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Page 170 Bone et al. J Transl Genet Genom 2022;6:169-78 https://dx.doi.org/10.20517/jtgg.2021.56

Keywords: Pitt-Hopkins syndrome, epilepsy, EEG, TCF4

INTRODUCTION
Pitt-Hopkins syndrome (PTHS) is a haploinsufficiency syndrome caused by loss of function variants of
transcription factor 4 (TCF4) on chromosome 18q21.2. It was first described in 1978 by Drs. Pitt and
Hopkins, and TCF4 was identified as the causative gene in 2007 . PTHS is an ultra-orphan disease with an
[1]
[2-4]
estimated prevalence of 1:225,000-1:300,000 . Clinically, patients with PTHS present with symptoms that
are similar to other more common neurodevelopmental syndromes such as Angelman syndrome and Rett
syndrome. Though PTHS patients often have characteristic facial features such as a narrow forehead, thin
lateral eyebrows, wide nasal bridge, ridge, or tip, flared nasal alae, full cheeks, prominent midface, wide
mouth, full lips, prominent cupid’s bow upper lip, and thickened or over-folded helices [1,2,5-7] . The
developmental phenotype is relatively homogenous, with profound developmental disabilities including
markedly delayed onset of ambulation and limited or absent speech . Individuals with PTHS have
[1,2]
impairments in adaptive behavior on standardized testing, with scores resembling profiles seen in patients
with Angelman syndrome . Patients with PTHS are also often affected by additional medical
[8,9]
comorbidities, including early-onset myopia (54%-88%), chronic constipation (70%-83%), and unsteady gait
with impaired mobility . Brain imaging is often normal but may demonstrate non-specific findings such
[1,3]
as corpus callosal dysplasia, bulging of the caudate heads, small hippocampi, temporal white matter
hyperintensities, delayed myelination, hypoplasia of the cerebellum, or ventriculomegaly [1,2,10] .

There are three types of paroxysmal events that PTHS patients may have: (1) abnormal breathing spells
(e.g., hyperventilation with or without apnea); (2) motor stereotypies; and (3) epileptic seizures. Nearly half
of patients with PTHS have spells of abnormal breathing, including hyperventilation, which may be
followed by apnea with rapid onset of cyanosis . Breathing spells are consistently only observed while
[1]
awake and do not have an ictal electroencephalogram (EEG) correlate . This suggests that breathing spells
[11]
are not epileptic events but could be a behavioral phenomenon or related to autonomic dysfunction. Motor
stereotypies are common and can include hand flapping, rocking, twisting, waving, or flicking hands, and
[4]
repetitively handling objects . The prevalence of epilepsy in PTHS is 37%-50%, with onset anytime between
the first year of life and adulthood , but more commonly within the first decade of life (2). In PTHS
[4]
patients with or without epilepsy, EEG can be normal or abnormal and can change over time . Seizures can
[4]
have variable semiology, including generalized tonic-clonic, atonic, focal motor, focal non-motor seizures,
and rarely infantile spasms . One case report identified a child with PTHS who had both migrating partial
[1]
[12]
seizures of infancy and infantile spasms . Apnea and hyperventilation spells are often misdiagnosed as
seizures, and to add to the diagnostic challenge, patients may show apnea or over-breathing just prior to
onset of a seizure .
[4]
A case series of 21 patients with PTHS and epilepsy found that the median age of seizure onset was two
years and that focal and generalized epilepsies occurred with the same prevalence. Further, patients with
seizure onset after age two were more likely to achieve seizure freedom. They also found that even in
patients with drug-resistant epilepsy, seizures became less frequent as patients aged. There were no cases of
sudden unexpected death in epilepsy or status epilepticus in their cohort, and over half (57%) had abnormal
EEG backgrounds. Focal epileptiform discharges were seen in 76%, 19% had generalized epileptiform
[3]
discharges, and only one patient (4%) had a normal EEG without epileptiform discharges .

Attempts to evaluate genotype-phenotype correlations have been inconclusive. Individuals with missense
[2]
mutations may be more likely to develop seizures as compared to other types of mutations . It has also