Autoimmune profiling suggests paraneoplastic etiology in pediatric ROHHAD

Abstract

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.

ROHHAD syndrome spectrum in an adult: a possible new variant

“…PHOX2B mutations are absent similarly with other candidate genes like ASCL I, BDNF or HCRT [9], while partial response in some manifestations of hypothalamic disfunction has been achieved with immunoglobulins [10] and investigators have described an intrathecal synthesis of oligoclonal bands after CSF analysis [11], immune-cell infiltrates in the brain [12] and MRI signs of focal inflammation in the periaqueductal gray matter and hypothalamus [13]. Recently, Mandel-Brehm et al [14] have confirmed presence of autoantibodies to Zinc finger and SCAN domain-containing protein 1 (ZSCAN1) in 7 of 9 pediatric patients with tumor-associated ROHHAD. In our case, a complete panel for immune-mediated encephalitis was negative and immunoglobulins produced imperceptible results.…”