Novel Compound Heterozygous Variants in TGM1 and CYP4F22 in Two Newborns with Non-Syndromic Epidermal Differentiation...

Background: Congenital ichthyoses are a clinically and genetically heterogeneous group of Mendelian disorders of cornification. According to the 2025 classification, non-syndromic epidermal differentiation disorders (nEDDs) are categorized based on the biological function of the causative gene products. Variants in TGM1 cause a transglutaminase-related nEDD (TGM1-nEDD), typically corresponding to the traditional phenotype of lamellar ichthyosis (LI), whereas biallelic variants in CYP4F22 cause a lipid-metabolism-related nEDD (CYP4F22-nEDD), formerly classified as ARCI type 5. The latter form is characterized by impaired acylceramide synthesis and epidermal barrier dysfunction. Although CYP4F22-nEDD usually follows a persistent course, considerable phenotypic variability has been reported, including milder forms and self-improving collodion ichthyosis. Methods and Results: We report two unrelated Italian neonates with congenital ichthyosis, investigated by targeted next-generation sequencing (NGS). Patient 1 presented with a phenotype consistent with LI and carried compound heterozygous TGM1 variants: the known pathogenic c.1147G>A p.(Val383Met) variant, and the novel c.860C>T p.(Thr287Ile) variant, classified as likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) criteria. Patient 2 presented as a collodion baby and carried two heterozygous CYP4F22 variants: the known pathogenic nonsense variant c.1084C>T p.(Arg362Ter), and the previously unreported in-frame deletion c.543_545del p.(Ile181del), currently classified as a variant of uncertain significance (VUS). Because parental segregation analysis was unavailable, the allelic phase of the CYP4F22 variants could not be established, and molecular confirmation of autosomal recessive inheritance was not possible. Both patients showed marked clinical improvement during follow-up with topical emollient therapy alone. In Patient 2, the clinical course was consistent with a self-improving collodion ichthyosis phenotype. A structured literature review was performed to contextualize the clinical and molecular findings. Conclusions: These cases illustrate the clinical and genetic heterogeneity of nEDDs, and confirm the value of NGS in the management of neonates with congenital ichthyosis. The principal novelty of this report lies in the identification of previously unreported TGM1 and CYP4F22 sequence variants. While functional validation is lacking, integration of clinical and genetic findings with literature evidence may assist interpretation of rare variants and support genetic counselling.