Genetic Studies Of Pedigree Of Primary Hypertrophic Ostesarthropathy And Observation Of The Therapeutic Response To Etoricoxib

BackgroudPrimary hypertrophic osteoarthropathy(PHO)is a rare multi-organic and inherited disease characterized by digital clubbing,pachydermia and periosteal reaction.The inheritance of PHO is recessive inheritance in most case.Nowadays,two genes have been reported to be associated with PHO,15-hydroxyprostaglandin dehydrogenase and solute carrier organic anion transporter family,member 2A1(SLCO2A1).Defect of either gene will cause deregulation of prostaglandin which may explain many symptoms of PHO.The clinical diagnosis is required to eliminate secondary hypertrophic osteoarthropathy.The identifcation of SLCO2A1 or HPGD deficiency in patients with PHO has become an effcient approach to assist in clinical diagnoses.With the the knowledge of the disease and the development of sequencing technology,more and more sequence variants have been discovered.Further study are needed to investigate whether the newly discovered sequence variants is pathogenic and the difference of clinical phenotype between diverse variants so that expands the clinical phenotype-genotype spectrum of primary hypertrophic osteoarthropathy in order to fully elucidates the pathogenesis and the functions of the underlying genes.There are no permanent cure for PHO.Genetic studies have identified the impaired prostaglandin(PGE2)metabolism as a culprit for hypertrophic osteoarthropathy in PHO cases.This highlights the role of treatment with Non-Steroidal Anti-Inflammatory Drugs(NSAIDs),which act by inhibiting the biosynthesis of prostaglandins(PGE)by preventing the binding of arachidonic acid to COX enzyme active site.Etoricoxib,a selective cyclooxygenase-2 inhibitor,is common drugs at present which needs further studies to evaluate effects among PHO patients.Objectives(1)To analyse a case with complain about enlargements of limb and facial change in order to understanding the characteristics of primary hypertrophic osteoarthropathy.(2)To analyse clinical data and genes of the patient and his family,we explore pathogenicity of sequence variants in order to fully elucidates pathogenesis of genetics.(3)To observe therapeutic response to etoricoxib among PHO patient.Subject and MethodsSubject:a Han Chinese patient and his pedigree with primary hypertrophic osteoarthropathyMethods(1)The clinical data of the patient and his family members were collected and analyzed.(2)Sequence analysis of associated genes:Blood samples were drawn from the affected individuals and their available family members.The entire coding regions and sequences of the intron-exon region of causative gene of inherited diseases of bone,including HPGD and SLC02A1,were amplifed by polymerase chain reaction and sequenced by Sanger method after DNA was extracted.The sequencing results were compared with reference Sequence in the NCBI,searched for the sequencing variations in patient which were also screened in the family members.(3)Pathogenicity analysis of variants:The NCBI database was used to evaluate the conservatism and single nucleotide polymorphism(SNP).Bio-informatics tools,Polyphen2 and Mutation Taster,were used to predict the pathogenicity of sequence variants.According to the above analysis result,the related literatures and characteristic of pedigree,we made a comprehensive analysis of pathogenicity.(4)The patient treated with etoricoxib(60mg once daily)and rabeprazole(30 mg once daily),was evaluated at several time points(baseline,1,2 and 3 months).Results(1)The proband was Chinese Han middle-age man who initially presented with Enlargements of the terminal phalanges and toes in the young.The patient complained about gradual pain and swelling of both knee,wrist and ankle joints and progressive facial change such as facial furrows,seborrhea and acne.Radiographs showing periostosis of the hands,feet,and lower limbs.The patient describe that his paternal grandfather and grandmother had consanguineous marriage and his maternal grandfather had similar phenotype of PHO.(2)A compound heterozygous mutation in the SLC02A1 gene of proband was identifed,which contained two sequence variants(c.940+1G>A/p.?)in intron7 and(c.1790A>G/p.Tyr597Cys)in exon 13.Proband’s mother was heterozygous mutation(c.940+1G>A)carrier,while father was c.1790A>G.Proband and his younger sister had the same compound heterozygous mutation.Other family member were heterozygous mutation(c.940+1G>A or c.1790A>G)carriers.(3)There have been some cases that revealed mutation(c.940+1 G>A/p.?)in the SLC02A1 gene is primary pathogenic sequence variant in the patients with PHO.Sequence variants(c.1790A>G/p.Tyr597Cys))in the SLC02A1 gene in PHO disease have not been reported in a previous study,which clinical significance is unclear.c.1790A>G was rare sequence variants and p.597 was revealed to be highly evolutionarily conserved in diverse species.Sequence variants(c.1790A>G/p.Tyr597Cys)was predicted to be pathogenic by bio informatics tools,PolyPhen and MutationTaster.(4)The patient’s panchydermia,digital clubbing and joint swelling were improved significantly.The side effects were weak and drowsiness in the early treatment and intermittent abdominal discomfort through the treatment.Conclusion(1)The Patient with digital clubbing,pachydermia and periosteal reaction can be clinically diagnosed as having PHO after excluding the secondary hypertrophic osteoarthropathy.The identifcation of SLC02A1 or HPGD gene deficiency can assist in clinical diagnoses.(2)Sequence variant(c.940+1G>A/p.?)in the SLC02A1 gene is common pathogenic in the patients with PHO.Sequence variant(c.1790A>G/p.Tyr597Cys)was likely pathogenic.(3)Etoricoxib showed efficacy in alleviating PHO symptoms including panchydermia,digital clubbing and joint swelling with slight side effects.