P2.M250: Rethinking Rett: Unveiling the XY Factor

Introduction: Rett Syndrome is a neurodevelopmental disorder that is characterized by developmental regression, loss of speech and purposeful movements, gait ataxia, deceleration of head growth, seizures, and respiratory abnormalities. Approximately 90% of cases are due to mutations in the MECP2 gene on the X chromosome. The disorder was previously thought to exclusively affect females, with presumed lethality in males, given its X-linked dominant inheritance.

Case Description: A 2-month-old male born at 34 weeks gestational age presents to the emergency room (ER) after an unresponsive episode at home, requiring CPR.
Prenatal course was unremarkable. The infant was born via emergent cesarean section due to placental abruption. He was admitted to the Neonatal Intensive Care Unit (NICU) on CPAP, and weaned to room air on day of life (DOL) 3. He was noted to have hypotonia and feeding difficulties during his NICU course, with overall improvement at the time of discharge on DOL 45.
2 weeks later he presented to the ER described above with stable vital signs, but with profound hypotonia. He was readmitted to the NICU due to multiple apneic episodes, which resolved spontaneously without the need for any respiratory support. An extensive diagnostic evaluation for hypotonia was performed during this admission. Labs were notable for normal blood counts, renal and liver function. EKG, Echocardiogram and chest X-ray were normal. Swallow study was performed showing mild aspiration. Electroencephalogram (EEG) was notable for tonic abnormalities independent of neonate’s apneic episodes. Neuroimaging was normal and a metabolic work up was negative. Chromosomal microarray was significant for a MECP2 deletion with 90% mosaicism, consistent with Male Rett Syndrome.

Discussion: Evaluation of neonatal hypotonia requires a structured approach and can have a broad differential, including perinatal hypoxia, congenital, genetic/metabolic abnormalities, and/or neuromuscular etiologies. This neonate presented with hypotonia following placental abruption, which can result from hypoxic injury in the context of perinatal depression. This initial hypothesis could explain improvement in the given neonate during initial hospitalization. However, the persistent and worsening hypotonia following discharge raises suspicion for genetic and/or metabolic causes of hypotonia.

Male Rett Syndrome has a clinical spectrum that ranges from severe neonatal encephalopathy to milder developmental delays during childhood. This is due to various factors, including sporadic MECP2 mutations, mosaicism of the MECP2 gene, chromosomal abnormalities at affect the number of X chromosomes, such as Klinefelter’s Syndrome (XXY), or males with a known family history of Rett Syndrome. The given patient had 90% mosaicism to MEPC2 gene, which explains with the neonate’s second hospitalization and presentation with severe hypotonia.

Conclusion: Male Rett Syndrome is a disorder with a wide array of phenotypes and should be considered in neonates with a prolonged and worsening hypotonia beyond the newborn period.