DeCure for Goldberg-Shprintzen syndrome

Goldberg-Shprintzen syndrome and Shprintzen-Goldberg syndrome are distinct disorders that share a name but have different genetic causes. Shprintzen-Goldberg syndrome (SGS) is a connective tissue disorder with craniosynostosis, distinctive craniofacial features, skeletal abnormalities, marfanoid body habitus, aortic dilatation, and intellectual disability. Mutations in exon 1 of SKI account for roughly 90% of clinically diagnosed SGS cases. SKI regulates TGFβ signalling, so SGS, like Marfan and Loeys-Dietz syndromes, is thought to arise from deregulated TGFβ signals. SGS is molecularly heterogeneous and has been linked to mutations in three genomic loci, with a fourth region (15q25-qter) also implicated. Germline mosaicism has been reported in at least one SGS family. Additional features described in individual SGS patients include cranial asymmetry, hypotonia, osteopenia, hydrocephalus, intestinal malrotation, and an aberrant subclavian artery. No consensual clinical guidelines for managing SGS patients exist as of 2024.

Goldberg-Shprintzen syndrome (GOSHS) is an autosomal dominant disorder caused by loss-of-function variants in the kinesin binding protein gene (KIFBP). Fewer than 50 cases have been reported in the medical literature as of 2024. A 2020 study of nine new patients — seven with nonsense variants and two with missense variants, the first missense variants reported in GOSHS — found that missense variants led to reduced KIFBP expression while truncating variants resulted in complete lack of protein. No correlation was found between variant location and disease severity, nor between common Hirschsprung disease-associated SNPs and the development of Hirschsprung disease in GOSHS. The authors suggested that a threshold expression level of KIFBP may modulate phenotypic variability. The KIFBP protein is essential for cytoskeleton formation and neurite growth, interacting with microtubules and actin filaments. One 2024 case report noted that the patient was initially suspected to have meconium ileus with intestinal obstruction or cystic fibrosis before GOSHS was diagnosed.

The two syndromes are often confused in the literature, but the abstracts make clear they are genetically distinct: SGS is linked to SKI mutations and TGFβ signalling, while GOSHS is linked to KIFBP mutations and cytoskeletal function. Both remain poorly studied, with no established clinical management guidelines for either. What is missing are large, well-phenotyped patient cohorts to clarify the full spectrum of each disorder, functional studies connecting the molecular defects to specific organ system involvement, and prospective natural history data to inform clinical trial design. The small number of reported cases — fewer than 50 for GOSHS, and only a few hundred for SGS — means that genotype-phenotype correlations remain weak, and no targeted therapies have been proposed or tested.