Displasia ectodérmica hipohidrótica ligada al cromosoma X de novo por variante recurrente en un paciente mexicano / X-linked hypohidrotic ectodermal dysplasia by a de novo recurrent variant in a Mexican patient

Resumen Introducción: Las displasias ectodérmicas son un grupo de genodermatosis que se caracterizan por distrofia de las estructuras derivadas del ectodermo. De ellas, la variedad más común es la hipohidrótica, con una incidencia de 7/100,000 nacidos vivos observada en todos los grupos étnicos. La displasia ectodérmica hipohidrótica tiene distintas etiologías. La presentación más frecuente es la asociada a un patrón de herencia ligado al cromosoma X, causada por variantes patogénicas del gen EDA en Xq13.1. EDA codifica a la ectodisplasina A, una molécula de señalización que participa en la comunicación epitelio-mesénquima durante el desarrollo de la piel y los anexos. Caso clínico: Varón de 6 años con las características clínicas cardinales de la displasia ectodérmica hipohidrótica ligada al cromosoma X (DEHLX), que incluyen hipotricosis, oligodoncia e hipohidrosis. El análisis del gen EDA por secuenciación directa mostró la presencia de la variante patogénica c.466C>T, p.Arg156Cys, rs132630313 con presentación de novo en el paciente. Esta variante ya ha sido reportada en diferentes poblaciones, incluyendo familias mexicanas, y constituye un punto caliente para mutación en EDA. Se analizaron los hallazgos clínicos, la etiología y el manejo de la DEHLX, en la que de manera reciente se ha planteado la posibilidad de otorgar tratamiento prenatal para prevenir sus manifestaciones clínicas. Conclusiones: Se pone de relevancia que el análisis molecular en pacientes con DEHLX corrobora el diagnóstico clínico y permite brindar asesoramiento genético con bases moleculares.

Abstract Background: Ectodermal dysplasias are a group of genodermatoses characterized by dystrophy of ectodermal derived structures. The most frequent presentation of the ectodermal dysplasias is the hypohidrotic type, which has an incidence of 7/100,000 newborns and has been described in all ethnic groups. The hypohidrotic ectodermal dysplasia (HED) has different etiologies, and it is more frequently associated with an X-linked pattern of inheritance caused by pathogenic variants of the EDA gene in Xq13.1. EDA encodes the protein ectodisplasin A, a signal molecule which participates in epithelium and mesenchymal development of the skin. Case report: A 6 year-old male patient with the main clinical characteristics of the X-linked HED including hypotrichosis, hypodontia and hypohidrosis. The direct sequencing analysis of EDA in our patient detected a de novo pathogenic variant, c.466C>T, p.Arg156Cys, rs132630313. This variant has been previously described in different ethnic groups, including Mexican families, and is considered a mutational hotspot. The clinical characteristics, etiology and management of the X-linked HED, including the possibility of prenatal therapy in order to avoid the clinical manifestations are discussed. Conclusions: The molecular analysis in patients with X-linked HED is of relevance, as it enables to confirm the clinical diagnosis and also, it allows a genetic assessment with molecular bases.

Detection of EDA gene mutation and phenotypic analysis in patients with hypohidrotic ectodermal dysplasia / 北京大学学报(医学版)

OBJECTIVE@#To detect the ectodysplasin A (EDA) gene mutation in patients with hypohidro-tic ectodermal dysplasia (HED), and to analyze the distribution pattern of missing permanent teeth and the systemic manifestation of HED patients with EDA gene mutation.@*METHODS@#Twelve HED families were enrolled from clinic for genetic history collection, systemic physical examination and oral examination. Peripheral blood or saliva samples were collected from the probands and the family members to extract genomic DNA. PCR amplification and Sanger sequencing were utilized to detect the EDA gene variations, which were compared with the normal sequence (NM_001399.5). The functional impact of EDA gene variants was then evaluated by functional prediction of mutation, conservation analysis and protein structure prediction. The pathogenicity of each EDA gene variation was assessed according to the stan-dards and guidelines of the American College of Medical Genetics and Genomics (ACMG). The systemic phenotype and missing permanent tooth sites of HED patients with EDA gene mutations were summarized, and the missing rate of each tooth position was analyzed and compared.@*RESULTS@#Eight out of twelve HED families were identified to carry EDA gene mutations, including: c.164T>C(p.Leu55Pro); c.457C>T (p.Arg153Cys); c.466C>T(p.Arg156Cys); c. 584G>A(p.Gly195Glu); c.619delG(p.Gly207Profs*73); c.673C>T(p.Pro225Ser); c.676C>T(p.Gln226*) and c.905T>G(p.Phe302Cys). Among them, c.164T>C(p.Leu55Pro); c.619delG(p.Gly207Profs*73); c.673C>T(p.Pro225Ser); c.676C>T(p.Gln226*) and c.905T>G(p.Phe302Cys) were novel mutations. The HED patients with EDA gene mutations in this study were all male. Our results showed that the average number of missing permanent teeth was 13.86±4.49, the average number of missing permanent teeth in the upper jaw was 13.14±5.76, the missing rate was 73.02%. And in the lower jaw, the average number of missing permanent teeth was 14.57±3.05, the missing rate was 80.95%. There was no significant difference in the number of missing teeth between the left and right sides of the permanent dentition (P>0.05). Specifi-cally, the maxillary lateral incisors, the maxillary second premolars and the mandibular lateral incisors were more likely to be missing, while the maxillary central incisors, the maxillary and mandibular first molars had higher possibility of persistence.@*CONCLUSION@#This study detected novel EDA gene pathogenic variants and summarized the distribution pattern of missing permanent teeth of HED patients, thus enriched the variation and phenotype spectrum of EDA gene, and provided new clinical evidence for genetic diagnosis and prenatal consultation.

Association Of Eda Gene Polymorphisms Rs 372024, Rs 3764746, Rs 3795170 In Skeletal Class I Cases With Dental Crowding

The EDA gene, associated with X linked hydrotic form of Ectodermal Dysplasia, its mutations could potentially lead to differential gene expression that causes large tooth phenotype, which has been suggested to cause dental crowding. We analyzed the association of genetic polymorphisms in EDA gene variants rs 372024, rs 3764746, and rs 3795170 among Skeletal Class I crowding cases using blood samples of 30 cases and 30 controls, which were subjected to PCR amplication and DNA sequencing. Based on the statistical analysis using the Z test we found CG and GG genotype for rs3764746 and GT and TT genotype for rs3795170 showed a statistically signicant result. These results suggest that EDA gene variants rs3764746 and rs3795170 could be genetic markers for dental crowding in our population while EDA gene variant rs372024 did not show any signicant association in our population. These ndings can provide in-depth knowledge, regarding the genetic inuences on the incidence of crowding of teeth.

EDA mutation screening and phenotype analysis in patients with tooth agenesis / 北京大学学报(医学版)

Objective:To screen the ectodysplasin A (EDA)gene mutation in the patients with non-syndromic tooth agenesis and ectodermal dysplasia,and to analyze the phenotype of missing teeth pattern in these two groups of patients.Methods:In the study,174 patients with tooth agenesis (143:non-syn-dromic,31:ectodermal dysplasia)and 451 health control volunteers were enrolled from the clinic,and the genome DNA was extracted from either peripheral blood or oral mucosal swab.The coding region of EDA gene was then amplified by PCR,sequenced and blasted to online NCBI database.The missing teeth were recorded for all patients,and the missing teeth from patients with EDA mutation were com-pared among the different dentition sites.Results:33 patients were identified with EDA mutation.In the non-syndromic patients,13 /143(9.09%)were identified with EDA mutation,while in patients with ec-todermal dysplasia,20 /31 (64.52%)were found with EDA mutation.Ten novel EDA mutations were identified (c.769G >C[p.G257R],c.936C >G[p.I312M],c.223G >A[p.E75K],c.1166C >T[p. P389L],c.133G >C[p.G45R],c.1109G >A[p.E370K],c.914G >T[p.S305I],c.916C >T[p. Q306X],c.602G >T[p.G201V],c.88 -89insG[p.A30GfsX69]).For each dentition site there was no statistic difference in the number of missing teeth between the left and right sides,so the number from both sides were combined later in the analysis.In the patients with EDA mutation,the non-syndromic pa-tients had fewer missing teeth (15.9 ±6.4 missing teeth for each,207 /364 in total)than the patients with ectodermal dysplasia (23.9 ±4.3,478 /560).In the non-syndromic patients with EDA mutation, the maxillay central incisors and first molars were less affected,with the same missing rate as 19.2% (5 /26).While the mandibular central incisors (with a missing rate of 76.9%,20 /26),the maxillary late-ral incisors (the missing rate:88.5%,23 /26 ),the mandibular lateral incisors (the missing rate:80.8%,21 /26),and the maxillary first premolars (the missing rate:80.8%,21 /26)were more likely to be missing.In the ectodermal dysplasia patients with EDA mutation,only maxillary central incisors (the missing rate:60%,24 /40),maxillary canines (the missing rate:70%,28 /40),mandibular ca-nines (the missing rate:67.5%,27 /40),maxillary first molars (the missing rate:65%,26 /40)and mandibular first molars (the missing rate:72.5%,29 /40)had higher possibility of persistence.Teeth at other dentition sites were more likely to be affected (the minimum missing rate:87.5%,35 /40). Conclusion:The findings would help to reveal the EDA gene and its function in ectodermal organogene-sis.

Molecular diagnosis of X-linked hypohidrotic ectodermal dysplasia families / 中华实用儿科临床杂志

Objective To explore the mutations of EDA gene in 2 X - linked hypohidrotic ectodermal dyspla-sia(XLHED)pedigrees,and provide clues for the XLHED diagnosis,genetic counseling and treatment. Methods Polymerase chain reaction and direct sequencing were used to analyze the coding sequences and their flanking sequences of the EDA gene in the patients,suspicious carriers,normal family members in 2 families and non - relative control sam-ples. Results In family 1,mutation c. 659 676del18,namely p. 220 225del(Gly - X - Y)6 which was located in (Gly - X - Y)19 collagen - like repeat domain,was found in the proband and other patient's EDA gene. In family 2,an insertion c. 118 - 119insT was found in the intracellular domain,which induces reading frame alteration from the 40th a-mino acid. The mutations found in the 2 families were consistent with the principle of mutation and phenotype co - sepa-ration,but these mutations were not found in the normal control samples. EDA gene analysis of fetal amniotic fluid sam-ple from Ⅲ - 1 in the family 1 was not found to have the same mutation as the proband,and the follow - up after birth proved normal for the baby. Conclusions EDA gene c. 118 - 119insT mutation found in the research is a novel muta-tion. Sequence analysis of EDA gene is an efficient method in XLHED diagnosis,and is beneficial for the genetic coun-seling and the genetic intervention of the disease in the affected families.

Gene mutation detection for a patient with anhidrotic ectodermal dysplasia / 实用口腔医学杂志

Objetive:To detect the gene mutation of a patient with anhidrotic ectodermal dysplasia. Methods: Genomic DNA was extracted from the peripheral blood of the patient and all the exon fragments were obtained by PCR. These fragments were sequenced directly. Results: In EDA gene a novel base transition was detected: -48A→G. Conclusion: There is a new base transition in EDA gene in this patient