Distinct features of three clinical subtypes in 533 patients with primary hypertrophic osteoarthropathy

Primary hypertrophic osteoarthropathy (PHO) is a rare genetic disorder classified into clinical subtypes and genetic subtypes. Previous clinical studies have primarily focused on case reports and family analyses, largely characterizing the genetic subtypes. However, there remains a long-standing gap in understanding the characteristics of the different clinical subtypes of PHO. This study aimed to determine the distribution of the three clinical subtypes of PHO and compare their clinical characteristics using a large global sample.

A systematic literature search was conducted in multiple databases to categorize cases into complete form (CO), incomplete form (IN), and fruste form (FR). Statistical analyses were performed to assess clinical differences in a retrospective study design.

Males predominated across all subtypes, whereas females were most prevalent in IN patients (51.1%). IN patients had the highest family history rate (62.1%). Age at onset peaked in adolescence for CO and FR patients, while IN patients exhibited bimodal peaks in early childhood and adolescence. Congenital diseases were more frequent in IN patients (7.8%, P = 0.021), while CO patients had a higher prevalence of digestive system diseases (12.2%, P = 0.007). Urinary prostaglandin E2 (PGE2) and PGE Metabolite (PGEM) were consistently elevated in CO and FR patients. In IN patients, urinary PGE2 levels were also increased, but the urinary PGEM levels showed equal proportions of elevation and reduction. Genetic analysis revealed that solute carrier organic anion transporter family member 2A1 (SLCO2A1) mutations were predominant in CO (95 cases, 73.1%) and FR (22 cases, 57.9%) patients, whereas hydroxyprostaglandin dehydrogenase (HPGD) mutations were most frequently associated with IN (25 cases, 73.5%).

The three clinical subtypes of PHO exhibited distinct characteristics with no clear correlation between clinical and genetic subtypes. These findings highlighted the clinical significance of PHO typing and provided valuable insights for diagnosis, differential diagnosis and subtype-specific management strategies.