Liu Y, Guo Y, Liu P, Li F, Yang C, Song J, Hu J, Xin D, Chen
Z. A case of
Pitt-hopkins Syndrome with de novo mutation in TCF4:
Clinical features and
treatment for epilepsy. Int J Dev Neurosci. 2018
Pitt-Hopkins syndrome (PTHS), belonging to the group of 18q-syndromes,
is a rare genetic disorder caused by mutations in TCF4. PTHS is characterized
by distinctive facial appearance, intermittent hyperventilation, intellectual
disability and developmental delay. Although patients with PTHS generally have
various systemic symptoms, most of them with a TCF4 mutation manifest the
central nervous system (CNS) disorders. We described the first Chinese case
with Pitt-Hopkins syndrome based on clinical presentations and genetic
findings. In addition to the typical features of PTHS, the girl also had
paroxysms of tachypnea followed by cyanosis and recurrent seizures.
Comprehensive medical examinations were performed including metabolic
screening, hepatic and renal function evaluation, abdominal and cardiac
ultrasounds. The presence of epileptic discharges in electroencephalography and
abnormal brain magnetic resonance imaging were found. High-throughput
sequencing was used to detect genetic mutations associated with CNS disorders.
Sanger sequencing was used to confirm the mutations in the patient. The c.2182C＞
(p.Arg728Ter) mutation was a de novo nonsense mutation at exon 18 in the TCF4
gene of the patient. In conclusion, we have identified a de novo nonsense
mutation of TCF4 carried by a Chinese girl with PTHS. The patient underwent
anti-epileptic therapy (sodium valproate, levetiracetam, clonazepam), resulting
in a reduction of the seizures.
Motojima T, Fujii K, Ohashi H, Arakawa H. Catathrenia in
Pitt-Hopkins syndrome associated with 18q interstitial deletion. Pediatr Int. 2018
Apr 6. doi:10.1111/ped.13514. [Epub ahead of print]
From the article.
Herein we report a case of catathrenia in a Japanese girl
with Pitt–Hopkins syndrome with an interstitial 8.6 Mb deletion that included
TCF4 and MBD2, as well as 26 other genes. Catathrenia is a phenotype of sleep
disorder, consisting of breath holding and expiratory groaning during sleep.
Given that sleep disturbance has not been well described in Pitt–Hopkins
syndrome, the present report of catathrenia could be valuable to explain its
Pitt–Hopkins syndrome is known to encompass sleep
disturbance as well as breathing abnormality.3 Whalen et al. showed that 42% of
patients with TCF4 molecular abnormalities had sleep disturbance, compared with
18% as reported in previous studies.3 Details of sleep disturbance in
Pitt–Hopkins syndrome have not been investigated, and catathrenia may represent
a form of parasomnia in this syndrome.
On polysomnography in a patient with Pitt–Hopkins syndrome,
physiological organization of rapid eye movement (REM) and non‐REM structures
associated with central apnea was noted for a short duration during the EEG
arousal period.4 TCF4, responsible for Pitt–Hopkins syndrome, defectively
interacts with the ASCL1‐PHOX‐RET pathway, which alters the development of the
Breathing abnormality in Pitt–Hopkins syndrome may be
tightly linked to sleep disturbance. Although there is no concrete evidence
that respiratory rhythm abnormality is involved in this subtype of parasomnia,
catathrenia as seen in the present case may be one of the significant features
explaining the complicated pathogenesis of this syndrome.
Sweetser DA, Elsharkawi I, Yonker L, Steeves M, Parkin K,
Thibert R. Pitt-Hopkins Syndrome. 2012 Aug 30 [updated 2018 Apr 12].
In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A,
editors. GeneReviews®[Internet]. Seattle (WA): University of Washington, Seattle;
Pitt-Hopkins syndrome (PTHS) is characterized by significant
global developmental delays with moderate to severe intellectual disability and
behavioral differences, characteristic facial features, and episodic
hyperventilation and/or breath-holding while awake. Speech is significantly
delayed and most individuals are nonverbal with receptive language often
stronger than expressive language. Other common findings are autism spectrum
disorder symptoms, sleep disturbance, stereotypic hand movements, seizures,
constipation, and severe myopia.
The diagnosis is suspected on clinical findings and
confirmed by identification on molecular genetic testing of a heterozygous
pathogenic variant in TCF4 or a deletion of the chromosome region in which TCF4
is located (18q21.2).
Treatment of manifestations: Developmental services for
infants (physical, occupational, and speech therapies); individualized
education plan for older children with strong consideration for early training
in alternative means of communication; behavioral management strategies;
possible treatment of abnormal respiratory pattern. Routine management of
seizures, myopia, constipation, scoliosis, and ankle instability. Surveillance:
Ongoing developmental assessments to tailor educational services to individual needs;
regular follow up with an ophthalmologist to monitor for high myopia and
strabismus; periodic reevaluation with a clinical genetics professional
regarding current information and recommendations.
PTHS is caused by haploinsufficiency of TCF4 resulting from
either a pathogenic variant in TCF4 or a deletion of the chromosome region in
which TCF4 is located (18q21.2). Most affected individuals have been simplex
cases (i.e., a single occurrence in a family) resulting from a de novo pathogenic
variant or deletion. The risk to sibs of a proband is low, but higher than that
of the general population because of the possibility of parental germline
mosaicism. Once the PTHS-related genetic alteration has been identified in an
affected family member, prenatal testing for a pregnancy at increased risk and
preimplantation genetic diagnosis are possible.
Marangi G, Zollino M. Pitt-Hopkins Syndrome and Differential
Diagnosis: A Molecular and Clinical Challenge. J Pediatr Genet. 2015
Pitt-Hopkins syndrome is an emerging neurodevelopmental
disorder caused by haploinsufficiency of the TCF4 gene on chromosome 18q21. It
is characterized by severe intellectual disability, seizures, microcephaly,
constipation and a distinctive facial gestalt. Although the overlapping
phenotype of microcephaly, epilepsy, absent speech and constipation represents
a challenge for the differential diagnosis with Angelman syndrome, Rett
syndrome and Mowat-Wilson syndrome, distinctive of Pitt-Hopkins syndrome are breathing
abnormalities, that can occur as either hyperventilation episodes or apnea
crises, and a typical facial dysmorphism, including bitemporal narrowing,
squared forehead, deep-set eyes, peculiar nose conformation, with broad nasal
bridge, down-turned nasal tip and flaring nostrils, typical shape of the mouth,
with a tented and M shaped upper lip, and widely spaced teeth. The occurrence
of these signs in variable association of uncoordinated movements, microcephaly
of postnatal onset, eye abnormalities, constipation, epilepsy and subtle brain
abnormalities is highly predictive of a TCF4 mutation, making it possible to
plan a genetic test of choice among severe encephalopathies. Angelman syndrome
represents the nosological condition closest to Pitt-Hopkins syndrome.