Cyclical Vomiting Syndrome in Individuals With BPTF Haploinsufficiency

Haploinsufficiency of the bromodomain PHD finger transcription factor (BPTF) gene, essential in chromatin remodeling, leads to a neurodevelopmental disorder characterized by dysmorphic facies, distal limb anomalies, neurological disturbances, epilepsy, and gastrointestinal symptoms.

Families with BPTF-related neurodevelopmental disorders, with or without gastrointestinal symptoms, were recruited through an international collaboration. Data were collected via questionnaires on demographics, clinical features, genetics, and comorbidities, focusing on cyclical vomiting syndrome (CVS). CVS was diagnosed using criteria from the International Classification of Headache Disorders, 3rd edition (ICHD-3). Genetic variants were analyzed for pathogenicity, and effectiveness of therapies was assessed.

We enrolled 15 individuals with likely pathogenic/pathogenic BPTF variants (median age: 8.8 years). Three individuals (20%) were diagnosed with CVS, and an additional four individuals (26.7%) met at least three of the ICHD-3 criteria for CVS. Among these seven individuals, the median age at onset of recurrent vomiting episodes was 3 years. In all seven individuals, recurrent vomiting episodes, typically lasting under an hour, were triggered by poor sleep (50%) and fever (66.7%). Acute therapy (ondansetron or domperidone) was administered in 42.8% of cases, and prophylactic therapy was provided in 57.1% of cases with cyproheptadine, levetiracetam combined with lamotrigine, and domperidone; all therapies were associated with clinical benefit. Episodes disrupted families' daily lives, causing emotional stress (85.7%) and routine disruptions (85.7%).

This study broadens the syndromic phenotype associated with BPTF haploinsufficiency, highlighting CVS as a core feature. The findings raise clinician awareness, guide management, and enhance understanding of this rare condition.