Ichthyosis follicularis with atrichia and photophobia (IFAP) syndrome is a rare genodermatosis characterized by a classic triad of follicular ichthyosis, alopecia, and photophobia. We report a Chinese patient displaying features of IFAP triad along with painful palmoplantar keratoderma, recurrent infections, periorificial keratotic plaques, nail dystrophy, and pachyonychia. Whole-exome sequencing revealed an intronic variant (NM_015884.3: exon7:c.970+5G>A) in the gene MBTPS2. Sanger sequencing confirmed that the variant segerated with phenotype in the family. Sequencing of cDNAs derived from the patient indicated the variant introduced a new splice donor site, leading to partial skipping of exon 7 (r.951_970del). An in vitro mini-gene assay also revealed abnormal splicing of exon 7. This study presents a case complicated with X-linked IFAP syndrome and Olmsted syndrome, and highlights the significance of using validation assays to identify the pathogenicity of intronic variants in MBTPS2.

The ichthyosis follicular with atrichia and photophobia syndrome (IFAP) is a rare X-linked multiple congenital malformation syndrome. Some male patients have additional features including brain anomalies, intellectual disability, ectodermal dysplasia, skeletal deformities, ear or eye anomalies and kidney dysplasia/hypoplasia (BRESEK syndrome) sometimes associated with Hirschsprung disease and cleft palate or cryptorchidism (BRESHECK syndrome). We report a 5 months-old male patient with the p.R429H mutation in MBTPS2 protein, which has been reported to be associated with the most severe phenotype of patients with IFAP/BRESHECK syndrome. This patient presented with a severe IFAP/BRESHECK phenotype including ichthyosis follicular, atrichia, photophobia, brain anomalies, global developmental delay, Hirschsprung disease and kidney hypoplasia. Additional features not previously reported in IFAP syndrome, include severe hypogammaglobulinemia and congenital rectourethral fistula.