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

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.

INTRODUCTION

Ichthyosis follicularis, atrichia, and photophobia (IFAP) syndrome is a rare X-linked recessive genetic disorder caused by mutations in the membrane-bound transcription factor peptidase, site 2 (MBTPS2) gene1. It is characterized by the triad of ichthyosis, manifesting as thorn-like projections of non-inflammatory follicular hyperkeratosis, total or subtotal atrichia from birth or shortly thereafter, and photophobia of varying degrees2. The disease severity varies, ranging from mild cases limited to the skin to the severe BRESHECK variant involving multiple extracutaneous features (brain anomalies, retardation, ectodermal dysplasia, skeletal deformities, Hirschsprung’s disease, ear/eye anomalies, cleft palate/cryptorchidism, and kidney dysplasia/hypoplasia)3. To date, approximately 25 different pathogenic MBTPS2 mutations have been identified. Here, we report a case of IFAP syndrome resulting from a novel missense MBTPS2 mutation. We diagnosed this patient with IFAP syndrome.

CASE REPORT

A 7-year-old boy presented with alopecia and persistent ichthyosis from birth. His mother recalled that he congenitally showed scanty scalp hair and eyebrows with generalized dryness and roughness of whole-body skin. The boy was born at 39 weeks by normal vaginal delivery and weighed 2.75 kg at birth. He visited our dermatology clinic at 17 months of age for the first time. At that time, he showed almost complete absence of scalp hair and eyebrows (Fig. 1A, B). A few hair follicles with short vellus hair were observed on dermoscopic examination (Fig. 1C). At the age of seven, he came back to our clinic because of persistent alopecia and rough skin. He showed total alopecia of scalp and eyebrows (Fig. 1D, E). Hair follicles were found to be absent on dermoscopy (Fig. 1F). On physical examination, spiky follicular hyperkeratotic papules were observed on the face and trunk (Fig. 2A~C). Generalized xerosis and ichthyotic scaly patches were observed on the entire body (Fig. 2D~F). In addition, he had been using artificial tears for several years due to severe photophobia. We received the patient’s consent form about publishing all photographic materials. Skin biopsy was performed from the hairless patch on the scalp and scaly patch on the lower extremity. Histopathological findings showed miniaturized hair follicles without perifollicular fibrosis on the scalp (Fig. 3A) and basketweave pattern hyperkeratosis on the lower extremity (Fig. 3B). Clinically, the features were suggestive of IFAP syndrome. Notably, the patient’s mother was also found to present similar but mild symptoms during her childhood. She had presented partial hairless patches on the scalp and a linear pattern of ichthyotic skin which gradually improved while growing up. Peripheral blood was sampled from the patient and his mother for MBTPS2 direct sequencing. In both samples, genetic analysis revealed a novel mutation in the MBTPS2 gene located in Xp22.1 which was a homozygous missense mutation of c.245T>C leading to an amino acid substitution from phenylalanine to serine (p.Phe82Ser) (Fig. 4A, B). This showed X-linked recessive inheritance (Fig. 4C). The diagnosis of IFAP syndrome was validated. Symptomatic therapy including emollients on the ichthyotic skin lesion and topical minoxidil solution on the scalp were prescribed to the patient.

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.

DISCUSSION

IFAP syndrome is an X-linked recessive congenital genetic disorder. It was first recognized as a distinct entity by MacLeod4 in 1909 and since then, over 60 cases have been reported worldwide5. According to an international consensus for the classification of inherited ichthyosis, IFAP syndrome is classified as a syndromic form of inherited ichthyosis6. Thus, the phenotype is observed not only on the skin but also in other organs, which can result into cerebral anomalies, retarded psychomotor development, photophobia, or renal anomalies.

In 2009, mutations in the MBTPS2 gene located on Xp22.11-p22.13 were reported to cause IFAP syndrome1. MBTPS2 contains 11 exons, and it encodes a membrane-embedded zinc metalloprotease, termed site-2 protease (S2P/MBTPS2) with 519 amino acids. It is essential for transcriptional regulation of cholesterol homeostasis and endoplasmic reticulum (ER) stress response. Deficiency in either of these, sterol or ER homeostasis, could disturb differentiation of epidermal structures and lead to the IFAP phenotype1. MBTPS2 gene mutations are associated with a variable spectrum of phenotype in genetic diseases. Those were also revealed as the genetic causes for IFAP syndrome with keratosis follicularis spinulosa decalvans (KFSD) syndrome, BRESHECK syndrome, and an X-linked form of Olmsted syndrome2. Clinically, KFSD syndrome can be differentiated from IFAP syndrome due to the presence of scarring alopecia because IFAP syndrome shows non-scarring alopecia7. However, both syndromes share multiple overlapping clinical features and are considered to be in the same genetic disorder spectrum. A unifying term, IFAP/KFSD syndrome has been suggested8. Currently, 25 pathogenic MBTPS2 mutations have been identified. To our knowledge, c.245T>C (p.Phe82Ser) is a novel homozygous missense mutation in the MBTPS2 gene, which has not been reported in Human Gene Mutation Database (HGMD), ClinVar Database, and Leiden Open Variation Database. Polyphen2 (http://genetics.bwh.harvard.edu/pph2) predicted it to be ‘probably damaging’ with a score of 1.000, and Mutation Taster (http://www.mutationtaster.org/) rated it as ‘disease-causing’.

MBTPS2 protein is composed of several transmembrane domains (TMs), and Bornholdt et al.2 identified possible correlations between the locations of the mutations and disease phenotypes. The MBTPS2 mutation in the TM2 and TM9 domains, near the N-terminal and the C-terminal amino acids, respectively, maintains higher residual catalytic activity that results in a mild phenotype of IFAP/KFSD. In contrast, a mutation in TM6-TM8 domains is associated with a severe phenotype of the IFAP/BRESHECK or the Olmsted syndrome. The mutation c.245T>C (p.Phe82Ser) in our case, located in TM2, led to a mild phenotype of IFAP syndrome with symptoms of only the classic triad (ichthyosis follicularis, atrichia, and photophobia). This is consistent with previous reports on genotype-phenotype correlations, so long-term prognosis of our patient may be favourable. Because of lionization or clonal skewed X-inactivation, female carriers may have milder phenotype with hairless patches and ichthyosiform skin changes in a linear mosaic pattern following Blaschko’s lines9. This explains the milder symptoms in our patient’s mother.

In summary, we found a novel missense mutation c.245T>C (p.Phe82Ser) in the MBTPS2 gene resulting in the IFAP syndrome. The mutation is located in the TM2 domain, which maintains a high residual catalytic activity resulting in mild classic symptom triad of IFAP phenotype. This case supports the previous research on genotype-phenotype correlation of MBTPS2 gene mutation.