P2.L240: Neurologic evaluation of megalencephaly- postaxial polydactyly- polymicrogyria- hydrocephalus (MPPH) syndrome in a neonate

Introduction: MPPH (megalencephaly- postaxial polydactyly- polymicrogyria- hydrocephalus) syndrome is a rare autosomal dominant neurodevelopmental disorder characterized by brain overgrowth and cortical malformation at birth. It is associated with de novo pathogenic variants in three genes coding for proteins involved in the regulation of cell growth and brain development in the central nervous system: AKT3, CCND2, or PIK3R2. Clinical diagnosis of MPPH syndrome is established with two core features— megalencephaly and polymicrogyria— and supported by other clinical findings including postaxial polydactyly, hypotonia, early-onset epilepsy, and developmental delay. Fewer than 100 cases of MPPH syndrome have been described as of 2021.

Case Description: We present the case of a female neonate born at 36 weeks and 1 day by spontaneous vaginal delivery at to a G3P3 mother. Pregnancy was complicated by chlamydia infection and non-immune rubella status. Prenatal sonogram was suspicious for an absent septum pellucidum. Birth head circumference was 35.7 cm (98.9th percentile on Fenton curve). The neonate was hypotonic on exam with symmetric reflexes and no involuntary movements. Head ultrasound demonstrated a cavum septum pellucidum, nodular gray matter heterotopia, and bilaterally underdeveloped sulci along the sylvian fissure. MRI brain showed symmetric migrational anomalies in the perisylvian and frontal regions with abnormal cortical thickening (pachygyria) and a gyral pattern along the bilateral frontal, parietal, and superior temporal lobes suggestive of polymicrogyria. Whole exon sequencing was positive for an PIK3R2 abnormality.

Discussion: This presentation of a neonate with hypotonia at birth, imaging findings of megalencephaly and bilateral perisylvian polymicrogyria (BPP), and a pathogenic PIK3R2 variant suggests a clinical and molecular diagnosis of MPPH syndrome. BPP can increase the risk of seizures, intellectual disability, and oromotor dysfunction in patients with MPPH syndrome. Megalencephaly can also cause developmental delays, seizures, and corticospinal dysfunction. Though our patient did not have hydrocephalus on imaging, hydrocephalus is common and presents in around 50% of patients with MPPH. Neurological surveillance for this condition includes frequent brain imaging with MRI to routinely assess for hydrocephalus, cerebellar tonsillar ectopia, and brainstem/spinal cord compression, as well as medulloblastoma. Additionally, given the high risk of developing epilepsy, there should be a low threshold to obtain an electroencephalogram to look for epileptiform activity.

Conclusion: MPPH syndrome is a rare genetic disorder that can present at birth with multiple neurologic deficits and requires close monitoring. Given that the prevalence of MPPH syndrome is extremely low, this case is one in very few reports of the clinical manifestations of this disorder. Further cases need to be reported to continue to refine neurologic evaluation and management of MPPH syndrome.