Severe allergic dysregulation due to a gain of function mutation in the transcription factor STAT6.

BACKGROUND: Inborn errors of immunity have been implicated in causing immune dysregulation, including allergic diseases. STAT6 is a key regulator of allergic responses. OBJECTIVES: This study sought to characterize a novel gain-of-function STAT6 mutation identified in a child with severe allergic manifestations. METHODS: Whole-exome and targeted gene sequencing, lymphocyte characterization, and molecular and functional analyses of mutated STAT6 were performed. RESULTS: This study reports a child with a missense mutation in the DNA binding domain of STAT6 (c.1114G>A, p.E372K) who presented with severe atopic dermatitis, eosinophilia, and elevated IgE. Naive lymphocytes from the affected patient displayed increased TH2- and suppressed TH1- and TH17-cell responses. The mutation augmented both basal and cytokine-induced STAT6 phosphorylation without affecting dephosphorylation kinetics. Treatment with the Janus kinase 1/2 inhibitor ruxolitinib reversed STAT6 hyperresponsiveness to IL-4, normalized TH1 and TH17 cells, suppressed the eosinophilia, and improved the patient's atopic dermatitis. CONCLUSIONS: This study identified a novel inborn error of immunity due to a STAT6 gain-of-function mutation that gave rise to severe allergic dysregulation. Janus kinase inhibitor therapy could represent an effective targeted treatment for this disorder.

Atypical Localization of Eczema Discriminates DOCK8 or STAT3 Deficiencies from Atopic Dermatitis.

PURPOSE: Autosomal recessive dedicator of cytokinesis 8 (DOCK8-/-) and autosomal dominant signal transducer and activator of transcription 3 (STAT3-/+) deficiencies are inborn errors of immunity (IEI) disorders present with the classic features of eczema and create a dilemma during differentiation from atopic dermatitis (AD). Therefore, an appropriate approach is required for eczema to diagnose DOCK8-/- and STAT3-/+ early. Here, we described a set of clinical and immunological variables, including atypical AD localizations and lymphocyte subsets, to differentiate DOCK8-/- or STAT3-/+ from AD. METHODS: This multicenter study involved 100 patients with DOCK8-/- and STAT3-/+ and moderate/severe AD. We recruited disease manifestations, including detailed localizations of eczema, infections, and allergy. Principle component analysis (PCA) was used to discriminate DOCK8-/- or STAT3-/+ from AD. RESULTS: There were 43 patients with DOCK8-/-, 23 with STAT3-/+, and 34 with AD. Pneumonia, severe infections, mucocutaneous candidiasis, and skin abscesses were commonly observed in DOCK8 and STAT3 deficiencies. Atypical skin involvement with neonatal rash, retro auricular, axillary, sacral, and genital eczema discriminate DOCK8-/- and STAT3-/+ from AD with high specificity ranges between 73.5 and 94.1% and positive predictive index ranges between 55 and 93.1%. Together with using absolute numbers of CD3+, CD4+, and CD8+ T cells, the combined clinical and laboratory features showed perfect differentiation between DOCK8-/- or STAT3-/+ and AD via PCA. CONCLUSIONS: The described features can be easily implemented by physicians providing early diagnosis of DOCK8 and STAT3 deficiencies.

Low Density Granulocytes and Dysregulated Neutrophils Driving Autoinflammatory Manifestations in NEMO Deficiency.

NF-κB essential modulator (NEMO, IKK-γ) deficiency is a rare combined immunodeficiency caused by mutations in the IKBKG gene. Conventionally, patients are afflicted with life threatening recurrent microbial infections. Paradoxically, the spectrum of clinical manifestations includes severe inflammatory disorders. The mechanisms leading to autoinflammation in NEMO deficiency are currently unknown. Herein, we sought to investigate the underlying mechanisms of clinical autoinflammatory manifestations in a 12-years old male NEMO deficiency (EDA-ID, OMIM #300,291) patient by comparing the immune profile of the patient before and after hematopoietic stem cell transplantation (HSCT). Response to NF-kB activators were measured by cytokine ELISA. Neutrophil and low-density granulocyte (LDG) populations were analyzed by flow cytometry. Peripheral blood mononuclear cells (PBMC) transcriptome before and after HSCT and transcriptome of sorted normal-density neutrophils and LDGs were determined using the NanoString nCounter gene expression panels. ISG15 expression and protein ISGylation was based on Immunoblotting. Consistent with the immune deficiency, PBMCs of the patient were unresponsive to toll-like and T cell receptor-activators. Paradoxically, LDGs comprised 35% of patient PBMCs and elevated expression of genes such as MMP9, LTF, and LCN2 in the granulocytic lineage, high levels of IP-10 in the patient's plasma, spontaneous ISG15 expression and protein ISGylation indicative of a spontaneous type I interferon (IFN) signature were observed, all of which normalized after HSCT. Collectively, our results suggest that type I IFN signature observed in the patient, dysregulated LDGs and spontaneously activated neutrophils, potentially contribute to tissue damage in NEMO deficiency.

A set of clinical and laboratory markers differentiates hyper-IgE syndrome from severe atopic dermatitis.

Hyper-IgE syndrome (HIES) patients may share many features observed in severe atopic dermatitis (SAD), making a diagnostic dilemma for physicians. Determining clinical and laboratory markers that distinguish both disorders could provide early diagnosis and treatment. We analyzed patients (DOCK8 deficiency:14, STAT3-HIES:10, SAD:10) with early-onset SAD. Recurrent upper respiratory tract infection and pneumonia were significantly frequent in HIES than SAD patients. Characteristic facial appearance, retained primary teeth, skin abscess, newborn rash, and pneumatocele were more predictable for STAT3-HIES, while mucocutaneous candidiasis and Herpes infection were common in DOCK8 deficiency, which were unusual in SAD group. DOCK8-deficient patients had lower CD3+ and CD4+T cells with a senescent phenotype that unique for this form of HIES. Both DOCK8 deficiency and STAT3-HIES patients exhibited reduced switched memory B cells compared to the SAD patients. These clinical and laboratory markers are helpful to differentiate HIES from SAD patients.

Acquired progressive lymphangioma: Case report with partial response to imiquimod 5% cream.

Acquired progressive lymphangioma (APL), or benign lymphangioendothelioma, is an unusual entity derived from vascular structures. Clinically and histopathologically it may resemble Kaposi's sarcoma and well-differentiated angiosarcoma, causing a diagnostic problem. We report an individual with APL initially diagnosed with Kaposi's sarcoma who underwent unnecessary laboratory testing. Imiquimod 5% cream stopped the progression of the lesion. Awareness of this rare entity may prevent patients from undergoing excessive testing. Imiquimod may be used as a safe, effective treatment option.

Successful treatment of pityriasis lichenoides chronica with narrow-band ultraviolet B therapy in a patient with Keratitis-Ichthyosis-Deafness syndrome: a case report.

Keratitis-ichthyosis-deafness (KID) syndrome is a rare genodermatosis causing ichthyosis-like skin lesions, keratitis, and deafness. Herein, we report a patient with this rare syndrome in association with pityriasis lichenoides chronica, which was succesfully treated with narrow-band ultraviolet B phototherapy despite our concerns regarding the increased risk of squamous cell carcinoma, hyperpyrexia, and keratitis.

Potentially Beneficial Effect of Hydroxychloroquine in a Patient with a Novel Mutation in Protein Kinase Cδ Deficiency.

Protein kinase C delta (PRKCD) has essential functions in controlling B-cell proliferation and apoptosis, development of B-cell tolerance and NK-cell cytolitic activity. Human PRKCD deficiency was recently identified to be causative for an autoimmune lymphoproliferative syndrome like disorder with significant B-cell proliferation particularly of immature B cells. Here we report a child with a novel mutation in PRKCD gene who presented with CMV infection and an early onset SLE-like disorder which was successfully treated with hydroxychloroquine.

Infantile Bullous Pemphigoid Treated Using Intravenous Immunoglobulin: Case Report and Review of the Literature.

We report a 5-month-old girl diagnosed with bullous pemphigoid who initially did not respond to systemic corticosteroids and dapsone but rapidly improved after the addition of intravenous immunoglobulin (IVIG) infusions. A literature search revealed anecdotal cases of infantile bullous pemphigoid treated with IVIG, although variable treatment regimens were used, and some resistant cases required additional medications such as rituximab for clinical remission.

Coexistence of aplasia cutis and nevus psiloliparus--report of a novel case.

Nevus psiloliparus is a type of mesodermal nevus of the scalp classically seen with encephalocraniocutaneous lipomatosis. The close association between nevus psiloliparus and aplasia cutis congenita is called didymosis aplasticopsilolipara. Although typically associated with neurologic, ocular, and skeletal findings, didymosis aplasticopsilolipara can be seen without the context of encephalocraniocutaneous lipomatosis.

A novel association of an uncommon pigmentation pattern: coexistence of cutis tricolor with intracranial teratoma and holoprosencephaly.

Cutis tricolor was first described in a 17-year-old male patient by Happle et al. as a rare coexistence of circumscribed hyperpigmentation and hypopigmentation close to each other on a background of normally pigmented skin. Cutis tricolor has been reported as an isolated cutaneous finding or in various associations. To the best of our knowledge, cutis tricolor in association with teratoma and holoprosencephaly has not been reported in the literature. Herein, we report a male patient who presented with a teratoma and a combination of whorl-like hypopigmentation together with hyperpigmented patches adjacent to each other on intermediately pigmented skin. This case report supports the view that cutis tricolor may be a marker of an underlying neurological abnormality.

Development of a quality of life scale for vitiligo.

BACKGROUND: No vitiligo-specific quality of life scale exists. OBJECTIVE: To develop a reliable and valid quality of life scale for vitiligo patients. METHODS: The content was derived from in-depth interviews with vitiligo patients. The internal consistency, test-retest reliability and validity of the scale, VLQI (Vitiligo Life Quality Index), were evaluated. RESULTS: Internal consistency was high with 30 patients and then with 183 patients (Cronbach's α 0.92 and 0.91). Test-retest scores were correlated (r = 0.86, p < 0.001). There was no difference between the test and retest scores (p > 0.05). VLQI was correlated with DLQI (Dermatology Life Quality Index) (r = 0.77, p < 0.001) and with the perceived severity by the patients (r = 0.57, p < 0.001). There was a significant relationship between the VLQI and the extent of the disease (p = 0.015). Factor analysis revealed six subscales. CONCLUSION: The VLQI is a valid and reliable instrument assessing quality of life of vitiligo patients.

Kidney and Urinary Tract Involvement in Epidermolysis Bullosa: Is Routine Follow-Up Necessary?

BACKGROUND: Several renal and urinary tract complications have been reported in patients with epidermolysis bullosa. OBJECTIVE: This study investigated kidney and urinary tract involvement in patients with epidermolysis bullosa. PATIENTS AND METHODS: Patients with epidermolysis bullosa in treatment at the Dermatology Unit were included in the study. Glomerular and tubular functions were investigated. RESULTS: The study included 16 patients (4 females, 12 males) of mean 11.1 years (SD = 8.1 years). Estimated GFR was normal in all patients except one with end-stage renal disease. Excluding this patient, the urinary albumin/creatinine ratio and the fractional excretion of sodium were normal. The mean beta-2 microglobulin/creatinine ratio was 278.8 µg/g, and it was abnormally high in 2 patients. The mean tubular phosphorus reabsorption was 92.6%; it was abnormally low in 1 patient. Severe kidney or urinary tract involvement was present in 2 patients with recessive dystrophic EB-generalized severe (RDEB-GS): one patient had obstructive bullous lesions in the urethra; the other had end-stage renal disease secondary to focal segmental glomerulosclerosis and was on peritoneal dialysis for 3 years. CONCLUSIONS: Assessment for renal and urinary tract involvement should become a routine part of the evaluation of patients with any type of EB, but especially of patients with RDEB-GS. Patients with mild tubular dysfunction need long-term follow-up to detect early deterioration of renal function.

Impact of psoriasis in the quality of life of children, adolescents and their families: a cross-sectional study.

BACKGROUND: Psoriasis is a chronic and inflammatory disease that impairs quality of life and causes psychological symptoms. Despite the high prevalence of psoriasis in pediatric patients, studies investigating the impact of psoriasis in the quality of life of children, adolescents and families are sparse. OBJECTIVE: To investigate the impact of psoriasis in the quality of life of children and adolescents with psoriasis and their families and to determine depression and anxiety levels of the patients. METHODS: A total of 58 patients with psoriasis aged 7-18 years (median age: 11) and a family member of each patient were included in the study. Children's Dermatology Life Quality Index (CDLQI), Family Dermatology Life Quality Index (FDLQI), Children's Depression Inventory (CDI) and State-Trait Anxiety Inventory for Children (STAIC) were used in the study. RESULTS: The median PASI score of the patients included in the study was 1.8. The median CDLQI and FDLQI scores in the study groups were 5 and 10, respectively. The median CDI score, STAIC-state and STAIC-trait scores of the patients were 6, 28 and 32.5, respectively. STUDY LIMITATIONS: Lack of a control group and patient assessment of disease severity. Relatively mild disease severity of the subjects. CONCLUSIONS: Psoriasis has a negative impact in the quality of life of children, adolescents and their families, even in the presence of mild disease. Considering that impairment in quality of life may be associated with psychosocial morbidity, a combined approach with medical therapy, family counseling and quality of life assessment may be beneficial in this patient group.

Neonatal lupus erythematosus: Report of a case with cutaneous, hematological and hepatobiliary findings.

Neonatal lupus erythematosus is an autoimmune disorder mainly affecting the heart and skin. It is the most common cause of congenital heart block. In addition, hematological, hepatobiliary and neurological involvement may occur. Herein, we report a 23-day-old infant presented with annular, erythematous, and scaly and atrophic lesions on the face and trunk. Based on the clinical, laboratory and histopathological findings, she was diagnosed as neonatal lupus erythematosus. Neonatal lupus eryhtematosus should be considered in infants presenting with annular skin lesions, and we present this case to highlight the value of high index of clinical suspicion in diagnosis.

Atypical presentations of eosinophilic fasciitis.

Eosinophilic fasciitis is an uncommon connective tissue disease that may mimic and overlap with other sclerosing disorders such as morphea and lichen sclerosus. Herein, we report four patients (two men and two women, aged 16-64 yeas) with eosinophilic fasciitis. There was overlap with both morphea and lichen sclerosus in 2 patients and with morphoea alone in 1 patient. Magnetic resonance imaging (MRI) was used for diagnosis in three patients and for assessing treatment response in one patient. Eosinophilic fasciitis may co-exist with morhoea and lichen sclerosus. In view of the overlapping clinical and histopathological features of these disorders, MRI may be helful in delineating the conditions by detecting involvement of fascia.

Impact of psoriasis in the quality of life of children, adolescents and their families: a cross-sectional study

Abstract: Background: Psoriasis is a chronic and inflammatory disease that impairs quality of life and causes psychological symptoms. Despite the high prevalence of psoriasis in pediatric patients, studies investigating the impact of psoriasis in the quality of life of children, adolescents and families are sparse. Objective: To investigate the impact of psoriasis in the quality of life of children and adolescents with psoriasis and their families and to determine depression and anxiety levels of the patients. Methods: A total of 58 patients with psoriasis aged 7-18 years (median age: 11) and a family member of each patient were included in the study. Children's Dermatology Life Quality Index (CDLQI), Family Dermatology Life Quality Index (FDLQI), Children's Depression Inventory (CDI) and State-Trait Anxiety Inventory for Children (STAIC) were used in the study. Results: The median PASI score of the patients included in the study was 1.8. The median CDLQI and FDLQI scores in the study groups were 5 and 10, respectively. The median CDI score, STAIC-state and STAIC-trait scores of the patients were 6, 28 and 32.5, respectively. Study limitations: Lack of a control group and patient assessment of disease severity. Relatively mild disease severity of the subjects. Conclusions: Psoriasis has a negative impact in the quality of life of children, adolescents and their families, even in the presence of mild disease. Considering that impairment in quality of life may be associated with psychosocial morbidity, a combined approach with medical therapy, family counseling and quality of life assessment may be beneficial in this patient group.