A novel EDA variant that causes X-linked hypohidrotic ectodermal dysplasia in a Chinese family

Abstract

Background: Hypohidrotic ectodermal dysplasia (HED) is a rare genetic disorder that affects the development of the skin, hair, nails, teeth, and sweat glands. Due to its rarity, there are currently few methods that can be applied to facilitate its diagnosis during the prenatal period. Although a prenatal ultrasonographic examination will detect early signs of the disease, there are few reports on specific prenatal ultrasonographic features of ectodermal dysplasia. Genetic diagnosis can confirm the disease, but the numerous gene variants that cause ectodermal dysplasia have not been fully identified.

Case presentation: Our case was a multiparous woman carrying a single male fetus who underwent a fetal ultrasound examination at 23 weeks of gestation. The examination revealed thin alveolar bone, with no presence of hypoechoic tooth germ tissue in both the upper and lower alveolar bones. The seven-year-old male proband in this family manifested a clinical phenotype of sparse hair and underdeveloped teeth, and trio-based whole-exome sequencing (WES) performed on both parents and the proband revealed a novel and likely pathogenic variant of the EDA gene (NM_001399.4: c.806G > T, p.Gly269Val) associated with X-linked HED (XLHED; OMIM:305100). Based on the results of the fetal ultrasound examination and the results of the proband's genetic testing, the couple ultimately decided to terminate the pregnancy. The DNA of the fetal skin tissue after the induced abortion was extracted for Sanger sequencing, and it was confirmed that the fetus possessed ectodermal dysplasia generated by the afore-mentioned EDA gene mutation.

Conclusions: Our study suggested that prenatal ultrasonography constituted an effective method for screening ectodermal dysplasia during pregnancy. In addition, our findings expanded the range of EDA variants in XLHED patients; and this discovery may now assist potential patients in receiving an accurate diagnosis, allowing them to make appropriate reproductive decisions.

Keywords: EDA c.806G > T; Hypohidrotic ectodermal dysplasia; Prenatal ultrasound screening; Whole-exome sequencing.

Fig. 1

Clinical features of patients with an EDA variation. A The proband shows dry and rough skin, gray complexion, thinning and lusterless hair, and partial loss of hair on the top occipital region of the head. B Thinning, raised, and light eyebrows. C A depressed nasal bridge and saddle nose. D Peg-like teeth in the upper alveolar bones. E A missing tooth in the lower alveolar bones. F Panoramic radiograph of the proband

Fig. 2

Comparison of facial ultrasound features between a normal fetus and a fetus with HED. A A healthy control fetus of the same gestational age. The axial-view image portrays normal alveolar bone as represented by round hypoechoic tooth germs that are arranged in an arch-like shape in the upper alveolar bone. B The fetus in our case. The axial-view image of the upper alveolar bone shows no hypoechoic tooth germs. C The axial-view image shows normal alveolar bone as represented by round hypoechoic tooth germs that are arranged in an arch-like shape in the upper alveolar bone. D The fetus in our case. The axial view shows the sharpened lower alveolar bone and no hypoechoic tooth germs. E A healthy control fetus of the same gestational age. The sagittal-view image of the profile shows a normal maxilla and mandible. F The fetus in our case. The sagittal-view image of the profile shows thick and everted upper and lower lips

Fig. 3

A Constructed family tree. Number 5 in line II is the afflicted fetus in this case. B WES identified a hemizygous variation in exon 7 of the EDA gene in the proband (NM_001399.4, c. 806G > T, p.Gly269val), and the mother was a heterozygous carrier for this variation; the father did not carry the variation. Sanger sequencing confirmed that the fetus harbored a heterozygous genotype for the variation. C Evolutionary conservation of amino acid residues as altered by p.Gly269Val across various species. NCBI accession numbers are as follows: Homo sapiens, NP_001005609.1; Gallus gallus, NP_001409628.1; Pan troglodytes, XP_009437490.1; Equus caballus, XP_014584436.2; Bos taurus, NP_001075212.1; Capra hircus, XP_017899470.1; Mus musculus, NP_001171408.1; and Rattus norvegicus, NP_001292172.1. Asterisk (*) denotes 269 Gly

Fig. 4

Schematic drawing of the EDA gene showing exonic structure and predicted protein motifs. TM, transmembrane domain; furin, furin cleavage site; collagen, collagen-like domain; TNF, tumor necrosis factor homology domain. We found the predicted protein motif information in Park, J Setal. 1996; and exonic data are from the UCSC Genome Browser (https://genome.ucsc.edu)