Background <p>Neonatal erythroderma has a broad differential and poses a diagnostic challenge due to clinical overlap between diagnoses. Netherton Syndrome, also known as SPINK5-syndromic epidermal differentiation disorder (SPINK5-sEDD), is a genodermatosis caused by mutations in the serine protease inhibitor Kazal-type 5 (SPINK5) gene located on chromosome 5q31–32. The clinical presentation varies widely, ranging from mild dermatitis to severe neonatal disease with life-threatening metabolic instability and sepsis. Diagnosis is confirmed by genetic testing, and management includes a multidisciplinary approach to prevent complications.</p> Case presentation <p>We present a case of a late preterm neonate presenting with temperature instability and plethoric appearance, with subsequent development of erythroderma, hypernatremia, poor weight gain, and polymicrobial bacterial infections, including Staphylococcus aureus meningitis. Dermatology, infectious disease, and immunology services were involved; the genetic testing revealed mutation in the SPINK5 gene, consistent with a diagnosis of Netherton Syndrome. She was managed with topical emollients, intravenous immunoglobulin, and nutritional support with ongoing care by a multidisciplinary team.</p> Conclusion <p>This case describes the neonatal presentation of Netherton Syndrome, a rare genodermatosis, with high morbidity and mortality earlier in life. Complications from Netherton Syndrome in this population typically include hypernatremia, failure to thrive, recurrent infections, and temperature instability. Early recognition of inflammatory dermatoses, including Netherton syndrome, is essential for timely diagnoses, management, and prevention of complications.</p>