Does It Run in Your Family? Inherited Truncating PSMD12 Variants Broaden the Phenotypic Spectrum of Stankiewicz-Isidor Syndrome

Alteration in the ubiquitin-proteasome system results in human disorders with neurological and/or autoinflammatory presentation. Haploinsufficiency of PSMD12, which encodes a subunit of the core component of the proteasome, causes Stankiewicz-Isidor syndrome (STISS), characterized by intellectual disability, autism spectrum disorder, craniofacial dysmorphisms, with or without other congenital anomalies, and autoinflammation. We described six patients (four adults) from two unrelated families carrying a known p.(Arg289*) or a novel p.(Tyr111*) PSMD12 variant. Portraying a completely penetrant condition with inter- and intra-familiar clinical variability, all individuals presented with developmental delay, intellectual disability, craniofacial, and skeletal anomalies. Novel findings in our cohort included unilateral ectopic fingernail, cholesteatoma, oligodontia, and the occurrence of an ovarian teratoma. Most subjects had acne, short stature, and developed obesity since late childhood. Eating behavior was reported. Good sociality and behavioral concern emerged as well. None presented clinical manifestations of autoinflammation and the detected IFN-I signature perturbations were not specific. Together with a complete literature review, we expanded the clinical spectrum of STISS, highlighting the relevance of inherited variants, and discussing challenges in diagnosis and management. We finally consider the intriguing role of PSMD12 in human development and propose to index “onychoheterotopia” among the Human Phenotype Ontology terms.