Exome sequencing enables diagnosis of X-linked hypohidrotic ectodermal dysplasia in patient with eosinophilic esophagitis and severe atopy

Abstract

X-linked hypohidrotic ectodermal dysplasia (XLHED) is the most common form of ectodermal dysplasia. Clinical and genetic heterogeneity between different ectodermal dysplasia types and evidence of incomplete penetrance and variable expressivity increase the potential for misdiagnosis. We describe a family with X-linked hypohidrotic ectodermal dysplasia (XLHED) presenting with variable expressivity of symptoms between affected siblings. In addition to the classical signs of hypohidrosis, hypotrichosis and hypodontia, the index patient—a 5 year old boy, also presented with a severe atopy phenotype that was not observed in the other two affected brothers. Exome sequencing in the index and the mother identified a pathogenic nonsense variant in EDA (NM_001399.4: c.766 C>T; p. Gln256Ter). This study highlights how exome sequencing was crucial in establishing a precise molecular diagnosis of XLHED by enabling us to rule out other differential diagnoses including NEMO deficiency syndrome, that was initially presented as a clinical diagnosis to the family.

Co-Occurrence of Hypohidrotic Ectodermal Dysplasia and Food Protein-Induced Enterocolitis Syndrome: A Report of a New Ectodysplasin A Variant

“…Atopic children are at greater risk of developing FPIES [10, 12], and children with EDs have significantly more chances to present atopic diathesis and IgE-mediated allergies [2, 4, 6]. A study of 347 HED patients investigating the occurrence of digestive manifestations and food allergies showed that more than one-third of HED patients had allergic reactions to specific foods [4], but this study did not identify any cases of FPIES.…”

“…At present, it is not possible to know whether FPIES in patients with EDs are related to a disturbance of the barrier functions of the skin and mucous membranes or whether they are full part symptoms of ED with a variable expression [4]. Some authors [2] suggest that manifestations of atopy may be part of the ED picture and base their argument on the absence of pathogenic variants predisposing to atopy. We also did not find any variants predisposing to atopy in the clinical exome.…”

“…EDA, EDAR, EDARADD, and WN-T10A genes are responsible for the HED phenotypes, each with different modes of transmission. These genes are involved in the TNFα pathway that lead to NF-κB activation [2].…”

“…Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated allergy that occurs with gastrointestinal symptoms and is reported to be associated with an increased risk of atopy [1]. The prevalence of atopic manifestations among ED patients is higher than in the general population [2]. However, the association of these 2 conditions has never been reported.…”

A Novel Ectodysplasin a Gene mutation of X-Linked Hypohidrotic Ectodermal Dysplasia

“…Ectodermal dysplasia (ED) is a series of clinically and genetically heterogeneous disorders, characterised by abnormal development of the ectodermal structures, such as nails, teeth, hair, or exocrine glands [1][2][3] , and with over 200 distinct clinical phenotypes. As the most common form of ED, approximately 95% Hypohidrotic ectodermal dysplasia (HED) 4 patients have X-linked HED (XLHED), 5 and 5% have autosomal dominant and recessive HED.…”