van Engelen N, van Santen H M, van Dijk F, Kleisman M M, Merks J H M, Schouten-van Meeteren A Y N, Kamping E J, Neveling K, Hoischen A, Jongmans M C J, Kuiper R P
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
Department of Pediatric Endocrinology, Wilhelmina Children's Hospital, Utrecht, The Netherlands.
Orphanet J Rare Dis. 2025 Aug 7;20(1):412. doi: 10.1186/s13023-025-03938-3.
Rapid-onset obesity, hypothalamic dysfunction, hypoventilation, autonomic dysregulation (ROHHAD) and neuroendocrine tumor (NET) is a very rare condition with an unknown etiology. While various potential causes have been hypothesized, including genetic and paraneoplastic autoimmune mechanisms, no definitive cause has been identified to date. This study aimed to explore whether patients with ROHHAD-NET share an underlying heritable genetic etiology.
We identified five female patients clinically suspected of having ROHHAD(-NET); among them in two patients a NET was found: a ganglioneuroma and a low grade cerebellar ganglion cell tumor with BRAF mutation. To identify potential pathogenic germline genomic variants, whole genome sequencing (WGS) was performed on germline DNA from all five patients, including four patient-parent trios. Furthermore, optical genome mapping (OGM) was performed for two patients to detect germline structural variants (SVs). Rare single nucleotide variants (SNVs) and small insertions/deletions (InDels) were identified through WGS and rare SVs affecting (non)-coding or regulatory regions were analyzed using both WGS and OGM. We explored a de novo, inherited autosomal dominant and autosomal recessive inheritance scenario. However, no candidate variants in a recurrently affected gene locus or genomic region were identified in two or more patients.
Our comprehensive genome-wide data analysis did not reveal evidence of a monogenetic cause for ROHHAD-NET. Whereas these findings do not exclude a genetic etiology for ROHHAD-NET, they strengthen the hypothesis of an autoimmune origin for symptoms of ROHHAD.
快速发作性肥胖、下丘脑功能障碍、通气不足、自主神经调节异常（ROHHAD）和神经内分泌肿瘤（NET）是一种病因不明的非常罕见的病症。虽然已经提出了各种潜在原因，包括遗传和副肿瘤性自身免疫机制，但迄今为止尚未确定明确的病因。本研究旨在探讨ROHHAD-NET患者是否存在潜在的可遗传基因病因。
我们确定了5名临床疑似患有ROHHAD（-NET）的女性患者；其中2名患者发现患有NET：1例神经节神经瘤和1例具有BRAF突变的低级别小脑神经节细胞瘤。为了鉴定潜在的致病性种系基因组变异，对所有5名患者的种系DNA进行了全基因组测序（WGS），包括4个患者-父母三联体。此外，对2名患者进行了光学基因组图谱分析（OGM）以检测种系结构变异（SV）。通过WGS鉴定了罕见的单核苷酸变异（SNV）和小插入/缺失（InDel），并使用WGS和OGM分析了影响（非）编码或调控区域的罕见SV。我们探讨了新发、常染色体显性遗传和常染色体隐性遗传的情况。然而，在两名或更多患者中未在反复受累的基因座或基因组区域中鉴定出候选变异。
我们全面的全基因组数据分析未发现ROHHAD-NET单基因病因的证据。虽然这些发现不排除ROHHAD-NET的遗传病因，但它们强化了ROHHAD症状自身免疫起源的假说。
