Discussion
In recent years, advancement in genetic science has solved many
‘atypical’ cases with no definite diagnosis. Defining the phenotype
allows physicians to actively screen for associated medical problems and
help with prognostication. Having a genetic diagnosis also helps with
future family planning .
HIDEA syndrome is a rare and novel autosomal recessive condition. It is
characterized by hypotonia, hypoventilation, intellectual disability,
dysautonomia, epilepsy, and eye abnormalities. Clinical presentation of
HIDEA syndrome may overlap with other genetic syndromes such as
Prader-Willi syndrome, Down syndrome and rapid onset obesity,
hypoventilation with autonomic dysfunction (ROHHAD syndrome) .
The first link between P4HTM and a human phenotype was described in 2014
in a large Finnish family where six family members had hypotonia,
profound intellectual disability, strabismus and coarse facial features
. In 2019, another 7 patients were reported with HIDEA syndrome with an
update of the previously reported 6 patients. 77% (N=10/13) were noted
to have epilepsy and 62% (N=6/13) were noted to have obstructive sleep
apnea. 69% (N=9/13) of patients had pneumonia or recurrent pneumonias.
The patients were also noted to have dysautonomia including constipation
(46%, N=6/13), hypothermia or hyperthermia and reduced sweating. 46%
(N=6/13) had a body mass index of more than 25 kg/m2.
In the reported literature of 21 patients presenting with HIDEA syndrome
so far, the clinical picture is usually associated with moderate to
severe neonatal hypotonia, central hypoventilation, severe to profound
intellectual disability, dysautonomia including constipation and thermal
dysregulation, high incidence of seizures (48%), and abnormal visual
behavior including roving or rotatory eye movements. There does not seem
to be any characteristic structural brain or structural eye
abnormalities. Brain magnetic resonance imaging were normal in most
patients 50% (9/18) of those who survived beyond infancy learned how to
walk. 44 % (8/18) never developed speech . 17 % (3/18) died in infancy
from respiratory tract infections, and 17% (3/18) died during childhood
from febrile respiratory illness. The oldest reported patient died at 61
from acute pneumonia . One other patient was also reported to have
hypothyroidism like the patient we report.
Out of the 21 reported patients with HIDEA syndrome (Table 1), 33%
(6/18) had obstructive sleep apnea. 58% (11/19) were reported to have
hypoventilation of which six had formal sleep studies and were confirmed
to have central hypoventilation. This is unlike peripheral
hypoventilation seen in patients with underlying neuromuscular disease
Amongst the initial 13 patients that were reported, 38% (5/13) required
nocturnal BiPAP, 7% (1/13) required BiPAP support throughout the day
and 7% (1/13) required high frequency nasal cannula support. Our
patient was similar with mixed central and obstructive apnea seen on
polysomnography and he also required BiPAP support throughout the day.
Table 1 summarizes the clinical features of patients with HIDEA syndrome
including our patient for comparison.
Prolyl 4-hydroxylases (P4Hs) are important enzymes in the synthesis of
collagen and the control of oxygen homeostasis. Two groups of P4Hs are
recognized: those that hydroxylate proline resides in collagen and those
that hydroxylase proline resides in hypoxia inducible factors (HIFs).
Endoplasmic reticulum transmembrane prolyl-4-hydroxylase (P4HTM ),
encoded by the P4HTM gene, is a special P4H localized to the
endoplasmic reticulum membrane, with the highest expression in the brain
and eye. The genetic defect leads to premature stop codons or affect
protein folding yielding an insoluble protein product that results in
the clinical characteristics of the syndrome. P4HTM deficiency is
postulated to be a mitochondrial disorder although the precise molecular
mechanisms leading to mitochondrial dysfunction remains unknown.
Abnormal HIF-1α levels have been reported in primary genetic
mitochondrial disease. Other possible targets for P4HTM include
the large subunit of RNA polymerase II and activating transcription
factor 4 (ATF4) of all nuclear-encoded mRNAs. Impaired function of RNA
polymerase II may affect mitochondrial function. These abnormalities
could explain the mitochondrial dysfunction observed in patients with
HIDEA syndrome.
Our case is a second reported premature infant to be diagnosed with
HIDEA syndrome. The first was an infant born at 32 weeks of gestation
with a low birth weight of 1.9 kg. He had persistent feeding
difficulties and was subsequently diagnosed with hypothyroidism at 1
month old. In view of his poor weight gain, he was started on
nasogastric tube feeding at 8 months old and was admitted to the
Pediatric Intensive Care Unit at 12 months old with frequent apneas
during an episode of bronchiolitis. He was also noted to have global
developmental delay with marked hypotonia. During his admission, he
developed oxygen dependence related to hypoventilation and bradypnea. He
subsequently required gastrostomy with fundoplication for severe
gastro-esophageal reflux. He also had spinal dural arteriovenous
fistula, mild hepatomegaly and left grade 2 hydronephrosis. His EEG had
evidence of focal seizures although he did not manifest any clinically .
Our patient is the first South East Asian patient to be formally
diagnosed with HIDEA syndrome. We postulate that infants with HIDEA
syndrome may have an increased risk of preterm birth and congenital
hypothyroidism and possibly even pyloric stenosis. Unlike other cases
reported in literature, this infant’s autonomic dysfunction manifested
as significant bradycardia since birth as well.
Thus, in consideration of the underlying etiology when faced with a
neonate with central hypoventilation, consideration should be made for
HIDEA syndrome as one of the differential diagnoses, especially when
hypoventilation is associated with neonatal hypotonia. While no
treatment exists for the intellectual disability and developmental
delay, establishing the clinical diagnosis can impact management of
hypoventilation, feeding issues and dysautonomia . Infant should undergo
a thorough evaluation including bloods investigations to rule of an
underlying neuromuscular disease, genetic syndrome, and mitochondrial
disease. Once diagnosed an infant should undergo polysomnography and
thyroid function tests. Early diagnosis of central hypoventilation will
allow for possible early tracheostomy which will help to protect the
airway especially as infants with HIDEA syndrome are prone to
significant bradypnea which may be more pronounced during intercurrent
respiratory tract infections which may result in significant morbidity
and mortality. Looking at the current available literature and comparing
the phenotypes reported to our case, our patient seems to have a severe
form of HIDEA syndrome requiring such high ventilator support at a young
age and thus, prognosis is guarded.