Pitt Hopkins-Like Syndrome 1 with Novel CNTNAP2 Mutation in Siblings

Abstract

Pitt Hopkins-like syndrome 1 (PTHLS1, OMIM # 610042) is an ultra-rare autosomal recessive condition with a prevalence of <1/1,000,000. Intragenic deletions of CNTNAP2 has been implicated in PTHLS1, however to our knowledge a compound heterozygous deletion of exon 4 and a c.1977_1989del13; p.V660Ffsx9 frameshift variant have not been published previously. In this case report, the proband is a seven year old female with PTHLS1, developmental delay, autism spectrum disorder, focal epilepsy, hypotonia, refractory errors, strabismus, and obstructive sleep apnea. Whole exome sequencing analysis revealed biallelic pathogenic variants of the CNTNAP2 gene. Proband has a three year old sister who has who has a similar phenotype including, developmental delay, epilepsy, gait abnormality, refractory errors, strabismus. Family variants were tested and she shared the same CNTNAP2 variants as her sister. The sisters described highlight two novel variants leading to PTHLS1. Genetic workup is essential in identification and management guidance in these populations.

Keywords: CNTNAP2; cortical dysplasia-focal epilepsy syndrome; developmental delay; epilepsy; intellectual disability; pediatrics; pitt Hopkins-like syndrome 1.

Figure 1.

Interictal EEG of proband demonstrating frequent right centrotemporal spikes and sharps. Ictal episodes not captured during EEG monitoring.

Figure 2.

Ictal EEG of proband's sibling demonstrating seizure onset right fronto-temporal region (A) and subsequent seizure spread to entire right hemisphere and left frontotemporal region (B).