Hereditary mucoepithelial dysplasia (HMD) is a rare autosomal dominant disorder characterized by non-scarring alopecia, skin and mucosal lesions, and keratitis. Autosomal dominant SREBF1-related Ichthyosis Follicularis, Atrichia, Photophobia (IFAP) syndrome is another rare, similar disorder. Both are now known to be caused by the same NM_004176.5(SREBF1):c.1579C>T variant, but were previously described as separate disorders. Here, we describe a case series of four novel patients that we diagnosed with SREBF1-related IFAP due to the NM_004176.5(SREBF1):c.1579C>T variant. We also performed a literature review and applied the ClinGen Lumping and Splitting criteria to these two disorders. Three of our four patients had significant gastrointestinal manifestations including gastroesophageal reflux disease and esophageal strictures/webs. To date, no gastrointestinal manifestations have been described in SREBF1-related IFAP. There are, however, multiple reports of these manifestations in cases of HMD. Applying the ClinGen Lumping and Splitting criteria demonstrated that these two previously distinct disorders are actually favored to be "lumped" into one. Taken together, a documented overlap in clinical features, the shared variant, and the gastrointestinal manifestations of our SREBF1-related IFAP patients provide evidence that HMD and SREBF1-related IFAP better represent variable expressivity of the same disorder. We propose using the unifying name of "SREBF1-syndromic epidermal differentiation disorder" (SREBF1-sEDD).

Hereditary mucoepithelial dysplasia (HMD) is a rare autosomal dominant dysplastic dyskeratotic epithelial syndrome caused by pathogenic variants in the SREBF1 gene. This syndrome is associated with a variety of ocular conditions, including cataracts, nystagmus, keratitis, meibomian gland dysfunction (MGD), and decreased visual acuity. We report the case of a boy followed from 1 to 7 years of age who had a confirmed HMD-associated variant in the SREBF1 gene. The patient has severe MGD, with resulting keratitis and photosensitivity, and bilateral glaucoma, which has not previously been reported in association with HMD. The gene affected in HMD negatively affects gap junctions and lipid biosynthesis, which are important in the stability of the trabecular meshwork.

Ichthyosis follicularis, atrichia and photophobia (IFAP) syndrome is a rare genetic genodermatosis. According to previous reports, in addition to MBTPS2 variants, variants in SREBF1 (encoding SREBP1) can also cause IFAP syndrome. SREBF1 variants can also result in hereditary mucoepithelial dysplasia (HMD). These two diseases exhibit some similar clinical features. We report two cases of IFAP syndrome with atypical clinical features associated with the c.1670G>A variant in the SREBF1 gene, and review the clinical characteristics of all reported cases of IFAP syndrome and HMD patients with SREBF1 variants to date. Whole-exome sequencing was performed for the two patients, and immunohistochemistry was performed on samples from psoriatic-like plaques on the right lower limb of one of the patients. A PubMed search was conducted to identify all patients with IFAP syndrome and HMD with SREBF1 variants. A missense variant c.1670G>A in SREBF1 was identified in our two patients. The heterozygous SREBF1 variant was not identified in their parents. Immunohistochemistry of samples from the psoriatic-like plaques on the lower limb from one of the patients showed enhanced staining for IL-17A and S100A8, with reduced nuclear translocation of SREBP1. We describe two cases of IFAP syndrome without apparent photophobia, one of which exhibited severe psoriasis-like plaques limited to the extensor sides of both lower limbs. Immunohistochemical results of the lower limb lesions showed partial resemblance to psoriatic lesions. In addition, a comparative review of the clinical features of all published HMD and IFAP syndrome cases is presented.

An 11-month-old boy with nonscarring alopecia was referred for ophthalmic evaluation because of photophobia from the age of 4 months. Whole-exome sequencing identified a heterozygous mutation in the SREBF1 gene, confirming the diagnosis of hereditary mucoepithelial dysplasia. Ocular examination revealed meibomian gland dysfunction and superficial corneal vascularization and opacity. Impression cytology of the sclerocorneal limbus revealed atypical epithelial cells. The patient received treatment for meibomian gland dysfunction, dry eye, and ocular surface inflammation. With appropriate management and close follow-up over 7 years, corneal opacity improved greatly.

This study aims to present ophthalmic manifestations of 2 infants with hereditary mucoepithelial dysplasia (HMD) related to SREBF1 mutation over a 5-year period. Two female infants with an unremarkable perinatal history were evaluated for photophobia that had been manifest since 3 months after birth and diffuse scalp alopecia. Complete ocular examinations under anesthesia were performed, as well as genetic and systemic workup. Both patients had vascularizing keratitis in both eyes, characterized by the growth of corneal new vessels from the 360 degrees periphery to the center and the formation of stromal leucomatous opacity at the leading edge. The keratitis partially regressed in response to topical corticosteroids and waxed and waned during the 5 years of follow-up. In addition, the loss of scalp hair developed in a cyclical pattern, causing diffuse scalp alopecia in the patients. Rheumatologic, nutritional, and developmental evaluations were within normal ranges. Whole-exome sequencing identified a heterozygous c.1669C>T (p.Arg557Cys) pathogenic variant in the SREBF1 gene associated with HMD in both patients. In pediatric patients with recurrent vascularizing keratitis and diffuse scalp alopecia starting early in life, HMD should be considered, and genetic tests and collaboration with dermatologists and pediatricians on the diagnosis should be provided.