DOCK11 deficiency in patients with X-linked actinopathy and autoimmunity.

Dedicator of cytokinesis (DOCK) proteins play a central role in actin cytoskeleton regulation. This is highlighted by the DOCK2 and DOCK8 deficiencies leading to actinopathies and immune deficiencies. DOCK8 and DOCK11 activate CDC42, a Rho-guanosine triphosphate hydrolases involved in actin cytoskeleton dynamics, among many cellular functions. The role of DOCK11 in human immune disease has been long suspected but, to the best of our knowledge, has never been described to date. We studied 8 male patients, from 7 unrelated families, with hemizygous DOCK11 missense variants leading to reduced DOCK11 expression. The patients were presenting with early-onset autoimmunity, including cytopenia, systemic lupus erythematosus, skin, and digestive manifestations. Patients' platelets exhibited abnormal ultrastructural morphology and spreading as well as impaired CDC42 activity. In vitro activated T cells and B-lymphoblastoid cell lines from patients exhibited aberrant protrusions and abnormal migration speed in confined channels concomitant with altered actin polymerization during migration. Knock down of DOCK11 recapitulated these abnormal cellular phenotypes in monocytes-derived dendritic cells and primary activated T cells from healthy controls. Lastly, in line with the patients' autoimmune manifestations, we also observed abnormal regulatory T-cell (Treg) phenotype with profoundly reduced FOXP3 and IKZF2 expression. Moreover, we found reduced T-cell proliferation and impaired STAT5B phosphorylation upon interleukin-2 stimulation of the patients' lymphocytes. In conclusion, DOCK11 deficiency is a new X-linked immune-related actinopathy leading to impaired CDC42 activity and STAT5 activation, and is associated with abnormal actin cytoskeleton remodeling as well as Treg phenotype, culminating in immune dysregulation and severe early-onset autoimmunity.

Comparison of incidence, causes and prognosis of adult and paediatric epidermal necrolysis: a French population-based study.

BACKGROUND: Epidermal necrolysis (EN), comprising Stevens-Johnson syndrome and toxic EN, is a rare and severe blistering reaction, mainly induced by drugs. Differences between paediatric and adult patients regarding incidence, causes and outcomes have been discussed but are based on a limited number of patients from small case series. OBJECTIVES: To directly compare the incidence, cause and prognosis of adult and paediatric EN. METHODS: We used data from the French Health System Database (1 January 2013-31 December 2022). We identified adult and paediatric patients hospitalized for EN using the International Classification of Diseases, 10th Revision codes combined with validated algorithms. Outcomes were the incidence of EN; the presence of a suspected drug before EN onset (defined as a new drug dispensation from 5 to 56 days prehospitalization); and in-hospital mortality. To estimate the association between paediatric EN and the presence of a suspect drug, we computed a multivariable logistic regression with odd ratios (ORs). To estimate the association with mortality, we computed a multivariable Cox proportional hazard ratio (HR) model. RESULTS: A total of 1440 patients [799 (55.5%) female] with EN were included, comprising 219 children and 1221 adults. Among children, the incidence of EN was 1.5 cases [95% confidence interval (CI) 1.3-1.7] per 1 million person-years vs. 2.6 cases (95% CI 2.5-2.7) in adults. Moreover, children had less chance of being given a culprit drug before the onset of EN [n = 93/219 (42.5%) vs. n = 829/1221 (67.9%)], with an adjusted OR of 0.43 (95% CI 0.32-0.59; P < 0.001), together with a better prognosis: the mortality rate in paediatric patients was 1.4% (95% CI 0.4-3.7) vs. 19.4% (95% CI 17.3-21.7) in adults. The adjusted HR for in-hospital mortality in children was 0.12 (95% CI 0.04-0.38; P < 0.001). CONCLUSIONS: Paediatric EN appears to be rarer, with less chance of being caused by drugs and has a better prognosis than adult EN. These results suggest the existence of different underlying pathophysiological mechanisms and clinical particularities between adult and paediatric patients with EN.

Epidermal necrolysis (or 'EN' for short) is a rare and severe disease. It involves a sudden loss of skin on the body (called 'epidermal and mucosal detachment'). In most cases, it is caused by a reaction of the immune system to certain medications. However, there can also be cases where the cause is unknown or cannot be determined. Previous research has suggested there could be differences between EN in children and adults, but no direct comparisons have been carried out yet. In this study, we used data from the French health system to look at the records of 1440 patients (219 children and 1221 adults) who had been hospitalized for EN. We found that childhood EN was rarer and was characterized by a lower incidence rate, including being less likely to be caused by medication. Children with EN had a better prognosis, including less chance of dying of EN, than adults. Our study results suggest there could be different mechanisms behind EN in adults and children, and highlights the importance of tailoring care to the needs of children with EN.

Drugs associated with epidermal necrolysis in children: A World Health Organization pharmacovigilance database analysis.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare life-threatening mucocutaneous reactions most often induced by drugs. To date, no large pharmacovigilance study has been conducted in the paediatric population. OBJECTIVES: To describe the spectrum of drugs associated with SJS-TEN in children through the analysis of cases reported in the WHO pharmacovigilance database (VigiBase). METHODS: Disproportionality study using data from VigiBase. All paediatric (age under 18 years) cases reported between January 1, 1967, and July 6, 2022, were included. For each molecule, a case-non-case study was performed to assess a potential pharmacovigilance signal by computing the lower end of the 95% credibility interval for the information component (IC025). We performed sensitivity analyses, (i) taking into account only cases reported by physicians and (ii) taking into account only cases reported in the last 10 years. RESULTS: Among 31,376,783 adverse drug reactions reported in VigiBase, 2,248,727 were paediatric cases and 7342 were encoded as paediatric SJS-TEN. Significant statistical pharmacovigilance signals were observed for 165 drugs. The two most represented drug classes were antiepileptics and anti-infectious drugs. The five drugs with the highest IC025 were lamotrigine (IC025 4.99), carbamazepine (IC025 4.88), phenobarbital (IC025 4.67), phenytoin (IC025 4.52) and nimesulide (IC025 4.23). Acetaminophen was significantly associated with paediatric SJS-TEN (IC025 2.85) and we also described various new suspected drugs. Vaccines had no significant pharmacovigilance signal. These results were confirmed with the sensitivity analyses. CONCLUSIONS: This study updates the spectrum of drugs potentially associated with paediatric SJS-TEN.

Clinical Features, Histological Characteristics, and Disease Outcomes of Mycosis Fungoides in Children and Adolescents: A Nationwide Multicentre Cohort of 46 Patients.

BACKGROUND: Our objective was to describe the clinical, histological characteristics, and disease outcome of a cohort of mycosis fungoides (MF) diagnosed during childhood including disease status at adulthood. METHODS: This is a retrospective multicentre survey of patients aged under 18 years at diagnosis with histologically confirmed MF. Patients' clinical and histological characteristics, treatments, and disease outcome (for patients followed for more than 12 months) were analysed. RESULTS: Forty-six patients were included (median age at diagnosis: 11 years; M:F sex ratio: 3:1) with 39 (85%) followed for at least 12 months. Thirty-nine patients (85%) had stage I MF. Hypopigmented patches were observed in 48% and folliculotropism in 43% patients. Immunophenotype of the skin infiltrate was predominantly CD8+ in 17% of patients. Initial management included a wait-and-see strategy in 6/39 (15%), skin-directed treatment in 27 (69%), and systemic treatment in 6 (15%) patients, respectively, with partial or complete clinical response (PR or CR) observed in 28 patients (72%). 14/39 patients (36%) relapsed after initial response. After a median follow-up period of 54 months, disease status at last news was PR or CR in 31/39 (79%), stable disease in 6 (15%), and progression in 2 (5%) patients. Histological transformation was observed in 3/39 (8%). Of the 15 patients followed until adulthood, 13 (87%) had persistent MF. DISCUSSION: This survey confirms the high frequency of hypopigmented and folliculotropic lesions and of CD8+ immunophenotype compared to adult MF patients. The long-term course is usually indolent but transformation may occur sometimes long after disease onset and the disease may persist during adulthood.

Hypophosphatemic rickets: A rare complication of congenital melanocytic nevus syndrome.

We report the case of a child who presented with a giant melanocytic nevus with numerous satellite nevi at birth and developed hypophosphatemic rickets due to excessive secretion of the FGF23 hormone. A NRAS c.182A>G (Q61R) mutation was identified in the lesional skin. The functional outcome was favorable with medical treatment.

Incontinentia pigmenti underlies thymic dysplasia, autoantibodies to type I IFNs, and viral diseases.

Human inborn errors of thymic T cell tolerance underlie the production of autoantibodies (auto-Abs) neutralizing type I IFNs, which predispose to severe viral diseases. We analyze 131 female patients with X-linked dominant incontinentia pigmenti (IP), heterozygous for loss-of-function (LOF) NEMO variants, from 99 kindreds in 10 countries. Forty-seven of these patients (36%) have auto-Abs neutralizing IFN-α and/or IFN-ω, a proportion 23 times higher than that for age-matched female controls. This proportion remains stable from the age of 6 years onward. On imaging, female patients with IP have a small, abnormally structured thymus. Auto-Abs against type I IFNs confer a predisposition to life-threatening viral diseases. By contrast, patients with IP lacking auto-Abs against type I IFNs are at no particular risk of viral disease. These results suggest that IP accelerates thymic involution, thereby underlying the production of auto-Abs neutralizing type I IFNs in at least a third of female patients with IP, predisposing them to life-threatening viral diseases.

Ocular sequelae of epidermal necrolysis: French national audit of practices, literature review and proposed management.

Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are serious and rare diseases, most often drug-induced, and their incidence has been estimated at 6 cases/million/year in France. SJS and TEN belong to the same spectrum of disease known as epidermal necrolysis (EN). They are characterized by more or less extensive epidermal detachment, associated with mucous membrane involvement, and may be complicated during the acute phase by fatal multiorgan failure. SJS and TEN can lead to severe ophthalmologic sequelae. There are no recommendations for ocular management during the chronic phase. We conducted a national audit of current practice in the 11 sites of the French reference center for toxic bullous dermatoses and a review of the literature to establish therapeutic consensus guidelines. Ophthalmologists and dermatologists from the French reference center for epidermal necrolysis were asked to complete a questionnaire on management practices in the chronic phase of SJS/TEN. The survey focused on the presence of a referent ophthalmologist at the center, the use of local treatments (artificial tears, corticosteroid eye drops, antibiotic-corticosteroids, antiseptics, vitamin A ointment (VA), cyclosporine, tacrolimus), the management of trichiatic eyelashes, meibomian dysfunction, symblepharons, and corneal neovascularization, as well as the contactologic solutions implemented. Eleven ophthalmologists and 9 dermatologists from 9 of the 11 centers responded to the questionnaire. Based on questionnaire results, 10/11 ophthalmologists systematically prescribed preservative-free artificial tears, and 11/11 administered VA. Antiseptic or antibiotic eye drops or antibiotic-corticosteroid eye drops were recommended as needed by 8/11 and 7/11 ophthalmologists, respectively. In case of chronic inflammation, topical cyclosporine was consistently proposed by 11/11 ophthalmologists. The removal of trichiatic eyelashes was mainly performed by 10/11 ophthalmologists. Patients were referred to a reference center for fitting of scleral lenses (10/10,100%). Based on this practice audit and literature review, we propose an evaluation form to facilitate ophthalmic data collection in the chronic phase of EN and we also propose an algorithm for the ophthalmologic management of ocular sequelae.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Series of 49 French Pediatric Cases.

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare and potentially fatal adverse reaction. It can be difficult to diagnose, even more so among children, because symptoms may mimic other commonly encountered pediatric conditions. OBJECTIVE: To describe clinical and laboratory features of DRESS syndrome in the pediatric population (age ≤18 years) and establish causative agents and treatment modalities. METHODS: This was a multicenter retrospective study of probable and definite DRESS cases (Registry of Sever Cutaneous Adverse Reaction score ≥ 4) in children hospitalized in 15 French university hospitals between 2000 and 2020. RESULTS: We included 49 cases. All children had fever and rash, 69.4% had lymphadenopathy, and 65.3% had facial edema. The most common organ affected was the liver (83.7%). Treatment consisted of topical corticosteroid in only 30.6% and systemic corticosteroid in 55.1%; 12.2% received intravenous immunoglobulin. Among probable and likely culprit drugs, 65% were antibiotics and 27.5% were antiepileptics, median time to DRESS symptom onset after initiation of 15 days (13 days with antibiotics and 21 days with antiepileptics). Twenty-seven children had allergy assessment for causative agents, 65.4% of whom had positive tests. CONCLUSIONS: Culprit drugs are frequently antibiotics and antiepileptic drugs, and onset is often less than 2 weeks after treatment starts, especially with antibiotics. Treatment with topical corticosteroids appears to be sufficient in the least severe cases. Treatment by systemic corticosteroid therapy remains the reference treatment in case of severe organ damage.