Stankiewicz-Isidor Syndrome

A number sign (#) is used with this entry because of evidence that Stankiewicz-Isidor syndrome (STISS) is caused by heterozygous mutation in the PSMD12 gene (604450) on chromosome 17q24.

Description

Stankiewicz-Isidor syndrome (STISS) is a neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, behavioral disorders, mild craniofacial anomalies, and variable congenital defects of the cardiac and/or urogenital systems (summary by Kury et al., 2017).

Clinical Features

Kury et al. (2017) reported 4 unrelated boys, ranging in age from 8 to 14 years, with a neurodevelopmental disorder. The patients had developmental delay with intellectual disability and abnormal behavior, including autism. Two patients had motor delay and 3 had speech delay. Other features were more variable, and included hypotonia, deafness, feeding difficulties, and thumb agenesis or hypoplasia. Three patients had variable cardiac abnormalities, including septal defects and patent ductus arteriosus, 2 had renal anomalies, such as fusion kidneys and duplicated ureters, and all had some kind of genital anomaly, such as hypospadias, micropenis, and cryptorchidism. Three patients were noted to have dysmorphic craniofacial features, 3 had low-set ears, 1 had retrognathia, and another had asymmetric facies with hypertelorism and large nose. One had eye tracking problems, another had cortical visual impairment with abnormal optic nerve heads, and a third had strabismus and horizontal nystagmus. Brain imaging in 1 patient showed a pineal cyst.

Cytogenetics

Kury et al. (2017) reported 6 unrelated children with a neurodevelopmental disorder associated with de novo heterozygous deletions of chromosome 17q24. The breakpoints of the deletions were different in each case, and the size of the deletions ranged from 0.62 to 4 Mb. All patients had delayed development with intellectual disability, and most also had delayed motor development and hypotonia with speech delay. One patient had seizures and another had deafness. Other features were highly variable, but included congenital cardiac (2 patients) and renal (4 patients) defects. Three had feeding difficulties. One boy had hypospadias and 1 girl had precocious puberty. All had dysmorphic craniofacial features, such as micro/retrognathia, hypertelorism, strabismus, low-set ears, short or long philtrum, high or prominent forehead, thin upper lip, and downturned corners of the mouth. Three patients had 2-3 toe syndactyly. Brain imaging was performed in 4 patients: 3 had normal imaging and 1 had cerebral atrophy with periventricular hypomyelination and a pineal cyst.

Molecular Genetics

In 4 unrelated patients with Stankiewicz-Isidor syndrome, Kury et al. (2017) identified de novo heterozygous truncating or splice site mutations in the PSMD12 gene (604450.0001-604450.0004). The mutations in 3 patients were found by trio-based whole-exome sequencing and confirmed by Sanger sequencing; the mutation in the fourth patient was found by exome sequencing. Studies of 1 patient's cells showed decreased amounts of full-length PSMD12, consistent with haploinsufficiency. Cells transfected with the mutation (604450.0001) showed presence of the mutant transcript, but absence of the predicted truncated protein, suggesting translation inefficiency or increased degradation of the mutant protein. Transfected cells also showed abnormal accumulation of high-molecular-weight ubiquitin-modified proteins, although proteasome catalytic activity was not impaired. The findings supported the biologic importance of PSMD12 as a scaffolding subunit in proteasome function during development, with a particular role in neurogenesis.

Animal Model

Kury et al. (2017) found that CRISPR/Cas9-mediated disruption of the psmd12 ortholog in zebrafish embryos resulted in smaller optic tecta, suggestive of microcephaly, renal tubule defects, and craniofacial abnormalities.