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

Abstract

Background: 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.

Methods: 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.

Results: 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%).

Conclusions: 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.

Keywords: Clinical subtypes; Genetic subtypes; Pachydermoperiostosis; Primary hypertrophic osteoarthropathy; Touraine-Solente-Gole syndrome.

Fig. 1

(A) Flow diagram illustrating the cases screening process in this study. (B) The number of patients categorized as CO, IN and FR across all cases. PHO: primary hypertrophic osteoarthropathy; CO: complete form; IN: incomplete form; FR: fruste form

Fig. 2

Demographic characteristics across the three clinical subtypes of PHO. Proportion of the three clinical subtypes across different gender (A) and races (B). (C) Rate of positive family history across each clinical subtype. (D) Differences in onset age across the clinical subtypes. PHO: primary hypertrophic osteoarthropathy; CO: complete form; IN: incomplete form; FR: fruste form

Fig. 3

Characteristics of clinical manifestations and comorbidities across the three clinical subtypes of PHO. Differences in clinical manifestations (A), the site of periosteal hyperplasia (B) and comorbidities (C) across each clinical subtype. (D) Proportion of each type of comorbid diseases across the three clinical subtypes. PHO: primary hypertrophic osteoarthropathy; CO: complete form; IN: incomplete form; FR: fruste form

Fig. 4

Characteristics of laboratory Indicators and genetic mutations across the three clinical subtypes of PHO. (A) Differences in Hb decline, ESR and CRP elevation, as well as changes in blood and urine PG levels across each clinical subtype. (B) The number of patients of PGE2 elevation across each clinical subtype. (C) Proportion of different changes in PGEM level across the three clinical subtypes. (D) Proportion of each type of genetic mutations across the three clinical subtypes. Comparison of gene replacements (E) and gene deletions (F) across three clinical subtypes. PHO: primary hypertrophic osteoarthropathy; Hb: hemoglobin, CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; PG: prostaglandin; PGE2: prostaglandin E2; PGEM: Prostaglandin E Metabolite; CO: complete form; IN: incomplete form; FR: fruste form; SLOC2A1: solute carrier organic anion transporter family member 2A1; HPGD: hydroxyprostaglandin dehydrogenase