Rapid recovery in a child with febrile ulceronecrotic Mucha-Habermann disease following intravenous immunoglobulin administration.

Febrile ulceronecrotic Mucha-Habermann disease (FUMHD), a lymphocyte-mediated inflammatory skin disorder, is considered a severe variant of pityriasis lichenoides et varioliformis acuta that can lead to a fatal outcome if not managed in a timely fashion. Children with FUMHD can have systemic complications involving various organs. The scarcity of reported cases and the absence of well-designed studies or randomized clinical trials to evaluate different therapeutic modalities pose a major challenge in treating this potentially life-threatening disorder. We report a five-year-old child with FUMHD and seizures treated unsuccessfully with a combination of systemic steroids, methotrexate, dapsone, and oral erythromycin, who improved rapidly and achieved disease control with just a single infusion of low-dose intravenous immunoglobulin.

Fusion Landscape of Mycobacterial Envelope-Derived Lipid Vesicles with Intact Bacteria Dictates High Intracellular Drug Retention.

Membrane vesicles are critical regulators of pathogenic diseases. In tubercular infections, the use of mycobacteria derived vesicles as delivery vehicles to overcome drug resistance and complex treatment regimens has never been attempted. Here, we first address how these vesicles interact with their target cells, especially via membrane fusion. Membrane fusion between alike mycobacterial outer and inner membrane layer-derived lipid vesicles is shown to be driven by the structural, geometrical, and biophysical attributes of constituent lipids. The increased fusion of outer-membrane-derived vesicles with intact bacteria ensures enhanced intracellular drug levels and is presented as a "natural" antitubercular drug delivery vehicle.

Changing epidemiology of human enteroviruses (HEV) in a hand, foot and mouth disease outbreak in Vellore, south India.

PURPOSE: Hand Foot and mouth disease (HFMD) is a major childhood exanthematous disease causing outbreaks that have become a major public health threat in recent years. In Vellore district of Tamil Nadu, south India, occasional outbreaks are common among the paediatric age group, most commonly in those under 5years of age (U5s). CoxsackieA6, A4, A5, A9, A10, B2 and B5 are the common serotypes causing outbreaks. This study aimed to identify the molecular serotype of the causative agent, co-circulating in this region. METHODS: Adapting the WHO case definition, cases during an HFMD outbreak between October and December 2017, were identified by a clinical criterion of fever, mouth ulcers and rash in the extremities. Vesicle fluid from these lesions were collected in viral transport medium and transported cold to the Clinical Virology laboratory of a tertiary care hospital in Vellore. Identification of the causative agent was undertaken by two real time PCRs (EV1 and EV2) followed by sequencing the VP1-2C region and constructing a phylogenetic tree. RESULTS: Among the 31 HFMD patients included in this study, 23 (74.2%) were U5s, 3 (9.7%) were between 6 and 15 years and the remaining 5 (16.1%) were adolescents (>15 â€‹yrs). The outbreak ran a mild clinical course, with 22(71%) patients having fever as a prodromal symptom. Papulovesicular lesions characteristic of HFMD were present on all 31 (100%) patients' palms and soles, buttocks of 19 (61.3%), oral mucosa of 12 (38.7%), and all over the body in 4 (12.9%) patients. Coxsackie A6(75%) and Coxsackie A16(25%) were the pathogens associated with this outbreak. CONCLUSIONS: Changing epidemiology of HFMD was seen in this outbreak since; other serotypes apart from the classical Coxsackievirus serotypes causing HFMD outbreak were also found co-circulating. EV1 PCR was a better screening assay than EV2 PCR in this region. Continued surveillance and molecular serotyping are necessary for HFMD outbreaks in any region.

Genotype of autosomal recessive congenital ichthyosis from a tertiary care center in India.

BACKGROUND: Autosomal recessive congenital ichthyosis (ARCI) refers to non-syndromic ichthyosis caused by mutations in one of the 13 identified genes. There are limited data on the genotype of ARCI and its phenotypic correlation from India. OBJECTIVES: The aim of this study was to characterize the genotype of ARCI among patients from the Indian subcontinent. METHODS: Twenty-eight patients clinically diagnosed as ARCI were recruited prospectively from September 2017 to June 2019 (21 months). DNA was extracted from peripheral blood and analyzed for the 13 described ARCI genes-TGM1, ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, LIPN, NIPAL4, PNPLA1, SDR9C7, SLC27A4, SULT2B1, and CASP14 by next-generation sequencing using an in-house panel. The variants identified were confirmed by Sanger sequencing and compared with known pathogenic variants to establish pathogenicity. We also attempted to correlate the phenotype with the genotype. RESULTS: Among the 28 patients recruited (M = 17, F = 11), we identified phenotypes of congenital ichthyosiform erythroderma in 12 (42.9%), 8 with lamellar ichthyosis (28.6%), 5 with intermediate phenotype (17.9%), and 3 with bathing suit ichthyosis (10.7%). Pathogenic and likely pathogenic variants were identified in 22 (78.6%) patients, involving 7 out of the 13 known ARCI genes while 6 (21.4%) did not have pathogenic variants. These included TGM1 mutation in 6 (21.4%), ALOX12B and ALOXE3 in 4 (14.3%) each, NIPAL4 and PNPLA1 in 3 (10.7%) each, and ABCA12 and CERS3 in 1 (3.6%) patient each. Previously unknown pathogenic variants were found in 59.1 % of patients. CONCLUSIONS: Our patients with ARCI were found to have genotypes as previously described in other populations.

Clinicopathological Profile of Childhood Onset Cutaneous Mastocytosis from a Tertiary Care Center in South India.

BACKGROUND: Mastocytosis is characterized by clonal proliferation of mast cells in various organs and can have isolated cutaneous or systemic involvement. Childhood-onset mastocytosis (COM) is usually cutaneous and regresses spontaneously, while adult-onset mastocytosis (AOM) is often persistent with systemic involvement. There is limited data on COM from India. OBJECTIVE: To elucidate the clinicopathological profile of COM. METHODS: We conducted a retrospective chart review of all the patients with histologically proven COM (≤16 years), presenting over 11 years (January 2009 to December 2019) to the Dermatology Department. We compiled the demographic data, clinical characteristics (morphology, extent, distribution), laboratory investigations, histopathology findings, imaging (ultrasound abdomen), c-KIT mutation results, where available, and other associated abnormalities, and grouped them according to the WHO classification for mastocytosis. RESULTS: Among the 66 patients with COM (M: F-1.6:1), 89.4% had onset before 2 years of age. The subtypes were: maculopapular cutaneous mastocytosis (MPCM: 44, 66.7%); mastocytoma of the skin (MOS: 19, 28.8%); diffuse cutaneous mastocytosis (DCM: 2, 3%) and indolent systemic mastocytosis (ISM: 1, 1.5%). Blistering was observed in 29 (43.9%) and Darier sign was elicited in 47 (71.2%) patients. Serum tryptase was elevated in 9/21 (42.9%) patients, but none had systemic mastocytosis. Three patients had c-KIT mutations (two in exon 8 and one in exon 17). Most patients were managed symptomatically and the patient with ISM improved with imatinib. CONCLUSION: MPCM is the most common variant of COM and most patients had a disease onset before 2 years. Overall, COM had a good prognosis with rare systemic involvement, mitigating the need for extensive evaluation routinely in children.

Phenotypic variability of a TREX1 variant in Aicardi-Goutieres type 1 patients from the Indian subcontinent.

Aicardi-Goutieres Syndrome (AGS) is a heterogeneous genetic syndrome, manifesting early as encephalopathy and is associated with abnormal neurologic findings, hepatosplenomegaly, elevated liver enzymes, thrombocytopenia and intracranial calcification. The most severe neonatal type, AGS1, is caused by biallelic disease-causing variants in TREX1. In this study, we describe four patients with TREX1-related AGS1 whose phenotype overlaps with intra-uterine infections and neonatal lupus. Exome sequencing identified a previously reported TREX1 variant, c.223dup (NM_016381.5; p. Glu75GlyfsTer82) in all the four patients belonging to the Indian subcontinent. The functional consequence of the disease-causing variant was predicted by using a new combination of bioinformatics softwares. The recurrence of this pathogenic variant indicates a possible founder effect in TREX1 for AGS1 in this population. The phenotypic variability in those with this founder mutation can mimic intrauterine infections and neonatal lupus, thereby leading to misdiagnosis warranting a targeted genetic testing approach to be a part of the diagnostic workup to obtain a definite, early and cost-effective diagnosis in patients from Indian subcontinent with early onset encephalopathy.

Clinical profile of hereditary angioedema from a tertiary care centre in India.

INTRODUCTION: Hereditary angioedema (HAE) is a clinical condition which could be fatal if not identified and managed appropriately. Knowledge of this condition is mostly confined to individual case reports and literature reviews in India. In this retrospective study we describe HAE cases which presented to a tertiary care centre in India over a period of three and half years. MATERIALS AND METHODS: Clinical case records of forty-two HAE patients diagnosed based on clinical and laboratory features were accessed after due approval from the Ethics committee. C1 esterase inhibitor (C1 INH) and C4 levels were measured using nephelometry. All relevant data was entered into Microsoft EXCEL worksheet and analysed using simple statistical tools. RESULTS: Among the 42 patients diagnosed as having HAE, 37 had low C1INH levels and were diagnosed to have type 1 HAE. The remaining 5 had normal C1 INH levels and were considered probable HAE based on family history and response to HAE specific treatment. The median age of onset of symptoms was 15 years (range 5-49) and median age at diagnosis, 27.5 years (range 5-55). The median delay in diagnosis was 10 years (range 1-27 years). Family history of HAE was observed in 52.6% and 29% reported deaths in the family with HAE like disease. Low dose androgens or tranexamic acid or both were prescribed in 64.2% of the patients. Orofacial edema was the commonest clinical presentation (76%) followed by edema of the extremities (38%), GI tract symptoms (19%) and genital involvement (11.9%). CONCLUSION: Many cases of HAE may be going undetected in India. There is a need for clinical awareness and laboratory means to accurately identify and administer appropriate treatment.

The Diagnostic Value of Congenital and Nevoid Cutaneous Lesions Associated with Autism Spectrum Disorders in Indian Children- A Case-Control Study.

BACKGROUND AND AIMS: Cutaneous lesions are the defining features of several neurocutaneous syndromes like neurofibromatosis1(NF1), tuberous sclerosis complex (TSC), and Sturge Weber syndrome to name a few. With this background, we explored the possibility of identifying congenital and nevoid cutaneous markers that may help in the early recognition of autism spectrum disorders (ASD) in Indian children. The objective of this study was to measure the strength of association between congenital and nevoid cutaneous lesions and ASD among Indian children. METHODS: A case-control study was conducted from January 2018 to June 2018. 132 children (18 months-16 years of age) with ASD and equal number of age and sex-matched children without autism were studied. Diagnosis of ASD was based on DSM-5 criteria. All the children were examined for cutaneous lesions with special attention to nevoid and congenital conditions. The strength of association was measured using the diagnostic odds ratio (OR). RESULTS: The prevalence of congenital and nevoid lesions were higher in ASD group (OR = 3.12, P = 0.0001). Among them, pigmentary mosaicism of hyperpigmented type (OR = 2.76, P = 0.02) and café-au-lait macules (CALMs) (OR = 2.40, P = 0.001) were the most prevalent with hyperpigmented pigmentary mosaicism showing a higher association with autism. Atypical CALMs (OR = 2, P = 0.09) were also more prevalent in the ASD group though not statistically significant. CONCLUSION: The presence of hyperpigmented pigmentary mosaicism and CALMs warrant closer surveillance by the caregivers and physicians for evolving features of autism. Larger multicentric studies are required to validate these findings.

The Role of Frozen Section in the Rapid Diagnosis of Severe Cutaneous Adverse Drug Reactions.

CONTEXT: Early diagnosis is the mainstay in the management of severe cutaneous adverse reactions (SCARs) to drugs. AIMS: To study the role of frozen section in the rapid diagnosis of SCARs and the impact on outcome of the affected patients. SETTINGS AND DESIGN: A single-blind, hospital-based study was conducted from December 2014-July 2016. METHODS AND MATERIAL: We biopsied 32 adults with SCARs diagnosed by clinical features and standard criteria. The histopathological features seen on frozen sections were compared to that of paraffin blocks. The impact of rapid diagnosis on the clinical outcome was studied in toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP). STATISTICAL ANALYSIS: Z test was used to compare two proportions. Kappa statistic, sensitivity, specificity, positive predictive value, and negative predictive value of the frozen section diagnosis were calculated in TEN/SJS and DRESS using MedCalc software. RESULTS: Frozen and paraffin sections were done in TEN/SJS spectrum (13), DRESS (17), and AGEP (2). The sensitivity, specificity and kappa values for frozen section diagnosis in SJS/TEN and DRESS were 91.7%, 95%, 0.867 and 94.4%, 100%, 0.937 respectively. The concordance between frozen and paraffin section diagnosis was 100% in TEN, SJS, DRESS and AGEP. All the 6 patients with TEN and 2 with AGEP survived. Taking the worst-case scenario, the mortality in SJS was 28.6%. The mortality among patients with DRESS was 11.8%. CONCLUSIONS: Frozen section helps in the rapid diagnosis and early treatment of SCARs and differentiates it from diseases that mimic it.

Clinical Profile of Overgrowth Syndromes Consistent with PROS (PIK3CA-Related Overgrowth Syndromes)-A Case Series.

CONTEXT: PIK3CA-related overgrowth syndrome (PROS) is characterized by focal and disproportionate growth of acral body structures in a mosaic pattern with varied phenotypes. Clinical diagnostic criteria are available and testing of the mutation is recommended for diagnosis. Cutaneous features described in these conditions include epidermal nevi and vascular malformations which form part of the diagnostic criteria. AIMS: To detail the clinical profile of patients with presumptive PROS. SETTINGS AND DESIGN: We conducted a retrospective study of 15 patients with focal overgrowth of the extremities or macrocephaly who presented to the department of dermatology at a tertiary care hospital in South India. SUBJECTS AND METHODS: Data were collected through electronic medical records from July 2012 to April 2018 over 70 months. The criterion proposed by Keppler-Noreuil et al. was used for classifying them as presumptive PROS in the absence of genetic studies. STATISTICAL ANALYSIS USED: Descriptive analysis. RESULTS: There were nine males and six females; mean age of 12.10 years (range: 8 months to 73 years) with clinical features consistent with PROS. There was a higher frequency of vascular malformations (9/15, 60%) and of epidermal nevi (7/15, 46.6%) than that reported in the literature. Unusual features included focal acrochordons, blaschkoid hypopigmentation and linear papillomatous growths in the oral mucosa. CONCLUSIONS: This study provides data on the clinical features of patients with PROS from the Indian subcontinent. In resource-poor settings, clinical criteria may be adequate for diagnosis due to restricted accessibility of technically challenging diagnostic tests.

Peripheral Arteriovenous Malformations-A Case Series.

CONTEXT: Arteriovenous malformations (AVMs) are aggressive vascular malformations that often result in significant morbidity. Patients may present to a dermatologist due to associated skin changes. Early diagnosis is important as treatment is available to halt their progression toward irreversible destruction of adjacent tissues. AIMS: To study the clinical profile of peripheral AVMs presenting to the dermatologist and to provide a diagnostic algorithm. SETTINGS AND DESIGN: A retrospective study of patients of all age groups with peripheral AVMs who presented to the Department of Dermatology at a tertiary care hospital in India was performed. Syndromic forms were also included. SUBJECTS AND METHODS: We conducted a search of patients with peripheral AVMs, which were seen over a period of 51 months, i.e., from July 2014 to September 2018, from electronic medical records and reviewed their clinical details. STATISTICAL ANALYSIS USED: Descriptive statistics such as frequency, mean, and median were computed. RESULTS: We report a series of 13 patients with peripheral AVMs, which constituted 6.7% (13/193) of all vascular malformations during this period. Of these, 8.3% (1/12) belonged to Schobinger's stage 1, 41.7% (5/12) to stage 2, 50% (6/12) to stage 3, and one with subcutaneous involvement devoid of cutaneous changes. The most common location was the extremities, which was seen in 53.8% (7/13). Syndromic association was present in 46.2% (6/13). Management included embolization, surgery, and medical treatment. CONCLUSIONS: The proportion of peripheral AVMs out of all vascular malformations was similar to reported studies. The extremities were more frequently involved as compared to the head and neck. The diagnostic algorithm provided will help us to optimize investigations and direct early management.

Clinical, immunological profile and follow up of patients with pemphigus: A study from India.

BACKGROUND: Pemphigus has a protracted course and multiple factors influence its prognosis. The objective of this study was to describe the epidemiology and clinical profile of pemphigus patients and to study its influence on treatment end points. METHODS: : This was a retrospective chart review done in an Indian tertiary care hospital from December 1991 to December 2013. Patients with less than 3 months' follow up and those who had paraneoplastic pemphigus were excluded. RESULTS: : There were 132 patients with pemphigus, of which 118 (89.4%) had pemphigus vulgaris and 14 (10.6%) had pemphigus foliaceous. The time to disease control (TDC) was available for 100 patients (n = 100, 75.7%); patients with a minimum follow up of 3 months (n = 80) were included for studying the end points like time to first disease remission (TDR) and time to first disease relapse (TDRe). The median period of follow up was 23 months (range 3-245). Out of the 100 patients, 61.9% were on oral steroids with adjuvant therapy. The steroid dose required for disease control for n = 100, ranged from 0.2 to 1.5 mg/kg body weight. Of these, 60% were treated with steroid dose of 1 mg/kg, 22% with >1 mg/kg, and 18% with <1 mg/kg. The mean time to disease control (in months) in the group which received <1 mg/kg steroid was 1.02 ± 0.68, 1 mg/kg was 0.72 ± 0.51, and >1 mg/kg was 1.02 ± 0.62 (P = 0.017); with a significant difference between the groups 2 and 3 (P = 0.007), implying a faster disease control in those who received 1 mg/kg dose. This difference was significant after adjusting for the steroid sparing drugs taken at baseline (P = 0.009, C.I. - 1.44-13.59). The mean time to first disease remission (TDR) was 11.46 ± 2.06 months. Out of the 80 patients with a minimum follow up of 3 months, 75% had achieved either partial or complete remission. None of the other epidemiological, clinical or immunological parameters had an impact on the TDC or TDR. CONCLUSIONS: The epidemiological, clinical or immunological parameters had no impact on the treatment end points like time to disease control and time to first disease remission. The dose of steroids required for disease control higher than 1 mg/kg offered no advantage in the time to disease control as compared to 1 mg/kg. LIMITATIONS: The study was retrospective and disease severity scores were not applied. In view of the shorter follow up period, long term prognostic end points and mortality could not be well represented. The median period of follow up was 23 months. The serum anti- desmoglein antibody titres were not available at various treatment end points for correlation at different time intervals.