Genodermatoses, a group of inherited skin disorders, are characterized by significant genetic heterogeneity and clinical variability, often posing diagnostic and therapeutic challenges. Advances in next-generation sequencing (NGS) technologies, such as whole exome sequencing (WES) and clinical exome sequencing (CES), have transformed the diagnostic landscape by enabling comprehensive genetic analysis. This study aimed to investigate the molecular spectrum and clinical relevance of genetic findings in 43 patients diagnosed with genodermatoses. Demographic, clinical, and molecular data were collected, and genetic testing was performed using the MGI-Seq platform. Variants were analyzed for pathogenicity, zygosity, and novelty. Neurofibromatosis Type 1 (27.9%) and Epidermolysis Bullosa (23.2%) were the most common diagnoses, followed by Ichthyosis (16.2%) and Oculocutaneous Albinism (13.9%). Less frequent conditions included Ectodermal Dysplasia (6.9%) and single cases of Palmoplantar Keratoderma, PTEN Hamartoma Syndrome, Rothmund-Thomson Syndrome, Xeroderma Pigmentosum, and Megaconial Congenital Muscular Dystrophy (each 2.3%). Molecular findings underscored the genetic complexity of genodermatoses, with 42 distinct variants identified across 19 genes. Of these, 13 variants (31%) were novel, expanding the known molecular spectrum. The novel variants were detected in genes including NF1, COL7A1, ITGB4, COL17A1, NIPAL4, ALOX12B, KRT10, ST14, OCA2, and PTEN, highlighting the diagnostic value of comprehensive genetic analysis. The mean age at diagnosis varied significantly among conditions, reflecting the diagnostic challenges and clinical variability of genodermatoses. This study emphasizes the critical role of WES and CES in diagnosing genodermatoses and understanding their molecular basis, which enhances diagnostic accuracy and supports personalized management strategies. Congenital poikiloderma, also known as Rothmund-Thomson syndrome (RTS), is a rare genodermatosis of autosomal recessive (AR) inheritance characterized by a typical erythema facial (poikiloderma) of early-onset, associated with different clinical features including short stature, sparse scalp hair, absent or sparse eyelashes or eyebrows, juvenile cataracts, skeletal abnormalities, juvenile cataract, premature aging, and susceptibility to osteosarcoma. See Image. Poikiloderma Congenitale. There are 2 types of RTS. Type 1 is characterized by rapidly progressive, bilateral, juvenile cataracts. In contrast, congenital bone abnormalities and an increased risk of osteosarcoma in childhood and squamous cell carcinoma at an older age characterize type 2.

Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder characterized by a rash that progresses to poikiloderma. Other common features include sparse hair, eyelashes and eyebrows, short stature, variable skeletal abnormalities, dental defects, cataracts, hypogonadism, and an increased risk for cancer, especially osteosarcoma and skin cancer. RTS is caused by biallelic pathogenic variants in ANAPC1 (Type 1 RTS) or RECQL4 (Type 2 RTS). We present an African girl with Type 2 RTS caused by a nonsense variant and an intronic variant in RECQL4. The patient presented precocious puberty, which has not been previously reported in RTS and that was treated with a GnRH analog, and anal stenosis, which has only been reported once. This case highlights the need to consider deep intronic variants in patients with RTS when pathogenic variants in the coding regions and exon/intron boundaries are not identified and expands the phenotypic spectrum of this disorder.

Rare syndromic skin disorders may represent a diagnostic challenge. We report a unique case associating cutaneous manifestations and developmental delay. The affected 14 months old boy had poikiloderma, facial dysmorphism with deep-set eyes, atrichia, as well as nail dysplasia and non-descended testes. In addition, his psychomotor development was delayed. Exome sequencing and molecular karyotyping via array-CGH (oligo-array, 180k Agilent, design 22060) were performed. Mutations in RECQL4 (found in patients with RTS2) were first excluded. In the ANAPC1 gene, a novel combination of a recurrent intronic mutation (c.2705-198C>T) and a deletion of the second ANAPC1 allele was detected, thus confirming the clinical diagnosis of RTS1. The deletion on chromosome 2q13 comprised further genes and spanned 1,7 megabases. Heterozygous deletions in this region are known as 2q13 microdeletion syndrome and are associated with developmental delay, autism and facial dysmorphism. The genetic findings most probably explain both, the RTS1 features and the developmental delay. Genetic diagnosis in RTS is indispensable to confirm the specific subtype and its associated risks: juvenile cataracts are features of RTS1 (ANAPC1 gene), whereas a high risk of osteosarcoma is part of RTS2 (RECQL4 gene). Thus, the patient described here is at high risk for the development of juvenile cataracts and requires regular ophthalmologic examination. This case report underlines the necessity of thorough clinical diagnosis prior to genetic diagnosis of RTS1, since the recurrent intronic ANAPC1 mutation is otherwise missed.

Defects in DNA repair pathways and alterations of mitochondrial energy metabolism have been reported in multiple skin disorders. More than 10% of patients with primary mitochondrial dysfunction exhibit dermatological features including rashes and hair and pigmentation abnormalities. Accumulation of oxidative DNA damage and dysfunctional mitochondria affect cellular homeostasis leading to increased apoptosis. Emerging evidence demonstrates that genetic disorders of premature aging that alter DNA repair pathways and cause mitochondrial dysfunction, such as Rothmund-Thomson syndrome, Werner syndrome, and Cockayne syndrome, also exhibit skin disease. This article summarizes recent advances in the research pertaining to these syndromes and molecular mechanisms underlying their skin pathologies.