PRRT2 gene variant in a child with dysmorphic features, congenital microcephaly, and severe epileptic seizures: genotype-phenotype correlation?

Abstract

BackgroundMutations in Proline-rich Transmembrane Protein 2 (PRRT2) have been primarily associated with individuals presenting with infantile epilepsy, including benign familial infantile epilepsy, benign infantile epilepsy, and benign myoclonus of early infancy, and/or with dyskinetic paroxysms such as paroxysmal kinesigenic dyskinesia, paroxysmal non-kinesigenic dyskinesia, and exercise-induced dyskinesia. However, the clinical manifestations of this disorder vary widely. PRRT2 encodes a protein expressed in the central nervous system that is mainly localized in the pre-synaptic neurons and is involved in the modulation of synaptic neurotransmitter release. The anomalous function of this gene has been proposed to cause dysregulation of neuronal excitability and cerebral disorders.Case presentationWe hereby report on a young child followed-up for three years who presents with a spectrum of clinical manifestations such as congenital microcephaly, dysmorphic features, severe intellectual disability, and drug-resistant epileptic encephalopathy in association with a synonymous variant in PRRT2 gene (c.501C > T; p.Thr167Ile) of unknown clinical significance variant (VUS) revealed by diagnostic exome sequencing.ConclusionSeveral hypotheses have been advanced on the specific role that PRRT2 gene mutations play to cause the clinical features of affected patients. To our knowledge, the severe phenotype seen in this case has never been reported in association with any clinically actionable variant, as the missense substitution detected in PRRT2 gene. Intriguingly, the same mutation was reported in the healthy father: the action of modifying factors in the affected child may be hypothesized. The report of similar observations could extend the spectrum of clinical manifestations linked to this mutation.

The Spectrum of PRRT2-Associated Disorders: Update on Clinical Features and Pathophysiology

“…Beyond paroxysmal neurological disorders, there is preliminary evidence that heterozygous PRRT2 mutations might also cause intellectual disability and/or developmental delay ( 26 , 27 , 38 ), a suggestion supported by their invariable presence in cases with 16p11.2 deletions ( 39 – 41 ) and homozygous PRRT2 mutations ( 27 , 42 – 44 ). The latter evidence, along with initial demonstrations that PRRT2 mutations can possibly cause brain structural alterations ( 27 , 44 ), is of crucial importance since it implicates PRRT2 in neurogenesis and brain development, as discussed below.…”

“…The latter evidence, along with initial demonstrations that PRRT2 mutations can possibly cause brain structural alterations ( 27 , 44 ), is of crucial importance since it implicates PRRT2 in neurogenesis and brain development, as discussed below. However, it should be noted that, in the context of 16p11.2 deletions, phenotype severity might be owing to deletion of adjacent genes and, therefore, the association of intellectual disability and heterozygous PRRT2 mutations ( 26 , 27 , 38 ) requires additional confirmation.…”

The Evolution of the Role of Imaging in the Diagnosis of Craniosynostosis: A Narrative Review

“…This process leads to characteristic skull deformities, facial asymmetry, and impairment of brain development [ 1 ]. “Single” synostosis, when premature closure affects one cranial suture, or “compound” synostosis, affecting more than one sutures [ 2 , 3 ], may occur as a primary condition (isolated or in a syndromic form), or secondary to various underlying causes, such as metabolic, intracranial, teratogenic or hematological conditions [ 4 , 5 ].…”

“…Craniosynostosis affects male children more frequently than females (4:1), and it often occurs already at birth, but it becomes increasingly noticeable during the first months of life as a cranial deformity [ 4 , 5 ].…”

Sutures ultrasound: useful diagnostic screening for posterior plagiocephaly

“…SP is a form of non-syndromic or syndromic craniosynostosis due to premature fusion of one or more cranial suture. Positional molding is a distinct entity caused by intrauterine restriction or by postnatal deformational forces [2][3][4][5][6][7][8][9]. Following the "Back to sleep" campaign introduced by American Heart Association to prevent SIDS, the incidence of positional plagiocephaly has increased significantly [10].…”