A Novel MBTPS2 Start Codon Mutation Causes a Mild Ichthyosis Follicularis with Atrichia and Photophobia Phenotype

Ichthyosis follicularis with atrichia and photophobia (IFAP; MIM 308205) syndrome is a rare, X-linked, oculocutaneous human disorder, which is caused by mutations in the gene MBTPS2. We report a Chinese family with one affected child, whose parents were not affected. A 5-year-old boy presented with the IFAP triad of symptoms: ichthyotic scaling, complete lack of hair and mild photophobia. His parents were not related, and there was no similar illness history or familial history of atopy. The skin manifestations included mild xerosis with follicular hyperkeratosis, which gave a mild thorn-like sensation with palpation (Fig. 1). Complete atrichia affected the scalp, eyebrows and eyelashes. Pachyonychia, angular cheilitis and perianal psoriasiform lesions were present. Ophthalmic examination indicated that the patient had mild photophobia. There was no evidence of seizures, mental retardation, chronic rhinitis, diarrhoea, epilepsy, or a propensity to chronic infections or inguinal hernia. The patient’s weight and height, verbal communication ability and psychomotor development were all within normal limits, and his hearing was adequate. Following informed consent, DNA was taken from the proband and his clinically unaffected parents for mutation analysis by next-generation and Sanger sequencing, using a gene probe consisting of 541 genetic loci of genodermatoses. This analysis revealed a heterozygous start codon mutation, c.2T>C, in the MBTPS2 gene, which results in the mutation p.M1?, changing the start codon and preventing the initiation signal of polypeptide chain synthesis (Fig. 2a). No mutation was detected in either of the parents (Fig. 2b,c), and the mutation was not detected in 100 unrelated healthy Chinese individuals (200 alleles) by Sanger sequencing. The mutation was also absent from the public database, suggesting that the mutation was most likely the deleterious mutation in this patient. IFAP syndrome is generally accepted as a rare X-linked recessive genodermatosis caused by mutations in MBTPS2. The MBTPS2 protein is essential for cholesterol homeostasis and endoplasmic reticulum stress response. Deficiency in cholesterol homeostasis in the stratum corneum could contribute to barrier function abnormalities, which in turn could lead to disturbed differentiation of epidermal structures, resulting in the IFAP phenotype. The clinical severity of the IFAP phenotype has large variation. X linkage was predicted because the full phenotype is found in males only. It has been reported that female carriers with missense MBTPS2 mutations may present with a variable phenotype ranging from severely affected to total absence of IFAP symptoms. Moreover, a female patient with IFAP who had congenital diffuse hypotrichosis was found to harbour no MBTPS2 mutation, suggesting genetic heterogeneity of IFAP, and the possible existence of an autosomal inheritance form. In conclusion, we report a patient presenting with a clinical constellation of follicularis ichthyosis, nonscarring alopecia, photophobia, pachyonychia, perianal and perioral psoriasiform lesions, which was highly suggestive of IFAP syndrome. The proband’s mother denied having any symptoms reminiscent of IFAP. Screening of all genes in the candidate disease gene region identified only one potential diseasecausing variant, a heterozygous change c.2T>C in Correspondence: Dr Ming Li, Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China. E-mail: liming01@xinhuamed.com.cn