Syndromic epidermal differentiation disorder associated with steroid sulfatase deficiency (STS-sEDD) is a hereditary disorder of keratinization caused by mutations or deletions in the STS gene. Although historically classified as a dermatological condition, accumulating evidence indicates that STS-sEDD represents a multisystem disorder with significant neuropsychological, endocrine, and cardiological involvement. Psychosocial consequences substantially increase disease burden, highlighting the need for integrated and multidisciplinary care. The aim of this paper is to summarize current knowledge on the biological, clinical, neuropsychological, and psychosocial aspects of STS-sEDD and to identify gaps and challenges in contemporary clinical practice. A purposive, non-systematic review of Polish- and English-language literature published between 1960 and 2025 was conducted. The analysis included articles retrieved from PubMed, Scopus, and Google Scholar databases, as well as materials produced by patient advocacy organizations. Literature selection was carried out in two stages (abstract and full-text review) by two independent reviewers, using keyword sets related to genetic, clinical, neurodevelopmental, and psychosocial domains. Available data indicate that approximately 85-90% of STS-sEDD cases result from complete deletion of the STS gene. Larger deletions within the Xp22.3 region lead to contiguous gene syndromes and are associated with additional manifestations, including attention-deficit/hyperactivity disorder, autism spectrum disorder, endocrine abnormalities, and cardiac arrhythmias. Clinically, STS-sEDD is characterized by typical cutaneous findings accompanied by subtle cognitive and neurodevelopmental deficits, which may also be observed in female carriers. Beyond its medical features, STS-sEDD is associated with stigmatization, reduced quality of life, and significant emotional distress affecting both patients and their families. Evidence suggests that therapeutic education and structured psychological support improve daily functioning and coping. STS-sEDD should therefore be recognized as a multisystem condition requiring early diagnosis and coordinated, interdisciplinary management. The implementation of comprehensive care models has the potential to substantially improve outcomes and quality of life for affected individuals.

A significant number of inherited neurodegenerative metabolic diseases (NMDs) arise from altered lipid metabolism, including impaired degradation of sphingolipids and dysfunction in organelle-related machineries involved in lipid processing and trafficking. These lipid dysregulations profoundly impact cellular membranes, signaling pathways, and myelin integrity, contributing to the complex and multisystemic clinical phenotypes characteristic of NMD, which often complicate diagnosis and delay treatment initiation. Here, we present a high-throughput, multiplex LC-MS/MS method for the analysis of an extended panel of NMD biomarkers in plasma and dried blood spots. One-step sample extraction and targeted LC-MS/MS acquisitions in positive and negative ionization allowed the simultaneous measurement of 13 diagnostic biomarkers associated with GM1 and GM2 gangliosidosis, Fabry, Gaucher, and Krabbe diseases, acid sphingomyelinase deficiency, Niemann-Pick disease type C, X-linked adrenoleukodystrophy, peroxisomal biogenesis disorders (Zellweger syndrome), metachromatic leukodystrophy, and mental retardation, enteropathy, deafness, neuropathy, ichthyosis, keratoderma (MEDNIK)/MEDNIK-like syndromes, a disorder of cellular trafficking. The method was analytically and clinically validated, confirming the diagnosis of all targeted NMDs in samples from 89 patients. Additionally, the method allowed the differentiation of X-linked adrenoleukodystrophy from peroxisomal biogenesis disorder and revealed the elevation of C18- and C16-sulfatides in Krabbe disease and MEDNIK syndrome, respectively. This multiplex assay enhances diagnostic efficiency and expands the discovery of novel biomarkers, enabling the quantification of diagnostic markers for a wide range of NMDs. The method is suitable for diagnosis of NMD, as a first- or second-tier test in neonatal screening, as confirmatory testing of variant of unknown significance in genetic panels and for longitudinal monitoring in treatable diseases.

The X-linked Ichthyosis Follicularis, Alopecia, and Photophobia syndrome type-2 (IFAP-2), is a condition that has been linked to a c.1579C>T mutation in the SREBF1 gene. However, the molecular implications of the mutation in Meibomian glands (MG) remain unknown. The goals of our project were to elucidate the biochemical factors associated with IFAP-2 and develop approaches for unbiased diagnosing this condition. Meibum samples were collected from normal subjects and a patient with IFAP-2-like signs and symptoms. Genetic analysis of the abnormal subject revealed the same c.1579C>T (p.Arg527Cys) mutation in the SREBF1 gene that was previously associated with IFAP-2. The meibum samples were analyzed using liquid chromatography-mass spectrometry (LC-MS), and the data were compared using multivariate statistical approaches. The LC-MS provided detailed information on the differences between the Meibomian lipid profiles of normal subjects and the IFAP-2 patient, specifically in saturated and unsaturated wax esters (SWE and UWE). Our data showed that IFAP-2 meibum was enriched with SWE which increased the SWE/UWE ratio to highly abnormal levels. The higher melting temperature of SWE compared to that of UWE correlated well with poor expressibility and abnormal thickness of IFAP-2 meibum. Thus, our study demonstrated possible links between the p.Arg527Cys mutation in SREBP1 protein, upregulation of SWE in the IFAP-2 meibum, and MG dysfunction. It also showed that LC-MS can be used as a sensitive and informative tool to reveal minute differences in the Meibomian lipidomes of the subjects with MG dysfunction, and identify molecular markers of the conditions.

The X-linked Ichthyosis Follicularis, Alopecia, and Photophobia syndrome type-2 (IFAP-2), is a condition that has been linked to a c.1579C>T mutation in the SREBF1 gene. However, the molecular implications of the mutation in Meibomian glands (MG) remain unknown. The goals of our project were to elucidate the biochemical factors associated with IFAP-2 and develop approaches for unbiased diagnosing this condition. Meibum samples were collected from normal subjects and a patient with IFAP-2-like signs and symptoms. Genetic analysis of the IFAP-2 subject revealed a c.1579C>T (p.Arg527Cys) mutation in the SREBF-1 gene that was previously associated with IFAP-2. The meibum samples were analyzed using liquid chromatography-mass spectrometry (LC-MS), and the data were compared using multivariate statistical approaches. The LC-MS provided detailed information on the differences between the Meibomian lipid profiles of normal subjects and the IFAP-2 patient, specifically in saturated and unsaturated wax esters (SWE and UWE). Our data showed that IFAP-2 meibum was enriched with SWE which increased the SWE/UWE ratio to highly abnormal levels. The higher melting temperature of SWE compared to that of UWE correlated well with poor expressibility and abnormal thickness of IFAP-2 meibum. Thus, our study demonstrated possible links between the p.Arg527Cys mutation in SREBP1 protein, upregulation of SWE in the IFAP-2 meibum, and MG Dysfunction. It also showed that LC-MS can be used as a sensitive and informative tool to reveal minute differences in the Meibomian lipidomes of the subjects with MG Dysfunction, and identify molecular markers of the conditions.

Ichthyosis follicularis, alopecia, and photophobia (IFAP) syndrome is a rare X-linked genodermatosis with follicular hyperkeratosis, non-scarring alopecia, and ocular abnormalities. Female cases are very uncommon and typically manifest with a milder phenotype, though severe presentations can occur. Orthopedic complications are not commonly described in IFAP. We present a 10-year-old girl with congenital alopecia and diffuse follicular hyperkeratosis who, despite lacking photophobia, progressed to develop flexion contractures of the knees and equinus deformities of the ankles, resulting in marked restriction of mobility. Ophthalmological examination demonstrated mild astigmatism and decreased visual acuity without corneal disease. Skin biopsy histopathology demonstrated orthokeratotic hyperkeratosis, acanthosis, and follicular plugging, which was in line with IFAP syndrome. The patient underwent posterior soft tissue release of the knees and Achilles tendon lengthening, which led to marked postoperative functional improvement in ambulation. This case expands the phenotypic range of IFAP syndrome by describing a non-classical female presentation with no photophobia but with extreme musculoskeletal contractures requiring surgery. It emphasizes the need for early identification and multidisciplinary treatment, such as orthopedic intervention, to avert long-term disability and enhance the quality of life. Ichthyosis follicularis, alopecia, and photophobia syndrome (IFAP) is an uncommon genetic condition that affects the skin, hair, and eye tissues predominantly. It is usually seen in males, as the syndrome is linked with the presence of the X chromosome. In this report we describe a unique case of a 10-year-old girl. At birth, she had a complete baldness on the scalp, eyebrows, and eyelashes, and had coarse, thickened epidermic skin over her entire body. Differently from the rest of the IFAP patients, she never had intolerance to light (photophobia). With increasing age, she developed extensive stiffness and contractures in the legs, making it impossible for her to walk. After several assessments, the diagnosis of IFAP syndrome was confirmed through skin biopsy. The patient was then treated with orthopedic surgery that relaxed tightened tissues in her legs and lengthened her Achilles tendons, followed by a physiotherapy protocol. These treatments led to better leg positioning as well as increased autonomy in her walking functions. This case is useful as one that demonstrates that IFAP syndrome is possible in females and that the presentation can be unusual compared with the typical form. It further indicates the importance of a team, including dermatologists, orthopedic surgeons, and rehab specialists, working in unison. Prompt diagnosis and collaborative care can very much enhance the quality of life and functioning in patients with this rare disease.