チャージ症候群

BACKGROUND: CHARGE syndrome is a rare congenital genetic disorder caused by variants in CHD7 gene. The acronym "CHARGE" represents its primary features: coloboma of the iris or retina, heart defects, choanal atresia, retardation of growth and development, genital anomalies, and ear anomalies including hearing loss. Craniofacial and oral abnormalities are a significant component of its clinical spectrum and often complicate conventional dental care, necessitating reliance on pharmacological behavior management techniques. CASE REPORT: We report the case of a 4-year-old boy with CHARGE syndrome who underwent full-mouth dental rehabilitation under general anesthesia. Owing to extensive dental disease, anticipated airway difficulty, and multiple systemic comorbidities, comprehensive multidisciplinary planning and specialized anesthetic management were undertaken. Treatment was completed successfully, with improved oral function and quality of life at follow-up. CONCLUSION: This case underscores the importance of meticulous treatment planning, specialized airway management, and perioperative monitoring, as well as the value of an interdisciplinary team in ensuring safe and effective care. To our knowledge, this is one of the few reports detailing the dental and anaesthetic considerations and management strategies for a child with CHARGE syndrome.

BACKGROUND: Subtotal petrosectomy (STP) is a radical otologic procedure aimed at complete eradication of diseased temporal bone air cells and creation of a closed, sterile cavity. While well established in adult otology, its role in pediatric patients remains insufficiently described. OBJECTIVES: To analyze current indications, outcomes and complication rates of subtotal petrosectomy in a pediatric population, with particular emphasis in age - related patterns of indications. MATERIALS AND METHODS: A retrospective review was conducted of 20 children (<18 years) who underwent STP between 2010 and 2024 at two tertiary referral centers. Patients were analyzed according to age groups (≤6 years vs. >6 years) and etiology, categorized as congenital (including congenital malformations, CHARGE syndrome and congenital CSF leaks) or acquired (cholesteatoma, chronic otitis media, traumatic and oncological lesions). Major and minor complications were recorded and analyzed using non - parametric statistical methods. RESULTS: The cohort included 15 boys and 5 girls with a mean follow-up of 4.3 ± 1.2 years. Congenital indications predominated in children ≤6 years, whereas acquired pathologies were significantly more common in older children (>6 years) (Fisher's exact test, p = 0.018). Patients treated for congenital indications were significantly younger than those with acquired pathologies (p = 0.0095). Major complications occurred in 2 of 20 patients (10%, 95% confidence interval 1,2-31,7%), including cholesteatoma recurrence requiring revision surgery and conversion to an open technique. Minor complications were observed in one patient (5%) and consisted of an abdominal hematoma). No cases of implant loss, permanent facial nerve palsy or wound dehiscence were observed. CONCLUSIONS: STP is a safe and effective procedure in selected pediatric patients, with low rates of major complications. Indications differ significantly by age, with congenital pathology predominating in younger children and acquired in older patients. In children, STP should be regarded not as salvage procedure but as a reconstructive strategy providing a stable anatomical foundation for long term hearing rehabilitation and disease control.

In eukaryotes, DNA is not a naked repository of genetic information but is tightly wound around histone octamers to form nucleosomes. While this packaging solves the spatial problem of fitting 2 meters of DNA into a microscopic nucleus, it creates a massive accessibility problem for DNA-templated events, including transcription, replication, and DNA repair. Here, we review how the chromodomain helicase DNA-binding (CHD) family of ATP-dependent nucleosome remodelers act as the molecular acrobats of the chromatin accessibility landscape. We highlight that the three CHD subfamilies represent a developmental division of labor: subfamily I maintains pluripotent chromatin accessibility, subfamily II drives lineage commitment through chromatin closure, and subfamily III establishes tissue-specific enhancer and promoter accessibility during organogenesis. By dynamically transforming chromatin architecture through nucleosome sliding, spacing, and ejection, CHD remodelers license the transitions between cell states, ensuring that the epigenetic landscape is reshaped for the specific needs of a stem cell today and a differentiated cell type tomorrow. We discuss how disruption of this licensing, through mutation or loss of family members, leads to severe neurodevelopmental disorders, including CHARGE syndrome, autism spectrum disorder, and intellectual disability. We close by raising outstanding questions including how CHD activity is regulated, how co-expressed paralogs coordinate their activities, and whether CHD dysfunction can be therapeutically targeted.

BACKGROUND: TANGO2 deficiency disorder is an ultra-rare autosomal recessive condition characterized by life-threatening metabolic crises with rhabdomyolysis and cardiac arrhythmias. Patients with 22q11.2 deletion syndrome are at increased risk when a pathogenic variant occurs in the remaining allele, yet this dual diagnosis remains underrecognized as clinicians often attribute all manifestations to the primary genetic condition. We report a case of a child with confirmed 22q11.2 deletion syndrome in whom a coexisting variant in the TANGO2 gene was diagnosed at the age of 5 after first metabolic crisis with rhabdomyolysis. CASE PRESENTATION: A girl with 22q11.2 deletion syndrome diagnosed in infancy exhibited global developmental delay and chronic excessive sleepiness attributed to her established diagnosis. At age 5, she experienced her first metabolic crisis during pneumonia with severe rhabdomyolysis (creatine kinase >100,000 U/L), features inconsistent with isolated 22q11.2 deletion syndrome. Two additional metabolic crises occurred at age 7 before exome sequencing revealed a hemizygous TANGO2 variant c.536G>A, confirming TANGO2 deficiency. A previously unreported hemizygous missense variant c.536G>A (p.Gly138Glu) in the TANGO2 gene (NM_152906.7) was identified and verified by NGS-based deep amplicon sequencing and Sanger direct sequencing; segregation analysis confirmed paternal inheritance with the maternal allele deleted within the 22q11.2 region. Following diagnosis, B-vitamin supplementation, coenzyme Q10, L-carnitine, and gastrostomy tube placement were initiated to ensure consistent hydration and prevent prolonged periods without nutrition, a known crisis trigger. The patient achieved 4 years of crisis-free stability with reduced daytime sleepiness. At age 11, she remains stable without further crises. CONCLUSIONS: This case demonstrates that exome sequencing should be pursued early when atypical features emerge in patients with established genetic diagnoses. The sustained crisis-free period following gastrostomy placement supports proactive nutritional intervention in TANGO2 patients with feeding difficulties. Clinicians must recognize that microdeletion syndrome patients can harbor variants unmasking additional autosomal recessive conditions requiring distinct management.

Cancer-associated cachexia is a devastating syndrome characterized by progressive weight loss, reduced survival, and impaired responses to anticancer therapies. Growth differentiation factor 15 (GDF15), acting through its receptor GFRAL, has emerged as a key mediator of cachexia, yet effective and mechanistically defined strategies to neutralize this pathway remain limited. Here, we applied structure-guided de novo protein design to generate compact minibinders that selectively target the GDF15-GFRAL interaction interface. Using an integrated computational pipeline combining RFdiffusion, ProteinMPNN, and AlphaFold 3 structure prediction, we designed and experimentally validated high-affinity GDF15 minibinders with picomolar-range binding affinities and exceptional structural stability. Mutagenesis and charge-complementary rescue experiments confirm that these minibinders neutralize GDF15 through precisely engineered interface contacts. Functionally, the minibinders suppress GDF15-GFRAL signaling, inhibit downstream transcriptional responses, and robustly reverse cachexia in vivo across multiple tumor models, resulting in significant improvements in body weight and survival. Importantly, neutralization of GDF15 also restores sensitivity to anti-PD-1 immunotherapy in a GDF15-driven resistant tumor model. Combination treatment enhances CD8+ T cell infiltration and effector function within tumors, and its antitumor efficacy is strictly dependent on CD8+ T cells. Together, these findings demonstrate that de novo designed GDF15 minibinders can achieve potent, mechanism-defined neutralization of the GDF15-GFRAL axis in vivo, translating into robust physiological benefits and restoration of immunotherapy efficacy.