|Year : 2020 | Volume
| Issue : 3 | Page : 172-175
High penetrance of EDA pathogenic variants in Mexican female carriers with hypohidrotic ectodermal dysplasia
Constanza Garcia-Delgado1, Miguel Angel Noriega-Juárez1, Alicia Cervantes2, José D Abad-Flores3, Mirna Toledo-Bahena4, Adriana Valencia-Herrera4, Carlos A Mena-Cedillos4, América Villaseñor-Domínguez1, Adriana Sánchez-Boiso1, Yumiko Akaki-Carreño5, Blanca Del Río-Navarro6, Jesús Aguirre-Hernández7, Marisol López-López8, Marco Cerbón9, Verónica F Morán-Barroso1, Nancy Monroy-Jaramillo10
1 Department of Genetics, Children's Hospital of Mexico Federico Gómez, Mexico City, Mexico
2 Service of Genetics, General Hospital of Mexico Dr. Eduardo Liceaga/Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
3 Department of Genetics, National Institute of Neurology and Neurosurgery Manuel Velasco Suárez; Human Reproduction Research Unit, National Institute of Perinatology Isidro Espinosa de los Reyes, Mexico City, Mexico/Faculty of Chemistry, National Autonomous University of Mexico, Mexico City, Mexico
4 Department of Dermatology, Children's Hospital of Mexico Federico Gómez, Mexico City, Mexico
5 Department of Genetics; Department of Dermatology, Children's Hospital of Mexico Federico Gómez, Mexico City, Mexico
6 Department of Immunology and Allergy, Children's Hospital of Mexico Federico Gómez, Mexico City, Mexico
7 Laboratory of Genomics, Genetics and Bioinformatics, Children's Hospital of Mexico Federico Gómez, Mexico City, Mexico
8 Department of Biological Systems, Autonomous Metropolitan University-Xochimilco, Mexico City, Mexico
9 Human Reproduction Research Unit, National Institute of Perinatology Isidro Espinosa de los Reyes, Mexico City, Mexico/Faculty of Chemistry, National Autonomous University of Mexico, Mexico City, Mexico
10 Department of Genetics, National Institute of Neurology and Neurosurgery Manuel Velasco Suárez, Mexico City, Mexico
|Date of Submission||08-Nov-2019|
|Date of Decision||25-Feb-2020|
|Date of Acceptance||02-May-2020|
|Date of Web Publication||10-Sep-2020|
Dr. Nancy Monroy-Jaramillo
Insurgentes Sur 3877, La Fama, Tlalpan, 14269 Mexico City
Source of Support: None, Conflict of Interest: None
X-linked hypohidrotic ectodermal dysplasia (XLHED) is caused by EDA pathogenic variants. Female carriers show several clinical manifestations in variable percentages. We studied 11 Mexican heterozygous females with an EDA variant. The most frequent symptoms were similar to previous reports; however, two females (18%) reported dry eye syndrome, data rarely explored in carriers. The penetrance was 91% with clinical variability that might be related to the location of the mutation and/or to a skewed X-inactivation pattern. Our results highlight the importance of offering molecular testing to potential female carriers and support XLHED as an X-linked entity with incomplete penetrance in females.
Keywords: EDA gene, heterozygous EDA female carriers, hypohidrotic ectodermal dysplasia, penetrance, variable expressivity
|How to cite this article:|
Garcia-Delgado C, Noriega-Juárez MA, Cervantes A, Abad-Flores JD, Toledo-Bahena M, Valencia-Herrera A, Mena-Cedillos CA, Villaseñor-Domínguez A, Sánchez-Boiso A, Akaki-Carreño Y, Río-Navarro BD, Aguirre-Hernández J, López-López M, Cerbón M, Morán-Barroso VF, Monroy-Jaramillo N. High penetrance of EDA pathogenic variants in Mexican female carriers with hypohidrotic ectodermal dysplasia. Dermatol Sin 2020;38:172-5
|How to cite this URL:|
Garcia-Delgado C, Noriega-Juárez MA, Cervantes A, Abad-Flores JD, Toledo-Bahena M, Valencia-Herrera A, Mena-Cedillos CA, Villaseñor-Domínguez A, Sánchez-Boiso A, Akaki-Carreño Y, Río-Navarro BD, Aguirre-Hernández J, López-López M, Cerbón M, Morán-Barroso VF, Monroy-Jaramillo N. High penetrance of EDA pathogenic variants in Mexican female carriers with hypohidrotic ectodermal dysplasia. Dermatol Sin [serial online] 2020 [cited 2022 Dec 2];38:172-5. Available from: https://www.dermsinica.org/text.asp?2020/38/3/172/294706
| Introduction|| |
X-linked hypohidrotic ectodermal dysplasia (XLHED) is characterized by hypotrichosis, hypodontia, and hypohidrosis; it is caused by pathogenic variants of EDA gene in Xq12-q13, which encodes the ligand ectodysplasin A protein. XLHED is an X-linked disease (MIM #305100) affecting up to 1:10,000 hemizygous males, and clinical manifestations have been described in 67%–77% of female carriers,,,,, with percentages varying from 18.5% for facial characteristics to 100% regarding dental abnormalities.,,
| Methods|| |
We previously reported EDA pathogenic variants in a cohort of 13 Mexican male patients with XLHED and confirmed the carrier status for some of their mothers and grandmothers. In this study, we clinically reassessed six of those females and additionally included the clinical and molecular analysis of five new adult female relatives from that cohort with potential risk of being carriers. Informed consent for each participant was obtained for the clinical and molecular tests after a complete description of the study, with approval by the local research ethics committee (HIM 2013/011). In total, 11 confirmed XLHED female carriers belonging to six families (A–F) were included [Table 1] and [Figure 1]. The authors certify the authorization from the families of the participants for the use of clinical photographs.
|Table 1: Clinical and molecular profile of heterozygous female carriers with EDA pathogenic variants included in the study|
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|Figure 1: Upper section: Clinical phenotype of heterozygous females for EDA pathogenic variants [Photographs are identified according to Table 1]. Note, wide forehead, scarce, and curly hair and scarce eyebrows in individual A1; wide forehead and scarce eyebrows in A2; wide forehead and high hairline in B1; wide forehead, high frontal hairline, and scarce temporal region hair are observed in E1; high hairline in forehead and scarce hair in the temporal region in F1; and scarce hair and eyebrows in F3. Dental abnormalities are observed in C1 with some of the inferior dental arch teeth showing microdontia and a conic shape (the maxillary dental arch received dental treatment). In patient D2, note, wide lips, absent maxillary left incisive tooth, and dysplasia of maxillary right incisive tooth, and in D3, inferior dental arch microdontia and central tooth diastema. Lower section: Schematic EDA diagram showing the pathogenic variants present in the six described families. Two pathogenic variants were localized in the TNF domain, two in the furin cleavage site, one in the TM domain, and one deletion identified in family A affecting exon 1. Fam: Family, TM: Transmembrane domain, TNF: Tumor necrosis factor domain|
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| Results|| |
The age range of the participants was 22–59 years. In family A, both the mother and the maternal grandmother of a male patient were carriers of an EDA exon 1 deletion, and as was previously described by our group, they had an opposite skewed X-inactivation pattern. The most frequently identified symptoms among the evaluated females were hypohidrosis and hypotrichosis in 72.7% (8/11 females) and dental abnormalities in 63.6% (7/11), and a clinical history of recurrent upper respiratory tract infections was identified in 36%, all similar to reported values.,, Two unrelated females (2/11, 18%) reported dry eye syndrome and repetitive episodes of conjunctivitis. This clinical alteration has been referred in a low percentage in XLHED males and has been little explored in female carriers with EDA pathogenic variants; therefore, it would be worth to perform an ophthalmologic evaluation in the heterozygous females.
| Discussion|| |
In this XLHED female cohort, at least one out of eight clinical data investigated was present in the evaluated patients [Figure 1]. The individual D2 only referred recurrent airway infections, which per se cannot be solely attributable to XLHED; therefore, the penetrance in our cohort (10/11) could be estimated as high as 91%. These observations indicate that XLHED would have nearly full penetrance in heterozygous females, a conclusion not frequently reported for an X-linked recessive disease. The clinical intrafamilial variability observed in our cohort was higher than the interfamilial variability found in females with similar EDA pathogenic variants [Table 1], a situation that may be related to a nonrandom X-chromosome inactivation pattern. It is interesting to note that females with a pathogenic variant in the mutational hotspot in the furin cleavage site (exon 2 of EDA) presented most of the clinical features, highlighting the key role of this particular domain for the proper functioning of EDA.
Two recent communications have demonstrated that there are clinical manifestations in XLHED heterozygous females, with some of them even present from childhood. Both studies concluded that most XLHED heterozygous females show at least one HED clinical manifestation., Overall, the percentages of clinical manifestations reported are within the range observed in our cohort.
In conclusion, we clinically and molecularly assessed a cohort of 11 Mexican females, heterozygous for EDA pathogenic variants, where the most frequent clinical manifestations were hypohidrosis and hypotrichosis. The carriers for variants located in exon 2 showed more clinical manifestations than those with EDA pathogenic variants in other exons, excluding the grandmother in family A, who had an EDA exon 1 deletion and a confirmed skewed inactivation of the normal X chromosome. This study, albeit in a small sample, suggests that identifying clinical manifestations in the XLHED proband's mothers is of relevance, supporting a clinical follow-up, and a molecular diagnosis to offer genetic assessment to females at risk of being heterozygous for EDA pathogenic variants.,
As has been suggested in other X-linked diseases with variable expressivity in heterozygous females, and has been described in recent HED heterozygous female studies,,, our cohort of XLHED heterozygous females showed a spectrum of clinical manifestations in meaningful percentages, confirming that these disorders may not be described as recessive or dominant and should be referred only as X-linked with incomplete penetrance in females.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms and have the authorization from the families of the participants for the use of clinical photographs.
Financial support and sponsorship
This work was carried out with the support of Mexican Health Ministry Fondos Federales registry HIM 2013/011.
Conflicts of interest
There are no conflicts of interest.
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