ROHHAD syndrome and evolution of sleep disordered breathing

ROHHAD is a rare and fatal disease with a mortality rate of up to 50 to 60 % due to cardiorespiratory arrest. The diagnosis of ROHHAD can be extremely challenging as there is no single confirmatory diagnostic test, but the early recognition and intervention of this syndrome may minimize mortality [2, 9]. This study focused on SDB in children with ROHHAD syndrome, to ascertain how many children had NH at presentation, given that NH is defined as a cardinal feature of ROHHAD. This is important as excluding a diagnosis of ROHHAD of due to a lack of evidence of NH may result in catastrophic consequences.

In our study, only 2/6 patients had NH with it at baseline in our series. OSA was the most common SDB at presentation. Even though OSA has been documented in ROHHAD syndrome it’s not included in the diagnostic criteria. However, in our study, OSA was the initial presentation in regards of SDB. There was evidence of NH in all our patients but only over time. Moreover, we found that of the children studied, there was evidence for abnormal control of breathing during wakefulness with central pauses in breathing and associated oxygen desaturations.

Rapid onset obesity, a major presenting feature of ROHHAD syndrome was documented in all our children at a median age of 3.5 years, with one child presenting beyond 9 years of age, similar to other reported studies [2, 3, 7, 10]. The median age of onset of NH in our study was 7.2 years (range 5.3–14.7 years). In the largest case series thus far, Ize Ludlow and colleagues [2] report on the respiratory manifestations of 15 ROHHAD patients. All 15 patients had evidence for NH and 8/15 (53 %) had co-existent OSA and 4/15 (27 %) had cyanotic episodes. However, whether NH was present at diagnosis or evolved over time was not described. Alarmingly 9/15 (60 %) patients were reported to have had a cardiorespiratory arrest, much higher than in the current study (1/6, 17 %). Similarly in another case series of 13 patients with suspected ROHHAD, all 13 patients were reported as having NH and it is unclear if they had other pre-existing sleep related respiratory disorders [4].

The aforementioned case series and additional case reports offer a great deal of insight into the respiratory manifestations of ROHHAD syndrome [2, 5, 10–12].

Although NH is a definitive criteria of ROHHAD, children who fit all diagnostic criteria except NH in an overnight PSG need vigilant follow up with serial PSGs as NH may develop over time. As such, it is important to recognize that other sleep disorders may be associated with ROHHAD prior to catastrophic respiratory events.

Additional findings in our study showed evidence for hypoxemia during wakefulness, characterized in our study to be related to central pauses which may be an indicator of worse respiratory morbidity. Indeed, blunted chemosensory responses such as abnormal respiratory response to hypercapnia has been previously described in children with ROHHAD which may account for our observations [6]. These observations may be critically important in the context that other authors have suggested that early intervention with nocturnal artificial ventilation may improve daytime ventilation [13].

In our study 2/6 (33.3 %) patients were diagnosed with AH and treated with nocturnal Bi-level ventilation after the initial PSG. However, prior to a follow up PSG, one patient died following a cardiorespiratory arrest. The remaining 5/6 patients all required Bi-Level ventilation with 2/6 requiring supplemental oxygen during the day. In contrast to other studies, no patient required either invasive nor full time ventilatory support [2, 4, 5]. However, a child with significant daytime ventilatory abnormalities not controlled with oxygen therapy coupled with NH would likely require a tracheostomy and invasive ventilation but no patient in our series fit this criteria. Serial PSGs and repeated daytime monitoring will be necessary to ensure these patients are stable with their current ventilatory support. Interestingly, in a recent review of 51 cases of ROHHAD syndrome, 69 % required artificial ventilation via tracheostomy with 31 % requiring 24 h support which concur with data from other published case series [5]. The high incidence of invasive ventilation among those ROHHAD patients compared with our study may be related to more severe phenotype of ROHHAD associated with significant NH at a young age (mean age of invasive ventilation was 3.8 years). Furthermore, differences in clinical practice and use of Bi-level ventilation versus ventilation via a tracheostomy between countries could account for some of the variations observed in the mode of ventilation. Similar to the other published data, cardiorespiratory arrest is a manifestation of ROHHAD and one child in our study died from a sudden event [2–4].

The strength of our study was the inclusion of children with baseline PSGs before they were diagnosed with ROHHAD syndrome’. The limitations of our study include the retrospective design, lack of standardization with regards to timing of follow up PSG monitoring and the lack of a control group of similarly obese children to compare effects of a change in BMI that may have contributed to associated obesity-associated hypoventilation. Given the rarity of this condition, an additional, substantial limitation of our study, is the small number of patients included. Further, the daytime physiological monitoring could be performed only in 3/6 patients as 1 died and 2 were refused by the parents. Finally, we did not have pulmonary function tests on our patients to further explain abnormal gas exchange observed nocturnally. A larger multi centered study with children suspected of having ROHHAD is needed to confirm the findings of our study.

In summary, we have shown that children with suspected ROHHAD syndrome may not have NH at presentation but may only have evidence of mild OSA on their PSG. The absence of NH at presentation does not exclude ROHHAD, as NH may develop over time and thus only be evident with serial PSGs. Furthermore, we found evidence of abnormal breathing patterns during wakefulness with associated hypoxemia. Based on these findings, the authors would advocate for close and serial monitoring with PSGs of all children with suspected ROHHAD including daytime monitoring of cardiopulmonary variables once NH is evident. Importantly, the recognition of the spectrum of respiratory abnormalities associated with suspected ROHHAD syndrome at presentation and over time may be important in raising the index of suspicion for ROHHAD condition, and predispose to targeted interventions to limit associated morbidity and mortality.