A Case Of Short Stature Caused By ADAMTS17 Gene Variation And Literature Review

Objective:Summarized the clinical data of a child with Weill-Marchesani syndrome.Explore the pathogenic mechanism of ADAMTS17gene c.2137+1G>A(p.Asn424Asp)variant by bioinformatics analysis and in vitro function verification.Combined with the literature review to improve the understanding of Weill-Marchesani syndrome,reduce misdiagnosis and missed diagnosis,and achieve early diagnosis,treatment and improve the prognosis.Methods:Part One:Clinical data collection and gene functional verification1.Collected the clinical data of 1 short child in our hospital,verified the whole exome and Sanger sequencing,and achieved the bioinformatics analysis of the found ADAMTS17 gene variant c.2137+1G>A(p.Asn424Asp).2.ADAMTS17 wild-type and mutant plasmids were constructed to verify whether the newly discovered variant affected precursor m RNA splicing through the in vitro minigene splicing reporting system.Part Two:Literature reviewSearch terms with"Weill-Marchesani"and"ADAMTS17"were limited to titles or abstracts,and were searched in CNKI,Wanfang Database,Weipu Database and PUBMED.Retrospectively analyzed the clinical data of patients with Weill-Marchesani syndrome reported at home and abroad.Results:Part One:Clinical data collection and gene functional verification1.History of present illness:The patient,female,12.9 years old,was admitted to the pediatric department of our hospital due to"slow growth and development since childhood".Height:139.2cm,height SDS:-2.8,body mass index BMI:19.1 kg/m~2.Mild mentally retarded.The body was scattered with a dry rash with thick skin,short and thick toes,and stiff distal knuckles.Laboratory tests showed that hepatitis B surface antigen,hepatitis B e antigen,hepatitis B e antibody and hepatitis B core antibody were increased,alanine aminotransferase and aspartate aminotransferase were elevated,adrenocor-ticotropic hormone was reduced,25-hydroxyvitamin D was reduced,and insulin-like growth factor 1(precise):307.5ng/ml-0.9SD.Suspected:severe HBe Ag-positive chronic hepatitis B,congenital ichthyosis,congenital lens dislocation,growth retardation.2.Family history:The mother has hepatitis B.Father’s height:168cm,mother’s height:153cm,developmental age unknown.Target height:155.6cm,Target height SDS:-1.3.No family history of short stature and consangui-neous marriage.3.History of past illness:Ichthyosis was diagnosed 1 month after birth,chronic hepatitis B for 8 years,abnormal liver function for 3 years,lens dislocation was found 2 years ago and recieved"intraocular lens suspension".4.Sanger sequencing verified that the child had c.2137+1G>A(p.Asn424Asp)homozygous variant of the ADAMTS17 gene and genetic analysis suggests that the variant may be pathogenic and highly conserved.5.The functional verification of ADAMTS17 gene mutations in vitro showed that the classical splicing site c.2137+1G>A affected the normal splicing of ADAMTS17 gene.6.Diagnosis,treatment and follow-up:The effect of recombinant human growth hormone treatment for six months was poor.Follow-up to 15 years old,her height was still short.Part Two:Literature reviewA total of 69 patients with Weill-Marchesani syndrome in China were reported,and only 7 of them had completed gene detection,and the rest were diagnosed with clinical symptoms.1.There were 32 males and 37 females,aged from 2 to 71 years old,and20 cases had positive family history,14 of which were brothers and sisters.There were 10 cases whose parents had consanguineous marriage.2.WMS implicates multiple organs and has a variety of clinical manifestations.The most common clinical manifestations of WMS patients in China were ocular symptoms,with 68 cases(98.55%)of high myopia,48cases of glaucoma(69.57%),68 cases of spherical lens(98.55%),53 cases of ectopic lens(76.81%),16 cases of cataract(23.19%),35 cases of iris tremor(50.72%),6 cases of preiris adhesions(8.70%),and 3 cases of optic nerve atrophy(4.35%).At the same time,musculoskeletal diseases were manifested in 62 cases(89.86%)of short stature,31 cases(44.93%)of short head and neck,60 cases(86.96%)of short toes,and 21 cases(30.43%)of joint stiffness.The remaining symptoms included 12 cases(17.39%)of cardiovascular defects,6 cases of mental retardation(8.70%),10 cases(14.50%)of special facial appearance,2 cases of each symptom such as atopic macula,ptosis,scoliosis,six-finger deformity and inguinal oblique hernia,and 1 case of each symptom such as dental abnormalities,foramen retinal detachment,increased corneal thickness,angle dysplasia and reverse pupil block,iridocyclic cyst,posterior mass lesions of both eyes,iris defect,corneal topography,hepatoblastoma,syndactylosis,poor hearing,articular tenosynovitis and small head tip.Only 7 cases(10.14%)completed gene test.Fourty-seven cases(68.12%)were treated with surgery and 6 cases(8.70%)were treated with medicine.Conclusions:1.Weill-Marchesani syndrome is a rare connective tissue disorder with not enough gene tests.2.New variant c.2137+1G>A(p.Asn424Asp)of the ADAMTS17 gene may be pathogenic.3.This is the first patient with WMS combined with congenital ichthyosis reported by pediatrics in China and treated with recombinant human growth hormone,which provides a reference for the height treatment of children with WMS.