Abstract
Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation syndrome (ROHHADS) is a rare, but potentially lethal, pediatric disorder. To date, nearly 80 patients have been reported in the literature; however, the etiopathogenesis is still unclear and debated. Both genetic and paraneoplastic or immune-mediated causes have been supposed to be involved in this syndrome. Nonetheless, at this time, a diagnostic biomarker is not available and diagnosis is based exclusively on clinical criteria. Aiming to establish the immune-mediated pathogenesis, we report 2 children with a clinical picture consistent with ROHHADS and whose cerebrospinal fluid analysis disclosed an intrathecal synthesis of oligoclonal bands. Even if many aspects remain to be explained, this finding suggests that ROHHADS could share similar pathogenetic mechanisms with other immune-mediated central nervous system disorders, and even more important, it might pave the way to a therapeutic chance for these patients by means of immunotherapy.
Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation syndrome (ROHHADS), also known as late-onset central hypoventilation with hypothalamic dysfunction syndrome (LO-CHS/HD), represents a little-known, but probably underdiagnosed, condition. Since the first comprehensive review provided by Katz in 2000, 1 about 75 cases have been reported in the literature. 1 –5 Despite much progress in the knowledge of the clinical picture and evolution of ROHHADS, its etiopathogenesis remains unclear and debated. Given the similarities with central congenital hypoventilation syndrome (Ondine’s curse, MIM209880), a genetic cause was initially suggested. 6 However, neither mutations in paired-like homeobox 2B (PHOX2B), which is responsible for central congenital hypoventilation syndrome, nor in other candidate genes, have ever been identified in patients with ROHHADS. 2,3,5 Paraneoplastic and disimmune pathogenic mechanisms also have been considered. 7 –13 The frequent association with neural crest neoplasm 1 –4,9 and the finding of lymphocyte infiltrates in the hypothalamus of some patients 7,8 support this hypothesis. Moreover, a recent authoritative review by Armangue et al 13 included ROHHADS among the encephalitis for which an immune-mediated mechanism is strongly suspected. Nonetheless, to date, a diagnostic biomarker is lacking and the diagnosis is based exclusively on clinical criteria.
With the aim to corroborate the hypothesis that an immune-mediated process may play a key pathogenetic role in ROHHADS, we add to the pertinent literature the reports of 2 previously unreported children with a clinical diagnosis of ROHHADS whose cerebrospinal fluid analysis revealed the presence of oligoclonal bands, not present in serum.
Cases Description
Case 1
We report a 4-year-old boy, first child of Italian nonconsanguineous parents, with a history of miscarriage, delivered at term by cesarean section after an uncomplicated pregnancy. Birth weight was 4.080 kg, occipital-frontal head circumference 36.8 cm, and length 52 cm. No family history for genetic or neurologic diseases were reported. The perinatal period was uneventful. Weight, length, and psychomotor development were normal up to 24 months. At about 2 years of age, the child started to show hyperphagia, polydipsia, polyuria, and rapid weight gain (from 50th to 75th percentile to more than 95th percentile over a few months). Night snoring, increased pain threshold, frequent episodes of intense sweating, down gaze impairment, and photophobia were also reported. At the same time, psychomotor regression, involving particularly language skills and social interaction, became evident. A brain computed tomographic (CT) scan, performed 6 months after the clinical onset, gave unremarkable results.
In April 2010 (2 years 7 months), the child was admitted to a peripheral hospital because of sudden onset of cyanosis. A further rapid weight gain of about 2 kg and episodes of sleep apnea were noted by parents in the week before admission. Laboratory tests, including complete blood cell count, inflammatory markers, electrolytes, liver and kidney function tests, myocardial injury markers, lactate, and ammonia, were all normal. Chest radiograph, electrocardiograph, and echocardiograph did not show any significant findings. After admission, the child experienced a progressive worsening of clinical conditions, resulting in complete respiratory failure, requiring mechanical ventilation. He was then transferred to the pediatric intensive care unit of our hospital, where a large-spectrum antibiotic therapy was administered on suspicion of a severe respiratory infection. Despite the progressive improvement of his clinical condition, several extubation attempts failed and the patient underwent a tracheostomy. Drug dosage tests were negative, whereas endocrinologic tests revealed hyperprolactinemia and transitory hyperaldosteronism and hypocortisolism. The patient was treated with cortisone acetate for few days, with rapid normalization of aldosterone and cortisol plasma levels. Genetic tests for central congenital hypoventilation syndrome and Prader-Willi and Beckwith-Wiedemann syndromes were negative. A cerebrospinal fluid analysis revealed presence of oligoclonal bands consistent with an intrathecal synthesis of oligoclonal immunoglobulin G, whereas chemical-physical test, culture test, and neurotransmitters analysis in cerebrospinal fluid were normal. Because the major clinical criteria (hypoventilation after the age of 2 years and evidence of hypothalamic dysfunction) were fulfilled, a diagnosis of ROHHADS was made.
A CT scan of the chest and abdomen and measurements of catecholamines in urine were performed in order to exclude a neural crest tumor. Given the finding of intrathecal synthesis of oligoclonal bands, a disimmune mechanism was suspected and intravenous immunoglobulin treatment was started with the following dosing regimen: 1 g/kg/d for 2 days, followed by 1 g/kg/d per month for a total of 10 administrations. Over the months, the child experienced a gradual, though not complete, improvement of clinical condition in terms of weight loss, progression of psychomotor development, and independence from the ventilator. At the age of 4 years, the child needs ventilatory support only during sleep, and language skills and social interaction have improved. One year after the treatment was started, oligoclonal bands were absent in cerebrospinal fluid.
Case 2
We also report a 5-year-old girl, recently diagnosed with ROHHADS and still hospitalized at our pediatric neurologic unit. She is the first child of Italian healthy nonconsanguineous parents, delivered at term after a normal pregnancy. Up to 4 years of age, growth curve and psychomotor development were normal; afterwards, a weight gain of 10 kg in about 10 months associated with increased food intake was reported by the parents. Mild changes in behavior were also observed by parents and teachers at school during the last few months.
Blood examinations performed in April 2012 (4 years 6 months), 6 months after symptom onset, were normal except for the presence of a central hypothyroidism. In September 2012 (4 years 11 months), the girl came to our attention after a 2-week history of nocturnal hyperpyrexia and was not responding to antipyretic drugs, coupled with episodes of intense sweating. Physical examination and laboratory tests, including complete infectious and rheumatologic panels, were normal. Endocrinologic blood tests confirmed the presence of a central hypothyroidism, and therefore hormone replacement therapy was started. A brain magnetic resonance image was negative.
During the last 2 weeks, a nocturnal oxygen desaturation trend also has been noted. Blood gas tests, end-tidal carbon dioxide monitoring, and polysomnography have shown central alveolar hypoventilation. Because the major clinical criteria were met, ROHHADS has been diagnosed.
Also in this case, cerebrospinal fluid examination has just revealed the presence of an intrathecal synthesis of oligoclonal bands, whereas screening for neural crest neoplasms through catecholamine dosage in urine and chest and abdomen positron emission tomography–computed tomography are, to date, negative.
Discussion
ROHHADS is a rare clinical condition, usually affecting previously healthy children, characterized by rapid-onset weight gain, behavioral changes, cognitive impairment, vegetative dysfunction, variable signs of hypothalamic dysfunction (hyperprolactinemia, hypothyroidism, hypersomnia, and glucocorticoid deficiency), and central hypoventilation. 1 –5
To date, the pathogenesis and etiology of this complex disorder have not been clearly identified and explained. The diagnosis is based exclusively on clinical diagnostic criteria: (1) onset of alveolar hypoventilation after the age of 2 years and (2) evidence of hypothalamic dysfunction, as defined by one of the following findings: rapid-onset obesity, hyperprolactinemia, central hypothyroidism, disordered water balance, failed growth hormone stimulation test, corticotropin deficiency, or delayed or precocious puberty. 1 –4
A genetic basis has been originally supposed, on the basis of the similarities with central congenital hypoventilation syndrome and the report of familial occurrence 3 ; however, no mutations in PHOX2B, responsible for central congenital hypoventilation syndrome, have ever been found in subjects with ROHHADS. 2,3,5 Similarly, both broad screening of chromosomal abnormalities through array comparative genomic hybridization analysis as well as specific testing of candidate genes (brain-derived neurotrophic factor [BDNF], tyrosine kinase receptor B [TRKB], achaete-scute complex–like 1 [ASCL1], Necdin [NDN], 5-hydroxytryptamine receptor 1A [HTR1A], orthopedia [OTP], and pituitary adenylate cyclase activating polypeptide [PACAP]) have failed to identify a disease-causing genetic defect. 2,3,5 In addition, the recent report of a case of monozygotic twins discordant for ROHHADS phenotype 11 suggests the existence of alternative etiologies in the majority of patients.
A paraneoplastic mechanism is suggested in many cases, considering the frequent finding of an underlying neural crest tumor such as ganglioneuroma, neuroblastoma, or ganglioneuroblastoma, 1 –4,9 similarly to what happens in opsoclonus-myoclonus syndrome. 13 However, extensive and accurate blood and urine tests and imaging investigations did not indicate an underlying neoplasm in a significant number of the reported cases. 1 –3,10 On the other hand, the clinical evolution after tumor removal is not so clearly favorable and literature data on this issue are lacking. 7,9,11,12
Autoptic studies in subjects with a clinical phenotype consistent with ROHHADS have revealed lymphocytic infiltration in the hypothalamus, 7,8 and genetic factors predisposing to autoimmunity have been identified in some patients, 3 suggesting an immune-mediated pathogenesis in the so-called idiopathic form of ROHHADS. The favorable response to intravenous immunoglobulins reported by Huppke et al 10 and to high doses of cyclophosphamide described by Paz-Priel et al 12 further might support this hypothesis even if recovery was not complete (probably because of permanent hypothalamic damage). On the other hand, the poor clinical results obtained by Sirvent et al 9 with intravenous immunoglobulins, corticosteroids, and cyclophosphamide in other previously described cases, the small number of patients treated with immunotherapy, and the frequent absence of long-term follow-up have so far left it open to debate. Moreover, although the immune-mediated hypothesis is intriguing and plausible and although ROHHADS has recently been included among the strongly suspected pediatric autoimmune encephalitis, 13 none of the autoantibodies usually correlated to these neurologic syndromes have ever been identified in the serum or cerebrospinal fluid of subjects with ROHHADS, 7,9,10,12 and to date diagnostic immunologic biomarkers are unfortunately unavailable.
In our patients—the first one observed with a 2-year follow-up and the second one recently diagnosed at our hospital—the clinical picture is consistent with so-called idiopathic ROHHADS. The finding of intrathecal synthesis of oligoclonal bands in both cases might support the immune-mediated hypothesis. Moreover, even if spontaneous recovery cannot be excluded, the clinical improvement described in the first case, together with the disappearance of oligoclonal bands in cerebrospinal fluid after intravenous immunoglobulin treatment, may represent a further element in favor of this hypothesis.
The assay for oligoclonal bands compares the presence of immunoglobulin clones (generally immunoglobulin G) in both cerebrospinal fluid and serum. Each IgG band corresponds to an individual clone of immunoglobulin G that has been generated by the adaptive immune system in response to foreign or host antigen exposure. 14 In particular, the finding of oligoclonal bands in cerebrospinal fluid, and not in serum, indicates a synthesis of immunoglobulin clones exclusively within the central nervous system, by differentiated B cells from the bloodstream. Indeed, in some conditions, activated T and B lymphocytes are able to cross the blood-brain barrier also when it is intact. Within the central nervous system, B cells can differentiate into plasma cells producing immunoglobulins G intrathecally. 15 This is one of the mechanisms believed to be mainly involved in some autoimmune diseases of the central nervous system. 16
Even if oligoclonal band assay does not define the specificity of the immunoglobulin G clones, intrathecal synthesis of oligoclonal bands is a significant marker of immune activation within the central nervous system and is generally found both in immune-mediated and infectious disorders of the central nervous system.
14
In particular, in the presence of clinical, neurophysiologic, or neuroradiologic signs of demyelination, intrathecal synthesis of oligoclonal bands is helpful in supporting the diagnosis of multiple sclerosis, this finding being uncommon in other immune-mediated demyelinating diseases such as isolated optic neuritis, acute disseminated encephalomyelitis, transverse myelitis, and neuromyelitis optica. The other major disease group associated with intrathecal synthesis of oligoclonal bands is that of encephalitis, both infectious (herpes simplex virus, varicella zoster virus) and autoimmune, such as Rasmussen and anti-N-methyl-
To our knowledge, this is the first report of an intrathecal synthesis of oligoclonal bands in children with ROHHADS. In the vast majority of previously published cases, oligoclonal bands assay has not been mentioned; when reported, namely, in 4 patients, it has not shown any intrathecal synthesis of oligoclonal immunoglobulin. 9,10,12
Intrathecal synthesis of oligoclonal bands do not necessarily correspond to the presence of pathogenic autoantibodies; nonetheless, this finding could suggest the existence of a potentially treatable humoral and/or cell-mediated disimmune condition in children with otherwise unexplained ROHHADS, at least in some cases.
To date, it is not known whether intrathecal synthesis of oligoclonal bands in our patients corresponds to the presence of specific and/or pathogenic autoantibodies, such as in anti-NMDAR encephalitis, or whether it is just an epiphenomenon of a disimmune process. However, this finding may constitute a further possible in vivo evidence that an immune-mediated mechanism may play a role in ROHHADS and that at least some patients might benefit from an immune-modulatory treatment.
ROHHADS is apparently a rare disease even though the condition is probably underdiagnosed. General pediatricians, endocrinologists, pneumologists, oncologists, and neurologists who deal with children should be aware of the existence of ROHHADS. Because a significant number of patients experienced sudden cardiorespiratory arrest, delayed identification of disease may lead to life-threatening consequences. 1,4,7 In all patients who presented with a history of rapid-onset obesity, autonomic dysregulation, hypothalamic dysfunction, and respiratory pattern abnormalities, this diagnosis should be taken into serious consideration. A multidisciplinary team should be involved in the evaluation and care of these patients. When ROHHADS is suspected, extensive oncologic evaluation and survey have to be performed as a first step and patients should be investigated for intrathecal synthesis of oligoclonal bands or for other signs of immune dysregulation. If present, the tumor should be removed and the option of an immune-modulatory therapy should be carefully evaluated on a case-by-case basis. Intravenous immunoglobulin might be considered as possible first-step immunotherapy, especially if intrathecal synthesis of oligoclonal bands have been detected; afterwards, an adjunctive immunosuppressive therapy (eg, cyclophosphamide, rituximab, mycophenolate) could be needed in order to radically modify the natural course of the disease, as recently suggested in other autoimmune encephalitis, namely, anti-NMDAR encephalitis. 13
Further studies, preferably by means of multicenter collaboration, are needed to better define the role of immune response in ROHHADS and to provide an appropriate and shared management of this complex and still unknown disease.
Footnotes
Acknowledgments
This work was done at the Division of Pediatrics of the University of Padua, Italy. We thank all the health professionals involved in the care of the child reported in this work, in particular Professor Anna Maria Laverda. We thank the children and their family for their kind collaboration.
Author Contributions
SS, EP, and IT conceptualized the work and prepared first draft and revisions of the manuscript; AP, FB, and GP contributed to the clinical care of the patients and to the discussion; AS and PM revised the manuscript.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Ethical Approval
The clinical management of the patients reported in this study conformed to the guidelines provided by our institutional review board.