Abstract
Primary hypertrophic osteoarthropathy (HOA) is a rare condition with no identifiable cause, accounting for 3%–5% of all HOA cases. It is challenging to identify incomplete primary HOA, which can be misdiagnosed as other hypertrophic periostitis diseases. At least two of the four criteria set by Borochowitz and Rimoin (1990) must be present to diagnose primary HOA. Diagnostic difficulties due to incomplete or atypical manifestations are common. We present a case of incomplete primary PHOA at Hanoi Medical University Hospital in Vietnam. A 37-year-old male presented with ankle joint pain for nearly four years. X-ray and magnetic resonance imaging showed periostitis in the tibias and fibulas, which could not exclude Camurati–Engelmann disease. Finally, gene sequencing on the Illumina MiSeq system identified a missense mutation (c.295C>T) in the solute carrier organic anion transporter family member 2A1 (SLCO2A1) gene on chromosome 3. Our case report and literature review aim to improve specialists' understanding of incomplete primary HOA and reduce the frequency of missed diagnoses.
Introduction
Hypertrophic osteoarthropathy (HOA) is an uncommon condition defined by the abnormal proliferation of osseous and dermal tissues. It has two forms: primary HOA (PHOA) and secondary. Primary or idiopathic HOA is rare, accounting for 3–5% of all cases [1–3]. At least two of the four criteria set by Borochowitz and Rimoin (1990) must be present to diagnose PHOA: family history, finger clubbing, pachyderma, and bone pain with periostitis on X-ray [2]. Recent sequencing studies have associated mutations in the 15-hydroxyprostaglandin dehydrogenase (HPGD) and solute carrier organic anion transporter family member 2A1 (SLCO2A1) genes with PHOA. These genes encode proteins regulating inflammatory mediators such as prostaglandin [4–6]. We report a clinical case of incomplete PHOA presenting with ankle pain, periostitis in bilateral lower leg bones, a SLCO2A1 gene mutation, and no evidence of pachyderma or finger clubbing. This report aims to increase understanding of the clinical signs and genetic mutations associated with PHOA, which must be distinguished from secondary HOA to avoid misdiagnosis.
Case report
A 37-year-old male presented to the Outpatient Department with the chief complaint of ankle joint pain for four years. He had no history of chronic obstructive pulmonary, malignant, hepatic, cardiovascular, or rheumatic disease. There was also no history of a similar manifestation in his family members. The pain was dull, continuous, and often exacerbated by movement. A month ago, the pain worsened, and his lower legs became hypertrophic. Physical examination found no sign of heat and redness in the ankles, finger clubbing, thick folded skin on the forehead, or blepharoptosis. However, soft tissues surrounding the ankles were swollen, and he had difficulty in ankle flexion (Fig. 1).
Swelling in the dorsum of the feet (A) and no finger clubbing (B)
Citation: Imaging 15, 2; 10.1556/1647.2023.00145
Laboratory analyses showed a normal erythrocyte sedimentation rate and C-reactive protein concentration and a negative Rheumatoid factor test. Thyroxine, thyroid-stimulating hormone, uric acid, total calcium, and alkaline phosphatase levels were in the normal range. Knee and ankle radiographs showed irregular periosteal reaction in the tibias and fibulas and no bone marrow infiltration (Fig. 2). An abnormal periosteal reaction in the tibia and fibula, along with swollen surrounding tissues, were seen by MRI, which is indicative of Camurati-Engelmann disease (Fig. 3).
Radiograph and CT scanner of the lower legs showing irregular periosteal reaction of the right tibia and fibula (arrows) (A). The cortexes of two bones seem to be thick, dense and have an unchanging form (B). Periosteal proliferation is predominantly localized to the diaphyses with some benign features: solid, continuous and lobulated (C). Periosteal reaction extends to involve a small part of tibia's metaphysis
Citation: Imaging 15, 2; 10.1556/1647.2023.00145
MRI showed irregular periosteal reaction in the tibias and fibulas and swollen surrounding tissues (arrows). There was decreased signal in T2-weighted (A) and fat-saturated T1-weighted (B) coronal images. However, there was increased signal in fat-saturated T2-weighted (C) and fat-saturated T1-weighted (D, E) axial images consistent with Camurati–Engelmann disease
Citation: Imaging 15, 2; 10.1556/1647.2023.00145
The patient's blood was drawn for gene sequencing using the Illumina MiSeq platform. A missense mutation was identified in the SLCO2A1 gene on chromosome 3 (133,973,765 bp), which encodes a prostaglandin transporter. The c.295C>T mutation in the SLCO2A1 gene truncates the encoded prostaglandin transporter (p.Arg99Cys). However, no pathogenic or likely pathogenic variants were identified in the transforming growth factor beta 1 (TGFB1) gene. According to the Borochowitz and Rimoin criteria, we established a diagnosis of incomplete PHOA, which manifested with diffuse periosteal reaction, a SLCO2A1 gene mutation, and no typical pachyderma.
The patient was prescribed non-steroidal anti-inflammatory drug (NSAID) therapy (etoricoxib at 90 mg/day), alendronic acid (70 mg/week), Vitamin D (5600 UI/week), calcium carbonate (1,250 mg/day), and Vitamin D3 (125 mg/day). His ankle pain significantly reduced after one month. However, it still bothered him when exercising strenuously. He was instructed on how to maintain bisphosphonates and engaged in rehabilitation.
Discussion
Friedreich initially identified pachydermoperiostosis as “hyperostosis of the entire skeleton” in 1868 [2]. The phrase “cutis verticis gyrate,” coined by Unna in 1907 [1], refers to the thick, transversely folded scalp and forehead skin. According to Jajic, this illness is present in 0.16% of people [6]. Most afflicted individuals are men, with a male-to-female ratio of 9:1 [5].
PHOA's etiology is incompletely understood. It has been associated with the HPGD and SLCO2A1 genes [7]. Its pathogenesis is believed to be primarily driven by elevated prostaglandin E2 (PGE2) levels due to impaired SLCO2A1-mediated selective uptake across the plasma membrane and/or HPGD-mediated intracellular degradation [8]. In PHOA patients, hyperhidrosis, acro-osteolysis, periostitis, arthritis, and pachyderma are caused by cytokine-mediated tissue remodeling and vascular stimulation, which are believed to be due to elevated PGE2 levels [9].
Its onset usually occurs in adolescence, and it progresses slowly over 10 years with alternating symptomatic and asymptomatic periods. [3] Its most common clinical manifestations are polyarthritis, coarsening facial features and furrowing of the skin on the face and scalp, seborrhea, blepharoptosis, and hyperhidrosis. PHOA is divided into three forms: (1) complete (pachyderma and periostitis), (2) incomplete (no pachyderma), and (3) fruste (prominent pachyderma with few skeletal lesions). Irregular periostitis and new bone formation are common in the upper and lower extremities but rare in the skull and spine. Periostitis along the bones, including the distal diaphysis, accounts for 80%–97% of all cases and often has irregular borderlines [3, 7, 8]. Diagnostic difficulties due to incomplete or atypical manifestations are common. Gastrointestinal involvement (e.g., Crohn's and peptic ulcer disease), bone marrow fibrosis, and congenital heart disease usually become evident in PHOA patients after several years and can be easily missed.
Our patient had incomplete clinical features with only shin bone pain but no pachyderma. MRI showed irregular periostitis in the right tibia and fibula diaphysis with swollen surrounding soft tissue. With these clinical symptoms and MRI findings, our primary diagnosis was diaphyseal dysplasia (Camurati–Engelmann). Camurati–Engelmann disease is believed to be caused by an irregular periosteosis in the bone diaphysis. However, proximal muscle weakness and gait changes are not appropriate.
Therefore, we conducted a sequencing test to detect a TGFB1 gene mutation to confirm the diagnosis. However, we discovered a heterozygous mutation in the SLCO2A1 gene that was classified as having unknown function according to ClinVar and the America College of Medical Genetics; no TGFB1 pathogenic/likely pathogenic variants were detected. Several recent studies have shown that HPGD and SLCO2A1 gene mutations are associated with PHOA. Both genes encode proteins regulating inflammatory mediators such as prostaglandins. Mutations in the HPGD and SLCO2A1 genes inactivate the prostaglandin transporting and degrading processes, leading to excess prostaglandins, especially PGE2. Therefore, NSAIDs can improve skin and bone lesions by inhibiting PGE2 production. Common skin involvements in PHOA include seborrhea, blepharoptosis, acne, coarsening facial features and furrowing of the scalp skin, hyperhidrosis, erythematous lesions at the joints, and a burning sensation in the hands and feet. However, no skin lesions were observed in our case.
Conclusions
In summary, primary or idiopathic HOA is uncommon. Its incomplete form with bone involvements leads clinicians to easily misdiagnose it as other bone dysplasia conditions. In these cases, it is important to thoroughly collect the clinical symptoms, disease onset, and excluded signs and to perform genetic mutation tests. Incomplete PHOA appears rare but responds to NSAID treatment and has a good prognosis.
Author's contributions
Pham HT and Do-Thi HT contributed equally to this article as first authorship. Pham HT and Do-Thi HT: Case file retrieval and case summary preparation. Pham HT and Nguyen MD: preparation of manuscript and editing. Luu CL and Nguyen MD: Critical revision and response to reviewer. All authors read and approved the final manuscript.
Funding sources
Nil.
Conflict of interests
The authors declare that they have no competing interests.
Ethical statement
Our institution does not require ethical approval for reporting individual cases or case series. Written informed consent was obtained from the patient(s) for their anonymized information to be published in this article.
Availability of data and materials
Data and materials used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Consent for publication
Not applicable.
Acknowledgments
None to declare.
References
- [1]↑
Mangupli R, Daly AF, Cuauro E, Camperos P, Krivoy J, Beckers A: Primary hypertrophic osteoarthropathy due to a novel SLCO2A1 mutation masquerading as acromegaly. Endocrinol Diabetes Metab Case Rep 2017; 2017: 17–0013.
- [2]↑
Nayak HK, Rajkumar VD, Kumar N, Kar P: Primary hypertrophic osteoarthropathy (incomplete form) in young adults: A case report and review of literature. BMJ Case Rep 2012; 2012: bcr2012007745.
- [3]↑
Zhang Z, Xia W, He J, Zhang Z, Ke Y, Yue H, et al.: Exome sequencing identifies SLCO2A1 mutations as a cause of primary hypertrophic osteoarthropathy. Am J Hum Genet 2012; 90: 125–132.
- [4]↑
Seifert W, Kühnisch J, Tüysüz B, Specker C, Brouwers A, Horn D: Mutations in the prostaglandin transporter encoding gene SLCO2A1 cause primary hypertrophic osteoarthropathy and isolated digital clubbing. Hum Mutat 2012; 33(4): 660–664.
- [5]↑
Uppal S, Diggle CP, Carr IM, Fishwick CW, Ahmed M, Ibrahim GH, et al.: Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy. Nat Genet 2008; 40(6): 789–793.
- [6]↑
Wallace S.E. and Wilcox W.R. (1993). Camurati-Engelmann disease. GeneReviews®. University of Washington, Seattle, Seattle (WA).
- [7]↑
Guo T, Yang K, Liu L, Tan ZP, Luo H: Identification of two novel mutations in the SLCO2A1 prostaglandin transporter gene in a Chinese patient with primary hypertrophic osteoarthropathy. Mol Med Rep 2017; 15(5): 2977–2982.
- [8]↑
Lee S, Park SY, Kwon HJ, Lee CH, Kim OH, Rhee Y: Identification of the mutations in the prostaglandin transporter gene, SLCO2A1 and clinical characterization in Korean patients with pachydermoperiostosis. J Korean Med Sci 2016; 31(5): 735–742.
- [9]↑
Joshi A, Nepal G, Shing YK, Panthi HP, Baral S: Pachydermoperiostosis (Touraine-Solente-Gole syndrome): A case report. J Med Case Rep 2019; 13(1): 39.
