Article Type : Case Report
Authors : Stathos J, Pecson I, Galvis AE, Saqueton C, Holly A, Nakamura C
Keywords : Pitt-Hopkins Syndrome; Brain imaging
Pitt-Hopkins Syndrome (PTHS) is an unusual
and rare genetic disorder caused by inadequate translation of the TCF4 gene,
which initiates embryologic neuronal differentiation. The hallmarks of the
disease include motor delays, absent speech, autism spectrum disorder (ASD),
and intellectual disability. In addition to the cognitive delays, PTHS can be
evidenced somatically with atypical brain imaging, abnormal facial features,
and severe medical comorbidities including irregular breathing episodes.
Generally, there are periods of alternating hyperventilation and apnea
occurring while awake. The cause of these spells is unknown at this time.
Treatment with acetazolamide has been shown to usually be effective in
preventing these episodes. We present a case of a 9-year-old female with
suspected PTHS admitted to the Pediatric Intensive Care Unit (PICU) for
hyperventilation with severe, debilitating apneic events that were unresponsive
to acetazolamide.
Pitt-Hopkins Syndrome
(PTHS) is an extremely rare neurodevelopmental disorder that is caused by a
variant of the TCF4 gene, located on chromosome 18q21.2. This gene is involved
in embryologic neuronal differentiation. The syndrome was originally described in
1978 with abnormal facial features, intellectual delay, and irregular breathing
patterns. It can also present with seizure disorder and severe constipation.
The exact prevalence of this disease is not known, but there have only been
approximately 500 confirmed cases worldwide [1-3]. Currently, there is no cure
for the disease, and treatment is focused on preventative and symptomatic care.
Due to the rarity of the disease, common sequela resulting in hospitalization
and additional care is lacking. However, it stands to reason that the most
common reasons would be based on the severity of their constipation, seizures,
and/or respiratory patterns. Although the etiology is unknown, treatments for
constipation and epilepsy are often effective in the PTHS population [1,4]. An
important, and fairly unique, feature of PTHS are the abnormal breathing
spells, the exact mechanism is still under investigation. Approximately 50% of
all patients with PTHS exhibit a paroxysmal breathing pattern of
hyperventilation with or without resulting apnea. It has been described as
rapid breathing with a period of breath-holding afterwards, which could be
either psychogenic or physiologic in nature. This period of apnea can be long
enough to induce cyanosis [1,5-6]. Generally, acetazolamide has been used to
treat these spells, but the mechanism for its effectiveness is hypothetical in
nature [5-6]. Caffeine has been long used to reduce apneic actions in the
pediatric population, generally in cases of apnea of prematurity. As a methylxanthine,
its mechanism of action is well defined. It acts both centrally and
peripherally to stimulate the medullary respiratory centre, and thus increase
carbon dioxide sensitivity, reducing hypoxic respiratory depression [7-8]. Due
to this effect, caffeine can theoretically be used to reduce other types of
apnea besides apnea of prematurity.
A
9-year-old female with a history of developmental delay and seizure disorder
initially presented to the emergency department (ED) with multiple breakthrough
seizures. On the day prior to admission, she was in her regular state of health
until her parents noticed she was having more seizures than normal and
exhibiting unusual type of activity. When she was brought to the ED, she had
several more seizures with desaturations (oxygen saturation dropping into the
30-50% range) and associated cyanosis. These episodes were neither extensive
nor lasting any longer than 15 seconds, but frequent enough to require the
patient to be admitted to the PICU. Despite of these changes in her clinical
status, all of her labs were grossly unremarkable. She remained afebrile and
had no indications of infection. Her anti-epileptic medication was increased
resulting in reduction of seizure activity. The patient was initially placed on
high flow nasal cannula, but was rapidly weaned to room air. She continued to
have intermittent episodes of hyperventilation followed closely by apneic
events, causing desaturations and cyanosis. She was started on acetazolamide,
but with minimal change to her breathing patterns. The patient then underwent a
polysomnogram, which was performed while she was awake. It revealed significant
hyperventilation followed by central hypopneas (30 episodes, the longest
lasting 38 seconds) and the lowest recorded oxygen saturation of 37%. Due to
the patient’s lack of response to acetazolamide, she was started on caffeine
and exhibited rapid improvement. She had a 24-hour period where there were no
desaturations. She was discharged with oral caffeine and a pulse oximeter for
home monitoring.
pths is an unusual and
rare genetic disorder caused by inadequate translation of the tcf4 gene. The
hallmarks of the disease include motor delays, absent speech, autism spectrum
disorder, and intellectual disability. In addition to the cognitive delays,
pths can be evidenced somatically with atypical brain imaging, abnormal facial
features, and severe medical comorbidities including irregular breathing
spells. Generally, there are episodes of hyperventilation and associated
variable apnea occurring while awake. The cause of these spells is unknown at
this time. Treatment with acetazolamide has been shown to usually be effective
in preventing the episodes. Caffeine has been given for apneic episodes in
neonates for a significant amount of time, leading to understanding of its side
effects. However, it is not commonly used in older pediatric populations [7-8].
Although the exact mechanism for pths-based apnea is still under investigation,
it seems clear that the hyperventilation prior to the apneic episodes induces a
hypocapnic state in patients. In similar fashion to shallow water blackouts,
this allows the patient to metabolize through their store of oxygen without a
significant respiratory drive [9]. Due to caffeine increasing the sensitivity
of chemoreceptors to carbon dioxide, patients with hyperventilation-based
apneas cannot achieve such hypoxic states as easily. The diagnosis of pths was
subsequently confirmed. The application of caffeine for different types of
apnea needs additional research. However, the use of caffeine in patients with
pths and apnea should be considered, especially if it is refractory to other
treatment modalities.