Mutation Analysis Of A Child With Atypical Progeroid Syndrome And Review Of The Literature

Objectives:In this study,clinical,laboratory and imaging data of a child with atypical progeroid syndrome(APS)were collected to analyze the clinical characteristics of APS.Genetic testing of the patient and his parents was conducted to identify the pathogenic gene and genetic mode of this family.The clinical data of the child in this study and 37 Chinese patients with progeroid syndromes related to the LMNA gene mutation reported in the literature from 2009 to 2020 was analyzed,in order to further understand the incidence in our country,clinical characteristics,to improve clinicians and patients’ understanding of the disease.Methods:(1)Clinical,laboratory and imaging data of the progeroid child were collected.And Follow-up visit for 2 years was conducted to know about the progress of the disease.(2)Peripheral venous blood samples were obtained from 3 family members including the patient and his parents,and genomic DNA was extracted from these blood samples for Sanger sequencing.The hazard of mutation site was analyzed by SIFT,polyphen-2 and Mutation Taster online software.(3)The previous case reports or literature about LMNA mutations of APS in last 17 years were retrieved from databases such as CNKI,Wan Fang data,VIP data,Pub Med to analyze the Mutation-prone area of LMNA gene of patients with APS.Clinical data of 37 Chinese patients with progeroid syndromes related to the LMNA gene mutation reported in the literature from 2009 to 2020 were collected to analyze the clinical and genetic characteristics.Results:(1)The clinical characteristics of the child that was diagnosed as APS included short stature,over-crowding teeth,thin skin and subcutaneous fat reduction of trunk and extremities,visible superficial veins on both lower limbs,and presenile face such as partial hair loss,protruding eyes,small mouth and thin lips.Dry skin throughout the body with mottled hyperpigmentation and hypopigmentation,contracture of the little fingers of both hands,limited squatting and malnutrition of toenails can also be seen.The clinical features were consistent with the diagnose of APS.No obvious abnormity was observed in routine laboratory examinations and imaging examinations.Follow-up observation of the patient for 2 years,it was found that clinical symptoms of the patient increased.(2)One mutation(c.1762T>C,p.C588R)was identified in the patient,but no mutation was found in parents of the patient.The results of SIFT,polyphen-2 and Mutation Taster online software showed that the mutant site was harmful to protein function.(3)The literature review found that 31 different pathogenic mutations in APS have been reported,which mainly distributed in exons 1,2 and 11 of the LMNA gene.And most of the mutations are heterozygous.(4)This study summarizes 37 Chinese patients with progeroid syndromes related to the LMNA gene mutation from 2009 to March 2020,include 1 patient in this study,there are 38 cases in total.Among them,19 cases were diagnosed with Hutchinson-Gilford progeria syndrome(HGPS),8 cases were diagnosed with mandibular dysplasia with type A lipodystrophy(MADA)and 11 cases were diagnosed with APS.Among the 19 HGPS patients,the median age of diagnosis was 2.8 years old.Among the 8 MADA patients,the median age of diagnosis was4.1 years old.Among the 11 APS patients,the median age of diagnosis was 18 years old.All patients were not given special treatment.Conclusions:(1)The clinical characteristics of the patient was consistent with APS,but not be in line with other types of premature diseases such as classic HGPS or MADA.(2)The patient had a heterozygous mutation p.C588 R mapping in the exon 11 of the LMNA gene.No mutation was found in the parents of the patient,so it can be speculated that the mutation p.C588 R was a de nove mutation.According to the clinical features and the result of gene detection,the patient was conformed of APS and the heterozygous mutation p.C588 R is the pathogenic mutation.(3)This was the first reported case of APS with p.C588 R mutation in Asia,which further enriches the database of LMNA gene mutations and lays a certain foundation for genetic counseling and prenatal genetic diagnosis.(4)In China,the incidence of progeroid syndromes associated with LMNA gene mutations is low.Due to the slow progress of APS and atypical symptoms at an incipient stage,the median age of diagnosis of APS is greater than that of HGPS and MADA.