Rahsan Gocmen

Learning Points: Intracranial hypertension (IH) is a rare but significant central nervous system complication of cystinosis that clinicians should be aware of. Routine ophthalmological examinations are vital not only for monitoring corneal cystine crystals but also for the early detection of papilledema, which may be the sole presenting sign of IH. As life expectancy in cystinosis patients improves with cysteamine treatment, close monitoring for neurological complications and central nervous system involvement becomes increasingly important.

Introduction: Tuberous sclerosis complex (TSC) is a neurocutaneous disorder caused by pathogenic variants in the TSC1 or TSC2 genes and exhibits marked phenotypic variability. Although TSC2 variants are typically associated with more severe clinical manifestations, certain missense alterations may lead to mild and limited phenotypes. In this report, we describe a family in which the heterozygous TSC2 (NM_000548.5): c.3061G>A, p.(Glu1021Lys) variant was identified in three individuals, and we present the associated mild, atypical, and variable clinical features in these patients. Case Presentation: Clinical evaluations, neuroimaging (brain MRI), and genetic analyses were conducted in the proband and family members. Segregation analysis of the identified variant was performed in the mother and one sibling. Findings were compared with previously reported mild TSC2 missense variants in the literature. The proband exhibited neurodevelopmental delay, treatment-resistant epilepsy, hypopigmented macules, and EEG abnormalities. Whole-exome sequencing revealed the TSC2 (NM_000548.5): c.3061G>A (p.Glu1021Lys) variant in a heterozygous state. Sanger sequencing confirmed the same heterozygous variant in the mother and in one sibling, both of whom had hypopigmented macules. Other family members suspected of having TSC also demonstrated limited cutaneous features but were not genetically tested due to family preference. None of the affected individuals showed cortical tubers, subependymal nodules (SEN), or subependymal giant cell astrocytoma (SEGA) on neuroimaging. Likewise, there was no evidence of renal involvement (angiomyolipoma) or cardiac rhabdomyoma—typical major features of TSC. The phenotypic distribution was characterized by predominant cutaneous findings, mild neurological involvement, and minimal imaging abnormalities. Conclusion: The phenotype observed in this family suggests that the TSC2 c.3061G>A (p.Glu1021Lys) variant may be associated with a mild TSC2 missense presentation. Although notable intrafamilial heterogeneity was present, the absence of SEN, SEGA, renal, and cardiac manifestations—combined with predominantly cutaneous findings—is consistent with previously described mild TSC2 variant patterns. These observations highlight the importance of clinical surveillance in carriers and emphasize that mild TSC2 phenotypes may be easily overlooked in diagnostic evaluations. Keywords: Tuberous sclerosis, TSC2, p.Glu1021Lys, subependymal nodule, SEGA, mild phenotype, missense variant, intrafamilial heterogeneity