Primary hypertrophic osteoarthropathy: phenotypic variability and penetrance rate in heterozygotes for <i>SLCO2A1</i> variants

Primary hypertrophic osteoarthropathy (PHO) is a rare autosomal recessive disease caused by pathogenic variants (PVs) in <i>HPGD</i> and <i>SLCO2A1</i> genes whose phenotypes are, respectively, designated as PHOAR1 and PHOAR2. Recently, a dominant inherited form (PHOAD) was identified in <i>SLCO2A1</i> heterozygotes whose PHO penetrance is widely unknown, and data on phenotype are markedly limited. Our aim was to reveal the penetrance and extend/refine data on phenotype of <i>SLCO2A1</i> heterozygotes. Both genes were sequenced using Sanger sequencing. The 4 probands had a typical complete form (CF) of PHO. Mean ages at symptom onset and clinical diagnosis were, respectively, 18.5 ± 2.7 (16-22) years and 22 ± 3.4 (18-26) years. They were homozygotes for <i>SLCO2A1</i> (p.Q188R, p.C420F, p.A176T; p.G104^*) PVs; 2 were novel variants. We focused on 14 <i>SLCO2A1</i> heterozygous screened relatives from 3 families: 5 elderly individuals (mean age: 78 ± 6.7 [72-86] years) of the parental generation were affected, 2 by incomplete form (IF) and 3 with isolated digital clubbing (IDC). Combining our 14 carriers and 33 reported so far, the estimated overall PHO penetrance was 70%, being significantly higher in men (83% vs 50%; <i>p =</i> .024) and individuals carrying truncated <i>SLCO2A1</i> PVs (88% vs 53%; <i>p =</i> .053). In turn, the periostosis penetrance rate in women was 28% (5/18), including our oldest patient (86 years). In the probands, the predominant phenotypes were CF (64%) and IF (36%). Among screened carriers, phenotypes were IDC (41%) followed by IF and fruste form (FF) (28%, each), whereas IDC and FF were the predominant phenotypes in screened men and women, respectively. As a novelty, we uncovered an incomplete penetrance of PHO in <i>SLCO2A1</i> heterozygotes, with higher rates in elderly individuals, males, and those with truncated PVs. Regarding phenotype, PHO is more pronounced in males, periostosis is likely more frequent in females than previously documented in PHOAR2, and IDC may represent a distinct clinical feature in <i>SLCO2A1</i> heterozygotes.