A Novel Mutation in the MBTPS2 Gene Resulting in Ichthyosis Follicularis, Atrichia, and Photophobia Syndrome

Abstract

Ichthyosis follicularis, atrichia, and photophobia (IFAP) syndrome is a rare genetic disorder caused by mutations in the MBTPS2 gene. It is characterized by ichthyosis and alopecia from birth. Photophobia may be present in infancy or early childhood. Its mode of inheritance is X-linked recessive; thus, it mostly affects male. The disease severity varies, ranging from mild cases limited to the skin to the severe variant involving multiple extracutaneous features. A 7-year-old boy presented with scanty hair on scalp and eyebrows at birth. On physical examination, scaly patches were observed on the whole body and spiky follicular hyperkeratotic papules were observed on the face and trunk. He also suffered from severe photophobia. Histopathological examination of the scalp showed miniaturized hair follicles without perifollicular fibrosis. Genetic analysis revealed a novel mutation in the MBTPS2 gene which was a homozygous missense mutation of c.245T>C leading to an amino-acid substitution from phenylalanine to serine (p.Phe82Ser). We diagnosed this patient with IFAP syndrome. To date, 25 pathogenic MBTPS2 gene mutations have been identified. To our knowledge, c.245T>C is a novel homozygous missense mutation in the MBTPS2 gene, which has not been reported in Human Gene Mutation Database, ClinVar Database, and Leiden Open Variation Database. Previous reports suggested genotype-phenotype correlations in the MBTPS2 gene mutations. Supported by a previous notion that genotype correlates with phenotype, this novel mutation can be a predictive factor for the mild form of IFAP syndrome, restricted to the classic symptom triad.

Keywords: Alopecia; Ichthyosis; Missense mutation; Photophobia.

Fig. 1. Complete loss of scalp hair (A) and eyebrows (B) was observed during the first visit (17-month-old). (C) A few hair follicles with short vellus hairs were shown on dermoscopy. At the age of seven, he showed total alopecia of the scalp (D) and eyebrows (E). (F) Hair follicles were almost absent as suggested during dermoscopy.

Fig. 2. Spiky follicular hyperkeratotic papules were observed on both cheeks (A, B) and trunk (C). Scaly patches were observed on extremities (D, E) and buttocks (F).

Fig. 3. (A) Miniaturized hair follicles without perifollicular fibrosis were observed on scalp (H&E, ×40). (B) Basket-weave pattern hyperkeratosis was observed on the lower extremity. Inlet: high-power view of epidermis (H&E, ×40; Inlet: H&E, ×400).

Fig. 4. Diagnostic exome sequencing of the the patient and his mother showed that X-linked recessive inheritance pattern. (A) Hemizygous mutation of c.245T>C detected on the Xp21.1 of the proband. (B) His mother was heterozygous for the same mutation. (C) Pedigree chart of the patient’s family. The arrow indicates the proband.