Rapid‐onset Obesity with Hypothalamic Dysfunction, Hypoventilation and Autonomic Dysregulation (ROHHAD), is a severe pediatric disorder of uncertain etiology resulting in hypothalamic dysfunction and frequent sudden death. Frequent co‐occurrence of neuroblastic tumors have fueled suspicion of an autoimmune paraneoplastic neurological syndrome (PNS); however, specific anti‐neural autoantibodies, a hallmark of PNS, have not been identified. Our objective is to determine if an autoimmune paraneoplastic etiology underlies ROHHAD.

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ZSCAN1 Autoantibodies Are Associated with Pediatric Paraneoplastic ROHHAD

Chronic intermittent hypoxia aggravates skeletal muscle aging by down-regulating Klc1/grx1 expression via Wnt/β-catenin pathway.

Rapid-onset Obesity with Hypoventilation, Hypothalamic Dysfunction and Autonomic Dysregulation is a rare and complex pediatric syndrome with unknown etiology. The disease hallmark is sudden and severe obesity in early childhood, with a later onset of central hypoventilation, responsible for high mortality. We present the case of a 2.5-year-old boy with sudden weight gain starting after 12 months of age (18 kg in a year) and hypoventilation in the setting of acute nasopharyngitis, requiring Non-Invasive Ventilation (NIV) initiation. Additionally, he presented symptoms and signs of autonomic disturbance, neurodevelopmental delay and behavior disorders. High prolactin, leptin and insulin were also present. Despite periodic adjustment of settings and adherence to NIV and great efforts to control food intake, he remained morbidly obese and died during an infectious intercurrence at 6 years of age. This case illustrates the challenging diagnosis and treatment/management of this rare syndrome, which can have a variable and not always complete presentation and has no specific diagnostic test available. Identifying hypoventilation and NIV treatment is essential to decrease morbimortality. However, most patients do not live past ten years old.

A rare and challenging case of ROHHAD (Rapid-onset Obesity with Hypoventilation, Hypothalamic Dysfunction, Autonomic Dysregulation) syndrome

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare pediatric disorder with hypoventilation and a high mortality risk. Diagnosis is made clinically and her significant overlap between other clinical and genetic disorders. This article will describe and define ROHHAD, discuss key clinical features, and differentiate it from other disorders. 

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD)

ROHHAD (Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation and Autonomic Dysregulation) is a rare, yet severe pediatric disorder resulting in hypothalamic dysfunction and frequent sudden death. Genetic and other investigations have failed to identify an etiology or diagnostic test. Frequent co-occurrence of neuroblastic tumors (NTs) and cerebrospinal fluid inflammation point to an autoimmune paraneoplastic neurological syndrome (PNS); however, specific anti-neural autoantibodies, a hallmark of PNS, have not been identified. Here, we screened antibodies from a curated cohort of ROHHAD patients (n=9) and controls (n=150) using a programmable phage display of the human peptidome (PhIP-Seq). Our ROHHAD cohort exhibited frequent association with NTs (8/9) and features consistent with autoimmune etiology. Autoantibodies to Zinc finger and SCAN domain-containing protein 1 (ZSCAN1) were discovered and orthogonally validated in 7 of 9 ROHHAD patients, all of whom had NTs, and shown to be absent in non-ROHHAD pediatric patients with NTs. Notably, human ZSCAN1 expression was confirmed in ROHHAD tumor and healthy human hypothalamus. Our results support the notion that tumor-associated ROHHAD is a pediatric PNS, potentially initiated by an immune response to peripheral NT. ZSCAN1 autoantibodies may aid in an accurate diagnosis of ROHHAD, thus providing a means toward early detection and treatment. Lastly, given the absence of the ZSCAN1 gene in rodents, our study highlights the value of human-based approaches in addition to the classical rodent-based approaches for detecting novel PNS subtypes.

https://medrxiv.org/content/10.1101/2021.06.04.21257478v1.full.pdf

Autoimmune profiling suggests paraneoplastic etiology in pediatric ROHHAD

Objective To characterize the clinical presentation of sleep-disordered breathing and respiratory patterns at rest and during a 6-minute walk test (6MWT) in children with rapid-onset obesity, hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD) syndrome. Methods Retrospective study of children with ROHHAD who had a diagnostic baseline polysomnography, daytime cardiorespiratory monitoring at rest and a 6MWT. Polysomnography data were also compared with BMI-, age- and sex-matched controls. Results Of the 8 children with ROHHAD, all 8 (100%) had obstructive sleep apnea (OSA) and 2/8 (25%) had nocturnal hypoventilation on their baseline polysomnography. Comparing the ROHHAD group to the control group, there were no significant differences in the median [IQR] obstructive apnea-hypopnea index (OAHI) (11.1 [4.3-58.4] vs 14.4 [10.3-23.3] events/hour, respectively; p=0.78). However, children with ROHHAD showed a significantly higher desaturation index compared to the control group (37.9 [13.7-59.8] vs 14.7 [4.3-27.6] events/hour; p=0.05). While awake at rest, some children with ROHHAD experienced significant desaturations associated with central pauses. During the 6MWT, no significant desaturations were observed, but two children showed moderate functional limitation. Conclusions Among children with ROHHAD, respiratory instability may be demonstrated by a significant number and severity of oxygen desaturations during sleep in the presence of OSA, with or without nocturnal hypoventilation, and oxygen desaturations with central pauses at rest during wakefulness. Interestingly, during daily activities that require submaximal effort, children may not experience oxygen desaturations. Early recognition of respiratory abnormalities and targeted therapeutic interventions are important to limit associated morbidity and mortality in ROHHAD. This article is protected by copyright. All rights reserved.

Sleep‐Disordered Breathing, Respiratory Patterns during Wakefulness and Functional Capacity in Pediatric Patients with Rapid‐Onset Obesity with Hypothalamic Dysfunction, Hypoventilation and Autonomic Dysregulation (ROHHAD) Syndrome

Ann Yeh

Papers

Sleep‐Disordered Breathing, Respiratory Patterns during Wakefulness and Functional Capacity in Pediatric Patients with Rapid‐Onset Obesity with Hypothalamic Dysfunction, Hypoventilation and Autonomic Dysregulation (ROHHAD) Syndrome