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ROHHAD Syndrome

ROHHAD syndrome is a rare entity of unknown etiology that usually manifests in early childhood. ROHHAD is short for rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation. Furthermore, the disease is associated with a predisposition to tumors of neural crest origin, which is why the abbreviation ROHHAD-NET is occasionally found in literature. Knowledge gaps regarding the causes of ROHHAD syndrome impede the development of causal therapies and only supportive care can be provided to affected individuals. Results on the long-term outcome of ROHHAD patients are not available because the disorder has only recently been defined as an entity different from late-onset congenital central hypoventilation syndrome.


Presentation

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]:

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].

Raynaud Phenomenon
  • Features matching ROHHAD syndrome such as rapid-onset obesity, alveolar hypoventilation, central hypothyroidism, hyperprolactinemia, Raynaud phenomenon and hypothalamic hypernatremia were detected in the patient.[ncbi.nlm.nih.gov]
  • The pale appearance of the fingers was considered to be due to Raynaud’s phenomenon ( Figure 1 ). Alterations in body temperature and Raynaud’s phenomenon were attributed to autonomic dysfunction.[jcrpe.org]
  • Acanthosis nigricans was identified in the axilla and neck and coldness in hands and feet suggestive of Raynaud phenomenon was noted. The other system findings were found to be normal.[docksci.com]
Enuresis
  • […] dysregulation Ophthalmological manifestations 87 Thermal dysregulation 73 NA Gastrointestinal dysmotility 67 Altered perception of pain 53 Altered sweating 53 NA Cold hands and feet 40 Bradycardia 33 NA Syncopal episodes 6 / Other findings Hearing loss NA Enuresis[doi.org]
  • A course of rituximab 5 resulted in temporary normalization of appetite and temperature instability, reduced enuresis, and improved neuropathic pain, sweating, and interpersonal skills.[pediatrics.aappublications.org]
  • Hyperactivity Morning headaches Poor school performance and mathematical ability Poor focus and visual-spacial skills Poor memory and analytical thinking Dyspnea Sleep-related symptoms may include the following: Habitual snoring Restless sleep Nocturnal enuresis[emedicine.medscape.com]
Heat Intolerance
  • Additional features at presentation in children being evaluated for suspected ROHHAD syndrome included hypothalamic dysfunction, adipsia, diaphoresis, heat intolerance, behavioral problems and cardiorespiratory arrest.[doi.org]
Pathologist
  • Study staff then forward completed information to a pathologist who will then proceed with removal and recovery of the donation. Study staff will work directly with the pathologist in charge of the donor's body.[luriechildrens.org]
Sneezing
  • Nervousness Noisy breathing Pain or tenderness around the eyes and cheekbones Painful or difficult urination Pale skin Pinpoint red spots on the skin Pounding in the ears Rapid weight gain Runny nose Shortness of breath Skin rash Slow or fast heartbeat Sneezing[rohhad.blogspot.com]
Blurred Vision
  • A list of common side affects: Abdominal pain Back pain Black, tarry stools Bleeding gums Bloating or swelling of the face, arms, hands, lower legs, or feet Blood in the urine or stools Blurred vision Chest pain Confusion Convulsions Cough or hoarseness[rohhad.blogspot.com]
Small Hand
  • Another disorder associated with problem behaviors and excessive eating, Prader-Willi Syndrome, was also considered but then discarded because the child lacked a history of neonatal hypotonia, or decreased muscle tone, and the characteristic small hands[hopkinsmedicine.org]
  • Mental retardation, hypotonia, small hands and feet, ocular findings and hypogonadism may also be present (2,10,12). Prader-Willi syndrome was not considered in the differential diagnosis of the first case due to the presence of precocious puberty.[jcrpe.org]
  • E, Image of the hands, showing small hands. F and G, Anthropometric measurements. F, Height and weight trajectory on the CDC 2000 growth curves. G, BMI curves for age.[doi.org]
  • The presentation of PWS is highly variable, and can also include the following additional symptoms: sleep-disordered breathing, hypopigmentation, small hands and feet, strabismus, reduced visual acuity, scoliosis, hip dysplasia, osteopenia, seizures,[ncbi.nlm.nih.gov]
Macrocephaly
  • The genetics team evaluated him at 20 months of age for hypotonia and dysmorphic facial features that included macrocephaly (head circumference, 52 cm; 3.12 SDS), hypertelorism, flat nasal bridge, prominent forehead, and anteverted nares ( Figure 1 A)[doi.org]
Brachydactyly
  • […] nonsense mutations (c.238C T, p.Arg80*; c.1297C T, p.Gln433*; c.1973G A, p.Trp658*; and c.2878C T, p.Arg960*) and several frameshift RAI1 mutations have been described previously ( 13, 14, 17 ) in patients with obesity, hyperphagia, dysmorphic facies, brachydactyly[doi.org]
Flat Affect
  • Abnormal behavior due to depression, psychosis, flat affect, and other mental disorders. Respiratory depression.[symptoma.com]
  • affect personality disorder, and selective mutism.[rarediseaseday.org]
  • affect 13 Psychosis 13 Behavioral outbursts 6 Bipolar disorder 6 Emotional lability 6 Obsessive-compulsive disorder 6 Oppositional-defiant disorder / 6 Tourette syndrome 6 NA Hallucinations 6 NA Self-injury NA Autonomic dysregulation Ophthalmological[doi.org]
Auditory Hallucination
  • There were episodes of mania and hypomania, auditory hallucinations, major anxiety, and combativeness.[pediatrics.aappublications.org]
  • Consultation was requested after a month of ROHHAD exacerbation, with severe anxiety, insomnia, and auditory hallucinations. Olanzapine and citalopram were helpful in controlling the symptoms.[pediatricfocus.wordpress.com]
Amenorrhea
  • FDA-approved indication: For induction of ovulation in women with hypothalamic amenorrhea due to a deficiency or absence in the quantity or pulse pattern of endogenous GnRH secretion.[rarediseases.info.nih.gov]
  • Our patient had developed secondary amenorrhea. Contrary to our expectations, the laboratory findings were consistent with hypergonadotropic hypogonadism and therefore sex hormone replacement therapy was started.[ncbi.nlm.nih.gov]
Echolalia
  • He lost most of his capability for speech other than echolalia and removed his tracheostomy tube multiple times a day.[chop.edu]
Cognitive Deficit
  • Other specific symptoms are: retinitis pigmentosa, polydactyly, syndactyly, hypogonadotrophic hypogonadism, developmental delay, cognitive deficit, genitourinary malformations, cardiovascular abnormalities, dental abnormalities, Hirschprung’s disease,[journals.viamedica.pl]
  • Metabolic decompensation is a life-threatening condition, too, and it may induce central nervous system damage that causes cognitive deficits.[symptoma.com]
Staring Spells
  • He has developed staring spells without electroencephalogram abnormalities. He was diagnosed with sensory-neural hearing loss.[doi.org]
Slurred Speech
  • In addition to dysfunction of endocrine, respiratory, and autonomic nervous systems, the patient developed daytime sleepiness, visual hallucinations, and episodic loss of facial muscle tone with slurred speech, suggestive of secondary narcolepsy and cataplexy[pediatricneurologybriefs.com]

Workup

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].

Mediastinal Mass
  • Chest CT and MR imaging showed a posterior mediastinal mass. Endocrinological investigation showed corticotrophin deficiency and central hypothyroidism treated with specific replacement therapies.[pesquisa.bvsalud.org]
  • She first presented to our children’s hospital with a suspected mediastinal mass on chest radiography.[pedinfect.portal.tools]

Treatment

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].

Prognosis

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].

Etiology

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].

Epidemiology

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].

Sex distribution
Age distribution

Pathophysiology

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.

Prevention

No recommendations can be given to prevent ROHHAD syndrome.

Summary

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.

Patient Information

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:

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.

References

Article

  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.
  3. Bougnères P, Pantalone L, Linglart A, Rothenbuhler A, Le Stunff C. Endocrine manifestations of the rapid-onset obesity with hypoventilation, hypothalamic, autonomic dysregulation, and neural tumor syndrome in childhood. J Clin Endocrinol Metab. 2008; 93(10):3971-3980.
  4. Weese-Mayer DE, Marazita ML, Rand CM, Berry-Kravis EM. Congenital Central Hypoventilation Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
  5. Amiel J, Laudier B, Attié-Bitach T, et al. Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome. Nat Genet. 2003; 33(4):459-461.
  6. Chow C, Fortier MV, Das L, et al. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome may have a hypothalamus-periaqueductal gray localization. Pediatr Neurol. 2015; 52(5):521-525.
  7. Paz-Priel I, Cooke DW, Chen AR. Cyclophosphamide for rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation syndrome. J Pediatr. 2011; 158(2):337-339.
  8. Lustig RH. Hypothalamic obesity: causes, consequences, treatment. Pediatr Endocrinol Rev. 2008; 6(2):220-227.
  9. De Pontual L, Trochet D, Caillat-Zucman S, et al. Delineation of late onset hypoventilation associated with hypothalamic dysfunction syndrome. Pediatr Res. 2008; 64(6):689-694.
  10. Grimberg A, Katz Kutikov J. Hypothalamus: Neuroendometabolic Center. In: Polin RA, Abman SH, Rowitch D, Benitz WE, eds. Fetal and Neonatal Physiology. 5 ed: Elsevier. 2017; 1451-1461.
  11. Katz ES, McGrath S, Marcus CL. Late-onset central hypoventilation with hypothalamic dysfunction: a distinct clinical syndrome. Pediatr Pulmonol. 2000; 29(1):62-68.

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Last updated: 2019-07-11 21:51