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Case Reports
. 2016 Jul:60:83-7.
doi: 10.1016/j.pediatrneurol.2016.03.011. Epub 2016 Apr 9.

PEHO Syndrome May Represent Phenotypic Expansion at the Severe End of the Early-Onset Encephalopathies

Pawel Gawlinski  1 , Renata Posmyk  2 , Tomasz Gambin  3 , Danuta Sielicka  4 , Monika Chorazy  5 , Beata Nowakowska  1 , Shalini N Jhangiani  6 , Donna M Muzny  6 , Monika Bekiesinska-Figatowska  7 , Jerzy Bal  1 , Eric Boerwinkle  8 , Richard A Gibbs  6 , James R Lupski  9 , Wojciech Wiszniewski  10
Affiliations
Case Reports

PEHO Syndrome May Represent Phenotypic Expansion at the Severe End of the Early-Onset Encephalopathies

Pawel Gawlinski et al. Pediatr Neurol. 2016 Jul.

Abstract

Background: Progressive encephalopathy with edema, hypsarrhythmia and optic atrophy (PEHO) syndrome is a distinct neurodevelopmental disorder. Patients without optic nerve atrophy and brain imaging abnormalities but fulfilling other PEHO criteria are often described as a PEHO-like syndrome. The molecular bases of both clinically defined conditions remain unknown in spite of the widespread application of genome analyses in both clinic and research.

Methods: We enrolled two patients with a prior diagnosis of PEHO and two individuals with PEHO-like syndrome. All four individuals subsequently underwent whole-exome sequencing and comprehensive genomic analysis.

Results: We identified disease-causing mutations in known genes associated with neurodevelopmental disorders including GNAO1 and CDKL5 in two of four individuals. One patient with PEHO syndrome and a de novoGNAO1 mutation was found to have an additional de novo mutation in HESX1 that is associated with optic atrophy.

Conclusions: We hypothesize that PEHO and PEHO-like syndrome may represent a severe end of the spectrum of the early-onset encephalopathies and, in some instances, its complex phenotype may result from an aggregated effect of mutations at two loci.

Keywords: PEHO; encephalopathy; neurodevelopmental disorder; optic atrophy; whole-exome sequencing.

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Conflict of interest statement

J.R.L. has stock ownership in 23andMe and Lasergen and is a paid consultant for Regeneron. J.R.L. is a coinventor on multiple U.S. and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the chromosomal microarray analysis and clinical exome sequencing offered in the Baylor Medical Genetics Laboratories (http://www.bcm.edu/geneticlabs/). Other authors have no disclosures relevant to the article.

Figures

FIGURE 1
FIGURE 1
Facial dysmorphic features, brain imaging studies and segregation analysis of disease-causing mutations in patient IMD1. The patient presented with typical progressive encephalopathy with edema, hypsarrhythmia and optic atrophy (PEHO)–associated dysmorphic features including microcephaly, facial edema, pear-shaped face, open mouth, downturned corners of the mouth. Brain imaging demonstrated cerebral and cerebellar atrophy. The patient was found with de novo mutations: ch16:56226501G>A (c.134G>A, p.Gly45Glu) in GNAO1 and chr3:57233922G>A (c.25G>A, p.Ala9Thr) in HESX1. (The color version of this figure is available in the online edition.)
FIGURE 2
FIGURE 2
Facial characteristic and brain magnetic resonance imaging demonstrating cerebral atrophy without cerebellar involvement in patient IMD3. Whole-exome sequencing (WES) analysis identified a de novo CDKL5 mutation, chrX:18606145C>T (c.626C>T, p.Pro209Leu). (The color version of this figure is available in the online edition.)
See this image and copyright information in PMC

References

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