X-Linked Lymphoproliferative Syndrome: A Spectrum of Clinical and Immunological Profile and Novel Pathogenic Variants from Chandigarh, India.

INTRODUCTION: X-linked lymphoproliferative syndrome (XLP) is a rare primary immune deficiency. Two types of XLP have been described: XLP-1 and XLP-2. METHODS: We found 7 patients with XLP (3 had XLP-1 and 4 had XLP-2) after reviewing the data from Pediatric Immunodeficiency Clinic from 1997 to 2021. RESULTS: Mean age at diagnosis was 3.8 years, and mean delay in diagnosis was 2.6 years. Five patients had recurrent episodes of infections. Four patients developed at least one episode of hemophagocytic lymphohistiocytosis (HLH) (2 with XLP-1 and 2 with XLP-2). Of these, 2 had recurrent HLH (both with XLP-2). Epstein-Barr virus (EBV) infection was detected in 2 (1 with XLP-1 and 1 with XLP-2). Both these patients had HLH. One child with XLP-2 had inflammatory bowel disease. Hypogammaglobulinemia was seen in 3 (2 with XLP-1 and 1 with XLP-2). Genetic analysis showed previously reported variants in 5, while 2 had novel variants (one in exon 7 of XIAP gene [c.1370dup p.Asn457Lysfs Ter16] and other had splice site variant in intron 1 of SH2D1A gene [c.138-2_138-1insG]). Episodes of HLH were managed with intravenous immunoglobulin (IVIg), methylprednisolone, oral prednisolone, cyclosporine, and rituximab. Inflammatory bowel disease was managed using oral prednisolone and azathioprine. One patient underwent haploidentical hematopoietic stem cell transplantation. One child with XLP-2 and WAS died because of fulminant pneumonia. DISCUSSION/CONCLUSIONS: XLP should be considered as a strong possibility in any patient with features of HLH, repeated infections with hypogammaglobulinemia, persistent EBV infection, and early-onset IBD.

Molecular profiling of an Indian EB cohort - a single centre experience.

INTRODUCTION: Epidermolysis bullosa (EB) encompasses rare hereditary skin conditions marked by skin fragility, nail dystrophy, and minor trauma-induced skin blisters. This study aims to identify genetic variants in Indian EB patients and examine the relationship between genotypic and phenotypic manifestations. MATERIAL AND METHOD: EB patients seen consecutively over a period of 5 years at Outpatient Department of Dermatology. Baseline demographic data, birth history, family history, skin manifestation at birth, past medical history, current cutaneous manifestations, and the evolution of the disease were assessed and recorded. Genetic variants were identified using targeted gene panel sequencing of 23 EB-related genes, and a genetic-phenotype analysis was performed. RESULTS: Our study included 65 patients with EB. Among 65 EB patients, 38 dystrophic EB cases (58.46%), 12 junctional EB (18.46%), 12 epidermolysis bullosa simplex (18.46%), and 3 Kindler EB (4.62%) were reported. Dominant and recessive forms of dystrophic EB accounted for 16.92% and 41.4%, respectively. We identified 75 unique genetic variants, 58.67% newly discovered and 41.33% previously reported. Compound heterozygous variations were more frequent (55.55%) than homozygous ones (44.44%) in recessive dystrophic EB patients. Junctional EB patients harboured LAMB3 gene mutations more frequently, while epidermolysis bullosa simplex patients showed KRT5 and KRT14 gene missense heterozygous mutations. Kindler EB patients had homozygous mutations in the FERTM1 gene. CONCLUSION: Our study unveiled several novel genetic variants; severe phenotypes associated with nonsense genetic variants. These findings offer valuable insights for future clinical assessments and tailored management strategies.

Primary Rosai-Dorfman disease of the central nervous system: A clinical, histological, and molecular appraisal.

Rosai-Dorfman disease (RDD) is characterized by clonal proliferation of S-100 positive histiocytes and variable emperipolesis. It commonly affects cervical lymph nodes. Central nervous system (CNS) involvement is extremely rare. We attempted to evaluate the Cyclin D1 expression and frequency of KRAS and BRAF mutations in the RDD involving the CNS. All patients with histopathologically diagnosed RDD involving CNS were recruited from 2011 to 2022. All cases were subjected to immunohistochemistry for CD68, CD163, S100, CD1a, GFAP, CD207, EMA, ALK, BRAFV600E, IgG4, IgG, and CyclinD1. The real-time polymerase chain reaction (RT-PCR) for hotspot mutation analysis of KRAS (exons 2, 3, and 4) and BRAF (V600E) was conducted on formalin-fixed paraffin-embedded tissue using a commercial kit (EntroGen). A total of seven cases were included. The median age was 31 years, with six men and one woman. It showed spinal cord (n = 4) and intracranial (n = 3) involvement. Histologically, all cases showed histiocyte-rich inflammation with evidence of emperipolesis. These histiocytes were positive for S100, CD68, CD163, and Cyclin D1, whereas negative for CD1a, CD207, and EMA. BRAF V600E was expressed in a single case. None of the control cases (demyelination and infarction) with histiocytic infiltrate showed Cyclin D1 expression. Four RDD cases showed increased IgG4-positive plasma cells (>10/HPF) and IgG4/IgG ratio (>40%). BRAF V600E mutation was detected in one case (14.28%), while none showed KRAS mutation. RDD involving CNS is extremely rare and diagnostically challenging. Nuclear Cyclin D1 expression along with S-100 positivity in the tumor cells is a strong diagnostic clue. BRAF and KRAS mutations are rare in CNS RDD.

Bugs' eyes and black monsters: Ascitic fluid cytology in an elderly male with hematochezia.

Anorectal malignant melanomas are rare, accounting for less than 2% of all melanomas. Malignant effusions developing secondary to malignant melanoma are highly uncommon. Herein, we present the cytomorphological features of a metastatic anorectal malignant melanoma presenting with ascites at the initial clinical presentation.

Giant skull base mass need not be a tumor - a rare presentation of IgG4-related disease.

BACKGROUND: Giant intracranial 'IgG4-related' lesions are uncommon. They may present as pachymeningitis or localized mass. Here we report, probably, the largest IgG4 skull base mass ever to be reported. CASE: A 40-year male presented with headache, diplopia, right-sided sensori-neuronal hearing loss, and left spastic hemiparesis. Magnetic resonance imaging showed a lesion of 8.5 cm extending from the paranasal sinuses to the right petroclival region with uniform contrast enhancement and T2 hypointensity. Endonasal biopsy revealed respiratory epithelium with fibrosis, and lymphoplasmacytic infiltrate having IgG4 positive cells >30/HPF suggestive of 'IgG4-related' disease. Serum IgG4 was within normal levels. With oral prednisolone 60 mg given daily for 6 weeks and then tapered off over 8 weeks, he improved symptomatically. CONCLUSION: Though rare, 'IgG4-related' disease can also present as a giant skull base mass and should be kept as a differential to fungal granulomas and meningiomas. As they improve dramatically with medical management, extensive skull base resection should not be planned before obtaining a tissue biopsy, especially when there is extension into paranasal sinuses and T2 hypointensity.

Radiation-induced intracranial rhabdomyosarcoma- A rare complication: Report of a case with literature review.

Radiation-induced sarcoma (RIS) of the central nervous system is an uncommon late complication of radiation therapy. We report a case of a 47-year-old male patient who underwent surgery followed by irradiation and chemotherapy with temozolomide for a frontal lobe gliosarcoma and presented 43 months later with a recurrent tumor in the same location with interval growth in the size of the lesion. Histology from surgical resection of the recurrent tumor revealed embryonal rhabdomyosarcoma (RMS). Adjacent brain parenchyma showed radiation-induced changes. There was no evidence of gliosarcoma at recurrence. In addition to the rarity of sarcomas arising following irradiation for glial tumors, this case represents one of the first reports of an intracerebral RMS arising in this setting.

Correlating clinical and laboratory diagnostic modalities in the diagnosis of epidermolysis bullosa in a resource-poor setting.

BACKGROUND: Mutational analysis and immunofluorescence antigen mapping (IFM) are recommended as the laboratory tools of choice for diagnosing EB. In the past, transmission electron microscopy (TEM) was considered the gold standard, and more recently, clinical diagnostic matrix (CDM) has shown good concordance with next-generation sequencing (NGS). METHODS: In this prospective diagnostic study, a skin biopsy was taken for TEM and IFM in consecutive patients with EB (aged >6 months) diagnosed clinically with CDM. Wherever possible, mutational analysis was done using targeted NGS. RESULTS: Of the 80 patients diagnosed with CDM, skin biopsy specimens of 42 patients were assessed using TEM, and of 59 patients using IFM. NGS was done in 39 patients. Taking NGS as the gold standard for diagnosing EB (n = 39 patients), the concordance with CDM, TEM, and IFM were estimated at 84.6% (33/39), 78.5% (11/14), and 76% (19/25) respectively. CDM showed a substantial agreement with NGS (k = 0.69, p < 0.001). CONCLUSIONS: In comparison to NGS, the highest concordance was seen with CDM followed by TEM and IFM in diagnosing major subtypes of EB.

A multicentric study on dermoscopic patterns and clinical-dermoscopic-histological correlates of basal cell carcinoma in Indian skin.

BACKGROUND: Literature on the dermoscopic patterns of basal cell carcinoma (BCC) in India is limited. AIM: To describe the dermoscopic pattern and dermoscopic-histopathological correlation in a large cohort of patients with BCC from India, with a particular focus on skin of colour (SOC). METHODS: This retrospective study was conducted under the aegis of the Dermatoscopy Society of India. Clinical details were collected, and two lead authors independently analysed dermoscopic images of BCC for a predefined set of characteristics. Histopathological slides/blocks were reviewed, and dermoscopic-histological correlation attempted. RESULTS: In total, 143 patients with BCC and skin phototypes IV-VI were included. The mean largest BCC diameter was 3.10 ± 3.68 cm and there was a significant but weak association between duration and largest dimension of the lesion (Spearman ρ = 0.33, P < 0.01). Nearly half of the cases were diagnosed with pigmented BCC and the most common histological subtype was nodular BCC (37.9%). Dermoscopically, blue-grey dots and arborizing vessels were the most common features (60.0%). Pigmentary changes were found in the majority of cases, and included blue-white veil, blue-grey ovoid nests and maple leaf-like areas. A third of our patients had short linear telangiectasia, polymorphic vessels and regular dotted vessels, and another third exhibited a dermoscopic rainbow effect. Arborizing vessels were significantly more common with micronodular (78.9%) and nodular variants (74.1%, P = 0.05), whereas regular dotted vessels (68.4%, P = 0.04), blue-white veil (84.2%, P = 0.02) were significantly associated with micronodular variant. CONCLUSION: The dermoscopic patterns of blue-white veil and regular dotted vessels are indicators towards micronodular BCC in SOC and can help in prioritizing treatment.

Medulloblastoma and esthesioneuroblastoma in a pediatric patient: a co-incidence or result of common genetic anomaly.

INTRODUCTION: Medulloblastoma is the commonest embryonal brain tumor in children. Their association with other neuroepithelial brain tumors is less known. Here we discuss a pediatric patient who developed esthesioneuroblastoma 2 years after treatment of medulloblastoma. MATERIALS AND METHODS: A 12-year-old male presented with features of raised intracranial hypertension, and radiology showed posterior fossa midline lesion. The tumor was excised, and biopsy revealed medulloblastoma (non-WNT non-SHH type). He received chemoradiation. Two years later he presented with loss of vision, and radiology revealed a sinonasal mass with subfrontal extension. Subtotal resection was done, and biopsy showed blue round cell tumor in favor of esthesioneuroblastoma. RESULT: Parents refused further treatment and the patient died 8months after the second surgery. CONCLUSION: Mixed embryonal and neuroepithelial brain tumors are rare. These may have a common genetic abnormality. They have an aggressive course and bear a poor prognosis.

Pediatric case of conidiobolomycosis: A rare entity.

Conidiobolomycosis caused by Conidiobolus species is an uncommon infection restricted to tropical and subtropical regions, usually affecting immunocompetent individuals. More than half of pediatric cases of conidiobolomycosis across the globe are from India. We report a case of subcutaneous conidiobolomycosis in an adolescent with development delay who responded to combined therapy with itraconazole and saturated solution of potassium iodide.

Walking the thin line-Low-grade oncocytic tumor of kidney: An emerging entity.

Low-grade oncocytic tumor (LOT) of kidney is a newly emerging provisional renal tumor entity that carries good prognosis. Here we present a case of low grade oncocytic tumor of kidney in a 68-year-old male with detailed immunohistochemical and ultrastructural description, to add to the existing knowledge about this entity. The importance of documenting low-grade oncocytoma in the literature is its indolent clinical behavior, characteristics gross and microscopic, and immunohistochemical features. The diagnosis of low-grade oncocytoma can be suspected on morphological ground but should be confirmed by immunohistochemistry.

Application of mucous membrane dermoscopy (mucoscopy) in diagnostics of benign oral lesions - literature review and preliminary observations from International Dermoscopy Society study.

Dermoscopy of mucosal surface termed "mucoscopy" is an upcoming offshoot of dermatological imaging. However, the literature on mucoscopy is limited to individual cases and small case series. An organized review or systematic analysis of mucoscopy is lacking. The aim of this review was to summarize the published literature on mucoscopic features of benign conditions affecting the oral mucosa and semi-mucosa. Additionally, the results of mucoscopic features of diseases, which have not been described before have been presented.

Diagnostic Dilemma of Cutaneous Tuberculosis: Opening of the Pandora's Box.

ABSTRACT: Tuberculosis in all forms, that is, pulmonary (PTB) or extrapulmonary (EPTB), is a universal health problem. Cutaneous tuberculosis (CTb) remains one of the least studied and often under-reported variants of EPTB because of its wide and protean clinical presentation. The diagnosis of CTb remains challenging because of lack of sensitive and specific investigations for its diagnosis. The sensitivity of some of the traditional tests is low because of low concentration of mycobacteria in paucibacillary lesions. Besides it is difficult to distinguish between M. tuberculosis (MTb) and other mycobacterial species in skin biopsies morphologically. Molecular methods may target either MTb DNA or RNA, and serve as promising tools in the diagnosis of various forms of CTb, with high sensitivity and rapidity. This review is focused on diagnostic challenges of CTb and to discuss various methods and newer technologies for diagnosing CTb. This will help the dermatologists and dermatopathologists to elucidate and accurately diagnose CTb from other infectious granulomatous dermatitis for appropriate timely treatment of the patient.

Oral mycophenolate mofetil in the treatment of acquired dermal macular hyperpigmentation: An open-label pilot study.

BACKGROUND: Literature on treating acquired dermal macular hyperpigmentation is sparse. AIMS AND OBJECTIVES: To assess treatment response of mycophenolate mofetil in patients having acquired dermal macular hyperpigmentation. MATERIAL AND METHODS: In this open-label, pilot study, patients of acquired dermal macular hyperpigmentation affecting at least the face and/or neck were included. Each participant was treated with mycophenolate mofetil 2 g/day for 24 weeks, with a follow-up of 12 weeks. Two aspects of disease severity were measured: activity (appearance of new lesions/extension of existing lesions), and degree of hyperpigmentation (measured using 'dermal pigmentation area and severity index'). Patient satisfaction was assessed on a scale of 0-10. RESULTS: Forty-three of 46 patients who were prescribed mycophenolate, completed the study (40 females, 6 males; mean disease duration 2.8 ± 1.4 years). Amongst 20 (43.5%) patients with active disease, stability was achieved in 17, after a mean duration of 6.1 ± 2.5 weeks (range 4-12 weeks; median 4; IQR 4 weeks). Mean dermal pigmentation area and severity index at baseline was 18.8 ± 7.1 and decreased to 13.7 ± 6.3 at 24th week (27.5 ± 14.7%; P < 0.001). A significant decreasing trend in dermal pigmentation area and severity index (P < 0.001) was observed, and first significant difference from baseline was noted at the 16th week (P 0.008). Less than 10%, >10-20%, >20%-30%, >30%-40%, >40%-50%, and >50% reduction in dermal pigmentation area and severity index was observed in 8, 5, 4, 15, 10 and 1 patients/patient respectively. The maximum mean grade of pre-treatment dermatoscopic severity was 3 ± 0.7, and decreased to 2.1 ± 0.8 on the face (P < 0.001) and 2.4 ± 0.7 on the neck (P < 0.001) post-treatment. There were 9 (20.1%) non-responders. Self-assessment scores of the rest of the patients fell in the range of moderate/fair improvement (>5 to 7). No significant correlation was seen between patient satisfaction score and degree of reduction in dermal pigmentation area and severity index (r -0.39). Three developed adverse effects (leucopenia, n = 1; transaminitis and hyperbilirubinemia, n = 2) that resolved following discontinuation of mycophenolate. CONCLUSION: Mycophenolate mofetil appears to be a promising treatment option in acquired dermal macular hyperpigmentation.

Analysis of 24 cases of epithelioid glioblastoma: Experience from a tertiary centre of North India.

BACKGROUND: Epithelioid glioblastoma (eGB) is a recently recognized and a rare variant of glioblastoma. This study aimed to describe the clinical, histological and immunohistochemical spectrum and outcome of eGB from a tertiary care hospital in north India. MATERIALS AND METHODS: Twenty four cases of eGB diagnosed over past 10 years were reviewed with detailed morphological and immunohistochemical analysis (GFAP, EMA, Vimentin, Myogenin, INI-1, Cytokeratin, Synaptophysin, CD99, S100, MelanA, IDH1, ATRX, p16, EZH2, Ki-67, and BRAF V600E mutant antibody). RESULT: The mean age was 29.9 years (3-54 years), with equal male and female patients. All had supratentorial tumor. All cases showed epithelioid cells in sheets; however, focal spindling (7 cases, 29.2%), grouping/nesting (6 cases, 25%) and papillary configuration (5 cases, 20.8%) were also noted. All showed microvascular proliferation (MVP) and all except one demonstrated areas of necrosis. INI1 was retained in all cases, while 2 showed patchy loss. EZH2 overexpression (>25%) was observed in 4 cases, while 5 cases showed loss of p16 expression. BRAF V600E mutant protein expression was seen in 12/23 (52.2%) cases. Outcome was available in 8 cases, out of which 6 (75%) experienced recurrence. The median survival was 25.5 months. Cases with tumor infiltrating lymphocytes had a better outcome. CONCLUSION: eGB is a distinct variant of glioblastoma which has predilection towards younger age group. It shows high percentage of BRAF V600E mutation and a subset of it shows longer survival. Cases with presence of tumor infiltrating lymphocytes are associated with better outcome.

Clinical, morphological and immunohistochemical analysis of 13 cases of phosphaturic mesenchymal tumor - A holistic diagnostic approach.

BACKGROUND: Phosphaturic mesenchymal tumor-mixed connective tissue (PMT-MCT) is a rare tumor characterized clinically by presence of tumor-induced osteomalacia (TIO), subsequent to elevated fibroblastic growth factor 23 (FGF23) levels. This study aims to analyse the morphological spectrum of PMT along with clinico-pathological correlation and immunophenotype profile of this rare tumor. MATERIALS AND METHODS: Detailed histological analysis of all tumors presenting with TIO over past 7 years was done retrospectively. Immunohistochemistry was performed in all cases for SATB2, STAT6, CD34, FGF23, ERG, S100 and smooth muscle actin (SMA). RESULTS: A total of 13 cases were analysed (8 female and 5 male) with mean age of 39.8 years. Five cases were arising from bone while 4 each from soft tissue and nasal cavity/paranasal sinus. All presented with hypophosphatemia, hyperphosphaturia, elevated serum FGF23 and features suggestive of osteomalacia. Histological examination revealed basophilic 'grungy' calcification seen in 7 (53.8%), osteoid formation in 8 (61.5%), chondroid matrix in 4 (30.8%), adipose tissue in 6 (46.2%), osteoclast-like giant cells in 9 (69.2%) and hemangiopericytomatous (HPC like) blood vessels in 7 cases (53.8%). HPC like vessels and adipose tissue were more common in nasal tumors while calcification was more common in tumors arising from bone. All cases showed immunoreactivity for SATB2 and clinical improvement following resection except one case with residual tumor. CONCLUSION: PMT shows varied histological pattern with various matrix components depending on the site of the tumor. Serum FGF-23 is a useful adjunctive marker for diagnosis.

Clinicopathological characteristics and outcomes in embryonal tumor with multilayered rosettes: A decade long experience from a tertiary care centre in North India.

BACKGROUND: Embryonal tumor with multilayered rosettes (ETMR) are a heterogenous group clinically, pathologically and topographically. Due to limited cases, data regarding its molecular genetics, pathology and prognostic factors is evolving. We retrospectively analysed our cohort of ETMR over last decade in order to study their clinicopathological characteristics and outcome. METHODS: Our cohort consisted of patients diagnosed with Embryonal tumor with abundant neuropil and true rosettes (ETANTR)/Ependymoblastoma (EBL)/ Medulloepithelioma (MEPL) over the past decade. Clinical details, including outcome and imaging data was retrieved. Histological analysis including immunohistochemical work-up was performed. RESULTS: Cohort included 15 patients with age range between 1 and 28 years and M:F ratio of 1.5:1. Supratentorial location predominated in comparison to tumors arising in posterior fossa. ETANTR and EBL patterns were equally distributed (40% each), followed by one case each of mixed pattern (EBL + ETANTR), MEPL and embryonal tumor, unclassified. All tumors readily expressed LIN 28A and INI-1 was retained. Recurrence with evidence of glial and rhabdoid differentiation was noted in a single patient 9 months following resection. Follow-up period ranged from 1 to 31 months, with overall median survival of 6.4 months. Eight patients were planned for adjuvant treatment following surgery, of which only four could complete it. All patients, except for one, succumbed to the disease. CONCLUSIONS: ETMR have a heterogenous morphology and gathers ETANTR, EBL, MEPL within its spectrum. Following treatment, the recurrent tumor may feature glial/rhabdoid differentiation. LIN28A is expressed in all cases, however should be interpreted in context of histology. Prognosis of ETMR remains dismal despite multimodal therapy.

Skin nodules and proptosis in a case of carcinoma urinary bladder: An unusual presentation.

Metastasis to the skin and orbit from bladder cancer is extremely rare. A 76-year-old diabetic male presented with skin nodules and proptosis of the left eye. Punch biopsy from the abdominal wall nodule showed malignant cells with perineural invasion. Immunohistochemistry showed features suggestive of metastatic urothelial carcinoma. We present this case of urothelial carcinoma of the urinary bladder presenting primarily with highly unusual nodular skin metastasis.

Persistent plaques after release from treatment in slit-skin smear negative leprosy patients: Wait and watch or adopt a proactive approach?

A subset of leprosy patients has clinical and histopathological activity in the form of persistent plaques and granulomas after completion of multidrug therapy (MDT) which can have significant impact on their quality of life. In the absence of clear guidelines regarding management of such patients, majority of the times they are treated either as late reversal reaction with corticosteroids or no active treatment is offered. We observed 11 patients of leprosy with persistent plaques after completing the 6/12-months MDT who were treated favorably with minocycline 100 mg once daily for 16 weeks. Complete clinical resolution was observed in 9/11 patients while two patients had partial improvement. Histopathological improvement in the form of disappearance of granulomas corroborated with the clinical improvement. All the patients tolerated the treatment well and hyperpigmentation was the only adverse effect noted. Minocycline may be considered as a useful and well tolerated therapeutic option for this subset of leprosy patients due to its immune modulatory and anti-inflammatory effects.

Self-healing juvenile cutaneous mucinosis, a sclerodermoid disorder simulating juvenile dermatomyositis: a case-based review.

Self-healing juvenile cutaneous mucinosis (SHJCM) is a rare childhood disease with characteristic cutaneous and rheumatic manifestations. Cutaneous manifestations include a combination of nodules affecting peri-articular (especially interphalangeal joints) and head and neck areas; and linearly arranged ivory white papules over an erythematous indurated skin. Despite a benign course, an abrupt onset of symptoms with extensive cutaneous involvement often leads to parental anxiety, overenthusiastic evaluation and sometimes aggressive treatment. A peculiar cutaneous distribution in SHJCM including nodular lesions and periorbital edema, arthritis and arthralgia in a few cases, may simulate juvenile dermatomyositis. It is, therefore, important for dermatologists and pediatricians to be aware of this entity. In this report, we describe two cases of SHJCM and briefly review similarly reported cases in children.