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Expanding the Phenotype of EBF3-related Disorders- A Case of Pierre Robin Sequence with Cleft Palate 

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction
Early B-cell Factor 3 (EBF3) is a member of the Collier/Olf/EBF (COE) family of transcription factors, which are involved in B-cell differentiation, bone development, and nervous system development. Pathogenic loss-of-function variants in the EBF3 gene are associated with Hypotonia, Ataxia, and Delayed Development (HADD) syndrome, initially described in 2016. This syndrome shares phenotypic similarities with 10q26 deletion syndrome, which includes the EBF3 locus. Clinical features of HADD syndrome typically include congenital hypotonia, neurodevelopmental delays, ataxia, vision problems, genitourinary anomalies, feeding difficulties, musculoskeletal abnormalities, short stature, and/or microcephaly. While mild facial dysmorphism is common, there is no distinctive facial phenotype. Gene expression data suggest that EBF3 haploinsufficiency may contribute to orofacial clefting. To the best of our knowledge, cleft palate is not commonly reported in affected individuals. This case report explores the clinical features of an infant with cleft palate and a maternally inherited pathogenic variant in the EBF3 gene.

Case Presentation
A female infant presented with a complex constellation of features including Pierre Robin sequence with micrognathia, a U-shaped cleft palate, glossoptosis, and congenital anomalies including a ventricular septal defect (VSD), left hydronephrosis, and bilateral small kidneys. She also demonstrated obstructive sleep apnea, oral motor incoordination, and oral motor delays.

Diagnostic Workup
Whole exome sequencing (WES) was performed, revealing a maternally inherited pathogenic variant in the EBF3 gene, specifically c.524_528del, p.(E175Afs*8). This variant was consistent with EBF3-related disorder. The mother, who had developmental delays, intellectual disability, and myopia, did not have a history of cleft palate.

Treatment and Management
The infant was initially managed with a G-tube for feeding difficulties and was scheduled for occupational therapy to address oral motor delays. Surgical management of the cleft palate was planned with a Furlow palatoplasty at 1 year of age. Close monitoring of her cardiac and renal conditions was also initiated, and regular developmental assessments were scheduled.

Outcome and Follow-Up
At her follow-up visit at 8 months of age, the VSD and left hydronephrosis had resolved, and her kidneys were of normal size for age. Her physical exam was notable for a tall forehead, cleft palate, micrognathia, tapered fingers, overlapping 2nd toes, and mild hypotonia. Her growth was appropriate, and she was continuing to thrive with G-tube feeds. She was about to initiate occupational therapy for her oral feeding difficulties.

Discussion
This case highlights the phenotypic variability associated with EBF3-related disorders, particularly the incomplete penetrance of cleft palate. While theoretical data suggest a possible link between EBF3 haploinsufficiency and orofacial clefting, cleft palate remains an uncommon feature in the literature. Our case contributes to the understanding of this rare genetic disorder and underscores the importance of genetic testing and early intervention for optimal patient management.

Conclusion
This case supports the hypothesis that loss-of-function variants in EBF3 may exhibit incomplete penetrance for cleft palate. Clinicians should consider EBF3-related disorder in the differential diagnosis of patients with Pierre Robin sequence and associated congenital anomalies, particularly in the context of neurodevelopmental delays and other systemic manifestations. Further research is needed to elucidate the full spectrum of EBF3-related phenotypes.

 

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