A Case of SREBF1‐Associated Ichthyosis Follicularis, Alopecia, and Photophobia Syndrome With Recurrent Alopecia

1.

Ichthyosis follicularis, alopecia, and photophobia (IFAP) syndrome is a rare genodermatosis characterized by widespread follicular hyperkeratosis, congenital nonscarring alopecia, and photophobia [1]. Traditionally linked to X‐linked MBTPS2 mutations (IFAP1), IFAP2 has recently been identified as an autosomal dominant form caused by SREBF1 variants encoding sterol regulatory element‐binding protein 1 (SREBP1) [1, 2]. Herein, we describe a male patient with SREBF1‐associated IFAP syndrome presenting with a unique pattern of recurrent alopecia.

A 29‐month‐old boy presented with congenital hypotrichosis involving the scalp and eyebrows, generalized follicular hyperkeratosis, and photophobia (Figure 1a,b). Starting at 7 months of age, he experienced intermittent episodes of spontaneous, diffuse scalp hair shedding—rather than localized patches—followed by partial regrowth, without clear periodicity or external triggers identified. Development was normal, and family history was unremarkable. Scalp biopsy revealed follicular hyperkeratosis and keratin plugs without peribulbar lymphocytic infiltrates or miniaturization, effectively ruling out alopecia areata (Figure 1c). Whole‐exome sequencing trio analysis identified a de novo heterozygous SREBF1 c.C1579T (p.R527C) variant, confirming IFAP2. Ophthalmologic examination showed corneal opacity, keratoconjunctivitis, and progressive photophobia. Bilateral cataract surgery was performed at age 5. Systemic acitretin (0.4 mg/kg every 1–3 days for 12 months) did not improve either cutaneous or ocular manifestations, despite concomitant topical keratolytics, emollients, and anti‐inflammatory agents (Figure 1d). The drug was discontinued due to mucocutaneous adverse effects, including angular cheilitis and perianal erythema.

FIGURE 1.

Clinical, dermoscopic, and histopathological findings of the patient. (a) Clinical photographs showing hypotrichosis of the scalp and eyebrows with variable hair density. (b) Dermoscopy reveals preserved follicular openings with keratotic plugs, broken hairs, and vellus hairs (Scale bar = 1 mm). These findings likely reflect hair shaft fragility inherent to SREBF1‐mediated metabolic disturbance. (c) Vertical sections of the scalp biopsy demonstrate characteristic histopathological features (hematoxylin and eosin stain). The scanning view (top‐left) shows prominent follicular hyperkeratosis and dilated follicular orifices (original magnification ×20), while a higher magnification of the upper follicle (bottom‐left) reveals a dense hyperkeratotic plug within the infundibulum (original magnification ×40). The mid‐follicular level (top‐right) exhibits mild perifollicular inflammation and intra‐follicular dyskeratotic material, likely reflecting metabolic disturbance (original magnification ×100). High‐magnification of the lower follicle (bottom‐right) displays the deep portion of the hair follicle (original magnification ×100). (d) Clinical photograph after 12 months of systemic acitretin treatment (0.4 mg/kg), showing persistent follicular hyperkeratosis and hypotrichosis without significant improvement.

This case underscores the distinct clinical trajectory of SREBF1‐associated IFAP. While the p.Arg527Cys variant in SREBF1 was primarily linked to atrichia or hypotrichosis in initial reports, our case—taken together with a recent observation of cyclic alopecia—highlights recurrent alopecia as a potential clinical hallmark of this mutation [1, 3]. In IFAP1, MBTPS2 mutations cause functional loss of site‐2 protease (S2P), a key enzyme in early hair follicle morphogenesis and epidermal differentiation, resulting in congenital atrichia or hypotrichosis [1, 2]. In contrast, SREBF1 mutations disrupt the transcriptional control of lipogenesis, leading to functional lipid dysregulation in the hair follicle outer root sheath and meibomian glands [1]. This is associated with abnormal meibum enriched in saturated wax esters and increased keratinocyte apoptosis, which may drive the cyclic alopecia phenotype [3]. Recently, hereditary mucoepithelial dysplasia (HMD) has been recognized to lie on the same clinical spectrum as IFAP2 due to shared pathogenic variants in the SREBF1 gene [2, 4]. Our case provides novel clinical insight into this phenotypic spectrum, suggesting that SREBF1‐related disorders may manifest as recurrent hair loss.

Furthermore, this metabolic divergence also supports the poor response to acitretin. Acitretin has shown moderate efficacy in improving follicular hyperkeratosis and corneal erosions in IFAP1 [5]. However, it appears inadequate to normalize the profound lipogenic disturbance associated with SREBF1 mutations.

Finally, the progressive ocular involvement in our patient echoes prior observations of severe corneal and meibomian gland dysfunction in IFAP2. Unlike the primarily surface‐level keratitis often seen in IFAP1, SREBF1 mutations appear to drive a more aggressive ophthalmic phenotype.

Our case suggests that recurrent alopecia represents a useful clinical hallmark of SREBF1‐associated IFAP syndrome and that alternative, mechanism‐based therapeutic strategies are needed for optimal management.

Funding

The authors have nothing to report.

Ethics Statement

This case report was approved by the Institutional Review Board of Seoul National University Bundang Hospital (Approval No. B‐2606‐1048‐701). Written informed consent for publication was obtained from the patient's parent, and informed assent was obtained from the patient.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.