A Novel Frameshift Mutation In Kat6A Is Associated With Pancraniosynostosis
Jennifer Hall, BS, Fady Marji, MD, Joseph Losee, MD, Jesse Goldstein, MD
University of Pittsburgh, Pittsburgh, PA, USA.
PURPOSE: KAT6A syndrome is the result of a genetic mutation that disrupts histone acetylation, which gives rise to an intellectual disability syndrome with features including speech delay, cardiac anomalies, craniofacial dysmorphisms, and craniosynostosis. The purpose of this case report is to present the first reported case of a patient with KAT6A Syndrome found to have pancraniosynostosis.
METHODS: We report a 16 year old Caucasian female with severe intellectual disability, verbal dyspraxia, motor delay, focal seizures, and significant craniofacial dysmorphisms. She had undergone biochemical, metabolic, and genetic testing, but none demonstrated a clear basis for her phenotype. She recently underwent Whole Exome Sequencing (WES) which detected a novel heterozygous pathogenic variant: c.4254_4257del (p.Glu1419fs), in exon 17 of the KAT6A gene on chromosome 8 (NM_006766).
RESULTS: In the setting of increased seizure frequency, the patient underwent thorough neurological evaluation, which included computed tomographic (CT) imaging of the head. CT imaging demonstrated microcephaly, diffuse calvarial thickening, and pancraniosynostosis involving the metopic, sagittal, bilateral coronal and lambdoid sutures. Given a lack of papilledema, with normal visual evoked potential (VEP) results, increased intracranial pressure was ruled out. Increased epileptic episodes, which were likely due to pubertal hormonal levels, normalized via up-titration of levetiracetam. Due to the lack of both intracranial hypertension and significant cosmetic deformity, operative cranial vault remodeling was elected against, and clinical surveillance was pursued.
CONCLUSION: KAT6A syndrome ranges in severity and has overlapping features with other well categorized genetic syndromes which makes the diagnosis of this new syndrome based on phenotype alone very challenging. WES has become a powerful instrument in the investigation of de novo pathogenic variants as a common cause of KAT6A and other neurodevelopmental disorders which can be used to help more accurately diagnose patients.
Craniosynostosis has now been described in 9% of patients with KAT6A syndrome, some of which have required cranial vault remodeling. However, we describe the first reported case of KAT6A syndrome manifesting pancraniosynostosis; a rare entity involving concomitant premature fusion of more than three cranial sutures. Pancraniosynostosis may be related to a primary physiologic aberrancy with the affected cranial sutures, or due to secondary causes such as microcephaly seen in up to 25% of patients with KAT6A syndrome. Since patients with pancraniosynostosis typically possess an indistinct cranial morphology, they may present later in age with symptoms of elevated ICP requiring urgent surgical decompression, and subsequent "late cranial vault expansion".
As the number of patients found to have KAT6A de novo mutations continues to rise, practitioners must familiarize themselves with the inherent phenotypic features of this syndrome and subject these patients to exome sequencing for establishment of diagnosis. Additionally, evaluation by a craniofacial surgeon is imperative, as the finding of craniosynostosis may require operative intervention, the delay of which may be detrimental.
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