A Novel Large Deletion in the EVER1 Gene in a Family With Epidermodysplasia Verruciformis From India.

ABSTRACT: Epidermodysplasia verruciformis (EV) is a rare autosomal recessive genodermatosis due to mutations in EVER1 and EVER2 genes. The genetic profile of Indian patients with EV has not been previously studied. This report describes the clinical presentation and molecular analysis of a family with EV. Using genomic DNA from two affected probands and healthy controls (two other siblings), conventional polymerase chain reaction (PCR) was conducted with novel primer sets designed to amplify the coding and splice-site regions in the genes EVER1 and EVER 2. This revealed no amplification with a primer set for exons 16 to 18 in the EVER1 gene of both the probands. Subsequently, long-range PCR spanning the length of exon 15-20 and next-generation sequencing demonstrated a homozygous deletion of 2078 bp in the EVER1 gene (EVER1:c.2072_2278del). Screening the family revealed the same homozygous deletion (similar to index cases) in two other affected siblings. The parents and two asymptomatic siblings were heterozygous carriers for the deletion while one healthy sibling was negative. These results were validated with Sanger sequencing. This deletion in exons 17 and 18 of the EVER1 gene results in a frameshift, followed by a premature termination resulting in a severe phenotype. The identification and validation of this large deletion was detected using stepwise amplicon-based target enrichment and long-range PCR, respectively. In this family, this simple strategy greatly enhanced genetic counseling as well as early genetic diagnosis and screening. However, functional assays and larger studies are required to characterize and validate the genetic diversity among Indians with EV.

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.

Clinicopathological predictors of repeated recurrence in sinonasal inverted papilloma.

PURPOSE: To evaluate association between clinical and pathological findings and repeated recurrence in sinonasal inverted papilloma. METHODS: Retrospective cohort study conducted at a tertiary care teaching hospital included all patients operated for inverted papilloma from January 2010 to December 2019. Patients were categorized as primary and recurrent cases. Based on disease status at follow-up, they were subcategorized into 'primary with no recurrence' (PnR), 'primary with recurrence' (PwR), 'recurrent with no further recurrence' (RnR), and 'recurrent with further recurrence' (RwR) groups. Data including demography, clinical, endoscopic and pathological findings were collected and analyzed. RESULTS: Increased incidence of pale appearance of lesion in RnR group (p = 0.017), polypoidal appearance in primary group (p = 0.002) and fibrous appearance in the recurrent group (p = 0.002) were statistically significant. Predominant epithelium was combined respiratory and squamous epithelium in primary and recurrent groups and also in RnR group (p = 0.019), while it was squamous (p = 0.024) in RwR group. Epithelial hyperplasia was more common in primary and RnR groups. Oncocytic change, cystic dilatation, microabscess and squamous metaplasia were seen more in recurrent and RnR groups. Cytoplasmic glycogenation was more in recurrent and RwR groups. Stroma was predominantly edematous in all the groups. CONCLUSIONS: Patients with recurrence are younger and present earlier than those with primary disease. Fleshy appearance and pink/red colour of tumour, lining epithelium being squamous and cytoplasmic glycogenation could be considered as features predicting recurrence. Negative predictors of recurrence of IP include pale appearance of tumour, combined respiratory and squamous epithelium lining and squamous metaplasia.

Rhinofacial conidiobolomycosis: Clinical and microbiological characterisation and shift in the management of a rare disease.

BACKGROUND: Conidiobolomycosis is a rare tropical rhinofacial fungal infection which has not been well characterised. The available evidence in its management is sparse due to lack of clinical studies and the limited data on antifungal susceptibility patterns. OBJECTIVE: To analyse the clinical manifestations, antifungal treatment and outcomes of patients with conidiobolomycosis and to determine antifungal susceptibility profiles of the isolates. PATIENTS/METHODS: Retrospective analysis of data of all patients with a diagnosis of conidiobolomycosis confirmed by histopathology and culture at a tertiary care hospital from 2012 to 2019 was done. RESULTS: There were 22 patients, 21 males and one female, with a mean age of 37.1 years. Most common presenting symptom was nasal obstruction, found in 20 (90.90%) patients. Patients who presented within 12 months had a better cure rate (85%) compared to those who presented late (67%). Among the 19 patients who had a follow-up, good outcome was seen in 15 of the 17 (88.24%) patients who were on itraconazole or potassium iodide containing regimen. Of the six patients who received additional trimethoprim-sulphamethoxazole (co-trimoxazole), 67% showed good outcome with two patients showing complete cure and two patients still on treatment with significant improvement. High minimum inhibitory concentration (MIC) values were noted for azoles and amphotericin B, whereas co-trimoxazole showed lowest MIC ranges. CONCLUSION: Itraconazole and potassium iodide are reasonable first-line options for the treatment of conidiobolomycosis. Good clinical response to KI and comparatively lower MIC of co-trimoxazole are promising. Further studies are required for developing clinical breakpoints that can predict therapeutic outcomes.

An unusual case of keratinopathic icthyosis: a diagnostic conundrum.

Epidermolytic ichthyosis (EI) is a rare inherited ichthyosis related to heterozygous mutations in the Keratin 1 or Keratin 10 genes. Because of the broad phenotypic spectrum, it is sometimes difficult to differentiate it from other keratinopathic ichthyoses (KI) in clinical practice. We report an intriguing case of KI presenting as generalized ichthyosis in a reticulate pattern surrounding islands of normal skin, epidermolytic hyperkeratosis and binucleate cells on histopathology, and heterozygous mutation in KRT10. Through this case, we would like to demonstrate the importance of genetic studies and genotype-phenotype correlation in diagnosing such challenging cases.

High expression of S100 calgranulin genes in peripheral blood mononuclear cells from patients with Takayasu arteritis.

BACKGROUND: Toll-like receptors (TLR) 1 to 4 are highly expressed in aorta. Activation of TLR4 causes transmural arteritis in Human temporal artery-SCID chimera model. Neither TLR-4 nor its ligands have been studied in TA patients as yet. Aim of this study was to examine the expression of TLR4 and its endogenous ligands in peripheral blood mononuclear cells (PBMCs) of patients with Takayasu arteritis (TA). METHODS: mRNA expression of TLR4, RAGE and various endogenous TLR4 ligands were quantified in PBMCs of 24 TA patients and 19 sex and age matched healthy controls by real time PCR using specific primers and SYBR Green qPCR master mix. S100A8/A9 and S100A12 were measured in cell culture supernatant of PBMCs from TA patients and healthy controls, both in un-stimulated state as well as, after lipopolysaccharides (LPS) stimulated cultures for 4 h. Expression of S100A8/A9 in aortic tissues was assessed by immunohistochemistry. RESULTS: The mRNA expression of S100A8, S100A9, S100A12 and TLR4 were higher, while expression of RAGE and HSP70 were lower in TA as compared to healthy controls. Induction with LPS led to increase in secretion of both S100A8/A9 and S100A12 levels in TA as well as healthy controls. The fold of induction, measured by LPS stimulated/unstimulated control was higher in healthy controls [2.88 (1.7-3.53) fold] as compared to TA [1.345 (1-1.82) fold]; p < 0.05. Numerically, S100A8/A9 was also higher in healthy controls [2.04 (1.7-5.6) fold] as compared to TA [1.38 (1.09-3.6) fold], but it didn't reach statistical significance; p = 0.129. Mild to moderate intensity expression of S100A8/A9 protein was noted in aortic tissues from patients with TA. CONCLUSION: mRNA expression of TLR4 and its ligand S100A8, S100A9, and S100A12 in PBMCs of TA patients was higher as compared to healthy controls. LPS stimulation led to higher induction of S100A12 secretion in healthy controls as compared to TA. Expression of S100A8/A9 was detected in inflamed aortic tissues from patients with TA.

Salt-induced swelling transitions of a lamellar amphiphile-Polyelectrolyte complex.

We report salt-induced swelling transitions of a lamellar complex of the anionic polyelectrolyte, poly(acrylic acid sodium salt) (PAANa), and the cationic amphiphile, didodecyldimethylammonium chloride (DDAC). Increasing the concentration of NaCl in the solution is found to lead to a collapsed → swollen → collapsed transition of the complex. The swelling transition is driven by an abrupt increase in PAANa adsorption on DDAC bilayers above a threshold salt concentration. The lamellar periodicity of the swollen phase is not determined by the thickness of the adsorption layer, and additional mechanisms have to be invoked to understand the extent of its swelling. The swelling transition is not observed for the highest molecular weight of PAANa used, but a gradual transformation between the two collapsed structures is seen on increasing the salt concentration. The polyelectrolyte chains desorb from the bilayers at a very high salt concentration, in a process similar to the well-known destabilization of complexes of oppositely charged polyelectrolytes. However, unlike the PAANa chains, the polymer-free bilayers do not disperse uniformly in the solution. Instead, they form a collapsed lamellar stack containing very little water due to the van der Waals attraction between them. The occurrence of an abrupt swelling transition at intermediate salt concentrations in this system contrasts sharply with the gradual swelling reported in other complexes with increasing salt concentration. Furthermore, this behavior does not seem to have been anticipated by theories of complexation of oppositely charged macroions. More experiments are required for a clear understanding of the interactions stabilizing the different phases observed in this system.

Varied presentation of sinonasal phosphaturic mesenchymal tumour: report of a case series with follow-up.

PURPOSE: Phosphaturic mesenchymal tumour (PMT) of the paranasal sinuses is a rare tumour that is associated with oncogenous osteomalacia causing predominant musculoskeletal symptoms. We present a series of eight patients diagnosed to have PMT of the paranasal sinuses with varied presentation and highlight the appropriate evaluation required to arrive at the diagnosis. METHODS: Retrospective review of eight patients diagnosed to have PMT-causing tumour-induced osteomalacia with follow-up data. RESULTS: Eight patients, 4 males and 4 females, aged 36-67 years (mean = 44 years) presented with vague musculoskeletal symptoms (6 patients) or epistaxis (3 patients). Six patients were found to have hypophosphatemia, phosphaturia and raised FGF-23 levels preoperatively. All eight patients were found to have a tumour in the nose and/ paranasal sinuses with one patient having intracranial extension. All patients were treated with endoscopic excision of these tumours which resulted in resolution of symptoms and normalisation of biochemical abnormalities. In addition, one patient required a craniofacial resection. Histopathological features were consistent with PMT mixed connective tissue variant. Two atypical patients were seen. The longest follow-up was for 5 years and there was no evidence of recurrence during the follow-up period in any patient. CONCLUSION: Diagnosis of PMT of the paranasal sinuses causing oncogenous osteomalacia requires a high index of suspicion when there are no ENT symptoms. Appropriate biochemical tests and histopathology lead to the correct diagnosis. Total endoscopic surgical excision leads to a good outcome.

Study of pathogenic T-helper cell subsets in Asian Indian patients with Takayasu arteritis.

The relapses and refractory disease are a challenge in the management of patients with Takayasu arteritis (TAK). We quantified pathogenic CD4 + memory T helper cells bearing surface markers CD161 and/or p-glycoprotein (MDR1) in patients with TAK. Peripheral blood mononuclear cells of 21 patients with TAK and 16 age-matched controls were stained with anti-CD3, anti-CD4, anti-CD45RA, anti-CD161 and anti-p-glycoprotein antibodies and subjected to flow cytometry by FACS ARIAIII. Eighteen patients underwent follow-up immunophenotyping. Intracellular staining for interleukin-17 and interferon-γ was performed for 18 patients and 11 controls. Surgical arterial biopsies of 6 TAK and 5 non-inflammatory controls were subjected to immunohistochemistry with anti-CD161 and anti-p-glycoprotein. At baseline the frequency of MDR1 + CD4 + and CD161 + MDR1 + CD4 + memory T cells was higher in TAK than controls (p = 0.002 and 0.01, respectively). After stimulation, the frequency of IFN-y + CD161 + cells was higher in TAK than controls (p = 0.028). Modal fluorescence intensity of CD161 + MDR1 + CD45RA - CD4 + cells was higher in active as compared with stable disease (p = 0.041). At 6 months, MDR1 + and CD161 + MDR1 + memory CD4 + T cells decreased significantly only in patients who had complete/partial response to treatment (p = 0.047 and 0.02, respectively). To conclude, MDR1 + and MDR1 + CD161 + CD4 + memory T-helper cells are increased in patients with TAK. These cells decreased only in patients with response to treatment during subsequent follow-up.

Myofibroblast and pro-fibrotic cytokines in fibrosis of IgG4-related disease (IgG4-RD) patients from South Asia: preliminary data.

INTRODUCTION: Fibrosis is a typical pathological characteristic in IgG4-RD patients and often irreversible. There exists a lack of suitable markers for detection of earlier onset of fibrosis in various organs in IgG4-RD patients. Hence, this study aims at analysing ambispectively the myofibroblasts and the pro-fibrotic cytokines, IFN gamma and IL-33 involved in IgG4-RD associated fibrosis in South Asian patients. METHOD: Archived biopsy samples of definite/probable/possible cases of IgG4-RD, classified according to diagnostic criteria, taken from patients who attended the OPD and IPD of our tertiary care centre during January 2015-January 2020 were chosen for this study. The paraffin sections were examined qualitatively for fibrosis and the excessive collagen deposition by Hematoxylin & Eosin and Masson's Trichrome staining. Also, the presence of alpha-Smooth muscle actin (α-SMA) expressing myofibroblasts and the involvement of pro-fibrotic cytokines (IFN-gamma, IL-33) were assessed by Immunohistochemistry and scored semi-quantitatively (+mild, ++moderate, +++ severe). Serum IL-33 levels were analysed by indirect Elisa (R & D Systems). RESULTS: Myofibroblasts were present in 10/12 biopsy samples, in moderate levels in 4 (33%) and very high levels (+++) in 3 (25%) of the patients. IFN-gamma was expressed at low levels in 6 (50%) and absent in 6 (50%). All patients showed IL-33 expression with very high levels in tissue (6, 50%), as well as in serum samples. CONCLUSION: The findings of this study reinforce the role of myofibroblasts and profibrotic cytokines like IL-33 in fibrosis of Ig4-RD patients, pointing to their potential as earlier predictive markers of onset and extent of fibrosis.

Pott's puffy tumor: An unusual complication of rhino-orbito-cerebral mucormycosis.

Objective: To describe clinicoradiological features and surgical outcomes in a series of nine patients with rhino-orbito-cerebral mucormycosis (ROCM) who presented with Pott's puffy tumor (ROCM-PPT). Methods: The records of nine patients with ROCM-PPT seen between March 2020 and December 2021 were analysed. Clinical features, radiology, histopathology, operative findings, management and outcome were noted. Frontal sinus pneumatisation and outflow tract configuration was compared between patients and controls with ROCM and no PPT. Results: ROCM-PPT was diagnosed in 9 of 284 (3.2 %) patients with ROCM seen during the study period. There were six (66.7 %) males and the median age was 54 (IQR 46-60) years. Eight (88.9 %) patients had diabetes mellitus and seven (77.8 %) had been COVID-19 positive. Radiological features of osteomyelitis, subperiosteal abscess formation and dural enhancement were seen in all patients. No significant differences in pneumatisation or frontal sinus outflow tract configuration were noted between patients and controls. All patients underwent a craniectomy with frontal bone debridement and frontal sinus exteriorisation. All patients were treated with anti-fungal agents for several months. All patients had symptomatic improvement at a median follow-up of 21 (IQR 18-23) months. Repeat CT/MRI scans showed disease regression/resolution in six out of eight (75 %) patients with follow-up imaging, and stable disease in two others. Conclusions: ROCM-PPT is a rare, delayed complication of mucormycosis that was seen in larger numbers during the recent COVID-19 pandemic. Aggressive debridement of osteomyelitic bone and antifungal therapy results in a good outcome.

A Comparative Study of Acute Invasive Fungal Sinusitis During the First and Second Waves of the COVID-19 Pandemic.

We aimed to compare the demography, clinical profile, histopathology, fungal culture, radiology, surgery performed, medical therapy and outcomes of patients with acute invasive fungal sinusitis seen during the first and second waves of the COVID-19 pandemic by retrospectively reviewing their case records. Of 238 patients, 43(18.1%) presented during the first wave and 195(81.9%) during the second wave. Patients seen during the first wave were older (p = 0.04) and more likely to have visual impairment (p = 0.004), frozen eye (p = 0.012), altered sensorium (p = 0.007) and stage 3 disease (p = 0.03). Those seen during the second wave were more often COVID-19 positive and had newly diagnosed diabetes mellitus (p = 0.04)and stage 1 disease (p = 0.03). Most patients had a positive culture for Rhizopus species during both waves. Histopathology showed broad aseptate hyphae in all patients but angioinvasion was seen more often during the first wave (p = 0.04). The majority of patients were treated with endoscopic+/- open debridement followed by intravenous amphotericin B and oral posaconazole. While the overall survival rate was similar (first wave 65.1%; second wave 79%; p = 0.106), mortality after discharge was greater during the first wave (11.6% vs 1.5%; p = 0.001). Mortality was higher in patients with stage 3 disease (p = 0.003). Significant differences in clinical presentation, histopathology, radiological stage of disease and post-discharge survival were noted between the two waves of the COVID-19 pandemic, the causes for which were multi-factorial.

A novel X-chromosomal microdeletion encompassing congenital hemidysplasia with ichthyosiform erythroderma and limb defects.

We report an unusual phenotype of congenital hemidysplasia with ichthyosiform erythroderma and limb defects syndrome most likely resulting from a novel X-chromosomal microdeletion encompassing the promoter region and exon 1 of the nicotinamide adenine dinucleotide phosphate steroid dehydrogenase-like protein gene, the neighboring gene CETN2, and more than 10 kb of noncoding deoxyribonucleic acid.

Different types of fungal sinusitis occurring concurrently: implications for therapy.

The purpose of this study is to describe the clinical and histopathological features, management and outcome of a series of patients with simultaneous occurrence of invasive and non-invasive fungal sinusitis (mixed fungal sinusitis). The histopathological records of patients with fungal sinusitis seen over the last 6 years were reviewed. The clinical, histopathological, treatment and follow up details of all cases with mixed fungal sinusitis were noted. Six cases of mixed fungal sinusitis with concurrent occurrence of chronic granulomatous fungal sinusitis and allergic fungal sinusitis (AFS) were seen during the study period. Most (83.3 %) had bilateral disease. All patients had undergone prior endoscopic sinus surgery at least once within the previous 2 years. Histopathological features showed predominance of invasive disease in half the patients. Except for one patient who did not report for follow up, all patients with predominant chronic granulomatous fungal sinusitis received systemic antifungal therapy and inhaled steroids. Those with predominant features of AFS received oral and inhaled steroids. Five patients with mixed fungal sinusitis who had follow up ranging from 6 months to 5 years were disease free following treatment. Mixed fungal sinusitis should be recognized by the surgeon and pathologist as a separate category of fungal sinusitis whose treatment depends on accurate histological diagnosis. A good outcome may be expected with appropriate therapy.

A Rare Case of Ameloblastic Carcinoma of Maxilla.

Ameloblastic carcinoma is an odontogenic neoplasm with combined features of ameloblastoma and carcinoma on histopathological examination. Its prognosis is dominated by risk of local recurrence and distant metastasis. We report our patient because of the rare site and to highlight the importance of early, aggressive surgical treatment and regular follow-up.

Chronic Granulomatous Invasive Fungal Sinusitis in Patients With Immunocompetence: A Review.

OBJECTIVE: We aimed to study the literature on chronic granulomatous invasive fungal sinusitis to elucidate the changing trends in the management of the disease. DATA SOURCES: Using specific keywords, we searched the PubMed, PubMed Central, and Scopus databases over the past 50 years, which yielded 938 articles in the English language. REVIEW METHODS: Scrutiny of 147 relevant articles revealed 15 homogenous case series (255 cases of histologically proven chronic granulomatous fungal sinusitis alone) and 8 heterogeneous case series (patients with other types of fungal sinusitis included), which were analyzed in detail (all with >5 cases each). CONCLUSIONS: The disease typically affected middle-aged adults with immunocompetence. Most reports were from Sudan, India, and Saudi Arabia. A slowly progressive orbital, cheek, or palatal mass with proptosis (88.2%) or sinonasal symptoms (39.2%) was typical. Ethmoid (57.2%) and maxillary (51.4%) sinuses were chiefly affected with intracranial extension in 35.1%. Aspergillus flavus (64%) was the most frequent isolate reported. Endoscopic excision (78.8%) followed by azole therapy was the preferred treatment in recent reports. Orbital exenteration and craniotomy were infrequently performed. Complete resolution or improvement was reported in 91.3% of patients. Mortality ranged from 5.9% to 22.2%. There is a trend in the literature toward less radical and disfiguring surgery and preferential use of azoles, with good outcomes even in advanced cases. IMPLICATIONS FOR PRACTICE: Chronic granulomatous fungal sinusitis should be diagnosed on the basis of well-defined histopathologic features. A combination of endoscopic sinus surgery and azole therapy usually yields good outcomes.

Hyperacute Graft-Versus-Host Disease of the Skin following Allogeneic Stem Cell Transplantation: A Paediatric Case Series.

Hyperacute GVHD (HaGVHD) is a rare complication of hematopoietic stem cell transplantation (HSCT) occurring before engraftment, a syndrome commonly involving skin and/or gut and/or liver, with increased morbidity and mortality. Myeloablative conditioning (MAC) regimes and mismatched donor transplants have an increased risk for HaGVHD. There is a higher chance of steroid-refractoriness and chronic GVHD in those who develop HaGVHD. There is limited literature about HaGVHD, especially in the paediatric age group. This retrospective single-centre case series included five paediatric patients who underwent HSCT between 1st April 2013 and 31st July 2015 at a tertiary care centre in South India, who fulfilled the criteria for HaGVHD as per criteria by Kim et al. and whose follow up data was available. We noted their risk factors, clinical course and prognosis. There were five paediatric HaGVHD patients. The risk factors noted among them were MAC regimen in three and mismatched unrelated donor sources in three. Two had steroid-refractory disease, four went on to develop chronic GVHD and three died of GVHD or treatment-related complications. A high index of suspicion is necessary to recognize HaGVHD, especially in patients with known risk factors developing a fever with rash post-HSCT.