Preliminary Study On Clinical Of Characteristics And Genetics Of Short Stature Caused By Rare Monogenetic Mutations

PurposeShort stature is one of the most concerned fields for endocrinologists and pediatricians.The etiology of short stature is complex and diverse,as well as phenotypes of these patients vary from each other,so standardized consultation,physical examination,hormone detection and radiological examination can help to confirm the diagnosis.With the strengthening of perinatal care,diseases leading to growth and development disorders are gradually reduced,such as growth hormone deficiency,hypothyroidism,and more short stature patients have no obvious abnormalities biochemically.The extensive applications of next-generation sequencing provide strong technical support for etioligical diagnosis of these short stature patients.In this study,216 short stature patients with unknown causes accepted genetic tests in order to definite the etiology and provide guidance for further treatment.Objectives and MethodsFrom May 2017 to Feburary 2020,216 short stature patients with unclear etiology were included and received detailed clinical evaluation.Clinical,biochemical and radiological materials were collected.Meanwhile,approximately 2～3 ml peripheral blood of patients and their related family members were collected for further DNA extraction,and patients were accepted whole-exome sequencing（WES）while verification was performed among the proband’s family members by Sanger sequencing.Clinical phenotypes and genetic results of these patients were sorted out for further statistical analysis.Through literature review,clinical and genetic characteristics of patients with COMP,ACAN or NPR2 gene mutations were systematically summarized.Results1.In this study,40 patients were detected carrying with gene mutations related to osteochondral dysplasia among 216 short stature patients with unknown etiology,accounting for 18.52%.Among them,mutations of collagen family genes are the most common,accounting for 5.09%.Then followed by ACAN and NPR2 gene mutations,accounting for 4.17%and 3.24%,respectively.2.Two patients were detected carrying with COMP heterozygous mutations,which resulted in pseudoachondroplasia（PSACH）.Their main clinical characteristics were severe short stature accompanied by short limbs.Their mutations were c.1417₁419delGAC and c.1552G>A,which were known pathogenic mutations.This study summarized clinical and genetic characteristics of all reported Chinese PSACH patients.These patients’heights were usually under-5 standard deviation score（SDS）,accompanied by skeletal dysplasia,such as short limbs,brachydactyly,enlargement of long bones’ metaphysis and scoliosis,etc.The hot spot mutation of COMP gene is c.1417₁419delGAC.3.In this study,9 patients who manifested as short stature and nonspecific skeletal malformation were detected carrying with ACAN heterozygous mutations.In addition to short stature,these patients often had atypical skeletal malformations,such as mild midface hypoplasia,brachydactyly,mild scoliosis etc.Through literature review,it was found that about 1/3 patients had advanced bone age,which suggested that advanced bone age can help make diagnosis,but this characteristic is not a necessary condition for diagnosis.Growth promoting and inhibiting advanced bone age may help improve these patients’ heights to a certain extent.4.In this study,7 patients with NPR2 mutations were detected,including 6 patients with short stature and nonspecific skeletal malformations and 1 patient with acromesomelic dysplasia,Maroteaux type（AMDM）caused by NPR2 compound heterozygous mutations.Clinical manifestations of both two types of patients were short stature,short limbs,brachydactyly,spinal and thoracic deformities,however,manifestations of AMDM patients were more severe than short stature patients caused by NPR2 heterozygous mutations.Through literature review,it was found that NPR2 heterozygous mutations accounted for a certain proportions of idiopathic short stature patients,up to 6%.Growth hormone treatment can improve patients’ heights who carried with NPR2 heterozygous mutations,but the therapeutic effect was quite different among individuals.ConclusionFor short stature patients with unknown causes and nonspecific skeletal dysplasia,further genetic tests can be carried out to find potential pathogenic genes.WES combined with Sanger sequencing verification can help make an accurate diagnosis and guide further treatment in the field of short stature.