Touraine-Solente-Gole syndrome: pathogenic variant in SLCO2A1 presented with polyarthralgia and digital clubbing

To the best of our knowledge, this is the second genetically confirmed case of PHO in a Portuguese patient (first variant c.644 C > T), both made at our department. This homozygote variant of SLCO2A1 gene has been previously described by Diggle et al. in 4 brothers with PHO from a consanguineous hispanic family of colombian ancestry [4, 5].

As highlighted in previous literature, PHO is categorized into two different types: PHO type 1 and 2, caused by pathogenic variants in HPGD and SCLCO2A1 genes, respectively. Both genes deficiency causes increased level of PGE2, due to a defect in degradation (HPGD) and transport (SCLCO2A1) of PGE2. High concentrations of plasma PGE2 promote osteoblast activity, fibroblast growth and increased collagen and extracellular matrix production, which is the major characteristic of bone and soft tissue findings. PHO type 1 patients usually present digital clubbing in early childhood, and other symptoms, such as patent ductus arteriosus or delayed closure of the cranial sutures. PHO type 2 individuals are diagnosed after puberty or in early adulthood. Pachydermia occurs in both types, but severe cutis gyrata only in the SLCO2A-deficient group. Radiologically, periosteal bone deposition is seen in both groups, but acroosteolysis is much more prominent in the HPGD-deficient group. Myelofibrosis has been associated to SLCO2A1 group [6, 7].

Our patient presented a complete form of hypertrophic osteoarthropathy with onset in puberty, as seen in patients with homozygous SCLO2A1 mutations. Clinical history, physical examination, and plain radiographs were very suggestive. Plain films permit the evaluation of periostosis, with radius, ulna, tibia and fibula most commonly affected. Another frequent finding is acro-osteolysis of the distal phalanges.

The differential diagnosis depends on the presenting phenotype and age of onset and includes secondary hypertrophic osteoarthropathy, thyroid acropachy, and acromegaly. Secondary causes of hypertrophic osteoarthropathy, which are much more frequent (95% cases), especially those associated to lung neoplasia and, to a lesser degree, to hepatic cirrhosis, cardiopathy and chronic obstructive pulmonary disease, should be excluded, especially when dermatological signs are not prominent. The presence of arthralgia or arthritis might suggest systemic connective tissue diseases, such as JIA. In this case, osteoarticular ultrasound showed no joint effusions, but instead a layer of irregular echogenic tissue in thickness surrounding the femur and tibia without increased vascularity on Doppler. Awareness of the significance of digital clubbing under these circumstances and absence of synovitis on ultrasound is likely to prevent misdiagnosis.

After excluding secondary causes of hypertrophic osteoarthropathy and other differential diagnoses, genetic studies may be useful to confirm the diagnosis and classify the PHO type. The identification of the mutation contributes not only to confirm diagnosis, but also to support future genetic counseling and prevention of associated disease complications.

Currently available therapeutic options are palliative and directed toward amelioration of the patient complaints. Clinical improvement of musculoskeletal symptoms can be achieved by nonsteroidal anti-inflammatory drugs, as verified in our patient. PGE2 is a lipid mediator derived from arachidonic acid through the action of enzymes, including the ubiquitous tissue constitutive isoform cyclooxigenase (COX-1) and the inflammatory/tumor-induced isoform (COX-2). Inflammatory marker levels including CRP and ESR were found to be high at baseline and subsequently declined after COX-2 inhibitor treatment, signifying a decline in inflammation with decreasing levels of PGE2. In addition, bisphosphonates, hydroxychloroquine, tamoxifen citrate, octreotide and colchicine have been reported as effective therapies in refractory cases. Plastic surgery should be reserved for extreme cases to remove excess of facial skin or to reduce finger clubbing [8, 9].

Finally, it needs to be underlined that a patient presenting with clubbing should be classified as having PHO only after careful scrutiny fails to reveal an underlying secondary cause. Meticulous follow up is mandatory to screen for rare complications like myelofibrosis.

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