BACKGROUND: Cogan´s syndrome is a rare, presumed autoimmune vasculitis of various vessels characterized by interstitial keratitis and vestibular impairment accompanied by sensorineural hearing loss. Due to the rarity of Cogan´s syndrome in children, therapeutic decision making may be challenging. Therefore, a literature search was performed to collect all published paediatric Cogan´s syndrome cases with their clinical characteristics, disease course, treatment modalities used and their outcome. The cohort was supplemented with our own patient. MAIN TEXT: Altogether, 55 paediatric Cogan´s syndrome patients aged median 12 years have been reported so far. These were identified in PubMed with the keywords "Cogan´s syndrome" and "children" or "childhood". All patients suffered from inflammatory ocular and vestibulo-auditory symptoms. In addition, 32/55 (58%) manifested systemic symptoms with musculoskeletal involvement being the most common with a prevalence of 45%, followed by neurological and skin manifestations. Aortitis was detected in 9/55 (16%). Regarding prognosis, remission in ocular symptoms was attained in 69%, whereas only 32% achieved a significant improvement in auditory function. Mortality was 2/55. Our patient was an 8 year old girl who presented with bilateral uveitis and a history of long standing hearing deficit. She also complained of intermittent vertigo, subfebrile temperatures, abdominal pain with diarrhoea, fatigue and recurrent epistaxis. The diagnosis was supported by bilateral labyrinthitis seen on contrast-enhanced magnetic resonance imaging. Treatment with topical and systemic steroids was started immediately. As the effect on auditory function was only transient, infliximab was added early in the disease course. This led to a remission of ocular and systemic symptoms and a normalization of hearing in the right ear. Her left ear remained deaf and the girl is currently evaluated for a unilateral cochlear implantation. CONCLUSIONS: This study presents an analysis of the largest cohort of paediatric Cogan´s syndrome patients. Based on the collected data, the first practical guide to a diagnostic work-up and treatment in children with Cogan´s syndrome is provided.

• Keywords
• Children, Clinical characteristics, Cogan´s syndrome, Course, Outcome, Practical approach,
• MeSH
• Apraxias * congenital   MeSH
• Cogan Syndrome * complications   diagnosis   therapy   MeSH
• Child MeSH
• Keratitis * diagnosis   therapy   complications   MeSH
• Humans MeSH
• Hearing Loss, Sensorineural * diagnosis   etiology   therapy   MeSH
• Prognosis MeSH
• Disease Progression MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Review MeSH

Hereditary mutations in polynucleotide kinase-phosphatase (PNKP) result in a spectrum of neurological pathologies ranging from neurodevelopmental dysfunction in microcephaly with early onset seizures (MCSZ) to neurodegeneration in ataxia oculomotor apraxia-4 (AOA4) and Charcot-Marie-Tooth disease (CMT2B2). Consistent with this, PNKP is implicated in the repair of both DNA single-strand breaks (SSBs) and DNA double-strand breaks (DSBs); lesions that can trigger neurodegeneration and neurodevelopmental dysfunction, respectively. Surprisingly, however, we did not detect a significant defect in DSB repair (DSBR) in primary fibroblasts from PNKP patients spanning the spectrum of PNKP-mutated pathologies. In contrast, the rate of SSB repair (SSBR) is markedly reduced. Moreover, we show that the restoration of SSBR in patient fibroblasts collectively requires both the DNA kinase and DNA phosphatase activities of PNKP, and the fork-head associated (FHA) domain that interacts with the SSBR protein, XRCC1. Notably, however, the two enzymatic activities of PNKP appear to affect different aspects of disease pathology, with reduced DNA phosphatase activity correlating with neurodevelopmental dysfunction and reduced DNA kinase activity correlating with neurodegeneration. In summary, these data implicate reduced rates of SSBR, not DSBR, as the source of both neurodevelopmental and neurodegenerative pathology in PNKP-mutated disease, and the extent and nature of this reduction as the primary determinant of disease severity.

• MeSH
• Apraxias genetics   pathology   MeSH
• Charcot-Marie-Tooth Disease genetics   pathology   MeSH
• DNA Breaks, Double-Stranded * MeSH
• DNA Repair Enzymes genetics   MeSH
• Fibroblasts metabolism   pathology   MeSH
• Phosphotransferases (Alcohol Group Acceptor) genetics   MeSH
• DNA Breaks, Single-Stranded * MeSH
• Humans MeSH
• Microcephaly genetics   pathology   MeSH
• Mutation genetics   MeSH
• DNA Repair genetics   MeSH
• X-ray Repair Cross Complementing Protein 1 genetics   MeSH
• Seizures genetics   pathology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• DNA Repair Enzymes MeSH
• Phosphotransferases (Alcohol Group Acceptor) MeSH
• PNKP protein, human MeSH Browser
• X-ray Repair Cross Complementing Protein 1 MeSH
• XRCC1 protein, human MeSH Browser