Metabolic Dysfunction in Shashi-Pena Syndrome: A Novel Pathologic ASXL2 Frameshift Variant
Sharbel Khoury1, Divya Singh2, Ali Jamal2
1Saint Louis University School of Medicine, 2SSM Health Cardinal Glennon Children's Hospital-St. Louis University
Background:
ASXL2 is a member of the Additional sex combs (Asx)-like gene family, essential for embryonic development and homeostasis. Germline truncating variants are associated with Shashi-Pena syndrome (SHAPNS), an ultra-rare disorder, characterized by macrocephaly, dysmorphic features, feeding difficulties, hypotonia, and developmental delay. Metabolic dysfunction has been less well described.
Design/Methods:
We report the clinical presentation, genetic evaluation, and hospital course of a neonate with dysmorphic features and persistent hypoglycemia. Whole exome sequencing (WES) was performed using next-generation sequencing with high coverage and quality thresholds.
Results:
A 34-week male infant, born via cesarean section to a primigravida with chronic hypertension, intrauterine growth restriction, and footling breech presentation, developed hypoglycemia on day 2 of life with inappropriately elevated insulin levels consistent with neonatal hyperinsulinism requiring initiation of diazoxide therapy. Dysmorphic craniofacial features (frontal bossing, depressed nasal bridge, low set ears, retrognathia, bulging eyes, and temporal wasting), truncal hypotonia, and congenital heart defects (patent foramen ovale and a small, restrictive mid-muscular ventricular septal defect) were additionally noted Chromosomal microarray and brain magnetic resonance imaging were unremarkable. WES revealed a novel heterozygous frameshift variant in ASXL2 (NM_018263.4, c.2889_2293del, p.Gln764Serfs*2), classified as likely pathogenic. The patient required prolonged neonatal intensive care (72 days), and gastrostomy tube placement for feeding difficulties and metabolic instability owing to failed trial of diazoxide wean.
Conclusions:
This case identifies a novel ASXL2 variant and broadens the phenotypic spectrum of SHAPNS, highlighting its association with neonatal hyperinsulinism and multisystem involvement. Recognizing this link is critical to avoid misattributing hypoglycemia to prematurity or poor intake, and to guide timely management and genetic counseling.
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