ROHHAD Publications
FAQ
What is ROHHAD?
The syndrome known as ROHHAD stands for Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation. It is an ultra-rare autonomic and respiratory pediatric disorder with approximately 100 to 200 cases reported worldwide. ROHHAD syndrome typically presents unexpectedly in early childhood, generally between 1.5 and 7 years of age, after seemingly typical physical and mental development. The full phenotype is described as "unfolding" over time, often, though not always, emerging in the order of the acronym.
The acronym is often expanded to ROHHAD-NET because Neuro-Endocrine Tumours (NETs) are a common, late feature, reported in approximately 40–56% of patients. These tumors are typically ganglioneuromas or ganglioneuroblastomas, located along the sympathetic chain or in the adrenal gland. Other recognized characteristics include metabolic features (e.g., insulin resistance, impaired glucose tolerance, type 2 diabetes mellitus) and neuro-psychiatric/behavioral symptoms (e.g., aggression, irritability, anxiety).
The diagnosis of Rapid-Onset Obesity with Hypoventilation, Hypothalamic Dysfunction, and Autonomic Dysregulation (ROHHAD) is entirely clinical, as there are no definitive biomarkers, genetic tests, or confirmatory diagnostics. It requires recognition of a distinct pattern of symptoms and the exclusion of overlapping conditions. The acronym ROHHAD reflects its hallmark features, though their onset and sequence vary among patients.
Key diagnostic features include:
Rapid-Onset Obesity (R): Often the first sign, occurring between 1.5 and 7 years in previously healthy children, with rapid weight gain (typically 20–30 pounds within months). This is considered an early marker of hypothalamic dysfunction.
Hypothalamic Dysfunction (H): Diagnosed by the presence of at least one endocrine abnormality beyond obesity. Common features include hyperprolactinaemia (an early and consistent sign), central hypothyroidism, growth hormone deficiency, ACTH deficiency, disordered water balance (e.g., AVP deficiency), and abnormal puberty (delayed or precocious).
Central Hypoventilation (H): A life-threatening feature, typically emerging after age 2. It is driven by impaired autonomic control of breathing, starting with sleep-related hypoventilation (e.g., obstructive sleep apnoea), and may progress to daytime hypoventilation.
Autonomic Dysregulation (AD): Presents with variable symptoms such as temperature instability, altered sweating, cardiovascular abnormalities (e.g., bradycardia, arrhythmias), gastrointestinal issues, ophthalmologic signs (e.g., strabismus, ptosis), and reduced pain sensitivity.
Exclusion of other conditions is essential. CCHS must be ruled out via PHOX2B genetic testing, Prader–Willi Syndrome (PWS) should be excluded through genetic testing, and structural brain or pituitary anomalies must be evaluated with MRI.
How is ROHHAD diagnosed?
When was ROHHAD first described?
The condition that is now formally known as ROHHAD was first described in the literature in 1965. The disorder was initially described in a case report by Fishman et al.. They detailed the case of a 2.7-year-old boy who experienced dramatic weight gain (10.4 kg over nine months), hypoventilation, hypercarbia, and was diagnosed with diabetes insipidus. Fishman et al. named this child’s condition “primary alveolar hypoventilation syndrome (‘Ondine’s Curse’)”. In 2000, the disorder was subsequently described in a series of patients by Katz et al., who named this specific clinical disorder Late-Onset Central Hypoventilation with Hypothalamic Dysfunction (LO-CHS/HD). Katz et al. proposed that CCHS was likely distinct from the later-presenting patients who also had obesity and hypothalamic issues. In 2007, the acronym ROHHAD was officially introduced and proposed, along with diagnostic criteria, by Ize-Ludlow et al., to improve patient identification. This established the differentiation of ROHHAD from congenital central hypoventilation syndrome (CCHS) based on the absence of the PHOX2B gene mutation in ROHHAD patients. Finally, in 2008, the acronym was later expanded to ROHHAD-NET (ROHHAD neural crest tumor) by Bougnères et al. to include the risk of neural crest tumors (NETs), which are observed in about 40–50% of patients
What are the core features/ hallmarks of ROHHAD?
The diagnostic hallmarks of ROHHAD syndrome can be organized around four core features, often summarized by the acronym ROHHAD: rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation. The first and most recognizable sign is rapid-onset obesity, which typically emerges in early childhood between 1.5 and 7 years of age, with a median onset of 3.1 years. Previously healthy children may gain 20–30 pounds over a short period of 3–12 months, often accompanied by hyperphagia. This feature is considered the earliest marker of hypothalamic dysfunction.
Hypothalamic dysfunction usually follows, appearing months to years after obesity onset, most often between ages 4 and 8. For diagnosis, rapid-onset obesity must be accompanied by at least one additional feature of hypothalamic dysfunction. Common endocrinopathies include hyperprolactinemia, disorders of sodium and water balance such as central diabetes insipidus or hypernatremia, central hypothyroidism, growth hormone deficiency, and adrenal insufficiency. Pubertal disturbances are also frequent, ranging from advanced to delayed puberty or hypogonadotropic hypogonadism.
Hypoventilation represents a defining and life-threatening component of the syndrome, as it is the leading cause of death due to cardiorespiratory arrest. By definition, alveolar hypoventilation must appear after age two, with a median onset around 5.3 years—approximately two years after the onset of obesity. It often begins as obstructive sleep apnea and progresses to nocturnal central hypoventilation. This abnormal respiratory control reflects impaired autonomic regulation and an attenuated ventilatory response to hypoxia and hypercapnia.
Autonomic dysregulation symptoms typically emerge between ages 3 and 11. These disturbances can involve thermal instability with episodes of hypo- or hyperthermia, cardiovascular abnormalities such as bradycardia, arrhythmias, or syncope, gastrointestinal dysmotility including chronic constipation or diarrhea, altered pain perception with an elevated pain threshold, and ophthalmologic findings such as strabismus.
A frequent but not universal association is the development of neuroendocrine tumors (NETs). Between 40% and 56% of patients develop neural crest-derived tumors, most commonly benign ganglioneuromas or ganglioneuroblastomas. These tumors often appear early, with 70% detected within two years of the initial weight gain and a median age of occurrence of 4.75 years.
The cause of ROHHAD syndrome remains unknown despite extensive investigation. No specific diagnostic or genetic biomarkers have been identified, and its pathophysiology is still debated. Three main theories have been proposed, with a likely interplay between them: genetic/epigenetic, autoimmune and paraneoplastic, and neuro-anatomical.
Despite thorough genetic testing, no consistent monogenic cause has been found. Studies including whole exome sequencing, whole genome sequencing, and candidate gene analysis have not identified shared variants among ROHHAD patients. PHOX2B, which defines CCHS, and genes linked to respiratory control and hypothalamic function (e.g., BDNF, HCRT, ASCL1) have been ruled out. Given this, epigenetic mechanisms or somatic mosaicism, mutations present only in CNS cells, are being explored. This is supported by cases of monozygotic twins with discordant phenotypes and the frequent presence of neuroendocrine tumors, which may arise from neural crest-derived tissues.
There is mounting evidence that ROHHAD may have an immune-mediated or paraneoplastic origin. Anti-ZSCAN1 antibodies, detected in several patients both with and without associated neuroendocrine tumors, have emerged as a promising but still unvalidated diagnostic marker. Additional signs of central nervous system (CNS) inflammation—such as cerebrospinal fluid oligoclonal bands, anti-hypothalamic and anti-pituitary antibodies, and post-mortem findings of hypothalamic encephalitis—further support an autoimmune basis. The occurrence of ROHHAD-NET cases points to a potential paraneoplastic mechanism, in which tumors provoke immune responses that secondarily damage the CNS. However, the persistence of symptoms even after tumor resection underscores the complexity of the disease. Partial clinical improvement with immunomodulatory therapies such as rituximab, IVIG, and cyclophosphamide suggests that an underlying inflammatory process contributes to disease expression.
ROHHAD is thought to involve dysfunction within CNS regions critical for autonomic and respiratory regulation, particularly the hypothalamus and brainstem. Hypothalamic impairment accounts for rapid-onset obesity and a broad spectrum of endocrine disturbances, while autonomic dysregulation drives manifestations such as temperature instability, cardiovascular abnormalities, and altered energy balance. Central hypoventilation likely reflects blunted ventilatory responses and impaired perception of oxygen and carbon dioxide fluctuations. Neuroimaging and autopsy studies occasionally demonstrate inflammatory changes in these regions, but neuronal loss is not consistently observed. This pattern favors the interpretation of functional disruption over widespread structural destruction, highlighting the subtle yet profound pathophysiology of the disorder.
What is the current understanding of ROHHAD's unknown etiology and pathophysiology?
Published ARticles
"Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD): a collaborative review of the current understanding" by Khaytin et al. (2023)
This article provides a comprehensive overview of the discovery, clinical presentation, management, and ongoing international search for the cause of this ultra-rare, complex, and potentially devastating disorder. The acronym ROHHAD is intended to alert physicians to the usual sequence or unfolding of the full phenotypic presentation. ROHHAD is considered a neurocristopathy with fewer than 200 known cases nearly 60 years after its first description. The features typically unfold in a sequential manner, though variations occur. The etiology remains enigmatic. Current investigation focuses on two prevailing, non-mutually exclusive theories:
1. Genetic/Epigenetic Basis: Despite extensive efforts, including whole exome and whole genome sequencing of large cohorts, a monogenic (single gene) basis has not been identified. The observation of monozygotic twins discordant for ROHHAD suggests a possible epigenetic dysregulation or a somatic mosaic pathogenic genetic variant restricted to the CNS.
2. Paraneoplastic Autoimmune Basis: This hypothesis is supported by variable evidence of inflammation and onset in previously healthy children. Supporting evidence includes: the frequent presence of NCTs, Inflammatory markers in the CSF (such as oligoclonal bands (OCBs) and elevated neopterin), pathologic evidence of encephalitis involving the hypothalamus and brainstem in some post-mortem studies, and the recent identification of a promising antibody biomarker: Anti-ZSCAN1 autoantibodies. The ZSCAN1 protein is highly expressed in the pituitary gland, hypothalamus, and pons.
The underlying pathophysiology is linked to the disruption of function in neural crest-derived structures, including the hypothalamus (causing defects in energy metabolism and endocrine issues) and the Autonomic Nervous System (ANS), leading to central control issues for breathing, temperature, and cardiac function. The management of ROHHAD is challenging and supportive, necessitating a well-synchronized multidisciplinary team led by a pediatrician, including specialists in endocrinology, pulmonology, sleep/autonomic medicine, and oncology.
Diagnosis and Monitoring: Because the phenotype unfolds over time, objective physiologic monitoring must be repeated at regular intervals (e.g., every 2–3 months initially). This includes serial sleep studies, evaluation of awake physiologic recording, and endocrine bloodwork.
Respiratory Support: Hypoventilation requires aggressive intervention, frequently starting with Bi-level Positive Airway Pressure (BPAP) and often progressing to 24-hour artificial ventilation via tracheostomy, as it is life-support.
Tumor Screening: Children under age 7 must be monitored every 3–4 months for NETs using chest X-ray and abdominal ultrasound.
Research: Future efforts must focus on collaboration, including the ROHHAD International Consortium (ROHHAD IC) and international registries, to advance knowledge, establish objective diagnostic biomarkers (like ZSCAN1 antibodies), and find targeted treatments to decrease the disease burden and reverse the unfolding of the phenotype.
ROHHAD (Rapid-onset Obesity with Hypoventilation, Hypothalamic Dysfunction, Autonomic Dysregulation) Syndrome-What Every Pediatrician Should Know About the Etiopathogenesis, Diagnosis and Treatment: A Review by lazea et al. (2021)
This article provides a comprehensive overview of this ultra-rare pediatric disorder that has an unknown and debated etiology. The review emphasizes the importance for pediatricians to recognize this condition early to avoid complications, as it is associated with high morbidity and mortality rates (50–60%).
The etiology of ROHHAD syndrome is still obscure. Three main etiopathogenetic hypotheses have been formulated: genetic theory, epigenetic theory, immunologic theory
Diagnosis: The diagnosis is challenging due to the unknown etiology and the absence of specific laboratory findings or confirmatory genetic tests. It is based solely on the presence of the clinical markers (rapid-onset obesity, hypoventilation, hypothalamic dysfunction, and autonomic disturbances) and the exclusion of CCHS by the absence of the PHOX2B gene mutation. Sequential comprehensive evaluation by a multidisciplinary team (pediatrics, pulmonology, endocrinology, oncology, etc.) is essential.
Treatment: Therapeutic options are supportive and addressed to each clinical disturbance, involving a multidisciplinary team. Treatment includes strict caloric intake for obesity, specific hormone replacement for endocrine disorders, and artificial ventilation during sleep or continuous ventilatory support to prevent sudden death from hypoventilation. Neural crest tumors require surgical removal. Careful monitoring of these children is essential to limit morbidity and mortality.
Full article: ROHHAD (Rapid-onset Obesity with Hypoventilation, Hypothalamic Dysfunction, Autonomic Dysregulation) Syndrome-What Every Pediatrician Should Know About the Etiopathogenesis, Diagnosis and Treatment: A Review-Web of Science Core Collection
ROHHAD(NET) Syndrome: Systematic Review of the Clinical Timeline and Recommendations for Diagnosis and Prognosis by harvengt et al. (2020)
This article is a systematic review of published case reports, supplemented by a new patient case, conducted to establish a comprehensive clinical timeline for the symptoms of this rare and potentially fatal disease. The systematic analysis reviewed literature published since 2007, and collected individual data from 43 patients who met the clinical criteria for ROHHAD syndrome (defined as rapid-onset obesity + central hypoventilation + at least one other sign of hypothalamic dysfunction). The analysis established a detailed median timeline for the unfolding of the syndrome (right). They propose detailed guidance for diagnosis and multidisciplinary follow-up in the absence of reliable biomarkers. Key recommendations include:
1. Early Suspicion: ROHHAD should be considered for any child presenting with rapid and early obesity.
2. Hypoventilation Screening: Polysomnography should be performed annually for a minimum of 5 years in cases of high suspicion, as central hypoventilation was diagnosed in 83% of patients within the first 5 years of obesity onset.
3. NET Surveillance: Due to the early detection window for tumors, annual screening is recommended, with alternating use of chest/abdominal MRI and 123I-MIBG scintigraphy every 6 months during the first 2 years after the onset of rapid weight gain
Additional articles
The Enigma That Is ROHHAD Syndrome: Challenges and Future Strategies-Web of Science Core Collection