Midfacial Toddler Excoriation syndrome (MiTES): case series, diagnostic criteria and evidence for a pathogenic mechanism.

BACKGROUND: PRDM12 polyalanine tract expansions cause two different disorders; Midfacial Toddler Excoriation Syndrome (MiTES) - itch with normal pain sensation associated with homozygous 18 alanines (18A), and congenital insensitivity to pain (CIP) with normal itch with homozygous 19A. Knowledge of the phenotype, genotype, and disease mechanism of MiTES is incomplete. Why PRDM12 18A versus 19A can cause almost opposite phenotypes is unknown; no other poly-alanine or poly-glutamine tract expansion disease causes two such disparate phenotypes. METHODS: We assessed the genotype and phenotype of 9 new, 9 atypical, and 6 previously reported patients diagnosed with MiTES. Using cell lines with homozygous PRDM12 of 12A (normal), 18A (MiTES) and 19A (CIP) we examined PRDM12 aggregation and subcellular localisation by image separation confocal microscopy and sub-cellular fractionation western blotting. RESULTS: MiTES presents in the first year of life, and in all cases the condition regresses over the first decade leaving scarring. The MiTES phenotype is highly distinctive. Features overlapping with PRDM12-CIP are rarely found. The genotype-phenotype study of PRDM12 polyalanine tract shows that 7A -15A are normal; 16A -18A are associated with MiTES; 19A leads to CIP; and no clinically atypical MiTES cases had an expansion. PRDM12 aggregation and sub-cellular localisation differ significantly between 18A and normal 12A cell lines and between 18A and 19A cell lines. MiTES is a new protein aggregation disease. CONCLUSION: We provide diagnostic criteria for MiTES, and improved longitudinal data. MiTES and CIP are distinct phenotypes despite their genotypes varying by a single alanine in the PRDM12 polyalanine tract. We found clear distinctions between the cellular phenotypes of normal, MiTES and CIP cells.. We hypothesise that the developmental environment of the trigeminal ganglion is unique and critically sensitive to prenatal and postnatal levels of PRDM12.

Phototherapy for vitiligo: A narrative review on the clinical and molecular aspects, and recent literature.

BACKGROUND: Vitiligo is characterized by depigmented patches resulting from loss of melanocytes. Phototherapy has emerged as a prominent treatment option for vitiligo, utilizing various light modalities to induce disease stability and repigmentation. AIMS AND METHODS: This narrative review aims to explore the clinical applications and molecular mechanisms of phototherapy in vitiligo. RESULTS AND DISCUSSION: The review evaluates existing literature on phototherapy for vitiligo, analyzing studies on hospital-based and home-based phototherapy, as well as outcomes related to stabilization and repigmentation. Narrowband ultra-violet B, that is, NBUVB remains the most commonly employed, studied and effective phototherapy modality for vitiligo. Special attention is given to assessing different types of lamps, dosimetry, published guidelines, and the utilization of targeted phototherapy modalities. Additionally, the integration of phototherapy with other treatment modalities, including its use as a depigmenting therapy in generalized/universal vitiligo, is discussed. Screening for anti-nuclear antibodies and tailoring approaches for non-photo-adapters are also examined. CONCLUSION: In conclusion, this review provides a comprehensive overview of phototherapy for vitiligo treatment. It underscores the evolving landscape of phototherapy and offers insights into optimizing therapeutic outcomes and addressing the challenges ahead. By integrating clinical evidence with molecular understanding, phototherapy emerges as a valuable therapeutic option for managing vitiligo, with potential for further advancements in the field.

Whole-body and targeted narrowband ultraviolet B phototherapy effectively stabilize acral vitiligo with negligible repigmentation beyond wrists and ankles: Results from a split-body randomized controlled trial.

BACKGROUND: Narrowband ultraviolet B (NB-UVB) phototherapy promotes stability and repigmentation in vitiligo. No studies have compared targeted NB-UVB with whole-body NB-UVB in treatment of acral vitiligo. OBJECTIVES: This randomized split-body study compared whole-body NB-UVB with targeted NB-UVB in inducing stability and repigmentation in acral vitiligo. METHODS: Thirty-two patients with bilaterally symmetrical acral vitiligo lesions (distal to elbows and knees) were recruited. Patients received whole-body NB-UVB treatment, with one hand and one foot shielded until elbow and knee, followed by targeted NB-UVB treatment on the shielded side. Patients were assessed at 4-week intervals for 24 weeks using Vitiligo Disease Activity (VIDA) score, Vitiligo Skin Activity Score (VSAS), Vitiligo Area Scoring Index (determined through fingertip method, using the method to calculate facial-VASI) and degree of repigmentation. RESULTS: After 12 weeks, 87.5% of patients achieved a VIDA score of 3, with none having active disease at 24 weeks. Over 50% repigmentation was observed in 42.2% and 37.5% of limbs in whole-body and targeted groups, respectively (p = .95). No improvement in F-VASI scores of hands and feet (distal to wrist and ankles) was noted with either modality over the 24-week period. CONCLUSION: Our study showed comparable repigmentation rates between whole-body and targeted NB-UVB groups. Limited effectiveness of phototherapy in repigmentation of hands and feet underscores an important therapeutic gap.

A prospective observational study correlating possible novel biomarkers with disease severity and antihistamine response in chronic spontaneous urticaria.

Background: Role of complement fraction 5a (C5a), interleukin (IL)-9, and apolipoprotein (apo) A-IV as biomarkers of disease severity and antihistamine response in chronic spontaneous urticaria (CSU) remains elusive. Objective: To identify the role of C5a, IL-9, and apo A-IV as potential biomarkers in predicting disease severity and antihistamine response in CSU patients. Methods: This was a prospective observational study of 95 patients and 42 controls. Serum analysis of C5a, IL-9, and apo A-IV was done using enyzme linked immunosorbent assay kits. Also, serum IgE and anti-thyroid peroxidase (TPO) levels were assessed in all patients. All patients were started on oral levocetirizine 5 mg at baseline and dose was titrated upwards to maximum of 20 mg based on response. Patients were categorized into antihistamine responders or nonresponders as per their disease response. Serological markers, serum IgE, and anti-TPO were correlated with baseline disease severity and antihistamine response. Results: C5a levels were significantly higher in cases as compared to controls (P = 0.004). Significantly higher IL-9 levels were observed in antihistamine responders than nonresponders (P = 0.008). Baseline urticaria severity demonstrated a statistically significant positive and negative correlations with IL-9 (ρ = 0.277, P = 0.007) and apo A-IV (ρ = -0.271, P = 0.008) levels, respectively. Levels of serum IgE (P = 0.031) and anti-TPO (P = 0.039) were significantly higher in antihistamine nonresponders compared to responders. Conclusions: IL-9 and apo A-IV might be potential novel biomarkers to predict urticaria severity. Higher IL-9 might be a predictor of antihistamine response. Elevated anti-TPO and serum IgE might predict poor antihistamine response.

A prospective observational study validating the CET score as a screening tool in suspected DRESS syndrome.

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) is an idiosyncratic severe cutaneous adverse reaction that may be potentially life-threatening. Recently, a simple scoring system for the early screening of DRESS patients was derived by combining hsCRP levels, the eosinophil count, and the total body surface area (CET score). The objectives of this study were validating the CET score, and calculating its lead time advantage and cost-benefits compared to RegiSCAR scoring. METHODS: This is a prospective observational case-control study, where 110 consecutive patients diagnosed with drug-induced maculopapular exanthema (MPE) were recruited during the 18 months of the study period. Patients were classified as cases (DRESS) and controls (MPE) using RegiSCAR score cut-off 2 (possible DRESS). They were also simultaneously screened using the CET score, based on which patients were classified as positive or negative. They were subsequently followed up on Day 15 for a second comparison and assessment of lead time and at 3 and 6 weeks to evaluate clinical response. RESULTS: Seventy cases and 40 controls were recruited. At a cut-off of >2.12, the CET score had a sensitivity of 94.3%, a specificity of 60%, a positive predictive value (PPV) of 80.5%, and a negative predictive value (PPV) of 85.7%. The median delay in diagnosing DRESS using RegiSCAR was around 14.5 hours. There was a median cost benefit of 12.1 USD in favor of the CET score. CONCLUSIONS: The CET score had good diagnostic performance in screening DRESS patients with a lead time of 14.5 hours and fewer costs incurred.

Major histocompatibility complex (MHC) gene frequency in acquired dermal macular hyperpigmentation: a case control study.

BACKGROUND: Human leukocyte antigen (HLA) allele frequencies have a known association with the pathogenesis of various autoimmune diseases. METHODS: We recruited 31 Indian patients of acquired dermal macular hyperpigmentation (ADMH) and 60 unrelated, age-and-gender-matched healthy controls. After history and clinical examination, 5 ml of blood in EDTA vials was collected. These samples were subjected to DNA extraction and the expression of HLA A, B, C, DR, DQ-A, and DQ-B was studied. RESULTS: There was a predominance of females with a gender ratio of 23 : 8 and the most common phototype was Fitzpatrick type IV (83.9%). There was a significant association of HLA A*03:01 (OR: 5.8, CI: 1.7-17.0, P = 0.005), HLA B*07:02 (OR: 5.3, CI: 1.9-14.6, P = 0.003), HLA C*07:02 (OR: 4.3, CI: 1.8-9.6, P = 0.001), HLA DRB1*10:01 (OR: 7.6, CI: 1.7-38.00, P = 0.022), and HLA DRB1*15:02 (OR: 31.0, CI: 4.4-341.8, P < 0.001) with patients compared to controls, whereas HLA DQB*03:01 was less associated with patients compared to controls (OR: 0.2, CI: 0.0-0.6, P = 0.009). CONCLUSION: Patients with ADMH are more likely to have the HLA A*03:01, HLA B 07*02, HLA C*07:02, HLA DRB1*10:01, HLA DRB1*15:02 and less likely to have the HLA DQB*03:01 allele. Larger cohort studies may thus be conducted studying these specific alleles.

Delays in diagnosis is the commonest proximate reason for mortality in hereditary angioedema: our experience at Chandigarh, India.

BACKGROUND: Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized clinically by recurrent episodes of non-pruritic subcutaneous and/or submucosal edema. Laryngeal edema is the commonest cause of mortality in patients with HAE. Prior to the availability of first-line treatment options for management of HAE, the mortality used to be as high as 30%. The mortality has significantly reduced in countries where first-line treatment options are available and patients can access these therapies. There is paucity of literature on the outcomes of patients with HAE in developing countries where availability and access to first-line treatment options is still a challenge. OBJECTIVE: To report our experience with mortality in patients with HAE and to report factors associated with death of these patients. METHODS: We carried out a record review of all patients diagnosed to have HAE between January 1996 and August 2022. Families with HAE who had reported death of at least one family member/relative because of laryngeal edema were studied in detail. RESULTS: Of the sixty-five families (one hundred and seventy patients) registered in the clinic, sixteen families reported death of at least one family member/relative because of laryngeal edema (total thirty-six deaths). Of these sixteen families, fourteen families reported that one or more family members had experienced at least one attack of laryngeal edema. One patient died during follow-up when she was taking long-term prophylaxis with stanozolol and tranexamic acid while remaining thirty-five patients were not diagnosed to have HAE at the time of their death. At the time of death of all thirty-six patients, at least one other family member had symptoms suggestive of HAE but the diagnosis was not established for the family. CONCLUSIONS: This is the largest single centre cohort of patients with HAE in India reporting mortality data and factors associated with death in these families. Delay in diagnosis is the commonest reason for mortality.

Mucocutaneous manifestations of chikungunya fever: an update.

Chikungunya is a viral disease transmitted by female Aedes mosquitoes that has been increasingly reported in many parts of the world across the geographical borders. In addition to fever and joint pain, mucocutaneous manifestations of chikungunya have been reported in 40-75% of infected patients. Dermatological manifestations of chikungunya are often under-recognized and misdiagnosed as clinicians are not sensitized or educated regarding these. The early-onset cutaneous manifestations of chikungunya fever, occurring within 1 month of the fever, include maculopapular rashes, vesiculobullous eruptions, Steven-Johnson syndrome/toxic epidermal necrolysis-like eruptions, flagellate lesions, scrotal dermatitis, oro-genital ulcers, and exacerbation of preexisting dermatoses like psoriasis. Hyperpigmentation, lichenoid eruptions, diffuse hair fall, and exacerbation of acne usually occur as a late manifestation. Diagnosis of these mucocutaneous manifestations can be challenging as they often resemble other common dermatoses. This review article elaborates on various mucocutaneous manifestations of chikungunya fever, based on literature review and authors' clinical experience.