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.