Dincy Peter

WRN mutations in Werner syndrome patients: genomic rearrangements, unusual intronic mutations and ethnic-specific alterations

Werner syndrome (WS) is an autosomal recessive segmental progeroid syndrome caused by null mutations at the WRN locus, which codes for a member of the RecQ family of DNA helicases. Since 1988, the International Registry of Werner syndrome had enrolled 130 molecularly confirmed WS cases from among 110 worldwide pedigrees. We now report 18 new mutations, including two genomic rearrangements, a deep intronic mutation resulting in a novel exon, a splice consensus mutation leading to utilization of the nearby splice site, and two rare missense mutations. We also review evidence for founder mutations among various ethnic/geographic groups. Founder WRN mutations had been previously reported in Japan and Northern Sardinia. Our Registry now suggests characteristic mutations originated in Morocco, Turkey, The Netherlands and elsewhere.

Ethnic‐specific WRN mutations in South Asian Werner syndrome patients: potential founder effect in patients with Indian or Pakistani ancestry

Werner syndrome (WS) is a rare autosomal recessive disorder characterized by multiple features consistent with accelerated aging. It is caused by mutations in the WRN gene, which encodes a RecQ type helicase. To date, more than 70 disease‐causing mutations have been reported. While founder mutations and a corresponding relatively high incidence of WS have been reported in Japan and Sardinia, such mutations have not been previously described among patients of South Asian descent. Here, we report two novel WRN mutations in three pedigrees. A homozygous c.561A>G mutation in exon 6 was identified both in a pedigree from Kerala, India and in a British patient of Pakistani ancestry. Although c.561A>G does not alter the corresponding amino acid (p.Lys187), it creates a cryptic splice site resulting in a 98 bp deletion at the mRNA level (r.557_654del98) followed by a frameshift (p.Lys187Trpfs*13). These two cases shared the same haplotype across the WRN gene, and were distinct from another Indian Werner patient with a homozygous stop codon mutation, c.2855 C > A (p.Ser952*), in exon 24. As the Indian population increases and the awareness of WS grows, we anticipate that more cases will be identified with these founder mutations among South Asian WS patients.

Toxicity and clinical outcomes in patients with HIV on zidovudine and tenofovir based regimens: a retrospective cohort study.

BACKGROUND Adverse drug reactions are a major concern with zidovudine/stavudine treatment regimens. The less toxic tenofovir regimen is an alternative, but is seldom considered due to the higher costs. This study compared adverse drug reactions and other clinical outcomes resulting from the use of these two treatment regimens in India. METHODS Baseline, clinical characteristics and follow-up outcomes were collected by chart reviews of HIV-positive adults and compared using univariate/multivariate analysis, with and without propensity score adjustments. RESULTS Data were collected from 129 and 92 patients on zidovudine (with lamivudine and nevirapine) and tenofovir (with emtricitabine and efavirenz) regimens, respectively. Compared to patients receiving the zidovudine regimen, patients receiving the tenofovir regimen had fewer adverse drug reactions (47%, 61/129 vs 11%, 10/92; p<0.01), requiring fewer regimen changes (36%, 47/129 vs 3%, 3/92; p0.01). With the propensity score, the zidovudine regimen had 8 times more adverse drug reactions (p<0.01). Opportunistic infections were similar between regimens without propensity score, while the zidovudine regimen had 1.2 times (p=0.63) more opportunistic infections with propensity score. Patients on the tenofovir regimen gained more weight. Increase in CD4 levels and treatment adherence (>95%) was similar across regimens. CONCLUSIONS Patients on a tenofovir regimen have better clinical outcomes and improved general health than patients on the zidovudine regimen.

Role of polymerase chain reaction in the diagnosis of Trichomonas vaginalis infection in human immunodeficiency virus-infected individuals from India (South)

BACKGROUND Trichomonas vaginalis is a protozoan parasite and an etiological agent for trichomoniasis, a sexually transmitted infection (STI). Fifty to eighty percentage of women with trichomoniasis are asymptomatic and in the absence of treatment the infection persists longer. AIM To evaluate the role of polymerase chain reaction (PCR) in the diagnosis of trichomoniasis and also to look at the frequency of infection among human immunodeficiency virus (HIV) infected women. METHODS A non-nested PCR was standardized to detect 102 bp size amplified product of the adhesin gene of T. vaginalis. The real time performance of this assay was performed with vaginal swab samples from 198 HIV-seropositive women who attended the infectious disease clinic and compared with wet mount and culture in Diamonds modified media. RESULTS Among the prospectively studied 198 HIV-infected women, 1 (0.51%) was positive by wet mount, 6 (3.03%) were positive by culture and 10 (5.02%) were positive by the PCR. There was a significant observed agreement between the PCR and culture (k=0.74, Z=10.7, P<0.0000). CONCLUSION Our study showed that the PCR assay for the amplification of adhesion gene is a highly sensitive method to screen the high risk group individuals like HIV-positive women for Trichomonas vaginalis compared to the culture. Testing algorithm should be, wet mount and if negative, test by PCR as it is rapid compared to culture which takes 7 days.

Is Ross Syndrome an Autoimmune Entity? A Case Series of 11 Patients

BACKGROUND Ross syndrome is diagnosed by the presence of segmental anhidrosis, areflexia, and tonic pupils. Fewer than 60 cases have been described in literature so far. There have been reports of presence of antibodies in such patients, suggesting an autoimmune pathogenesis. METHODS We describe the clinical profile in this case series of 11 patients with Ross syndrome and discuss the current status of autoimmunity in its pathogenesis and the management. RESULTS Of the 11 patients with Ross syndrome there was an almost equal sex distribution (male:female ratio was 1.17:1) and the mean age of onset of symptoms was 26 years. Patients took an average of 6 years to present to a tertiary center. Sixty-three percent of the patients presented with complaints of excessive sweating, whereas only 27% had complaints of decreased sweating over a particular area of the body. Only 45% of the patients had the complete triad of Ross syndrome, which included segmental anhidrosis, tonic pupil, and absent reflexes. Eighty-nine percent of the patients had documented absent sympathetic skin response on electromyography. The various markers of autoimmunity were negative in all patients who were investigated for the same in this series. Ninety percent of the patients were managed conservatively. CONCLUSIONS These findings suggest that, in Ross syndrome, generalized injury to ganglion cells or their projections are not purely autoimmune-mediated.

Role of oxidative and nitrosative stress in pathophysiology of toxic epidermal necrolysis and Stevens Johnson syndrome-A pilot study

Background: Oxidative and nitrosative stress caused by drug metabolism may be a trigger for keratinocyte apoptosis in the epidermis seen in toxic epidermal necrolysis (TEN) and Stevens Johnson syndrome (SJS). Aims: To estimate oxidative damage in the serum and to examine the role of nitric oxide in mediating epidermal damage in patients with TEN and SJS. Materials and Methods: A prospective study was conducted among TEN and SJS patients and controls in a tertiary care center between January 2006 and February 2010. Patients with a maculopapular drug rash without detachment of skin constituted the control group 1 (drug exposed). Patients without a drug rash constituted the control group 2 (drug unexposed). The serum values of protein carbonyls, malondialdehyde, conjugated diene and nitrates were measured. Two-group comparison with the non-parametric Mann–Whitney U test was used. Significance of differences if any was established using Pearsons Chi-square test. Results: Ten patients in the SJS-TEN group (study group), 8 patients in control group 1 and 7 patients in control group 2 were included. More than one drug was implicated in 4/10 patients in group 1 and 3/8 patients in group 2. SCORTEN of 0, 1 and 3 at admission were seen in 2, 6 and 2 patients, respectively. The serum values of protein carbonyls, malondialdehyde, conjugated diene and nitrates were not significantly increased in the study group when compared to the controls. Conclusions: There was no elevation of oxidative stress markers in patients with TEN and SJS as compared to the control population.

Skin fragility, woolly hair syndrome with a desmoplakin mutation - a case from India

(HAART) in human immunodeficiency virus (HIV) patients. Recently, a similar concept, which implies that discontinuation or abrupt tapering of systemic steroids and/or immunosuppressants increases the risk of opportunistic infection in non-HIV patients, has been proposed. DIHS is suggested to be a manifestation of the newly reported IRS. Kano et al. reported that three out of 28 patients with DIHS in their institute developed herpes zoster within 6 months after resolution. They speculate that the administration of systemic corticosteroids may alter the pathomechanisms of DIHS and lead to the later occurrence of herpes zoster. Herpes zoster usually occurs 2–3 months after the resolution of DIHS and is often associated with the reduction of corticosteroids. In contrast, it is unlikely that treatment with systemic corticosteroids was associated with the reactivation of VZV, because such treatment was not performed in the present case. The causative drugs of DIHS have immunosuppressive properties, and it was reported that a decrease in immunoglobulin levels and B-cell counts was induced by such drugs, which may primarily contribute to the reactivation of VZV. In contrast, CD4 T-cell numbers initially increase, which subsequently decrease coincident with clinical improvement of DIHS. Those alterations of lymphocyte subsets during the course may be related to subsequent occurrence of various viral reactivation. Unfortunately, we could not examine CD4 T-cell counts during the course. Moreover, dysfunction of regulatory T cells at the resolution phase contributes to opportunistic infection, which also may have played an important role in VZV reactivation in the present case.

Utility of tissue elafin as an immunohistochemical marker for diagnosis of acute skin graft-versus-host disease: a pilot study

The skin is the most common organ involved in acute graft‐versus‐host disease (GvHD). Because histopathology has limited utility in ruling out clinical mimics of acute skin GvHD, more accurate diagnostic techniques are required.

Setting sun pattern in dermoscopy of a scalp nodule

their size into skin tags if they are millimeters in diameter, fibroepithelial polyps when they are bigger (usually less than 5 cm), and giant fibroepithelial polyps when they reach a size larger than 5 cm. Fibroepithelial polyps tend to occur in frictional areas such as the axilla and neck, but can also occur in the groin, mouth, and vulvovaginal areas (with a predilection for the vagina). The incidence of their appearance in the vulvovaginal region is unknown. Risk factors to develop fibroepithelial stromal polyps are pregnancy, polycystic ovary syndrome, premenopausal females on hormone replacement therapy, obesity, diabetes mellitus, among others. Diagnosis is made clinically by the presence of a pedunculated, soft, flesh-colored to dark brown outgrowth of the skin, and confirmed by histopathology. Ultrasound, computed tomography, and resonance imaging can aid in the diagnosis by determining the origin of the tumor and blood supply. Differential diagnosis includes neurofibroma, viral warts, premalignant fibroepithelial tumor (Pinkus tumor), and malignant tumors such as aggressive angiomyxoma, sarcoma, and angiomyofibroblastoma. Microscopic examination reveals stellate and multinucleate stromal cells, which are positive for desmin, actin, vimentin, estrogen and progesterone receptors, and CD34-positive stromal cells. Fibroepithelial polyp is treated by simple complete surgical excision. Recurrence has been reported in a few cases, so follow-up is recommended.

Annular cutaneous sarcoidosis with systemic involvement

Sarcoidosis is a granulomatous disease involving multiple systems. Cutaneous involvement is present in 25% of patients. A 42-year-old woman presented with itchy skin lesions on her face for 5 years duration. She was found to have annular and discoid plaques with prominent overlying telangiectasia. A biopsy from the plaque was suggestive of sarcoidosis. On further evaluation, she was found to have both pulmonary and ocular involvements. Annular sarcoidosis is a rare variant of cutaneous sarcoidosis. We report this case to highlight this rare variant of sarcoidosis and discuss the various cutaneous manifestations of sarcoidosis.