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PubMed2026

Whole exome sequencing of paediatric patients with Cogan's syndrome to identify monogenic mimics.

OBJECTIVES: Cogan's syndrome (CS) is a rare variable vessel vasculitis, describing sensorineural hearing loss (SNHL), inflammatory ocular disease and vestibular dysfunction. We hypothesized that within paediatric-onset (p)CS, a proportion would have monogenic disease, either autoinflammatory and/or associated with SNHL. METHODS: Whole exome sequencing (WES) was performed and analysed using an in-house pipeline incorporating virtual gene panels for inflammation and SNHL; copy number variant analysis (ExomeDepth); and phenotype-driven variant prioritization (Exomiser). Genetic variants were interpreted by a multi-disciplinary team according to American College of Medical Genetics and Genomics guidelines. RESULTS: Ten patients with a clinical diagnosis of pCS were enrolled. Three/10 (30%) had a monogenic contribution to the phenotype based on Class 4/5 variants: de novo NLRP3 p.T915R (n = 1) associated with Cryopyrin-associated periodic syndrome; MYO7A p.K542Qfs*5 (n = 1) causing SNHL; and HBB homozygous p.E7V causing sickle cell disease (associated with hearing loss and uveitis). A further two cases had possible monogenic contribution with the following rare variants of uncertain significance (class 3): ADGRV1 compound heterozygous variants (n = 1) associated with Usher syndrome; and a novel ALPK1 p.H735P (n = 1), associated with Retinal dystrophy Optic nerve oedema Splenomegaly Anhidrosis Headache (ROSAH) syndrome. CONCLUSIONS: In children presenting with features suggesting CS, genetic screening should be considered before conferring this rare diagnostic label since at least 30% had an alternative monogenic contribution to the phenotype rather than true pCS, with implications for treatment and prognosis. We thus advocate for genetic testing using next-generation sequencing for patients presenting with pCS.

Humans↗
PubMed2026

Neonatal Aicardi-Goutières syndrome presenting with macrophage activation syndrome-like hyperinflammation and severe congenital glaucoma: a case report.

BACKGROUND: Neonatal-onset Aicardi-Goutières syndrome (AGS) is a rare monogenic type I interferonopathy that may mimic congenital infection and can present with severe multisystem inflammation. The distinction between primary hemophagocytic lymphohistiocytosis (HLH) and AGS-associated macrophage activation syndrome (MAS)-like hyperinflammation can be challenging in neonates. CASE PRESENTATION: We report a term neonate presenting with cholestatic jaundice, a generalized blueberry muffin-like ecchymotic-purpuric rash, cytopenias, hyperferritinemia, hepatosplenomegaly, intracranial calcifications, and severe bilateral congenital glaucoma. Extensive infectious evaluation was negative. The patient fulfilled five of eight HLH-2004 criteria, consistent with a severe MAS-like hyperinflammatory phenotype. Dexamethasone and intravenous immunoglobulin had been initiated at the referring center for presumed virus-associated HLH but were not continued after transfer to our unit. With persistent disease activity, negative microbiological studies, and neuroimaging strongly suggestive of a type I interferonopathy, ruxolitinib was initiated on day of life (DOL) 34 before molecular confirmation. Exome sequencing subsequently identified homozygous pathogenic variants in RNASEH2B and CYP1B1, supporting AGS type 2 and primary congenital glaucoma (glaucoma 3 A), respectively. Serial laboratory data showed sustained improvement after initiation of JAK1/2 inhibition, although the observational nature of a single case and other immunomodulatory exposures limit causal attribution. CONCLUSIONS: This case illustrates the clinical overlap between neonatal AGS and MAS-like hyperinflammation, underscores the potential role of early mechanism-based therapy in selected critically ill neonates with suspected interferonopathy, and emphasizes the importance of comprehensive genomic evaluation when severe ocular disease accompanies AGS. The identified CYP1B1 variant provides a strong molecular explanation for the patient's congenital glaucoma.

Humans↗
PubMed2026

Clinical and biochemical footprints of inherited disorders of autophagy.

Autophagy is an evolutionarily conserved lysosomal recycling system that integrates nutrient sensing, organelle quality control, proteostasis, cellular stress responses and metabolic adaptation. Autophagy is particularly relevant for post-mitotic tissue such as neurons, skin, and immune cells. Monogenic disorders disrupting autophagy or closely coupled endolysosomal trafficking pathways have recently emerged as a recognizable group of inherited metabolic diseases. These conditions are individually rare inborn errors of metabolism and collectively important because they bridge neurodevelopmental, neuromuscular and neurodegenerative disorders, including hereditary forms of Parkinson's disease, spastic paraplegias and neurodegeneration with brain iron accumulation. Multisystem involvement is common but variable. The prototypic disorder is EPG5-related Vici syndrome, in which defective autophagosome-lysosome fusion causes severe neurodevelopmental and multisystem disease. Other disorders may affect any step of the pathway, from phosphatidylinositol 3-phosphate effector biology and ATG conjugation/lipidation to autophagosome maturation, ATG9 trafficking, HOPS/CORVET-related vesicle trafficking (including VPS16 and VPS33A), autophagosome-lysosome fusion, autolysosome reformation and lysosome-mTOR signaling. Clinically, affected individuals commonly present with global developmental delay and/or intellectual disability, epilepsy, movement disorders including dystonia, parkinsonism, ataxia and spasticity, and both neuropathic and myopathic neuromuscular manifestations. A biphasic course with progressive neurodegeneration and variable multisystem (including ocular, cardiac, immunological, cutaneous and growth) involvement are important clinical clues. Diagnosis relies on careful phenotyping, brain MRI, targeted metabolic exclusion of mimics, genomic sequencing and functional assays in patient-derived cells as required. Supportive multidisciplinary management is essential. No disease-modifying therapy is currently established in humans, but pathway-based cellular assays, model systems and small-molecule or gene-replacement strategies are creating a rational therapeutic pipeline. Importantly, IEMbase dyadic nomenclature with system-level clinical annotations provides a standardized framework for quantifying shared phenotypic signatures across these ultra-rare conditions. This review summarizes pathobiochemistry, genetics, clinical presentation, diagnosis and treatment prospects for inherited disorders of autophagy.

Autophagosome↗