In other species: domestic cat , taurine cattle , central bearded dragon

Categories: Integument (skin) phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 305100 (trait) , 300451 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0010585: X-linked hypohidrotic ectodermal dysplasia

Mendelian trait/disorder: yes

Mode of inheritance: X-linked recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2005

Cross-species summary: Ectodermal dysplasias are disorders that affect two or more organs of ectodermal origin, such as hair follicles, teeth, sweat glands, or nails. EDA-related ectodermal dysplasias have X-linked inheritance and affected animals present with hypo/adontia, hypotrichosis, and a lack of many eccrine glands. Altered tear composition may result in keratoconjunctivitis sicca and reduced or absent airway mucus production may predispose to chronic respiratory infections.
Phene has been renamed in OMIA from 'Anhidrotic ectodermal dysplasia, EDA-related' to 'Hypohidrotic ectodermal dysplasia, X-linked, EDA-related' [29/07/2024]

Species-specific name: Ectodermal dysplasia, X-linked; X-linked hypohidrotic ectodermal dysplasia (XLHED); congenital hypotrichosis; anhidrotic ectodermal dysplasia

Species-specific symbol: XHED

Species-specific description: X-linked ectodermal dysplasia is an inherited skin condition characterized by absent or abnormal teeth, hypotrichosis, and absent sweat glands. Other signs include decreased tear production, decreased mucociliary clearance, and symmetrical hairlessness. Affected animals are more susceptible to pulmonary infectious disease than normal dogs. Chronic nasal and ocular discharges are common, as are corneal ulceration and chronic demodecosis. The causative mutation is a point mutation in the ectodysplasin (EDA, also called ED1) gene. The mode of inheritance is X-linked recessive. Breeding of affected animals or known carriers is not recommended. Edited by Dr. Margret Casal

Inheritance: Casal et al. (1997) showed that this disorder is X-linked recessive. Mosaic expression in females heterozygous for the causative mutation is possible (Casal et al., 2005). Moura et al. (2020) reported an interesting case of an affected male and its mother, both of whom were dead by the time the researchers gained access to the data, which precluded any DNA testing. From pedigree information alone, Moura et al. (2020) reported that "Through Bayesian inference, it was possible to establish that this case originated from a new mutation, with a 99.99% probability of the mother of the proband not being a carrier."

Mapping: A linkage analysis with 5 markers evenly spaced along the length of the X chromosome enabled Casal et al. (2005) to show that the XHED locus is located near the centromere, very near to one of the two comparative candidate genes, namely EDA (ectodysplasin).

Molecular basis: By adopting a comparative positional cloning approach, involving a linkage analysis as described in the Mapping section, Casal et al. (2005) discovered that the causative mutation of XHED in the colony of German shepherd dogs described by Casal et al. (1997) is a "nucleotide substitution (G to A) in the splice acceptor site of intron 8 . . . In the presence of the A residue, a cryptic acceptor site within exon 9 is used, leading to a frame shift and use of a premature stop codon that truncates the translation of both isoforms, EDA-A1 and EDA-A2, resulting in the absence of the TNF-like homology domain, the receptor-binding site of ectodysplasin." Using the genetic variant nomenclature of 2015, the causative variant can be described as c.910-1G>A (OMIA variant 361). In each of three affected mixed-breed dogs (two of which were brothers) from Israel, Waluk et al. (2016) reported that "the whole genome sequence data did not reveal any non-synonymous EDA variant in the affected dogs"but "the EDA transcript in the affected dogs lacked 103 nucleotides encoded by exon 2. We speculate that this exon skipping is caused by a genetic variant located in one of the large introns flanking this exon, which was missed by whole genome sequencing with the illumina short read technology. The altered EDA transcript splicing most likely causes the observed ectodermal dysplasia in the affected dogs. . . . The variant designation for this frame-shifting exon skipping on the transcript level is r.385_487del. The predicted variant on the protein level is p.Met129Valfs*112 and the predicted mutant protein lacks the functionally important collagen-like and TNF-signaling domains" (OMIA variant 1458). Hadji Rasouliha et al. (2018) reported a single base-pair deletion in the EDA gene (NM_001014770.2:c.842delT; NP_001014770.1:p.Leu281HisfsTer22) as the likely causal variant "in a litter of Dachshund puppies, of which four male puppies showed clinical signs of XLHED" (OMIA variant 1017). Vasiliadis et al. (2018) independently investigated the same Dachshund family and identified the same variant. Vasiliadis et al. (2018) described the variant as c.458delT as they referred to the ENSEMBL annotation, which lacks the first exon of the EDA gene. A comparison of the ENSEMBL and NCBI annotations of the canine EDA gene is given in Figure S1 of Hadji Rasouliha et al. (2018).

Clinical features: Affected animals are born with symmetrical hairlessness on the forehead and over the dorsal pelvic area. There is often a history of ophthalmia neonatorum (infection behind closed eye lids in neonates). Affected animals have absent or abnormal secondary hairs (Casal et al., 2005, Mauldin et al., 2009). A large number of teeth are missing. Premolars are rarely present and canines, when present, are thinner than normal and pointed outward. Teeth that are present are conically shaped. Most notably molars and incisors, when present, are misshapen and small (Lewis et al., 2010). Signs also include absent sweat glands, decreased tear production, decreased mucociliary clearance in the respiratory tract and symmetrical hypotrichosis. Affected dogs are more susceptible to pulmonary infectious disease than normal dogs. Chronic nasal and ocular discharge are common, as are corneal ulcerations (Casal et al., 2005, Casal et al., 2007, Mauldin et al., 2009).

Pathology: Ectodysplasin A is a key component in ectodermal appendage formation. The gene is transcribed as several splice variants, two of which encode the proteins EDA-A1 and EDA-A2. EDA-A1 binds the receptor EDAR. Anhidrotic ectodermal dysplasia is caused by failure of the ligand-receptor interaction during the development of skin and its appendages, which is necessary for correct development of hair follicles and tooth buds (Kowalczyk et al., 2011, Casal et al., 2005). Histological examination of hairless skin and foot pads shows an absence of hair follicles, adnexal structures, and eccrine glands. Bronchial, tracheal, and esophageal glands are also absent (Casal et al., 1997, Casal et al., 2007, Mauldin et al., 2009). Epidermal hyperpigmentation and orthokeratotic hyperkeratosis are common findings (Moura et al., 2004).

Prevalence: Because the mode of inheritance is X-linked recessive, the condition occurs more often in males.

Control: Breeding of affected animals or known carriers is not recommended.

Genetic testing: There is a test available to detect the causative mutation in the German Shepherd and in Dachshund.

Breeds: Basset Hound (Dog) (VBO_0200126), Belgian Shepherd Dog (Dog) (VBO_0200144), Bichon Frise (Dog) (VBO_0200163), Cocker Spaniel (Dog) (VBO_0200372), German Shepherd Dog (Dog) (VBO_0200577), Labrador Retriever (Dog) (VBO_0200800), Miniature Pinscher (Dog) (VBO_0200893), Mixed Breed (Dog) (VBO_0200902), Pekingese (Dog) (VBO_0200994), Poodle, Miniature (Dog) (VBO_0201051), Whippet (Dog) (VBO_0201421), Yorkshire Terrier (Dog) (VBO_0201448).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: