Thrombospondin type laminin G domain and epilepsy associated repeats is a protein involved in the expression of genes associated with the Notch signaling pathway that have major roles in ectodermal differentiation and neural tissue development; variants in thrombospondin type laminin G domain and epilepsy associated repeats have been shown to be associated with a variety of clinical presentations including dysplasia in the skin, nail, sweat glands, hair, or teeth and hearing abnormalities. Herein we report a patient presenting with bilateral profound sensorineural hearing loss. The patient was a 6-year-old Iranian girl of Fars ethnicity, born to a consanguineous marriage, who had flat audiogram in pure tone audiometry obtained from both ears and absence of any response in auditory brain response. We examined the patient for any form of ectodermal dysplasia or malformation in teeth, skin, hair, and nail and they were in normal figuration. In this study, a novel homozygous pathogenic variant in thrombospondin type laminin G domain and epilepsy associated repeats was identified (NM_144991.3: c.668C > T, p. Ser223Leu) using whole exome sequencing. Thrombospondin type laminin G domain and epilepsy associated repeats mutation presenting solely with hearing issues and lack of any ectodermal dysplasia was rare based on the review of previously reported cases. Given the high importance of these genetic disorders and the burden associated with them, the family members of these patients should pursue molecular genetic tests to identify the carriers and eliminate the risk of future occurrence of these phenotypes.

Pure hair and nail ectodermal dysplasia (PHNED) is a congenital disorder characterized by reduced or absent hair and dystrophic nails. PHNED is caused by pathogenic variants in genes involved in hair and nail development, including HOXC13. Previously reported biallelic HOXC13 pathogenic variants led to PHNED by either disrupting protein expression through nonsense-mediated decay or altering the DNA-binding affinity of the homeobox domain of HOXC13. Here, we report a case of HOXC13-related PHNED with a rare homozygous variant, c.931C>T, p.Arg311Trp. Similarly to previously reported missense variants, p.Arg311Trp resides in the homeobox domain of HOXC13 and was assumed to lead to the decreased transcriptional activity of target genes. However, in contrast with previously reported variants, in vitro overexpression assays revealed that the p.Arg311Trp variant decreases HOXC13 protein stability, which is corroborated by a series of in silico predictions. Computational models further suggest that p.Arg311Trp results in a structural rearrangement with loss of interhelical connection between Arg311 in α-helix 3 and Glu276 in α-helix 1. Altogether, our results suggest a novel molecular mechanism causative of PHNED, whereby biallelic pathogenic variants in HOXC13 may result in decreased protein stability and consequently decreased transcriptional activity of target genes essential for hair and nail development.

Complete scalp hair loss can be a source of distress for affected children and their families. In addition to infectious and trauma-related causes of hair loss, infants and children may present with total scalp alopecia arising from a range of genetic predispositions. Our objective with this review was to identify the common genetic conditions in children with complete scalp alopecia. The PubMed Database was reviewed for all articles from 1962 to 2019 containing the search terms related to genetic alopecia. The conditions with at least five reported cases in the literature were considered for the inclusion. All clinical trials, retrospective studies, and cases on human subjects and written in English were included. Six genetic conditions related to complete scalp alopecia were included in this review. The most common genetic conditions associated with total scalp hair loss include: alopecia totalis/Alopecia universalis (AU), atrichia with papular lesions, AU congenita, hereditary Vitamin D-resistant rickets type IIA, alopecia with mental retardation, and pure hair and nail ectodermal dysplasia. In children presenting with total scalp hair loss, a myriad of genetic and environmental factors may be the underlying cause. Increased awareness of potential genetic conditions associated with total scalp hair loss may assist in diagnosis, with improved the prognosis for the children.