Background: Smith–McCort dysplasia type 2 (SMC2) (OMIM#615222) is an exceptionally rare autosomal recessive skeletal disorder caused by biallelic variants in RAB33B. This gene encodes a Golgi-associated small GTPase that regulates intracellular trafficking and autophagosome formation. To date, only a limited number of cases have been reported, predominantly in populations with high consanguinity rates.

Methods: We present a male patient in his forties with progressive gait difficulties and skeletal anomalies since early childhood, including short trunk dwarfism, short stature, genu varum, and scoliosis, with preserved cognitive function. Genomic DNA was analyzed using whole exome sequencing (WES), followed by segregation analysis through Sanger sequencing for family members. Additionally, we performed a systematic review of the literature in PubMed and Google Scholar to summarize the clinical and molecular spectrum of SMC2.

Results: WES identified a homozygous nonsense variant in RAB33B (c.211C>T, p.R71*), predicted to introduce a premature stop codon and cause loss of function. Segregation analysis confirmed heterozygous status in his unaffected family members consistent with autosomal recessive inheritance. Multiple family members from consanguineous unions exhibited variable skeletal features compatible with SMC2 but without intellectual disability. The systematic review yielded 18 eligible studies, including 12 reporting genetic findings and 6 describing detailed clinical characteristics. Most patients carried pathogenic RAB33B variants, highlighting its pivotal role in SMC2.

Conclusion: This report broadens the clinical and genetic spectrum of SMC2 and underscores the importance of considering this rare disorder in the differential diagnosis of unexplained skeletal dysplasia. In regions with high consanguinity, a potential founder effect of RAB33B variants should be considered. Early molecular diagnosis and genetic counseling are critical for accurate risk assessment and reproductive decision-making.