Schinzel-Giedion Syndrome in One of Dizygotic Twins: Confirmation of a De Novo SET Binding Protein 1 (SETBP1) Variant and Classic Multisystem Phenotype

Schinzel-Giedion syndrome (SGS) is a very rare congenital disorder linked to de novo pathogenic variants in the SET Binding Protein 1 (SETBP1) gene. The condition is usually suspected from a recognisable craniofacial pattern, severe developmental delay, early neurological problems, and congenital abnormalities involving several organ systems. As the disorder is uncommon and presents with wide systemic involvement, diagnosis can be missed or delayed unless the clinical features are carefully recognised and followed by appropriate genetic testing. We report the case of a two-year-old girl who was delivered at 33 weeks and two days as the first-born infant in a dizygotic twin pregnancy. She showed a recognisable craniofacial phenotype along with severe developmental delay, hypotonia, early-onset seizures, progressive hydrocephalus, marked bilateral hydronephrosis with vesicoureteral reflux, recurrent urinary tract infections, a large secundum atrial septal defect, recurrent respiratory illness, congenital talipes equinovarus, and bilateral sensorineural hearing loss. Molecular analysis detected a pathogenic de novo SETBP1 variant, which confirmed the diagnosis of SGS. A heterozygous Glutaredoxin and Cysteine-Rich Domain Containing 1 (GRXCR1) variant of uncertain significance (VUS) was also identified, but it was not considered sufficient to account for the hearing loss, as GRXCR1-related hearing impairment is typically autosomal recessive and requires stronger supporting evidence. Her male co-twin was clinically normal and had no dysmorphic features, favouring a sporadic event in this twin pregnancy. This case underlines the importance of craniofacial dysmorphism as an early clue to SGS in a child with multisystem disease. It also shows why molecular results must be interpreted cautiously, especially when variants of uncertain significance are detected. Early genetic confirmation, counselling of the family, and coordinated care by paediatric neurology, nephrology, cardiology, genetics, and rehabilitation teams are essential for appropriate long-term management.