Expanding the phenotypic spectrum of TRAF7 syndrome: report of eleven new cases and literature review

Abstract

ABSTRACTTRAF7 syndrome, a multisystemic neurodevelopmental disorder caused by germline missense variants in theTRAF7gene, exhibits heterogeneous clinical presentations. We present a detailed description of eleven new TRAF7 syndrome cases, featuring eight distinct variants, including a novel one. Phenotypic analysis and a comprehensive review of the 58 previously reported cases outline consistent clinical presentations, emphasizing dysmorphic features, developmental delay, endocrine manifestations, and cardiac defects. In this enlarged collection, novelties include a wider range of cognitive dysfunction, with some individuals exhibiting normal development despite early psychomotor delay. Communication challenges, particularly in expressive language, are prevalent, necessitating alternative communication methods. Autistic traits, notably rigidity, are observed in the cohort. Also, worth highlighting are hearing loss, sleep disturbances, and endocrine anomalies, including growth deficiency. Cardiac defects, frequently severe, pose early-life complications. Facial features, including arched eyebrows, contribute to the distinct gestalt. A novel missense variant, p.(Arg653Leu), further underscores the complex relationship between germlineTRAF7variants and somatic changes linked to meningiomas. Our comprehensive analysis expands the phenotypic spectrum, emphasizing the need for oncological evaluations and proposing an evidence-based schedule for clinical management. This study contributes to a better understanding of TRAF7 syndrome, offering insights for improved diagnosis, intervention, and patient care.Key MessageTRAF7 syndrome, a complex neurodevelopmental disorder, exhibits variable cognitive outcomes, complex behavioral presentation and clinical complications emphasizing the need for tailored interventions and follow-up.