409 Next generation sequencing-directed treatment in a patient with two co-existing genodermatoses: Acrodermatitis enteropathica (AE) and recessive dystrophic epidermolysis bullosa (RDEB)

Abstract

Next generation sequencing (NGS) is helpful in diagnosing complex genetic phenotypes. Here we report a case with two co-existing heritable skin diseases. The proband, a 17-year-old female, born to consanguineous parents, demonstrated widespread refractory erythematous and desquamative plaques, generalized alopecia, and growth failure. She was clinically diagnosed with RDEB, based on the history of neonatal blistering, recurrent oral blisters and esophageal involvement. This diagnosis was confirmed by whole exome sequencing (WES) demonstrating a homozygous mutation, c.5820G>A, in COL7A1, and supported by aberrant expression of type VII collagen and reduced anchoring fibrils. This synonymous mutation replaces the last nucleotide of exon 70, and RNA-seq revealed aberrant splicing, including exclusion of exon 70 and retention of intron 70 sequences. The laboratory findings included decreased plasma zinc level [40 mg/dL, normal range 70-150 mg/dL], which was thought to be a sequela of EB-associated malabsorption. However, daily supplementation of diet with zinc at 1 mg/kg/per day did not alter the clinical presentation. Careful examination of the genomic database from WES revealed the presence of a homozygous missense mutation, c.653C>G; p.Pro218Arg, in SLC39A4, gene associated with zinc deficiency in AE. Now, increasing the supplementation of zinc to 3 mg/kg/per day resulted in rapid and dramatic resolution of the skin findings, with subsequent growth and weight gain. This case demonstrates the power of NGS in identifying two genetically unlinked diseases that led to effective treatment with major clinical benefits.