Background/Objectives: Tuberous sclerosis complex (TSC) is a rare, autosomal dominant genetic disorder caused by mutations in the TSC1 and TSC2 genes, which disrupt the regulation of the mammalian target of rapamycin (mTOR) pathway, a critical regulator of cellular growth. The disorder presents as a multisystem condition, with benign tumors (hamartomas) developing in organs such as the brain, skin, heart, kidneys, and lungs, leading to significant clinical variability and impact on quality of life. This review aims to summarize recent advances in the understanding of TSC pathogenesis and clinical variability and evaluate the therapeutic breakthroughs in targeted treatments. Methods: A narrative review was conducted using various available databases. We applied objective evaluation metrics, such as the impact factor of the journals and the citation count, to assess the quality of the studies. Results: Targeted therapies, particularly mTOR inhibitors (mTORis), have shown efficacy in reducing hamartoma size, improving neuropsychiatric symptoms, and enhancing patient outcomes. Despite these advances, variability in disease expression poses challenges in diagnosis and individualized management strategies. Conclusions: Challenges such as early diagnosis, optimizing long-term outcomes, and addressing residual unmet needs remain critical. Future research should prioritize precision medicine approaches and patient-centered care models within centers of expertise to improve treatment efficacy and quality of life for individuals with TSC.

Background and Objectives. Primordial dwarfism (PD) is a rare group of genetic conditions where individuals experience severe growth restriction, both in the womb and after birth. From as early as the fetal stage, those affected are significantly smaller than their peers. What makes PD distinct is its slow but steady growth pattern, resulting in proportionate dwarfism, where all parts of the body are equally shortened. Diagnosing and managing PD presents significant challenges due to its rarity and the wide range of clinical and genetic variability. The main conditions in this group include Seckel syndrome, Microcephalic Osteodysplastic Primordial Dwarfism (MOPD) types I/III, MOPD type II, Meier–Gorlin syndrome, and Silver–Russell syndrome (SRS). The first four—Seckel syndrome, MOPD types I/III, MOPD type II, and Meier–Gorlin syndrome—are associated with microcephaly, and together they are known as microcephalic PD. Given how uncommon PD is, establishing its exact incidence is difficult. It is estimated that about 4 million infants die within the first month of life, with 99% of these deaths occurring in the neonatal period. Materials and Methods. Accurately diagnosing PD requires meticulous evaluation, as it can be easily confused with other genetic disorders that also cause dwarfism. In this article, we present the case of a 10-year-old patient diagnosed with MOPD II, the most common and well-documented form of microcephalic PD. Results. Genetic analysis revealed a pathogenic variant in the PCNT (pericentrin) gene ((c.1550dup, p.Gln518Alafs*7), alongside a deletion of exons 37–41. Conclusions. This case sheds light on the clinical and genetic complexities of primordial dwarfism, underscoring the importance of timely and accurate diagnosis for effective patient care.

Introduction: Tuberous sclerosis complex (TSC) is a rare multisystemic genetic disorder characterized by the formation of benign tumors in various organs, including the central nervous system, skin, kidneys, and heart. The diagnosis is based on well-defined clinical criteria, such as those from Schwartz (2007) updated in 2012 by the International Tuberous Sclerosis Complex Consensus Group. The study aims to investigate the clinical, imaging, and molecular characteristics of patients diagnosed with tuberous sclerosis and to explore the correlation between specific genetic mutations (TSC1 and TSC2 genes) and the severity of clinical manifestations. Material and Methods: This is a retrospective longitudinal study of 13 patients diagnosed with tuberous sclerosis, identified in the records of the Bihor Regional Center for Medical Genetics (BRCMG) within the Bihor County Emergency Clinical Hospital from 1984 to 2024. Clinical, imaging, and molecular features were assessed. Patients were evaluated by a multidisciplinary team, including a geneticist, pediatrician, neurologist, psychiatrist, and psychologist. Clinical and imaging data were retrospectively collected from the congenital malformations and genetic disease records of BRCMG Bihor and statistically analyzed. Results: All patients showed clinical and imaging signs consistent with the diagnosis of tuberous sclerosis. Neurological manifestations were present in 83% of patients, including epilepsy and cognitive delays. Renal lesions were detected in 46% of cases, and dermatological lesions, such as facial angiofibromas, were observed in 69% of patients. Mutational variants identified in the TSC2 gene correlated with a more severe clinical presentation, including severe intellectual disability and treatment-resistant seizures, compared to variants in the TSC1 gene. Conclusions: Our study, although involving a small number of patients, highlights the clinical heterogeneity of tuberous sclerosis and the importance of a multidisciplinary approach in patient management. Early diagnosis and ongoing monitoring are essential to improving the quality of life for patients. Further studies are needed to assess the impact of therapeutic interventions and genetic correlations within the studied population.

Background: Neurocutaneous syndromes (NCS), including neurofibromatosis type 1 (NF1), tuberous sclerosis complex (TSC), and Sturge–Weber syndrome (SWS), are rare neurodevelopmental disorders frequently associated with epilepsy, cognitive impairment, and behavioural difficulties. Although caused by different genetic alterations, these disorders share biological mechanisms that influence brain development, neuronal connectivity, and network excitability. Beyond being a common neurological manifestation, epilepsy is increasingly recognized as an important factor influencing cognitive and behavioural outcomes in neurocutaneous syndromes. Methods: This narrative review summarizes current evidence on the relationship between epilepsy, cognitive dysfunction, and behavioural manifestations in major neurocutaneous syndromes. Attention is given to epileptogenic mechanisms, shared molecular pathways, and factors influencing long-term neurodevelopmental outcomes. Results: Epilepsy is consistently associated with cognitive and behavioural outcomes in neurocutaneous syndromes, particularly in disorders characterized by early-onset and treatment-resistant seizures. Early seizure onset, poor seizure control, and persistent network dysfunction have been associated with intellectual disability, executive dysfunction, attention deficits, autism spectrum features, and impaired adaptive functioning. In TSC and SWS, epilepsy burden is strongly associated with cognitive outcome, particularly in interaction with underlying structural, vascular, and molecular abnormalities. In neurofibromatosis type 1, cognitive and behavioural difficulties are more often related to altered neuronal connectivity and dysregulated signalling pathways, although epilepsy may further contribute to neurodevelopmental impairment in a subset of patients. Despite their distinct genetic origins, these disorders converge on dysregulated RAS/MAPK, PI3K/AKT/mTOR, and Gαq-mediated signalling pathways that influence both epileptogenesis and brain development. Conclusions: Despite their distinct genetic origins, major neurocutaneous syndromes converge on common pathways linking epilepsy, network dysfunction, and neurodevelopmental impairment. Understanding how these processes interact may facilitate earlier intervention and more accurate prognostic assessment, ultimately improving long-term outcomes for affected children.