X-Linked Hypohidrotic Ectodermal Dysplasia in Crossbred Beef Cattle Due to a Large Deletion in EDA

SIMPLE SUMMARY: Ectodermal dysplasias such as hypohidrotic ectodermal dysplasia (HED), are genetic conditions affecting the development and/or homeostasis of two or more ectodermal derivatives, including hair, teeth, nails, and eccrine glands. In particular, X-linked hypohidrotic ectodermal dysplasia-1 (ECTD1) in humans is characterized by a triad of signs comprising sparse hair, abnormal teeth, and anhidrosis or hypohidrosis. It has been reported in cattle, dogs, mice and rats. Until now, eight pathogenic variants in the bovine ectodysplasin A (EDA) gene causing ECTD1-like disorders have been found. Herein, five affected Red Angus-Simmental bull calves born over a 6-year period (2013–2019) in a single herd in the Western United States are reported showing an ECTD1-like syndrome. Calves were born with severe hypotrichosis and oligodontia. At age 1-week-old two calves died of severe pneumonia. Microscopic findings of the skin revealed small-caliber hair follicles with a mean density in flank skin slightly greater in affected animals than in control animals. Nasolabial, intranasal and tracheobronchial mucosal glands were absent, whereas olfactory glands were unaffected. Whole-genome sequencing (WGS) identified a 53 kb deletion of the X chromosome including parts of the EDA gene as well as the entire AWAT2 gene. The partial deletion of the EDA gene that is known to be associated with forms of ECTD1 is the most likely cause for the reported genodermatosis. Similar rare disorders in livestock are often not diagnosed at the molecular level due to lack of resources, short lifespan of the animals, and concerns for the producers’ reputation. ABSTRACT: X-linked hypohidrotic ectodermal dysplasia-1 (ECTD1) in people results in a spectrum of abnormalities, most importantly hypotrichosis, anodontia/oligodontia, and absent or defective ectodermally derived glands. Five Red Angus-Simmental calves born over a 6-year period demonstrated severe hypotrichosis and were diagnosed as affected with ECTD1-like syndrome. Two died of severe pneumonia within a week of birth. The skin of three affected calves revealed a predominance of histologically unremarkable small-caliber hair follicles. Larger follicles (>50 µm) containing medullated hairs (including guard and tactile hairs) were largely restricted to the muzzle, chin, tail, eyelids, tragus and distal portions of the limbs and tail. The mean histological density of hair follicles in flank skin of two affected calves was slightly greater than that in two unaffected calves. One affected calf was examined postmortem at 10 days of age to better characterize systemic lesions. Nasolabial, intranasal and tracheobronchial mucosal glands were absent, whereas olfactory glands were unaffected. Mandibular incisor teeth were absent. Premolar teeth were unerupted and widely spaced. Other than oligodontia, histological changes in teeth were modest, featuring multifocal disorganization of ameloblasts, new bone formation in dental alveoli, and small aggregates of osteodentin and cementum at the margins of the enamel organ. A 52,780 base pair deletion spanning six out of eight coding exons of EDA and all of AWAT2 was identified. Partial deletion of the EDA gene is the presumed basis for the reported X-chromosomal recessive inherited genodermatosis.