reduction in endometrial cancer risk. Possible benefits include preservation of fertility. Treatment increases the risk for venous thromboembolic complications. The nature of other metabolic and cardiovascular long-term effects i.e., whether positive or negative, are still to be investigated. CONCLUSIONS: Cyproterone acetate/ethinylestradiol provides effective treatment for PCO-related hyperandrogenic skin symptoms. This efficacy and additional benefits related to menstrual irregularities and endometrial cancer risk, have to be weighed against the risk of venous thromboembolic complications based on an individual benefit/risk evaluation.

Histopathological Diagnosis of Leprosy Type 1 Reaction with Emphasis on Interobserver Variation.

Upgrading typel lepra reaction or reversal reaction (RR) is an acute inflammatory complication of leprosy and a disparity exists between clinicians and pathologists for diagnosing a RR. Inter-observer variations among pathologists also compound this problem as no universally agreed diagnostic criteria exist. 120 biopsies and H&E stained slides were assessed by 3 pathologists. The pathologists were blinded to the clinical diagnosis and to each other's observations. Each pathologist assigned a likelihood of reaction by their histopathological observations as definitely reaction, probable reaction and no reaction. Clinicopathological correlation and interobserver agreement was analyzed statistically. Discordance between clinical and histopathological diagnosis was seen in 30.8% by pathologist 1 (P1), 23.7% by pathologist 2 (P2) and 34.5% bythe pathologist 3 (P3). Dermal edema, intragranuloma edema and epidermal erosion were consistent findings by all observers. Definite reaction was seen in 54.2% of cases by P1, 53.3% by P2 and 34.5% by P3. Kappa statistics for strength of agreement showed good agreement between 3 pathologists with P1 (κ = 0.83), P2 (κ = 0.61), P3 (κ = 0.62). RR are underdiagnosed on histopathological examination but this study shows that dermal edema, edema within the granuloma and partial obliteration of grenz zone by granuloma are reliable clues to diagnose a RR on histopathology.

Immunofluorescence mapping in inherited epidermolysis bullosa: a study of 86 cases from India.

BACKGROUND: Epidermolysis bullosa (EB) poses diagnostic challenges in infancy. In India, the diagnosis is largely clinical. There were no facilities to perform immunofluorescence mapping (IFM) until recently, and electron microscopy, which requires expertise to interpret, is limited to a few research laboratories. OBJECTIVES: To describe the patterns of IFM staining in the various forms of EB in Indian patients and to correlate these findings with clinical diagnosis. METHODS: We conducted a cross-sectional study of IFM findings in EB. Antibodies against type IV collagen, cytokeratin 14, laminin 332 and type VII collagen were used. Clinical correlation was performed in all cases, and concordance-discordance rates were calculated. RESULTS: Eighty-six patients with a diagnosis of EB were included in the study. There were 29 with EB simplex (EBS), 18 with junctional EB (JEB) and 15 with dystrophic EB (DEB). The remaining 24 cases included rare variants, cases with overlapping clinical features and cases where the type of EB was not known. On IFM diagnosis, there were 32 cases of EBS, 15 JEB, 17 DEB and two Kindler syndrome. Two cases were not EB and 18 were inconclusive. IFM could establish the type in 12 of 15 cases (80%) that had overlapping clinical features. Most of these cases were under 1 year of age. Overall the concordance was 57% and was seen best in cases of EBS. CONCLUSIONS: This is the first large study of IFM of the subtypes of EB in Indian patients. The study provides a framework for better understanding of EB in Indian patients and for better diagnosis and management, particularly in infancy.

Panniculitis with vasculitis.

Panniculitides encompass a great number of different entities; however, once a vasculitis has been detected histopathologically within the subcutaneous tissue, the differential diagnosis is mainly restricted to polyarteritis (panarteritis) nodosa (PAN), nodular vasculitis (NV), and Bazin's erythema induratum (EI). Patients with PAN may have the disease confined to the skin, but must be followed over a long period because many of them develop late systemic disease. The NV/EI group represents by far the most common type of lobular panniculitis with vasculitis; we prefer keeping the distinction between the two entities by underlining the equation NV positive tuberculin skin test = EI. Other lobular panniculitides with vasculitis are exceedingly rare and set in a systemic background which can be infectious (lepromatous leprosy panniculitides) or autoimmune/dysreactive (neutrophilic lobular panniculitis in rheumatoid arthritis, lobular panniculitis in inflammatory bowel disease).

Are significant numbers of abnormal cells lost on the discarded ThinPrep® broom when used for cervical cytology?

UNLABELLED: Are significant numbers of abnormal cells lost on the discarded ThinPrep® broom when used for cervical cytology? BACKGROUND: In view of a study with SurePath® showing that cells were lost on the broom if it was discarded, we decided to investigate whether cells were lost on the ThinPrep® (TP) broom, which is discarded according to the manufacturer's protocol. AIM: To determine whether significant amounts of cellular material are lost on the discarded TP broom, and whether the loss is operator dependent. METHODS: Three hundred and six women attending the Guy's Hospital Colposcopy Unit gave their consent for TP liquid-based cytology samples to be taken and the broom immersed in a second vial instead of being discarded. The cellularity of the first and second vials was compared by counting cells in 10 ×40 high-power fields (HPFs). The significance of cell loss was ascertained by correlating the likelihood of abnormal cells and transformation zone (TZ) material being present with the degree of cellularity of the two vials. RESULTS: More than 10 cells per HPF were seen in 3.2%, 19.4% and 35.8% of slides from the second vial taken by three experienced colposcopists, which was significantly different between them (P < 0.001); cellularity of the first vial was not significantly different between colposcopists but the one with highest cellularity in the first vial discarded most in the second. Abnormal cells were more likely to be seen in slides with more than 10 cells per HPF (P < 0.001) and with evidence of TZ sampling (P < 0.001), but there was no preferential loss of TZ material in the second vial. Of 126 slides with abnormal cells on the slides from the second vial, 113 (89.7%) were also present on the significantly more cellular first vial (P < 0.001). CONCLUSION: Abnormal cells were potentially lost on the broom, but were usually represented in the first vial. The likelihood of abnormal cells being discarded was operator dependent in this small study, but this did not affect the quality of the initial preparation. The likelihood of abnormal cells being seen on TP slides was dependent on their cellularity, which provided our laboratory with a criterion for the assessment of sample adequacy.

Invasive cervical cancer audit: why cancers developed in a high-risk population with an organised screening programme.

OBJECTIVES: To investigate why invasive cervical cancers developed in a high-risk urban population with an established screening programme and to place cancers in the context of high-grade cervical intraepithelial neoplasia (CIN) and cervical glandular intraepithelial neoplasia (CGIN) diagnosed during the same period of time. STUDY DESIGN: Observational study of CIN2+ (CGIN, CIN3 and CIN2) and invasive cervical cancer diagnosed at Guy's and St Thomas' NHS Foundation Trust in 1999-01, 2002-04 and 2005-07 and audit of screening histories of women with invasive cancer analysed according to route to diagnosis, histological type and International Federation of Obstetrics and Gynecology (FIGO) stage. RESULTS: There were 133 invasive cancers, 53 CGIN, 1502 CIN3 and 1472 CIN2. Screen-detected cancers in asymptomatic women comprised 48.9% of cancers and were successively more likely to be in younger age groups (P = 0.03); all except one were stage IA or IB1. Screen-detected IA cancers were more likely (P < 0.001) to be in women screened within 0.5-5.0 years (80.5%) than screen-detected fully invasive (58.3%) or symptomatic cancers (35.3%). Seventy-one (53.4%) women had been screened within 0.5-5.0 years; 11 had negative cytology within 0.5-3.5 years and two tests within 10 years. The other 60 had negative tests less frequently or had previous abnormal cytology, colposcopy or treatment. Potentially avoidable factors were often multiple, including false-negative cytology, high-grade cytology reported as low-grade and lapses in attendance either for routine or repeat screening, or for colposcopy or treatment. CONCLUSION: While often potentially avoidable, cancers in previously screened women tended to be early stage, detected by cytology and rare when compared with high-grade CIN.

Familial reactive perforating collagenosis: a clinical, histopathological study of 10 cases.

OBJECTIVE: To study the clinical and histopathological features of familial reactive perforating collagenosis (RPC). MATERIAL AND METHODS: Ten patients, including affected siblings in three, took part in the study. Parental consanguinity was present in one. Histopathological study was performed in all patients. RESULTS: The eruptions appeared mainly during infancy or early childhood as papules showing a central plug, which subsided within 10 weeks. Areas commonly affected were the face, extremities and trunk. Rare sites were the scalp, ears and buttocks. One pregnant woman, in whom RPC had first manifested around puberty, had relatively widespread lesions. In those with seasonal variation, recurrences were seen a little more frequently in summer than in winter owing to the longer duration of the former. Histopathology confirmed the diagnosis with follicular involvement in four cases. In two patients whose backs were also affected, the lesions went unnoticed, as they were small and inconspicuous. In addition, the brother of a girl with RPC who claimed to be free of the dermatosis, had facial scars suggestive of RPC in the past. CONCLUSIONS: Familial RPC can remain quiescent for a long period and the inherited defect not only shows extreme variability in expression but also demonstrates that lesions can be few and localized so as to escape notice in individuals and family members presenting with this benign, uncommon and self-subsiding dermatosis. In all patients topical retinoic acid was helpful in early regression. Sunscreens may mitigate the severity of RPC in those whose lesions are precipitated in summer but this needs further evaluation.

Non-responders to hepatitis B vaccination: a review.

Hepatitis B virus (HBV) infection is a major public health issue throughout the world and vaccination of those at risk is the main method of containment. Of healthy vaccinees, 5-10% fail to mount an adequate antibody response. The antibody levels of an unknown further fraction of vaccinees fall considerably over time rendering them at a potential risk of infection. The scope of this article is to review the factors that might influence the immune response to HBV vaccination, to review the methods used to overcome the problem of poor response and to discuss what possible guidelines are available or needed in treating these vaccinees.

Update in the pharmacological management of peptic ulcer haemorrhage.

The management of peptic ulcer haemorrhage still poses questions and controversies and this applies to the pharmacological mode. This review suggests that high-dose acid suppression is beneficial in reducing rebleeding and surgery rates. The choice of acid suppressant is far from conclusive, but emerging evidence suggests that proton pump inhibitors may be more effective than H2-antagonists. The only other drug which may be useful in selected patients is octreotide, but its universal use cannot be recommended.

Contraception.

The supremacy of combined oral contraceptives (OCs) is being challenged. For too long combined OCs have been seen as synonymous with contraception, helping to maintain ignorance of alternative methods. Further, the efficacy of these OCs and condoms is often compromised by incorrect or inconsistent use. We particularly welcome developments in male systemic methods, that allow men to share not only in conception but also in contraception, and methods that are completely forgettable once instituted, especially if usable by adolescents.

Cutaneous and paranasal aspergillosis in an immunocompetent patient.

A 26-year-old Libyan woman presented with asymptomatic nodulo-ulcerative skin lesions present for 1 year. Three years prior to presentation, she had experienced a nasal discharge followed by the development of a nodule in the nasal cavity and a plaque on the hard palate. These lesions had gradually increased in size and ulcerated, resulting in perforation of the nasal septum and palate. Two years later, the patient noticed the appearance of skin lesions: a nodule on the right thumb and numerous nodulo-ulcerative lesions on the extremities. General physical examination was normal with no significant lymphadenopathy. Examination of the oral cavity revealed perforation of the distal nasal septum, with a perforated nodular plaque involving the entire palate, associated with subluxation of the upper incisors (Fig. 1a). On skin examination, multiple firm nodules and nodulo-ulcerative lesions with a central eschar and raised margins were observed. The lesions ranged in size from 0.5 to 5 cm and were distributed on the right hand and fingers, left upper arm (Fig. 1b), left calf, and right thigh. Routine laboratory investigations (liver function tests, serum calcium, electrolytes, lipid profile, urine and stool culture studies) were normal. Immunoelectrophoresis disclosed normal levels of immunoglobulins IgG, IgA, and IgM. Serologic studies for human immunodeficiency virus (HIV) and syphilis, and a tuberculin test, were all negative. A Giemsa-stained tissue smear was negative for Leishmania tropica organisms. Radiological studies disclosed a slight haziness of the maxillary sinuses with perforation of the nasal septum. A chest X-ray was normal. Histopathologic examination of biopsies taken from both the palate and from ulcerated and nonulcerated skin lesions was performed, and all showed similar findings. The biopsy of a nonulcerated skin lesion showed pseudoepitheliomatous epidermal hyperplasia with neutrophilic microabscesses (Fig. 2a). A dermal diffuse and nodular granulomatous mixed infiltrate of lymphocytes, histiocytes, giant cells, numerous eosinophils, and neutrophilic microabscesses was seen in all tissues examined. Septate hyphae were present both within giant cells and free in the dermis (Fig. 2b). The hyphae were branching at a 45 degrees angle and were positive on periodic acid-Schiff and Grocott methenamine silver stains (Fig. 2c). Fungal culture studies of material taken from an ulcerated skin lesion grew Aspergillus flavus. Blood cultures were negative for Aspergillus sp. or other microorganisms. The patient was treated with intravenous amphotericin B, but the medication was discontinued due to her intolerance to the drug. She was subsequently lost to follow-up.

Acid suppression in peptic ulcer haemorrhage: a 'meta-analysis'.

BACKGROUND: The use of acid-decreasing agents in the management of peptic ulcer haemorrhage continues to be controversial. Most clinical trials examining the efficacy of these drugs contain small numbers of patients, making it difficult to draw conclusions about their efficacy. METHODS: We report a meta-analysis that examined the effect of these drugs in the management of peptic ulcer haemorrhage. Included studies were located using a search of the Medline database between 1980 and 1999. Studies were published in English, randomized and controlled by a placebo group. Mantel-Haenszel and blinded random models were used in conducting the statistical processing of this meta-analysis. RESULTS: Twenty-one randomized placebo-controlled trials were included. The total number of patients was 3566 and the mean study size was 170 (range 20-1005). Seventeen of the papers assessed the efficacy of H2-antagonists, three assessed proton pump inhibitors and one was concerned with antacid therapy. The meta-analysis showed a significant reduction in re-bleeding rates (odds ratio, OR 0.727, 0.618-0.855, P < 0.001) and surgery rates (OR 0.707, 0.582-0.859, P < 0.001) when acid decreasing agents are used for acute peptic ulcer haemorrhage. Mortality rates appear to be unaffected (OR 1.140, 0.818-1.588, P=0. 49). CONCLUSIONS: This meta-analysis demonstrates a significant beneficial effect of acid-decreasing agents in lowering re-bleeding and surgery rates, but demonstrated no effect upon mortality.

An update in the palliative management of malignant dysphagia.

BACKGROUND: Oesophageal cancer is generally associated with late presentation and poor prognosis. Therefore palliative surgery has been largely superseded by less invasive non-surgical techniques. Once palliation is indicated, the aims of the management should be: the maintenance of oral intake, minimizing hospital stay, relief of pain, elimination of reflux and regurgitation and the prevention of aspiration. METHODS: This study was a review of all published English language data on the palliation of malignant dysphagia between 1994-1999. The Medline and Bids databases were searched and other references were derived from the material perused. RESULTS AND CONCLUSIONS: Palliative treatment for oesophageal cancer should be individualized and relate to tumour stage, size and location, the patient's medical condition and his/her personal wishes. The palliative treatment largely includes self-expanding metal stents (SEMS), laser (including photodynamic therapy (PDT)) or a combination of the two to relieve symptoms, this may be employed with or without other treatments such as radiotherapy/chemotherapy (RT/CT) with the aim of reducing tumour bulk and possibly prolonging survival. A multi-disciplinary approach is vital in patients with advanced oesophageal cancer.