Clinical and Genetic Insights Into Aymé-Gripp Syndrome: Two Unrelated Cases With Additional Clinical Findings and Paternal Mosaicism.

Abstract

Aymé-Gripp syndrome is an ultra-rare autosomal dominant multisystem disorder caused by pathogenic variants in the MAF gene, typically affecting the N-terminal transactivation domain. It is characterized by craniofacial dysmorphism, early-onset cataracts, sensorineural hearing loss, developmental delay or intellectual disability, and variable neurological or skeletal anomalies. Here, we report two unrelated Turkish patients harboring heterozygous MAF variants within the glycogen synthase kinase 3 recognition motif, evaluated using clinical, neuroimaging, and molecular approaches. Targeted next-generation sequencing (NGS) and parental segregation analyses by NGS and Sanger sequencing were performed, and a literature review of cases published between January 2015 and April 2026 was conducted. Both patients presented with craniofacial and neurodevelopmental features. However, one patient showed no clinically detectable ocular abnormalities or hearing impairment at the time of evaluation. The detected variant in this patient was inherited from his asymptomatic father with low-level mosaicism (16% variant allele frequency in blood and 22% in buccal mucosa), representing the first reported case suggestive of paternal germline mosaicism in Aymé-Gripp syndrome. Literature review (n = 38) revealed consistent findings of sensorineural hearing loss (94.5%), cataracts (78.3%), developmental delay/intellectual disability (100%), epilepsy (68.5%), skeletal anomalies (72.7%), and cardiac involvement (55.1%). Additional features, including non-cataract ocular abnormalities, renal involvement, dermatologic findings, and hematological manifestations, have also been reported. All variants clustered within residues 54-69 of the transactivation domain. These findings provide clinically and molecularly relevant insights into Aymé-Gripp syndrome and highlight the importance of molecular diagnosis and the detection of parental mosaicism for accurate recurrence risk assessment and genetic counseling.