P3D320: Mowat-wilson Syndrome Presenting as Sleep Disordered Breathing in the Newborn Period

Introduction: Respiratory distress is a common chief complaint in the neonatal period. However, amongst term infants, true apnea is rare. We present the case of a newborn patient with paroxysmal respiratory distress during sleep who was found to have central and peripheral apnea and ultimately diagnosed with Mowat-Wilson Syndrome (MWS). MWS is an autosomal dominant disease with variable expressivity known to impact sleep but not clearly associated with apnea.

Case Description: The patient is a term infant male with his prenatal course complicated by identification of bilateral ventriculomegaly, agenesis of corpus callosum, and colpocephaly. Fetal cell-free DNA genetic screening was negative and maternal history was otherwise non-contributory. Delivery was uncomplicated. At approximately 24 hours of life, he demonstrated multiple apneic episodes requiring escalation of respiratory support to non-invasive positive pressure ventilation. Upon admission to the neonatal ICU, the patient continued to experience events consistent with sleep-disordered breathing. Further evaluation was significant for severe central and peripheral apnea with nocturnal hypoxemia, laryngomalacia, and septo-optic dysplasia. The patient was trialed on supplemental oxygen via nasal cannula; with this intervention, his apnea resolved. Whole-exome sequencing identified a ZEB2 mutation and the diagnosis of Mowat-Wilson syndrome. He was discharged home on oxygen supplementation.

Discussion: Mowat-Wilson syndrome’s clinical phenotype is diverse; the most common findings include abnormal facies, developmental delay and intellectual disability, Hirschsprung disease, and epilepsy. The causative ZEB2 gene plays a crucial role in embryologic nervous system development, including neural tube progression, neural crest cell migration, and cortical connections. This accounts for the extensive but highly variable neurologic phenotype of the disease, which may include sleep disturbances and brain malformations as described in this case.

The most common sleep changes reported with Mowat-Wilson syndrome include frequent or early sleep arousal, daytime hypersomnolence, parasomnias, and difficulty with sleep-wake transitions. It is also prudent to distinguish these events from nocturnal seizures. MWS-focused sleep studies available in the literature do not describe associated sleep apnea. It is important to note that patients’ sleep phenotype may be influenced by their comorbid anomalies, such as micrognathia or glossoptosis causing peripheral obstruction or agenesis of the corpus callosum contributing to central hypoventilation. In this case, the patient’s episodic respiratory distress only with sleep prompted a polysomnogram, which revealed significant central apnea.

Conclusion: This case report highlights central apnea as a rare cause of neonatal respiratory distress and reveals another potential element of sleep disturbance in patients with Mowat-Wilson syndrome. Parents of patients with this diagnosis should receive anticipatory guidance regarding sleep, including return precautions for signs or symptoms of sleep apnea. Multi-disciplinary care should involve evaluation by a sleep specialist or polysomnogram. Moreover, central apnea should be considered as an etiology for respiratory distress in newborns with known congenital brain abnormalities or syndromic features.