OBJECTIVE: To explore the genetic etiology of a child with Primary hypertrophic osteoarthropathy.
METHODS: A child who was admitted to Zhongnan Hospital of Wuhan University on July 27, 2021 was selected as the study subject. Genomic DNA was extracted from peripheral blood samples of the child and his parents and subjected to whole exome sequencing. Suspected splicing variant was verified by Sanger sequencing of family members. In vitro function was validated through a minigene assay, whilst the suspected exonic deletion was validated by long-fragment PCR.
RESULTS: Whole exome sequencing revealed that the child has harbored compound heterozygous variants of HPGD gene, including a heterozygous deletion (exon 3 del) derived from his father and a splicing variant (c.421+1G>T) derived from his mother. Long-fragment PCR verified that the child and his father had both harbored a 7 565 bp heterozygous deletion (c.218-1304_324+6156del), whilst the minigene assay proved that the splicing variant has resulted in skipping of exon 4.
CONCLUSIONS: The heterozygous c.218-1304_324+6156del deletion and the c.421+1G>T splicing variant of the HPGD gene probably underlay the pathogenesis in this child. Above finding has enriched the mutational spectrum of the HPGD gene and provided a basis for genetic counseling and prenatal diagnosis for this family.

BACKGROUND: Chronic enteropathy associated with SLCO2A1 gene (CEAS) results from loss-of-function variants in SLCO2A1, which encodes the prostaglandin transporter (PGT). CEAS follows an autosomal recessive inheritance pattern. To date, approximate 30 pathogenic variants have been reported in CEAS.
METHODS: We performed whole exome sequencing (WES) to screen for potential pathogenic variants in a patient suspected of having CEAS, and confirmed a variant in SLCO2A1 using Sanger sequencing. We established an in vitro minigene model to compare splicing between wild type (WT) and mutant transcripts. Quantitative polymerase chain reaction (qPCR) was used to evaluate SLCO2A1 transcription in the stomach and colon tissues from the patient and a healthy control (HC). The transcripts were further cloned and sequenced.
RESULTS: The patient had a novel, homozygous, recessive c.929A > G variant in exon 7 of SLCO2A1, which has not been previously reported in CEAS or PHO. This variant altered splicing, resulting in an exon 7-truncated transcript lacking 16 bases. No normal transcript was detected in the patient\'s stomach or colon tissue. qPCR also showed significantly decreased SLCO2A1 transcription compared to HC.
CONCLUSIONS: A previously unreported variant caused defective SLCO2A1 splicing and reduced mRNA levels in a patient with CEAS and PHO. This research enhances understanding of CEAS and PHO pathophysiology and aids genetic counseling and diagnosis.

BACKGROUND: Hypertrophic osteoarthropathy (HOA) is a rare and intricate hereditary disease. The appearance and functional deformity of the forehead caused by thickened folds are the main clinical manifestations of patients with hypertrophic osteoarthropathy. The cause of this disease is still unknown. Currently, surgical treatment has become one of the best strategies, mainly for improving the appearance of the forehead. There has been no literature report on the use of \"W\"-shaped skin flap resection for thickened forehead skin in patients with hypertrophic osteoarthropathy.
METHODS: All cases of hypertrophic osteoarthropathy in our department in the last 7 years, and previous literature on hypertrophic osteoarthropathy, were reviewed.
RESULTS: A total of 5 cases of hypertrophic osteoarthropathy in our department (mean age 21 years, all male patients) were reviewed. All patients underwent open surgery to remove the thickened skin on the forehead or the wrinkles and gyrus-shaped scalp. The jagged skin tissue was removed (8-9) cm × (1-2.5) cm × 0.5 cm. The folds and thickness of the frontal skin of the patients were greatly improved after the operation. Patient satisfaction with the treatment outcomes was unanimous. However, one case experienced a postoperative wound infection during follow-up. The utilization of the \"W\"-shaped excision technique allowed for the maximal removal of excessively diseased tissue, thereby facilitating a smoother resolution of the depression.
CONCLUSIONS: A total of 5 cases of hypertrophic osteoarthropathy were treated in our department, and all of them underwent frontal skin \"W\"-shaped excision, which was safe, feasible, and practical, and the postoperative results were satisfactory.
METHODS: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

暂无摘要。

BACKGROUND: The role of bisphosphonates (BP) in hypertrophic osteoarthropathy (HPOA) is unclear. We presented a case of primary HPOA and performed a systematic review of literature on the effect of BP on treatment response in primary and secondary HPOA.
METHODS: The study was prospectively registered in PROSPERO (CRD42022343786). We performed a PubMed literature search that restricted to the English language. We included patients diagnosed with primary or secondary HPOA who received BP. The primary endpoint assessed was the effectiveness of BP on response to pain or arthritis. Secondary outcomes included timing, degree, and duration of response, comparison to other HPOA therapies, impact of BP on radiology, bone scan, bone turnover markers, and adverse effects of BP.
RESULTS: Literature search retrieved only case reports. Forty-five patients (21 primary, 24 secondary HPOA) had received BP. Majority(88.3%) experienced improvement in pain or arthritis. Response was gradual for primary HPOA and within a median of 3 to 7 days for secondary HPOA after treatment with BP. Most patients had reduced bone scan uptake after BP. When other HPOA therapies were tried, half responded to BP after not having previously responded to other therapies, while a third received the treatments concurrently, making it difficult to attribute treatment response to a drug. Reporting of other secondary outcomes was very heterogenous and qualitative to draw conclusions. No major adverse effects have been reported for BP in HPOA.
CONCLUSIONS: Bisphosphonates provide an effective and safe treatment option for primary and secondary HPOA. However, there is a lack of randomized controlled trials.

暂无摘要。

Primary hypertrophic osteoarthropathy (PHO) is a genetic disorder mainly characterized by clubbing fingers, pachydermia and periostosis. Mutations in the HPGD or SLCO2A1 gene lead to impaired prostaglandin E2 (PGE2) degradation, thus elevating PGE2 levels. The identification of the causative genes has provided a better understanding of the underlying mechanisms. PHO can be divided into three subtypes according to its pathogenic gene and inheritance patterns. The onset age, sex ratio and clinical features differ among subtypes. The synthesis and signaling pathways of PGE2 are outlined in this review. Cyclooxygenase-2 (COX-2) is the key enzyme that acts as the rate-limiting step for prostaglandin production, thus COX-2 inhibitors have been used to treat this disease. Although this treatment showed effective results, it has side effects that restrain its use. Here, we reviewed the genetics, clinical features, differential diagnosis and current treatment options of PHO according to our many years of clinical research on the disease. We also discussed probable treatment that may be an option in the future.

Here, we highlight the case of a 31-yr-old man who had clinical features of primary hypertrophic osteoarthropathy (PHOAR) and harbored a homozygous variant (c.38C > A, p.Ala13Glu) in the HPGD gene, as indicated by whole-exome sequencing (WES). This variant has been previously classified by our laboratory as a variant of uncertain significance (VUS). However, another patient with the same phenotype and the same homozygous variant in HPGD was subsequently reported. In reassessing the variant, the absence of this variant in the gnomAD population database, supporting computational predictions, observation in homozygosity in two probands, and specificity of the phenotype for HPGD, all provide sufficient evidence to reclassify the HPGD c.38C > A, p.Ala13Glu variant as likely pathogenic.

暂无摘要。

BACKGROUND: Primary Hypertrophic Osteoarthropathy (PHO), also known as Touraine-Solente-Gole Syndrome, is a rare, multisystemic autosomal recessive disorder caused by pathogenic variants in the 15-hydroxyprostaglandin dehydrogenase (HPGD) or Solute Carrier Organic Anion Transporter Family Member 2A1 (SLCO2A1) genes. However, autosomal dominant transmission has also been described in some families with incomplete penetrance. PHO usually starts in childhood or adolescence, presenting with digital clubbing, osteoarthropathy, and pachydermia. We described a complete form of the syndrome in a male patient with a homozygous variant in the SLCO2A1 gene (c.1259G > T).
METHODS: A 20-year-old male was referred to our Pediatric Rheumatology Clinic with a five-year history of painful and swollen hands, knees, ankles and feet, prolonged morning stiffness and relief with non-steroidal antiinflammatory drugs. He also reported late onset facial acne and palmoplantar hyperhidrosis. Family history was irrelevant and parents were non-consanguineous. On clinical examination, he presented clubbing of the fingers and toes, moderate acne and marked facial skin thickening with prominent scalp folds. He had hand, knee, ankles and feet swelling. Laboratory investigations showed elevated inflammatory markers. Complete blood count, renal and hepatic function, bone biochemistry were normal, as well as immunological panel. Plain radiographs revealed soft tissue swelling, periosteal ossification and cortical thickening of the skull, phalanges, femur and toe acroosteolysis. Due to the absence of other clinical signs suggesting a secondary cause, we suspected PHO. A genetic study revealed a likely pathogenic variant, c.1259G > T(p.Cys420Phe), in homozygosity in the SLCO2A1 gene, thus confirming the diagnosis. The patient started oral naproxen with significant clinical improvement.
CONCLUSIONS: PHO should be kept in the differential diagnosis of inflammatory arthritis affecting children, often misdiagnosed as Juvenile Idiopathic Arthritis (JIA). 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.