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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.

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-GTPase involved in actin cytoskeleton dynamics, among many cellular functions. The role of DOCK11 in human immune disease has been long suspected but has never been described so far. We studied eight male patients, from seven 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 (B-LCL) of patients exhibited aberrant protrusions and abnormal migration speed in confined channels concomitant with altered actin polymerization during migration. A DOCK11 knock-down recapitulated these abnormal cellular phenotypes in monocytes-derived dendritic cells (MDDC) and primary activated T cells from healthy controls. Lastly, in line with the patients' autoimmune manifestations, we also observed abnormal regulatory T cells (Tregs) phenotype with profoundly reduced FOXP3 and IKZF2 expression. Moreover, we found a reduced T cell proliferation and an impaired STAT5B phosphorylation upon IL2 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 associated with abnormal actin cytoskeleton remodeling as well as Tregs phenotype culminating in immune dysregulation and severe early-onset autoimmunity.

Mastocytosis is a heterogeneous disease characterized by an abnormal accumulation of mast cells (MCs) in 1 or several organs. Although a somatic KIT D816V mutation is detected in ∼85% of patients, attempts to demonstrate its oncogenic effect alone have repeatedly failed, suggesting that additional pathways are involved in MC transformation. From 3 children presenting with both Greig cephalopolysyndactyly syndrome (GCPS, Mendelian Inheritance in Man [175700]) and congenital mastocytosis, we demonstrated the involvement of the hedgehog (Hh) pathway in mastocytosis. GCPS is an extremely rare syndrome resulting from haploinsufficiency of GLI3, the major repressor of Hh family members. From these familial cases of mastocytosis, we demonstrate that the Hh pathway is barely active in normal primary MCs and is overactive in neoplastic MCs. GLI3 and KIT mutations had a synergistic, tumorigenic effect on the onset of mastocytosis in a GCPS mouse model. Finally, Hh inhibitors suppressed neoplastic MC proliferation in vitro and extend the survival time of mice with aggressive systemic mastocytosis (ASM). This work revealed, for the first time, the involvement of Hh signaling in the pathophysiology of mastocytosis and demonstrated the cooperative effects of the KIT and Hh oncogenic pathways in mice with ASM, leading to the identification of new promising therapeutic targets.

PIK3CA -related overgrowth syndrome (PROS) is a genetic disorder caused by somatic mosaic gain-of-function mutations of PIK3CA . Clinical presentation of patients is diverse and associated with endocrine disruption. Adipose tissue is frequently involved, but its role in disease development and progression has not been elucidated. Here, we created a mouse model of PIK3CA -related adipose tissue overgrowth that recapitulates patient phenotype. We demonstrate that PIK3CA mutation leads to GLUT4 membrane accumulation with a negative feedback loop on insulin secretion, a burst of liver IGFBP1 synthesis with IGF-1 sequestration, and low circulating levels. Mouse phenotype was mainly driven through AKT2. We also observed that PIK3CA mutation induces metabolic reprogramming with Warburg-like effect and protein and lipid synthesis, hallmarks of cancer cells, in vitro, in vivo, and in patients. We lastly show that alpelisib is efficient at preventing and improving PIK3CA -adipose tissue overgrowth and reversing metabolomic anomalies in both animal models and patients.

Eosinophilic pustular folliculitis of infancy is a sterile, inflammatory dermatosis that mainly affects children younger than 36 months. The underlying physiopathologic mechanism is unclear. Clinical diagnosis is challenging, and a skin biopsy may be necessary. The literature data are sometimes contradictory, and a histologic series of eosinophilic pustular folliculitis of infancy cases has not been previously published.

International audience; No abstract available

Malignant superficial mesenchymal tumors are a very diverse group of neoplasms with few clinical and radiological discriminatory factors. Hence, some of these cancers are rarely suspected based on clinical and radiological grounds, others may be easily misdiagnosed, and the histological analysis of a biopsy or resection is central in the diagnostic process. In children, the age at presentation is a major element of the differential diagnosis. Some tumors have a very distinct epidemiology, while others may be seen at any age. More recently, the advances in molecular biology have greatly improved the diagnosis of mesenchymal tumors and new entities are still being described. In the present review, we provide an overview of the diversity of malignant superficial mesenchymal tumors in children, including new and/or rare entities. We discuss the important diagnostic features, be they clinical, histological, or molecular. Special attention was given to the genetic features of these tumors, particularly when they were helpful for the diagnosis or treatment.

Resume Introduction La mucinose cutanee juvenile auto-involutive (MCJAI) est une entite stereotypee chez l’enfant, caracterisee par l’apparition rapide de papules et nodules sous-cutanes sur le visage, le dos des mains et les regions periarticulaires, spontanement resolutives en un temps variable. Quelques cas chez l’adulte ont ete rapportes mais avec des aspects cliniques et histopathologiques plus heterogenes. Nous rapportons une MCJAI chez une femme adulte avec une presentation clinique superposable a celle de l’enfant. Observation Une patiente de 36 ans aux antecedents de maladie de Willebrand etait adressee en consultation pour l’apparition rapide de nodules sous-cutanes du visage, des mains et des grosses articulations ainsi qu’un œdeme peri-orbitaire. L’histologie sur exerese de 3 nodules montrait un depot de mucine dans le derme dissociant les fibres de collagene. Une maladie auto-immune, une neoplasie, une infection ainsi qu’une dysthyroidie ont ete eliminees. Il existait egalement un syndrome du canal carpien bilateral confirme a l’electromyogramme, chez cette patiente ayant une activite professionnelle manuelle. Un traitement par hydroxychloroquine n’a pas montre d’efficacite claire. A 1 an et demi d’evolution, les lesions avaient partiellement regresse. Conclusion Un tableau de MCJAI, decrit dans une population pediatrique, peut aussi exister plus rarement chez l’adulte. Peut-on conserver la denomination de mucinose juvenile?

Fibrosarcomatous transformation of dermatofibrosarcoma protuberans is associated with a significantly worse prognosis in adults, but is a very rare feature in the pediatric population. Here, we report a case that occurred in a child. The diagnosis of fibrosarcomatous transformation of dermatofibrosarcoma protuberans was confirmed by a histopathological assessment and fluorescence in situ hybridization. A comparison with eleven other patients reported in the literature revealed that the local recurrence and mortality rates in children are similar to those observed in adults.

Background Incontinentia pigmenti (IP) is a rare multisystemic X-linked dominant genetic disorder characterized by highly diagnostic skin lesions. The disease can be misdiagnosed in infants, and complications affecting the eyes and/or the brain can be severe. Our objective was to highlight the urgency of an appropriate diagnosis and management strategy, as soon as the first symptoms appear, and the need for a well-codified monitoring strategy for each child. Methods An in-depth literature review using a large number of databases was conducted. The selection criteria for articles were literature review articles on the disease, case series and retrospective studies based on the disease, clinical studies (randomized or not) on treatment, articles discussing patient care and management (treatment, diagnosis, care pathways), and recommendations. The research period was from 2000 until 2018. A group of multidisciplinary experts in IP management was involved, issued from different healthcare providers of the European Network for Rare Skin Diseases (ERN-Skin). The final recommendations have been submitted to two patient representative associations and to a general practitioner and a neonatal specialist prior to their finalization. Results and conclusion The diagnosis of IP must be promptly performed to detect potential extracutaneous manifestations, thus allowing the timely implementation of specific therapeutic and monitoring strategies. Eye involvement can be a therapeutic urgency, and central nervous system (CNS) involvement requires a very rigorous long-term follow-up. Assessments and patient support should take into account the possible co-occurrence of various symptoms (including motor, visual and cognitive symptoms).

Resume Le diagnostic des proliferations fibroblastiques et myofibroblastiques (PFMF) de l’enfant est difficile car la presentation clinique est souvent peu specifique. Les PFMF representent 12 % des tumeurs des tissus mous dans cette tranche d’âge, allant d’entites benignes ou reactionnelles jusqu’a des entites a potentiel incertain ou malignes. Le diagnostic final repose sur un faisceau de donnees cliniques (aspect, âge de l’enfant, siege, nombre de lesions, evolution) et histologiques. La biologie moleculaire permet egalement desormais de mieux classer certaines de ces entites, l’objectif restant de permettre la prise en charge therapeutique la plus adaptee possible notamment a l’avenir avec des possibilites de therapies ciblees.

Introduction: Pityriasis lichenoides (PL) is an infrequent skin disorder. The clinical manifestations are usually specific enough for a reliable diagnosis, although the histopathological assessment of a biopsy is sometimes needed to differentiate between PL and a range of other diseases. The objectives of this study were to review cases of PL managed in our hospital, confirm the classical histopathological features of PL, and identify signs that may be of value in the diagnosis of PL. Materials and Methods: All cases of PL assessed in our pathology department between January 2007 and December 2017 were retrieved, and all slides were reviewed. Cases were selected only if a diagnosis of PL was initially suggested by a dermatologist and then confirmed by the histopathological assessment. Results: Seventy-one cases met the study criteria. The following features were almost always present: vacuolar changes or necrotic keratinocytes (100%), both superficial and deep lymphocytic infiltrates (99%), and the infiltration of lymphocytes into the adnexal epithelium (97%). The inflammatory cells were always small- to medium-sized lymphocytes. There were no eosinophilic infiltrates. Superficial perivascular and/or intraepidermal red blood cells were observed in 83% of cases. Discussion: We highlighted the presence of a deep dermal lymphocytic infiltrate, with a "T-shaped" periadnexal arrangement along the full length of the follicular and sudoral epithelia. This might be a feature that enables the differentiation of PL from other diseases. Our findings also prompted a number of physiopathological hypotheses for PL. Conclusions: Our present results confirmed the classical histological aspects of PL and provided some useful new diagnostic features.

Contains fulltext : 249882.pdf (Publisher’s version ) (Closed access) ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity.

Resume Introduction Les syndromes d’immunodeficience congenitale sont rares et leur pronostic est mauvais. Ils debutent parfois par des signes cutanes isoles qui peuvent egarer le diagnostic et retarder une prise en charge specifique. Nous presentons un cas de syndrome IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked syndrome) qui illustre cette situation. Observation Un enfant de deux mois et demi etait vu pour une eruption psoriasiforme. Malgre des applications de dermocorticoides, les lesions evoluaient rapidement vers une erythrodermie ichtyosiforme. La biopsie cutanee trouvait des necroses keratinocytaires associees a un infiltrat lymphocytaire dermique dense, CD8+, epidermotrope. Les taux d’eosinophiles sanguins et d’IgE totales etaient eleves. Par la suite apparaissait une enteropathie avec diarrhees profuses, un choc hypovolemique et une septicemie entrainant un arret cardio-respiratoire. La presence de la mutation du gene FOXP3 conduisait au diagnostic de syndrome IPEX. L’evolution etait finalement favorable apres greffe de moelle allogenique. Discussion Le syndrome IPEX comporte principalement une enteropathie severe, des manifestations dermatologiques et un diabete de type I. Les symptomes debutent habituellement en periode neonatale precoce et l’evolution est souvent letale. Les lesions cutanees peuvent prendre un aspect eczematiforme, psoriasiforme ou ichtyosiforme. Elles constituent parfois le premier signe de la maladie et le diagnostic d’une dermatose inflammatoire benigne peut etre porte a tort. C’est le caractere severe de la dermatose et sa resistance aux dermocorticoides qui doivent alerter le clinicien. Conclusion La survenue d’une dermatose neonatale rapidement evolutive et resistante aux dermocorticoides doit inciter a la realisation d’une biopsie cutanee precoce. Si celle-ci montre un infiltrat lymphocytaire cytotoxique avec necroses keratinocytaires, elle orientera vers le diagnostic d’un deficit immunitaire primitif et permettra d’entreprendre rapidement un traitement specifique.

Lymphatic cystic malformations are rare genetic disorders mainly due to somatic gain-of-function mutations in the PIK3CA gene. These anomalies are frequently associated with pain, inflammatory flar...

AIMS The diagnosis of mastocytosis in skin biopsies can be challenging - particularly in cases with very few mast cells. More diagnostic criteria are needed. METHODS AND RESULTS We analyzed 103 skin biopsies from patients with mastocytosis and compared them with biopsies from inflammatory skin lesions and normal skin. Using CD117 immunostaining, we determined the mast cell distribution pattern, the percentage of mast cells in the inflammatory infiltrate, and the mast cell count per mm². We found that a sheet-like or subepidermal distribution of mast cells was specific for mastocytosis. The most significant feature was the percentage of mast cells and not the mast cell count. We found that a mast cell percentage above 40% was fully specific in both adults and children but lacked sensitivity, especially in adults. In children, all cases with a percentage below 40% harbored a number of mast cells above 90 per mm², allowing a straightforward diagnosis. In adults, the diagnosis was more challenging and cases with less than 40% of mast cells could be diagnosed on account of a number of mast cells above 40 per mm², with 88.5% sensitivity and 95.2% specificity. Additional signs might be useful in difficult cases. However, CD25 immunostaining was not useful. CONCLUSIONS We confirmed that the criteria currently applied in the bone marrow were not appropriate for the skin. Accordingly, we developed an algorithm for the diagnosis of mastocytosis in skin biopsies with a high level of interrater reproducibility (mean kappa 0.8).

Cutaneous histiocytoses constitute a heterogeneous group of diseases characterised by the cutaneous accumulation of cells with the cytological and phenotypic features of macrophages or dendritic cells. The clinical spectrum ranges from self-resolving, skin-limited conditions to severe, multiorgan disease with a high morbidity rate. Until recently, cutaneous histiocytoses were classified according to the immunophenotype of the pathological cells, with differentiation between Langerhans cell histiocytosis (LCH) [CD1a+, CD207 (langerin)+] and non-Langerhans cell histiocytosis (CD68+, CD163+, CD1a-, CD207-). Over the last 12 years, a number of new pathophysiological findings (in particular, molecular pathology results) regarding histiocytoses have contributed to a new classification based on molecular alterations, as well as on clinical and imaging characteristics and the phenotype. The most frequent entities in children are juvenile xanthogranuloma and LCH.

Mitochondrial DNA (mtDNA) has been suggested to drive immune system activation, but the induction of interferon signaling by mtDNA has not been demonstrated in a Mendelian mitochondrial disease. We initially ascertained two patients, one with a purely neurological phenotype and one with features suggestive of systemic sclerosis in a syndromic context, and found them both to demonstrate enhanced interferon-stimulated gene (ISG) expression in blood. We determined each to harbor a previously described de novo dominant-negative heterozygous mutation in ATAD3A, encoding ATPase family AAA domain-containing protein 3A (ATAD3A). We identified five further patients with mutations in ATAD3A and recorded up-regulated ISG expression and interferon α protein in four of them. Knockdown of ATAD3A in THP-1 cells resulted in increased interferon signaling, mediated by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Enhanced interferon signaling was abrogated in THP-1 cells and patient fibroblasts depleted of mtDNA. Thus, mutations in the mitochondrial membrane protein ATAD3A define a novel type I interferonopathy. ispartof: JOURNAL OF EXPERIMENTAL MEDICINE vol:218 issue:10 ispartof: location:United States status: published

Hypomelanosis of Ito (HI) is a skin marker of somatic mosaicism. Mosaic MTOR pathogenic variants have been reported in HI with brain overgrowth. We sought to delineate further the pigmentary skin phenotype and clinical spectrum of neurodevelopmental manifestations of MTOR-related HI. From two cohorts totaling 71 patients with pigmentary mosaicism, we identified 14 patients with Blaschko-linear and one with flag-like pigmentation abnormalities, psychomotor impairment or seizures, and a postzygotic MTOR variant in skin. Patient records, including brain magnetic resonance image (MRI) were reviewed. Immunostaining (n = 3) for melanocyte markers and ultrastructural studies (n = 2) were performed on skin biopsies. MTOR variants were present in skin, but absent from blood in half of cases. In a patient (p.[Glu2419Lys] variant), phosphorylation of p70S6K was constitutively increased. In hypopigmented skin of two patients, we found a decrease in stage 4 melanosomes in melanocytes and keratinocytes. Most patients (80%) had macrocephaly or (hemi)megalencephaly on MRI. MTOR-related HI is a recognizable neurocutaneous phenotype of patterned dyspigmentation, epilepsy, intellectual deficiency, and brain overgrowth, and a distinct subtype of hypomelanosis related to somatic mosaicism. Hypopigmentation may be due to a defect in melanogenesis, through mTORC1 activation, similar to hypochromic patches in tuberous sclerosis complex.

Necrotizing infundibular crystalline folliculitis is a rare condition characterized by folliculocentric waxy papules in the seborrheic areas of adult patients, with intrafollicular filamentous birefringent crystalline deposits as the histopathologic clue. Although the real pathogenesis of necrotizing infundibular crystalline folliculitis remains unclear, the intrafollicular material seems to be derived from an interaction between such superficial microorganisms as gram-positive bacteria (Propionibacterium acnes, Staphylococcus spp), Malassezia yeasts, and sebaceous lipids. Topical or systemic antiacne agents or antimycotics appear to be effective therapy.

International audience; BACKGROUND: Paediatric cutaneous granuloma with primary immunodeficiency (PID) is a rare condition. The physiopathology is unclear, and treatment is challenging. We report on 17 paediatric cases and review the literature.OBJECTIVES: To make dermatologists and dermatopathologists aware of the diagnostic value of skin granulomas in paediatric PID.METHODS: We collected data on 17 patients with cutaneous granulomas and PID registered with us and also reviewed 33 cases from the literature.RESULTS: Cutaneous granuloma was the presenting feature of the PID in 15 of the 50 collated cases. The lesions presented as red-brownish nodules and infiltrated ulcerative plaques, predominantly on the face and limbs. Scleroderma-like infiltration on a single limb was observed in 10% of the cases. The associated PID was ataxia-telangiectasia (52%), combined immunodeficiency (24%), cartilage-hair hypoplasia (6%) and other subtypes (18%). The granulomas were mostly sarcoidal, tuberculoid, palisaded or undefined subtypes. In some patients, several different histopathologic granulomatous patterns were found in the same biopsy. Some granulomas were associated with the presence of a vaccine strain of rubella virus.CONCLUSION: Cutaneous granulomas associated with a PID have a variable clinical presentation. A PID can be suspected when crusty, brownish lesions are found on the face or limbs. The concomitant presence of several histological subtypes in a single patient is suggestive of a PID.

Resume Le pathologiste doit se familiariser avec les principaux aspects de l'immunofluorescence directe en dermatologie, poser au mieux les indications de celle-ci, et apprendre a eviter les pieges potentiels. L'immunofluorescence directe est une technique de microscopie permettant la detection d'immunoglobulines/complexes immuns et de fractions du complement (IgG, IgA, IgM et C3) dans les tissus en utilisant des anticorps specifiques conjugues a de la fluoresceine et un microscope a fluorescence. Elle est indispensable en dermatopathologie pour le diagnostic des maladies bulleuses auto-immunes, telles que la pemphigoide bulleuse, le pemphigus, la dermatite herpetiforme, et peut se reveler utile egalement dans d'autres indications, telles que le lupus et les vascularites.

BRAF postzygotic activating mutations have been found in 50% of cases of syringocystadenoma papilliferum (SCAP)1 and in phacomatosis pigmentokeratotica (PPK)2,3 , also possibly caused by HRAS4 mutations. BRAF is a RAS-activating serine/threonine kinase of the MAP kinase pathway, resulting in cell growth and proliferation. BRAF mutations, particularly p.(Val600Glu), are frequently identified in melanoma and other human cancers5 . We report clinical presentations of three patients with postzygotic BRAF mutations in affected skin, identified by next generation sequencing (NGS).

Introduction Masses of the penis are uncommon, especially in the pediatric population, and they need to be promptly assessed and biopsied. We present what we believe to be the first case of rapidly recurring case of glans and foreskin verrucous epithelial hyperplasia, a premalignant lesion. The young patient, a 13-year-old uncircumcised teenager, presented an itching lesion growing over four months and rapidly recurring after resection.

Histiocytoses constitute a heterogeneous group of rare disorders, characterised by infiltration of almost any organ by myeloid cells with diverse macrophage or dendritic cell phenotypes. Histiocytoses can start at any age. Diagnosis is based on histology in combination with appropriate clinical and radiological findings. The low incidence and broad spectrum of clinical manifestations often leads to diagnostic delay, especially for adults. In most cases, biopsy specimens infiltrated by histiocytes have somatic mutations in genes activating the MAP kinase cell-signalling pathway. These mutations might also be present in blood cells and haematopoietic progenitors of patients with multisystem disease. A comprehensive range of investigations and molecular typing are essential to accurately predict prognosis, which can vary from spontaneous resolution to life-threatening disseminated disease. Targeted therapies with BRAF or MEK inhibitors have revolutionised salvage treatment. However, the type and duration of treatment are still debated, and the prevention of neurological sequelae remains a crucial issue.

Mitochondrial DNA (mtDNA) has been suggested to drive immune system activation, but the induction of interferon signaling by mtDNA has not been demonstrated in a Mendelian mitochondrial disease. We initially ascertained two patients, one with a purely neurological phenotype, and one with features suggestive of systemic sclerosis in a syndromic context, and found them both to demonstrate enhanced interferon-stimulated gene (ISG) expression in blood. We determined each to harbor a previously described de novo dominant-negative heterozygous mutation in ATAD3A, encoding ATPase family AAA domain-containing protein 3A (ATAD3A). We identified five further patients with mutations in ATAD3A, and recorded up-regulated ISG expression and interferon alpha protein in four of them. Knockdown of ATAD3A in THP-1 cells resulted in increased interferon signaling, mediated by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Enhanced interferon signaling was abrogated in THP-1 cells and patient fibroblasts depleted of mtDNA. Thus, mutations in the mitochondrial membrane protein ATAD3A define a novel type I interferonopathy.SummaryDominant-negative mutations in ATAD3A, a ubiquitously expressed mitochondrial protein, cause mitochondrial DNA-dependent up-regulation of type I interferon signaling in the context of neurological disease and autoimmunity, thereby defining a novel type I interferonopathy.