Diagnostic challenges in neonatal hypotonia: a comparative presentation of two cases with different etiologies

Abstract

Aim: To present two newborns with a clinically similar but etiologically distinct presentation of generalized hypotonia, emphasizing the differential distinction between peripheral and central causes through the use of modern diagnostic methods.
Methods: Two cases of newborns hospitalized in a tertiary center are described. The evaluation included perinatal data, clinical examination, laboratory and metabolic testing, neuroimaging (cranial ultrasound and brain MRI), electroencephalography (EEG), and extended genetic analysis using whole-exome sequencing (WES).
Case Presentation: In the first case, a term male newborn exhibited severe hypotonia, bulbar dysfunction, and progressive respiratory insufficiency from birth, with normal neuroimaging and electrophysiological findings. WES confirmed a pathogenic de novo ACTA1 c.547C>T (p.Arg183Cys) variant, consistent with a clinically severe form of nemaline myopathy. In the second case, a late-preterm newborn presented with hypotonia, respiratory distress, apneas, and subsequent development of tonic–clonic seizures. Neuroimaging revealed periventricular leukomalacia, thalamic hemorrhages, and an enlarged cisterna magna, while the EEG demonstrated multifocal epileptic activity, consistent with hypoxic-ischemic brain injury following perinatal asphyxia.
Conclusion: Although the initial presentation was nearly identical in both newborns, the etiology of hypotonia differed. A systematic and multilayered diagnostic evaluation is essential for distinguishing peripheral from central causes. Early implementation of genetic testing can accelerate the diagnosis of neuromuscular disorders, whereas timely recognition of perinatal asphyxia enables the application of proactive neuroprotective therapy. These cases underscore the importance of integrating clinical, neuroimaging, and genetic data in the assessment of hypotonic newborns.