Hypertrophic Osteoarthropathy: Clinical and Imaging Features.

Hypertrophic osteoarthropathy (HOA) is a medical condition characterized by abnormal proliferation of skin and periosteal tissues involving the extremities and characterized by three clinical features: digital clubbing (also termed Hippocratic fingers), periostosis of tubular bones, and synovial effusions. HOA can be a primary entity, known as pachydermoperiostosis, or can be secondary to extraskeletal conditions, with different prognoses and management implications for each. There is a high association between secondary HOA and malignancy, especially non-small cell lung cancer. In such cases, it can be considered a form of paraneoplastic syndrome. The most prevalent secondary causes of HOA are pulmonary in origin, which is why this condition was formerly referred to as hypertrophic pulmonary osteoarthropathy. HOA can also be associated with pleural, mediastinal, and cardiovascular causes, as well as extrathoracic conditions such as gastrointestinal tumors and infections, cirrhosis, and inflammatory bowel disease. Although the skeletal manifestations of HOA are most commonly detected with radiography, abnormalities can also be identified with other modalities such as computed tomography, magnetic resonance imaging, and bone scintigraphy. The authors summarize the pathogenesis, classification, causes, and symptoms and signs of HOA, including the genetics underlying the primary form (pachydermoperiostosis); describe key findings of HOA found at various imaging modalities, with examples of underlying causative conditions; and discuss features differentiating HOA from other causes of multifocal periostitis, such as thyroid acropachy, hypervitaminosis A, chronic venous insufficiency, voriconazole-induced periostitis, progressive diaphyseal dysplasia, and neoplastic causes such as lymphoma. ©RSNA, 2016.

Primary hypertrophic osteoarthropathy: ultrasound and MRI findings.

Primary hypertrophic osteoarthropathy is a rare genetic disorder related to failures in prostaglandin metabolism. Patients present with joint pain, limb enlargement, skin thickening and finger clubbing. Radiographs show characteristic periosteal reaction and thickening along the long bones. We present MRI and US findings in a child with the condition. Ultrasound showed echogenic tissue surrounding the long bones, presumably reflecting oedema and inflammatory tissue. Doppler sonograms demonstrated increased vascularity on the surface of some superficial bony structures.

Identification of the Mutations in the Prostaglandin Transporter Gene, SLCO2A1 and Clinical Characterization in Korean Patients with Pachydermoperiostosis.

Pachydermoperiostosis (PDP), or primary hypertrophic osteoarthropathy, is a rare genetic disease affecting both skin and bones. Both autosomal dominant with incomplete penetrance and recessive inheritance of PDP have been previously confirmed. Recently, hydroxyprostaglandin dehydrogenase (HPGD) and solute carrier organic anion transporter family member 2A1 (SLCO2A1) were reported as pathogenic genes responsible for PDP. Both genes are involved in prostaglandin E2 (PGE2) degradation. We aimed to identify responsible genes for PDP and the clinical features in Korean patients with PDP. Six affected individuals and their available healthy family members from three unrelated Korean families with PDP were studied. All of the patients displayed complete phenotypes of PDP with finger clubbing, pachydermia, and periostosis. Mutation analysis revealed a novel heterozygous mutation in the SLCO2A1 gene at nucleotide 302 causing a substitution of the amino acid isoleucine to serine at codon 101 (p.IIe101Ser) in affected individuals. We also identified known SLCO2A1 mutations, one homozygous for c.940+1G>A, and another compound heterozygous for c.940+1G>A and c.1807C>T (p.Arg603*) from two PDP families. Genetic analyses of the PDP patients showed no abnormality in the HPGD gene. Our study further supports the role of mutations in the SLCO2A1 gene in the pathogenesis of PDP and could provide additional clues to the genotype-phenotype relations of PDP.

Pachydermoperiostosis.

A case of Pachydermoperiostosis (PDP) presented to us in rheumatology clinic with complaints of enlargement and broadening of bilateral hands and feet, grade IV digital clubbing, coarsening of facial features, excessive sweating of the palms, soles during summers.

[Paraneoplastic syndromes and rheumatic diseases]. / Zespoly paranowotworowe a choroby reumatyczne.

Paraneoplastic syndromes, which are discussed in this paper, are a heterogeneous group of disorders associated with cancer, but not directly caused by the physical effects of the primary tumor or its metastases. May precede the appearance of the malignant process, occur simultaneously or disclose in the course of cancer. Paraneoplastic syndromes may be caused directly by toxins produced by tumor cells, occur in the course of hypersensitivity reactions, or be the result of release of intracellular antigens. Due to the often similar systemic symptoms it is very important to evaluate the association of rheumatic diseases and cancer. Most paraneoplastic rheumatologic syndroms are difficult distinguishable from idiopathic rheumatologic disorders. The most common paraneoplastic syndromes include rheumatoid arthritis (RA)-like syndrome arthritis, inflammatory myopathies, hypertrophic osteoarthropathy, vasculitis and Raynaud's phenomenon.

Aberrant CD200/CD200R1 expression contributes to painful synovium hyperplasia in a patient with primary hypertrophic osteoarthropathy.

We present a case of hypertrophic osteoarthropathy (PHO), with painful synovium hyperplasia involving both knees that was refractory to corticosteroid treatment. His rheumatoid factor and anti-CCP antibody was negative, and his serum ESR and CRP level was within normal range. Histological examination of the synovium obtained from his right knee revealed endothelial hyperplasia and vascular thickening without inflammation that was in association with aberrant expression of CD200/CD200R1, which highlighted the importance of aberrant CD200/CD200R1 in the regulation of the endothelial activation that contributed to the development of synovium hyperplasia in this PHO patient.

Novel pathogenic variants in SLCO2A1 causing autosomal dominant primary hypertrophic osteoarthropathy.

Primary hypertrophic osteoarthropathy (PHO), or pachydermoperiostosis, is characterized by a clinical association including digital clubbing, periostosis and pachydermia. SLCO2A1 and HPGD genes are both responsible for PHO. The pathology is classically defined as an autosomal recessive disorder with clinical variability ranging from a mild to more severe phenotype. However, the hypothesis for an autosomal dominant form suggested for a long time was only demonstrated for the first time in 2021 for SLCO2A1. We aimed to detect a second pathogenic variant by a deep sequencing of the entire SLCO2A1 and HPGD genes, associated with functional transcription analysis in PHO patients harboring only one heterozygous variant. Among 10 PHO patients, 4 presented a single pathogenic or probably pathogenic novel variant in SLCO2A1 in heterozygous status (NM_005630.3: c.234+1G > A, c.1523_1524delCT, c.1625G > A and c.31delC), and the others carried homozygous pathogenic variants. For heterozygous forms, we found no additional pathogenic variant in HPGD or SLCO2A1. PHO can be a dominant form with age at disease onset later than that for the recessive form. This dominant form is not exceptional in young adults. In conclusion, both modes of inheritance of PHO explain the clinical variability and the difference in age at disease onset. Molecular analysis is especially required in the incomplete form to distinguish it from secondary hypertrophic osteoarthropathy.

Cardiac metastasis and hypertrophic osteoarthropathy in recurrent infantile fibrosarcoma.

Cardiac metastasis and hypertrophic osteoarthropathy are both quite rare. We describe a patient presenting with hypertrophic osteoarthropathy as the first symptom of recurrent infantile fibrosarcoma (IF). During surgical resection of lung metastasis, the patient suffered sudden cardiac arrest. Autopsy demonstrated a metastatic lesion in the intraventricular septum of the heart, which is previously undescribed in the literature. This case demonstrates that IF can be aggressive despite its more typical benign course.

Bone Geometry, Density, Microstructure, and Biomechanical Properties in the Distal Tibia in Patients With Primary Hypertrophic Osteoarthropathy Assessed by Second-Generation High-Resolution Peripheral Quantitative Computed Tomography.

Periosteosis refers to pathological woven bone formation beneath the cortical bone of the long bones. It is an imaging hallmark of primary hypertrophic osteoarthropathy (PHO) and also considered as one of the major diagnostic criteria of PHO patients. Up to date, detailed information on bone quality changes in long bones of PHO patients is still missing. This study aimed to evaluate bone microarchitecture and bone strength in PHO patients by using high-resolution peripheral quantitative computed tomography (HR-pQCT). The study comprised 20 male PHO patients with the average age of 27.0 years and 20 age- and sex-matched healthy controls. The areal bone mineral density (aBMD) was assessed at the lumbar spine (L1 -L4 ) and hip (total hip and femoral neck) by dual-energy X-ray absorptiometry (DXA). Bone geometry, volumetric bone mineral density (vBMD), and microstructure parameters at the distal tibia were evaluated by using HR-pQCT. Bone strength was evaluated by finite element analysis (FEA) based on HR-pQCT screening at distal tibia. Urinary prostaglandin E2 (PGE2 ), serum phosphatase (ALP), beta-C-telopeptides of type I collagen (ß-CTX), soluble receptor activator of nuclear factor-κB ligand (sRANKL), osteoprotegerin (OPG), and neuronal calcitonin gene-related peptide (CGRP) were investigated. As compared with healthy controls, PHO patients had larger bone cross-sectional areas; lower total, trabecular, and cortical vBMD; compromised bone microstructures with more porous cortices, thinned trabeculae, reduced trabecular connectivity, and relatively more significant resorption of rod-like trabeculae at distal tibia. The apparent Young's modulus was significantly lower in PHO patients. The concentration of PGE2 , biomarkers of bone resorption (ß-CTX and sRANKL/OPG ratio), and the neuropeptide CGRP were higher in PHO patients versus healthy controls. PGE2 level correlated negatively with vBMD and estimated bone strength and positively with bone geometry at distal tibia. The present HR-pQCT study is the first one illustrating the microarchitecture and bone strength features in long bones. © 2021 American Society for Bone and Mineral Research (ASBMR).

Involvement of Wnt signaling in dermal fibroblasts.

Pachydermoperiostosis (PDP) is a rare disease characterized by unique phenotypes of the skin and bone, such as thick skin, implying that it may be caused by dysregulation of mesenchymal cells. The aim of this study is to examine the roles of dermal fibroblasts in the pathogenesis of pachydermia in association with Wnt signaling. The numbers of cultured fibroblasts were compared between healthy donors and PDP patients, and mRNA expression profiles in cultured dermal fibroblasts were examined by DNA microarray analysis and real-time reverse transcription-PCR. DKK1 and beta-catenin protein expressions were also evaluated by immunohistochemistry in the skin. To evaluate the in vivo roles of DKK1 in mice, DKK1 small interfering RNA was injected to the ears. We found that PDP fibroblasts proliferated more than control fibroblasts and that mRNA expression of a Wnt signaling antagonist, DKK1, was much lower in PDP fibroblasts than in normal ones. Consistently, decreased expression of DKK1 in fibroblasts and enhanced expression of beta-catenin were noted in PDP patients. Moreover, recombinant human DKK1 protein decreased the proliferation of dermal fibroblasts. In accord with the above human studies, intradermal injections of DKK1 small interfering RNA into mouse ears increased ear thickness as seen in PDP. Our findings suggest that enhanced Wnt signaling contributes to the development of pachydermia by enhancing dermal fibroblast functions.

Treatment of pachydermoperiostosis pachydermia with botulinum toxin type A.

BACKGROUND: Pachydermoperiostosis (PDP) is a rare hereditary disorder characterized by digital clubbing, periostosis, and pachydermia. Pachydermia results in leonine facies, a major cause of cosmetic and functional morbidity in these patients. Its treatment is usually surgical. So far, no medical treatment has been suggested to alleviate this morbidity. OBJECTIVE: We sought to assess the role of botulinum toxin type A (BTX-A) in improving the cosmetic appearance of pachydermia in patients with PDP. METHODS: Three patients with PDP were treated with BTX-A for their leonine facies. A total of 70 to 80 U were used to treat the upper third of the face. Photographs were taken at baseline and at 2 and 6 weeks after the injections. The patients were followed up periodically for at least 6 months. Wrinkle severity was assessed at relaxation using the 4-point facial wrinkle scale at baseline, week 6, and month 6. In addition, a subjective assessment of the improvement of the extent and depth of the facial rhytides/furrows over the upper third of the face was performed by the same investigator at week 6 and month 6. RESULTS: Using the subjective assessment of the improvement of wrinkles, all 3 patients exhibited a fair to excellent response at week 6 that started manifesting 1 week after the BTX-A treatment. All patients demonstrated a residual effect 6 months after the treatment. One patient exhibited a mild exacerbation of his ptosis. LIMITATIONS: Major limitations were the small number of patients and the administration of BTX-A injections and assessment of their response by a single unblinded physician. CONCLUSION: BTX-A is a simple procedure that may be of value in temporarily improving the cosmetic appearance of pachydermia in patients with PDP.

Pachydermoperiostosis with myelofibrosis and empty sella.

A case of pachydermoperiostosis presented to us in rheumatology clinic with complaints of pain and swelling in knee joints unresponsive to treatment, characteristic facial features, grade four clubbing of nails and broadening of distal parts of extremities. He also complained of fatiguability which was due to anemia. The natural history of the disease was reviewed and investigated.

Complete form of pachydermoperiostosis.

Pachydermoperiostosis (PDP) or primary hypertrophic osteoarthropathy (PHO) is a rare hereditary disease characterized by digital clubbing, pachydermia, and periostosis. Its pathogenesis is uncertain and the diagnosis is based on clinical and radiological data. A complete form of the syndrome is reported in a male patient with disease onset in adolescence, with compatible clinical and radiological findings, presenting the three cardinal findings as well as other associated manifestations, such as hyperhidrosis and acne.

Massive eyelid thickening in pachydermoperiostosis with myelofibrosis.

Pachydermoperiostosis is characterized by soft-tissue hyperplasia that gives patients a classic appearance of tarsitis leading to massively thickened tarsal plates and consequential ptosis. The authors describe a patient with the classic eyelid findings, the pathologic evaluation of the eyelid, and the presence of asymptomatic myelofibrosis.

Primary hypertrophic osteoarthropathy related gastrointestinal complication has distinctive clinical and pathological characteristics: two cases report and review of the literature.

BACKGROUND: Primary hypertrophic osteoarthropathy (PHO) is a rare disease related to HPGD and SLCO2A1 gene mutation. Gastrointestinal involvement of PHO is even rarer with unknown pathogenesis. Clinical features of GI complication in PHO mimics other auto-immune based bowel entities, such as inflammatory bowel diseases and cryptogenic multifocal ulcerous stenosing enteritis (CMUSE). We aimed to analyze the clinical, genetic, radiological and pathological features of Chinese patients with PHO and determine the difference between PHO patients presenting with and without GI involvement. METHODS: We reported two PHO cases with gastrointestinal involvement and reviewed all the studies of PHO in Chinese population published from January 1, 2000, to April 30, 2018. Clinical and genetic presentations of PHO in Chinese patients were analyzed. We compared the characteristics of those patients with gastrointestinal involvement against those without. RESULTS: The two patients were both males with complete-form PHO for more than 10 years. GI related symptoms included diarrhea, chronic gastrointestinal hemorrhage, incomplete intestinal obstruction, anemia, and edema, which were unresponsive to etoricoxib treatment. Radiological examinations revealed segmental intestinal stenosis and thickened intestinal wall. Endoscopic findings included multiple ulcers and mucosal inflammation. Both patients had mutations of SLCO2A1 according to sequence analysis. The surgical pathology revealed chronic inflammation involving the intestinal mucosa and submucosa, similar to histological changes in CMUSE. According to the systemic review of 158 Chinese patients with PHO, 17.2% had gastrointestinal involvement, including peptic ulcer, gastric polyps, hypertrophic gastritis, and segmental intestinal stenosis. Patients with gastrointestinal involvement were more likely to have anemia (40.0% vs. 4.5%, P < 0.001), hypoalbuminemia (16.7% vs. 0.9%, P = 0.003), and myelofibrosis (19.0% vs. 0.9%, P = 0.002) than those without. Most patients with gastrointestinal complication had SLCO2A1 mutation (86.7%, 13 /15). CONCLUSIONS: Digestive tract involvement is uncommon in patients with PHO and often presents with anemia, and hypoalbuminemia resulted from intestinal inflammation. The intestinal pathologic characteristics are distinct from Crohn's disease but similar to CMUSE. Mutations in SLCO2A1 might be the pathogenic cause of GI involvement of PHO. NSAIDs may not be effective for PHO patients with gastrointestinal complications.

Hypertrophic osteoarthropathy in an adult macaque.

OBJECTIVE: To evaluate through differential diagnosis whether hypertrophic osteoarthropathy was present on an adult macaque skeleton. MATERIALS: Skeletal remains of a well-preserved adult macaque (Macaca) of unknown species curated by the archaeology department at University College London. METHODS: Macroscopic and radiographic evaluation of pathological lesions. RESULTS: Widespread bilateral and symmetrical periosteal new bone growth primarily affecting the limbs was observed. CONCLUSION: A careful differential diagnosis of the lesions and comparison with previously published cases of hypertrophic osteoarthropathy among humans and non-humans suggests this animal displays a case of Hypertrophic osteoarthropathy. SIGNIFICANCE: Only been three reported cases of HOA in non-human primates have been reported, and all were apes. This study serves as the first reported case of HOA among non-hominoid simians, providing a detailed description of the skeletal lesions to aid future with paleopathological analyses. LIMITATIONS: Small sample sizes for comparison and lack of context for this specimen limits discussion of the scope of this disease among non-human primates. SUGGESTIONS FOR FURTHER RESEARCH: Re-evaluate skeletal collections which have not been subject to recent osteological and pathological analysis.