Biallelic SLCO2A1 variants in two siblings with primary hypertrophic osteoarthropathy and possible chronic...

Pathogenic variants in the SLCO2A1 gene are responsible for two rare monogenic disorders: primary hypertrophic osteoarthropathy (PHO) and chronic enteropathy (CEAS). The clinical and genetic characteristics of individuals with either PHO or CEAS have been extensively documented in previous studies. However, the clinical and genetic features of patients presenting with both PHO and CEAS concurrently remain largely unknown. This study aims to elucidate the clinical and genetic features of patients with overlapping PHO and CEAS.

We evaluated two affected individuals from the same family presenting with both PHO and possible CEAS. Next, a systematic literature review was conducted across the PUBMED, EMBASE, and China National Knowledge Infrastructure (CNKI) databases, covering the period from January 1, 2000, to November 30, 2025. Clinical and genetic data from the literature cohort and our index were collected and analyzed.

Two novel compound heterozygous variants (NM_005630.3: c.232G>T and c.1929C>G) in the SLCO2A1 gene were identified in our two familial patients. In the broader cohort (n=54), the disease demonstrated prominent sexual dimorphism. Males accounted for 75.9% (41/54) of the cohort and typically presented with classic PHO phenotypes, including cutis gyrata, pachydermia, digital clubbing, periosteal thickening, and arthralgia. In contrast, female patients primarily presented with gastrointestinal manifestations, such as ulcers, abdominal pain, obstruction, diarrhea, mucosal abnormality, and bleeding. Genetic analysis revealed that the variant allele frequencies of NM_005630.3: c.940+1G>A and c.1807C>T were 25.9% and 25%, respectively, across the entire cohort.

This study identified two novel compound heterozygous variants (NM_005630.3: c.232G>T and c.1929C>G) in SLCO2A1, thereby expanding the variant spectrum of SLCO2A1. Furthermore, our systematic analysis identifies distinct, sex-biased clinical phenotypes in patients with concurrent PHO and CEAS. Based on these findings, we propose a gender-specific clinical consideration to enhance the identification and management of SLCO2A1-associated disorders.