ROHHAD Syndrome

Pregnancy, birth, neonatal period, and infancy are generally uneventful; the onset of symptoms of ROHHAD syndrome doesn't usually occur before the age of 2-4 years [1] [2]. At this age, pediatric patients present with acute-onset, rapidly progressive obesity. At the same time, their growth velocity rate decreases, which may eventually lead to the diagnosis of short stature [3].

Patients soon develop additional symptoms consistent with endocrine dysregulation, dysfunction of the autonomic nervous system, behavioral disorders, and respiratory depression [1] [2]:

• The patients' median age at the onset of obesity is 3 years. In ROHHAD syndrome, it is induced by hyperphagia, an early symptom of hypothalamic dysfunction. The body weight of affected children may increase by more than 10 kg in less than half a year.
• Additional symptoms of hypothalamic dysfunction and autonomic dysregulation tend to manifest a few months later. Endocrine alterations comprise, but are not limited to, electrolyte and water imbalances resulting in polyuria/polydipsia, hypothyroidism and thermal dysregulation, growth hormone deficiency, hyperprolactinemia, and precocious or delayed puberty. Common symptoms of dysautonomia are pupillary anomalies and strabismus, constipation, chronic diarrhea, and hyposensitivity to pain. Additionally, autonomic dysregulation predisposes to tumors of neural crest origin. Ganglioneuroblastoma and ganglioneuroma have most frequently been diagnosed in affected children. These tumors preferentially develop in the adrenal glands [3].
• Abnormal behavior results from depression, psychosis, flat affect, and other mental disorders.
• Years may pass after the onset of hypothalamic and autonomic dysfunction until respiratory disorders become evident. In this regard, obstructive sleep apnea usually precedes central alveolar hypoventilation. Affected children may experience cyanotic episodes or suffer a cardiorespiratory arrest.

It should be noted that the order of the onset of symptoms described herein applies to only 80% of patients. In the remainder of cases, rapid-onset obesity develops later in the course of the disease [2].

Anamnestic data and the child's medical history are essential for the diagnosis of ROHHAD syndrome. There are no confirmatory tests, so the diagnosis must be based on clinical findings obtained over the year-long course of the disease. However, owing to the rarity of ROHHAD syndrome, awareness is low, and the majority of patients is initially misdiagnosed with endocrine disorders. Such errors are not usually rectified before respiratory depression manifests: Despite the rather late onset of hypoventilation, this symptom is the most common cause of referral for further diagnostics, of extending the list of differential diagnoses [2] [3]. Besides ROHHAD syndrome, one of the disorders to be found on that list is late-onset congenital central hypoventilation syndrome [4]. There is a considerable clinical overlap between both entities, but late-onset congenital central hypoventilation syndrome has been related to mutations of the PHOX2B gene, so genetic studies may be carried out to rule out the latter [5]. Structural anomalies of the brain may be ruled out after brain imaging, but non-specific abnormal findings in magnetic resonance imaging are not uncommon in ROHHAD patients [2].

Beyond that, the following diagnostic tools should be employed to assess the degree of severity of obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation, point by point [2]:

• Measurement of height and weight, calculation of body mass index
• Evaluation of the hypothalamic-pituitary axis and the secretion of antidiuretic hormone, possibly by realizing biochemical analyses of blood samples, water deprivation tests, stimulation and suppression tests
• Respiratory physiological assessment during wakefulness and sleep
• Computed tomography or magnetic resonance imaging of the thorax and abdomen to visualize neural crest tumors [3]

Tissue samples may be obtained from tumors of neural crest origin, either by biopsy or during their surgical removal. The histological examination of such samples generally confirms the absence of mitotic activity, nuclear atypia, inflammatory infiltrates and necrotic foci [3].

Causal treatment is not available, and ROHHAD syndrome is currently considered non-curable. However, immunomodulatory therapies have resulted in clinical improvements. In this context, immunoglobulins, cyclophosphamide, and rituximab have been administered to affected individuals, as well as steroids and mycophenolate [6] [7].

Otherwise, a multidisciplinary approach is required to address the complaints of individual patients and to provide symptomatic relief. The primary goals of symptomatic ROHHAD therapy are to ensure adequate ventilation during wakefulness and sleep, and to avoid metabolic decompensation. With regard to the former, the majority of ROHHAD patients becomes dependent on artificial ventilation during childhood. In some cases, ventilation during sleep may be sufficient [2]. The results of blood sample analyses and endocrinological tests have to be evaluated before starting hormone replacement therapy or administering other drugs to counter the consequences of ROHHAD syndrome. Furthermore, body weight reduction may occasionally be achieved by means of strict diets and exercise programs, but the patients' compliance is vital to the success of this measure [2]. In other cases, patients continue to gain weight despite caloric restrictions [8].

Affected children should undergo quarterly follow-ups to monitor the course of the disease and to recognize changes in their ventilation demand and endocrinological state. Additionally, thoracic and abdominal imaging should be repeated each year to assure an early diagnosis of possibly developing tumors of neural crest origin [2]. If tumors are detected, their surgical removal should be considered. Other therapies are not usually required to treat ROHHAD-associated neoplasms [9].

Despite the extent of deficiencies in regulatory circuits and feedback loops, ROHHAD is rarely fatal. One of the patients described by Ize-Ludlow et al. had reached adulthood at the time of the study [2]. Furthermore, most ROHHAD patients experience normal mental development and are able to achieve certain degrees of independence in their daily life [1]. On the other hand, it should be noted that alveolar hypoventilation and cardiorespiratory arrest as well as metabolic decompensation may lead to sudden death [3] [9]. Indeed, the severity of respiratory depression seems to be the most important prognostic factor for long-term survival [1].

The etiology and pathogenesis of ROHHAD syndrome remain unknown. It has been speculated that autoimmune processes underlie the disease, but it has not yet been possible to associate ROHHAD with the presence of specific autoantibodies. Similarly, it has been hypothesized that ROHHAD patients suffer the consequences of impaired neuronal development. This hypothesis is based on the fact that mutations of the PHOX2B gene cause central hypoventilation syndrome, which in its late-onset congenital form largely resembles ROHHAD syndrome [4]. Recurrence in siblings has been reported and supports the hypothesis of a genetic component in ROHHAD development [9].

ROHHAD syndrome is a rare entity, and less than 100 cases have been described to date [1]. Both boys and girls may be affected. The patients' median age at symptom onset is 3 years, but the disease may manifest at any time during the first decade of life [2].

It is beyond the scope of this article to give a detailed description of the diversity of neurons in the hypothalamic and peripheral neuroendocrine system, but it shall be stated that the respective cell populations differ with regards to their development, gene expression, and antigenic characteristics. For instance, there are two neurosecretory systems involved in hypothalamic hormone secretion, namely the magnocellular and parvocellular systems. The magnocellular system consists of specialized large neurons, the hypothalamo-neurohypophysial tract, and the neurohypophysis. Its main products are antidiuretic hormone and oxytocin. The parvocellular system is composed of smaller neurons that produce hypophysiotropic hormones [10].

On the other, the clinical presentation of ROHHAD patients is very heterogeneous and patients may present with symptoms attributable to deficiencies in the magnocellular system, parvocellular system, or even other neuronal populations. Respiratory depression is characteristic of ROHHAD syndrome and is usually explained by an impairment of the respiratory center in the brain stem [1]. Thus, it is increasingly difficult to determine the lowest common denominator that would support a hypothesis of a genetic or autoimmune trigger of ROHHAD syndrome.

No recommendations can be given to prevent ROHHAD syndrome.

ROHHAD syndrome has initially been considered an uncommon variant of central hypoventilation syndrome: The latter may be congenital or acquired, and symptom onset of the congenital variant has occasionally been observed to be delayed until early childhood. The corresponding condition has been named late-onset congenital central hypoventilation syndrome. In isolated cases, additional symptoms of hypothalamic dysfunction were observed in affected individuals [11].

Because the triggers of the aforementioned conditions have been unknown, it was difficult to determine the limits of single diseases and to define distinct entities. This changed in 2003, when central hypoventilation syndrome was first related to mutations of the PHOX2B gene [5]. Such mutations could not be detected in those suffering from the late-onset congenital central hypoventilation syndrome with hypothalamic dysfunction, suggesting differences in etiology and pathogenesis. Further differences became evident when clinical data of the respective patients were analyzed, which highlighted the necessity for defining a separate entity [2].

The term "rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation" has first been used by Ize-Ludlow et al., who evaluated data of 23 patients presumably suffering from the same childhood disease. They tested whether these pediatric patients were carrying PHOX2B mutations or mutations of genes related to the development and maintenance of neuronal populations, but the authors were unable to identify the triggers of ROHHAD syndrome [2].

The question as to the causes of this rare multisystem disorder has still not been answered, which impedes the development of causal therapies. So far, only symptomatic treatment can be provided to patients suffering from ROHHAD syndrome.

ROHHAD is short for rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation. These are the clinical hallmarks of ROHHAD syndrome, a very rare entity of as-of-yet unknown etiology. In detail, the following symptoms consecutively manifest in children aged 2-4 years:

• Hyperphagia leading to acute-onset, rapidly progressive obesity.
• Decrease of growth velocity rate.
• Electrolyte and water imbalances resulting in polyuria/polydipsia.
• Hypothyroidism.
• Thermal dysregulation.
• Precocious or delayed puberty.
• Pupillary anomalies and strabismus.
• Constipation or chronic diarrhea.
• Hyposensitivity to pain.
• Development of benign tumors in the autonomic nervous system.
• Abnormal behavior due to depression, psychosis, flat affect, and other mental disorders.
• Respiratory depression.

Due to knowledge gaps regarding the triggers of ROHHAD syndrome, its clinical heterogeneity, and slowly progressive course, an early diagnosis is rarely achieved. Confirmatory tests are not available. The diagnosis of ROHHAD syndrome must be based on clinical findings and it takes years until the clinical picture becomes clear.

Causal treatment is not available. Patients benefit from a multidisciplinary approach to therapy comprising artificial ventilation, hormone replacement therapy, and other types of pharmacotherapy aiming at symptomatic improvements. Affected individuals have to undergo regular follow-ups to possibly readjust their treatment regimen to their current needs.

Data regarding the long-term outcome of ROHHAD syndrome are not available. The severity of respiratory depression seems to be the most important prognostic factor, with respiratory failure being the most common cause of the sudden death of ROHHAD patients. Metabolic decompensation is a life-threatening condition, too, and it may induce central nervous system damage that causes cognitive deficits. On the other hand, ROHHAD patients may experience normal mental development and be able to achieve certain degrees of independence in their daily life. As of today, it is not possible to give a reliable prognosis for particular patients.

1. Ibáñez-Micó S, Marcos Oltra AM, de Murcia Lemauviel S, Ruiz Pruneda R, Martínez Ferrández C, Domingo Jiménez R. Rapid-onset obesity with hypothalamic dysregulation, hypoventilation, and autonomic dysregulation (ROHHAD syndrome): A case report and literature review. Neurologia. 2017; 32(9):616-622.
2. Ize-Ludlow D, Gray JA, Sperling MA, et al. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation presenting in childhood. Pediatrics. 2007; 120(1):e179-188.
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