Rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation as a paraneoplastic syndrome in neuroblastoma: case report

Abstract

Background

Neuroblastoma, the most common extracranial solid tumour in childhood, is occasionally associated with paraneoplastic syndromes. These syndromes can occur before tumour diagnosis or recurrence. Notably, approximately 40% of patients with rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) have underlying neural crest tumours, such as ganglioneuromas or ganglioneuroblastomas. ROHHAD may also manifest as a paraneoplastic syndrome in neuroblastomas. Here, we describe three neuroblastoma cases with ROHHAD to help improve oncologists’ recognition of ROHHAD as a paraneoplastic entity.

Case Description

The three neuroblastoma cases (two females, one male) were diagnosed at 102, 44, and 9 months of age, respectively. The histopathological subtypes included ganglioneuroblastomas (n=2) and a neuroblastoma (n=1). Rapid-onset obesity occurred at 95 months (7.9 years), 33 months (2.8 years), and 72 months (6 years) of age. All three children underwent resection of their primary tumour, with one receiving adjuvant chemotherapy. For the treatment of ROHHAD, case 1 received immunomodulatory therapy comprising glucocorticoids, intravenous immunoglobulin (IVIG), and rituximab; case 2 did not receive immunotherapy; and case 3 was treated with oral prednisone therapy. All cases demonstrated sustained survival at last follow-up.

Conclusions

ROHHAD syndrome may manifest as a paraneoplastic phenomenon in neuroblastoma patients. Oncologists should suspect ROHHAD in children with neuroblastoma who develop rapid-onset obesity, even in the absence of classic features such as hypoventilation or hypothalamic endocrine dysregulation. Implementing a multidisciplinary collaborative approach to care will enable early recognition and intervention. This will critically impact patient prognosis by facilitating prompt tumour surveillance while significantly improving long-term survival rates.

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Key findings

• Management of rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) can have a significant effect on patient outcomes, ranging from an earlier cancer diagnosis to improved prognosis and life expectancy.

What is known and what is new?

• ROHHAD is a rare syndrome presenting in early childhood. It is associated with high morbidity and 50–60% mortality.

• ROHHAD syndrome can occur as a paraneoplastic complication of neuroblastoma. The current treatment for ROHHAD primarily focuses on supportive care, which requires collaborative implementation by a multidisciplinary team. The close monitoring of affected children is critically important.

What is the implication, and what should change now?

• ROHHAD is a paraneoplastic syndrome that can occur in patients with neuroblastoma. Its clinical manifestations can be highly heterogeneous. This necessitates early recognition by oncologists and coordinated multidisciplinary consultations to implement targeted symptom management.

Introduction

Neuroblastoma is the most common paediatric extracranial solid malignancy, exhibiting diverse manifestations, including paraneoplastic phenomena (1). Paraneoplastic syndromes comprise complex symptom constellations arising independently of direct tumour effects (e.g., mass invasion or compression). These syndromes are primarily driven by two pathophysiological mechanisms: (I) ectopic secretion of biologically active substances from neoplastic tissue, and (II) immune-mediated tissue injury. Their highly heterogeneous clinical manifestations often complicate diagnosis, delaying the initiation of therapy for both the primary malignancy and the paraneoplastic syndrome (2). They typically manifest clinically prior to diagnosis of the primary neoplasm or tumour recurrence (3). To our knowledge, opsoclonus-myoclonus syndrome (OMS) is the most prevalent paraneoplastic syndrome associated with neuroblastoma. In contrast, rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD)—a rare neuroendocrine disorder—has a significant disease burden characterized by severe multisystem complications and 50–60% mortality (4). Here, we describe ROHHAD as a paraneoplastic syndrome manifesting in three neuroblastoma patients. It is intended that this case series will enhance the recognition and timely diagnosis of paraneoplastic phenomena in paediatric oncology. We present these cases in accordance with the CARE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-269/rc).

Case presentation

Case 1

Case 1 was a boy aged eight years and five months. His birth weight was 2,900 g. He achieved normal psychomotor developmental milestones and remained medically unremarkable until age 7.9 years, when his parents observed marked rapid weight gain (8.5 kg within six months). Two months after the onset of weight gain, he developed recurrent fatigue and hypersomnolence (sleeping 15–17 hours/day). Later, the child developed recurrent antibiotic-unresponsive fever with temperatures fluctuating between 37.8 and 40 °C, in addition to emotional instability (irritability, irascibility, and blunted effects), accompanied by a complete lack of insight and child-like regression.

Physical examination demonstrated obesity [height 130 cm, weight 38.5 kg, body mass index (BMI) 22.7 kg/m² (Z-score +4.49, >99th percentile)], drowsiness with apathetic facies, bilateral ptosis, mildly sluggish pupillary light reflex, tachycardia [heart rate 130–160 beats per minute (bpm)], and body temperature 39.5 °C.

Laboratory findings revealed normal inflammatory markers, complete blood count (CBC), hepatic/renal function, thyroid-stimulating hormone (TSH), cortisol (08:00/00:00/16:00), adrenocorticotropic hormone (ACTH), prolactin, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). However, decreased insulin-like growth factor 1 (IGF-1) (36.1 ng/mL) and free thyroxine (fT₄, 5.71 pmol/L) were noted, with intermittent severe hyponatremia (109.4–136.2 mmol/L) and hypochloraemia (81.6–101.7 mmol/L). Details can be found in Table 1.

Table 1. Laboratory findings at the time of diagnosis.

Parameters	Case 1			Case 2			Case 3
	Value	Reference		Value	Reference		Value	Reference
ACTH (pg/mL)		0.0–46			0.0–46			0.0–46
8:00	30.7			64.6			<5
0:00	17.1			25.1			–
16:00	15.1			34.6			–
Cortisol (μg/dL)		5–25			5–25			5–25
8:00	7.49			17.4			2.05
0:00	6.6			6.05			–
16:00	2.79			12.7			–
Prolactin (ng/mL)	17.24	2.74–26.72		113.85	2.74–26.72		5.6	3.1–15.8
FSH (IU/L)	2	0.4–2		1.66	1.3–5		0.3	1.5–5
LH (IU/L)	0	<0.4		0.009	<0.07		0	<0.2
TSH (mIU/L)	1.633	0.4–6.0		1.826	0.4–6.0		1.036	0.4–6.0
fT4 (pmol/L)	5.71	8.37–29.6		7.98	8.37–29.6		9.32	8.37–29.6
fT3 (pmol/L)	3.2	2.75–9.9		5.17	2.5–9.0		6.11	2.5–9.0
Total T3 (nmol/L)	0.484	1.078–3.388		1.73	1.08–3.84		2.078	1.078–3.388
Total T4 (nmol/L)	60.1	51.5–173.8		83.72	51.48–173.75		115.7	51.5–173.8
BUN (mmol/L)	1.91	2.7–7		7.27	2.5–6.5		2.98	2.5–6.5
Creatinine (μmol/L)	57.3	27–66		31	19–44		34.8	27–66
Serum Na (mmol/L)	109.4–136.2	135–145		147–162.1	135–145		136.1–142.8	135–145
Serum K (mmol/L)	3.93–4.02	3.7–5.2		3.96–5.43	3.9–5.4		3.66–4.19	3.7–5.2
Serum CL (mmol/L)	81.6–101.7	98–110		109.9–123.9	98–110		101.1–103.5	98–110
IGF-1 (ng/mL)	36.1	40–255		143	18–172		397	55–277
AFP (ng/mL)	1.35	0.0–9.0		5.55	0.0–9.0		1.14	0.0–9.0
HCG (IU/L)	1.5	≤2.5		1.6	≤2.5		2	≤2.5
NSE (ng/mL)	22.6	≤25		21.92	0.05–15.3		24.1	≤25

ACTH, adrenocorticotropic hormone; AFP, alpha-fetoprotein; BUN, blood urea nitrogen; fT₃, free triiodothyronine; fT₄, free thyroxine; FSH, follicle-stimulating hormone; HCG, human chorionic gonadotropin; IGF-1, insulin-like growth factor 1; LH, luteinizing hormone; NSE, neuron-specific enolase; Serum CL, serum chloride; Serum K, serum potassium; Serum Na, serum sodium; Total T3, total triiodothyronine; Total T4, total thyroxine; TSH, thyroid-stimulating hormone.

Polysomnography confirmed obstructive sleep apnoea syndrome, 95% during wakefulness, 94% in non-rapid eye movement (NREM), and 93% in rapid eye movement (REM), with a nadir at 88%. Nasopharyngoscopy demonstrated the absence of an identifiable structural obstruction within the upper airway. Daytime wakefulness, peripheral oxygen saturation (SpO₂) ranged from 88–90% in room air.

Brain scans showed cerebral atrophy (Figure 1); spine and pituitary magnetic resonance imaging (MRI) showed no structural abnormalities. Computed tomography (CT) demonstrated bilateral scattered ground-glass opacities, bronchial wall thickening in the lower lobes, and hyperaeration in the distal lung fields. Abdominal contrast-enhanced CT revealed an 8.5 cm × 7.9 cm × 5.0 cm retroperitoneal mass (Figure 2A). Positron emission tomography-CT (PET-CT) showed no distant metastasis, and cytological examination excluded bone marrow involvement. Serum neuron-specific enolase (NSE), vanillylmandelic acid (VMA), and homovanillic acid (HVA) levels were within the normal reference ranges. Histopathological examination of the mass biopsy confirmed a peripheral neuroblastic tumour. Subsequent resection of the primary tumour identified an intermixed ganglioneuroblastoma with favourable histology; there were no abnormalities in MYCN amplification, 1p36 deletion, or 11q23 rearrangement.

Figure 1.

Cranial MRI demonstrated prominent sulci throughout all cerebral lobes bilaterally. MRI, magnetic resonance imaging.

Figure 2.

Imaging studies of primary tumour sites in three paediatric patients. (A) Abdominal contrast-enhanced CT revealed an 8.5 cm × 7.9 cm × 5.0 cm retroperitoneal mass. (B) Chest CT revealed a 7.6 cm × 6.2 cm × 7.1 cm mediastinal mass. (C) Cervical MRI demonstrated a 3.1 cm × 5.2 cm × 2.9 cm right neck mass. (D) CT detected a 3.01 cm × 1.59 cm × 1.74 cm right neck mass. CT, computed tomography; MRI, magnetic resonance imaging.

The symptom profile of rapid-onset obesity, hypoventilation (hypoxemia on room air, SpO₂ 85–90%), hypothalamic dysfunction (decreased IGF-1 and fT₄), intermittent severe hyponatremia, autonomic instability, and pathologically confirmed ganglioneuroblastoma provided compelling evidence supporting a diagnosis of ROHHAD syndrome.

The patient received combination immunosuppressive therapy comprising intravenous immunoglobulin (IVIG) at 2 g/kg/dose for two cycles, methylprednisolone pulse therapy [20 mg/kg/day intravenous injection (IV) for three days], and rituximab (375 mg/m²) for one cycle. On the second day of IVIG therapy, the patient exhibited increased responsiveness and a mild reduction in hypersomnolence when compared to baseline. By the fourth day of IVIG administration, an effective alleviation of symptoms and a decline in peak temperature (maximum recorded temperature 38.5 °C) were evident. However, persistent manifestations included recurrent central hyperthermia, tachycardia, central hypoventilation, central hypothyroidism, intermittent hyponatremia, and hypochloraemia. SpO₂ was maintained at ≥95% during both wakefulness and sleep with supplemental oxygen.

Case 2

Case 2 was a girl aged eight years and eight months. She had a normal birth weight (3,100 g). She achieved age-appropriate developmental milestones and remained healthy until age 2.8 years when she developed abrupt-onset obesity with altered body habitus, chronic hypodipsia requiring caregiver-guided hydration, cold acrocyanosis, and hyperhidrosis. Subsequently, she developed behavioural abnormalities characterized by irritability, aggression, destructive behaviours, communication deficits, sleep disturbances (initial insomnia), limb oedema, dyspnoea, and perioral cyanosis necessitating emergent intubation and intensive care unit (ICU) admission. At age 3.7 years, the child presented to medical oncology with left-sided strabismus and ptosis.

Physical examination was as follows: weight 21.4 kg, height 101 cm, BMI 20.9 kg/m² (Z-score +4.22, >99th percentile), left-sided strabismus with ipsilateral ptosis, bilateral anisocoria (brisk right and sluggish left pupillary light reflexes), and tachycardia (102–120 bpm) with desaturation (SpO₂: 85–90%).

Laboratory analyses revealed normal CBC, hepatic/renal function, cortisol (08:00/00:00/16:00), ACTH (00:00/16:00), FSH, IGF-1, TSH, and fT₄. However, there was decreased LH (0.009 IU/L), elevated 08:00 ACTH (64.6 pg/mL) and prolactin (113.85 ng/mL), and hypernatremia (147–162.1 mmol/L) with hyperchloremia (Cl⁻, 109.9–123.9 mmol/L). Karyotype and whole-exome sequencing were unremarkable. See Table 1 for details.

Chest CT revealed a 7.6 cm × 6.2 cm × 7.1 cm mediastinal mass (Figure 2B), with elevated urinary HVA and serum NSE (34.5 ng/mL). Bone marrow biopsy showed no metastasis. Tumour biopsy confirmed intermixed ganglioneuroblastoma (MYCN/1p36/11q23 negative). After four cycles of chemotherapy (carboplatin 200 mg/m² d1–2, etoposide 150 mg/m² d1–2, vincristine 1.5 mg/m² d1, doxorubicin 25 mg/m² d1–2, cyclophosphamide 750 mg/m² d1–2 + mesna 300 mg/m² d1–2) which resulted in significant tumour reduction, the mass was completely resected.

Postoperative behavioural improvement consisted of reduced aggression. SpO₂ was maintained at >98%with supplemental oxygen via nasal cannula (2 L/min).

Case 3

Case 3 was a 7.3-year-old girl with a birth weight of 4,000 g (>90th percentile) and length of 55 cm (75th percentile). Her neonatal course was unremarkable.

At nine months of age, she presented with progressive dyspnoea and a neck mass. Cervical MRI demonstrated a 3.1 cm × 5.2 cm × 2.9 cm right neck mass (Figure 2C) suggestive of neuroblastoma. Post-resection pathology confirmed differentiated neuroblastoma. Serum NSE remained normal. Without adjuvant chemotherapy, surveillance imaging revealed local recurrence six months postoperatively: CT detected a 3.01 cm × 1.59 cm × 1.74 cm right neck mass (Figure 2D). Management consisted of active surveillance; serial ultrasonography showed stable disease without dimensional progression.

At age four years, the child exhibited behavioural abnormalities including excessive talking, affective flattening, irritability, impulsivity, sudden nocturnal screaming, sleep-related breath-holding sensations, and nocturia. Psychiatric evaluation at a local hospital suggested attention-deficit/hyperactivity disorder (ADHD). Atomoxetine therapy was initiated but failed to ameliorate the behavioural symptoms. At age six years, the child developed polyphagia with polydipsia, hyperhidrosis, polyuria, nocturia, and diarrhoea, accompanied by rapid weight gain (from 17.5 to 40 kg in one year).

The child subsequently developed acute cyanosis, depressed respirations, and unresponsiveness during sleep, requiring emergent intubation and transfer to the ICU. There, she received immunomodulatory therapy (corticosteroids/IVIG) and nocturnal non-invasive ventilation (NIV), maintaining sleep SpO₂ at ~90% with the resolution of nocturnal breath-holding episodes.

Physical examination revealed notable obesity [weight 39.5 kg, height 120 cm, BMI 27.4 kg/m² (Z-score +8.15, >99th percentile)] and sluggish eye movements.

Laboratory analyses revealed normal CBC, hepatic/renal function, TSH, fT₄, morning ACTH, serum sodium/chloride, and LH. Cortisol (2.05 µg/dL) and FSH (0.3 IU/L) were decreased, while IGF-1 was elevated (397 ng/mL). See Table 1 for details.

Polysomnography confirmed extremely severe obstructive sleep apnoea [apnoea-hypopnea index (AHI): 77.3 events/h, mean SpO₂ during sleep: 86%, nadir SpO₂: 44%]. Laryngoscopy showed that the pharyngeal plane was narrowed, and the inspiratory phase was narrowed by 50% when breathing calmly. The patient was commenced on nocturnal NIV in the form of biphasic positive airway pressure (BIPAP); her SpO₂ reached 90% during sleep.

Therapy comprised of oral prednisone (5 mg/d), intranasal desmopressin spray, and nocturnal BiPAP ventilation [ResMed Lumis150 variable positive airway pressure (VPAP) spontaneous/timed (S/T); S/T mode: expiratory positive airway pressure (EPAP) 5 cmH₂O, inspiratory positive airway pressure (IPAP) 14 cmH₂O, respiratory rate (RR) 25/min, inspiratory time (Ti) 1.0 s, FiO₂ 21%], which maintained SpO₂ at ~90% and resolved the sleep disorder.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from each participant’s parents for the publication of this case report and the accompanying images. A copy of the written consents is available for review by the editorial office of this journal.

Discussion

Neuroblastoma is a malignant neoplasm of embryonal origin, arising from primordial neural crest cells within the adrenal medulla and sympathetic chain ganglia. As the most prevalent extracranial solid malignancy in children, it accounts for approximately 15% of all paediatric cancer-related deaths. The clinical manifestations exhibit widespread heterogeneity, dictated by the primary tumour location and the presence or absence of paraneoplastic syndromes (5). A paraneoplastic syndrome refers to the dysfunction of anatomically remote organs or tissues resulting from a primary tumour. These syndromes occur not by direct invasion or metastasis, but through immune-mediated processes triggered by the cancer itself, such as autoantibodies or cytokines (6). Neuroblastoma and ROHHAD manifestations represent concurrent components of ROHHAD and neural tumour (ROHHAD-NET) syndrome.

ROHHAD syndrome is a rare paediatric disorder characterized by rapid-onset obesity together with hypoventilation, autonomic dysregulation, and hypothalamic endocrine dysfunction; it is frequently associated with neuroendocrine tumours (7). The diagnosis of ROHHAD syndrome in neuroblastoma patients poses significant challenges, frequently leading to diagnostic and therapeutic delays. This underscores a gap in the recognition of ROHHAD as a neuroblastoma-associated paraneoplastic syndrome. Oncologists must improve their awareness of this phenomenon—particularly its paraneoplastic manifestations—as current diagnostic criteria, while providing initial guidance, often fail to capture the temporal asynchrony of symptom onset. The identification and validation of biomarkers for ROHHAD syndrome are critically important to facilitate its early diagnosis and elucidate its pathogenesis.

Studies indicate that neuroblastoma patients with OMS exhibit improved oncologic outcomes compared to their non-OMS counterparts. These tumours are well-differentiated and metabolically inactive (8,9). Studies have also demonstrated that neuronally differentiated cells with a higher degree of differentiation in neuroblastoma are able to secrete neurotransmitters such as catecholamines (10). In OMS-associated neuroblastomas, a tumour microenvironment (TME) enriched with CD8⁺ T lymphocytes and B lymphocytes may underlie paraneoplastic pathogenesis (11).

Mandel-Brehm et al. demonstrated seropositivity for anti-ZSCAN1 autoantibodies in patients with ROHHAD-NET syndrome—all of whom had ganglioneuroma or neuroblastoma (12). However, in a cohort of five patients with ROHHAD syndrome, Serafim et al. reported no tumour detection during extended clinical surveillance or pre-mortem evaluations, indicating that patients with idiopathic ROHHAD syndrome should also be tested for anti-ZSCAN1 autoantibodies (13). In addition, Nakamura-Utsunomiya et al. reported that anti-ZSCAN1 autoantibodies may also be useful to evaluate disease severity and the need for immunosuppressive treatment in patients with ROHHAD syndrome not associated with a tumour (14). As a highly specific biomarker for ROHHAD, ZSCAN1 autoantibody detection offers potential utility for early disease identification, including during the pre-symptomatic phase. Therefore, ZSCAN1 antibody (ZSCAN1abs) testing is recommended as part of the diagnostic workup in cerebrospinal fluid (CSF) for suspected ROHHAD syndromes, regardless of the presence or absence of a tumour.

Although rapid-onset obesity serves as a hallmark of hypothalamic dysfunction, diagnostic confirmation necessitates at least one additional feature—central hypothyroidism, growth hormone dysregulation, sodium homeostasis impairment, hyperprolactinemia, adrenocortical insufficiency, or pubertal disorders (15). In addition, behavioural problems, psychotic disorders, intellectual disabilities, and mood disorders have been observed in 60% of reported cases (15). Our patients with neuroblastoma had a rapid onset of obesity, hypoventilation requiring ventilator support, electrolyte disorder, behavioural problems, and hormone secretion abnormality; these are among the most common reported features of this syndrome.

No treatment guidelines have been established for ROHHAD syndrome complicated by neuroblastoma in paediatric patients. Complete tumour resection is considered the treatment of choice. All of our patients underwent tumour resections; however, tumour resection does not prevent the progression of ROHHAD or lead to the reversal of ROHHAD syndrome. Most patients are treated based on their symptoms. It is thought that autoimmunity may play a role in ROHHAD (16). Immunomodulatory therapies—including glucocorticoids and IVIG—have been administered in selected cases, demonstrating partial symptomatic improvement in these patients (17). In this study, one patient received immunotherapy (including IVIG and rituximab) after the diagnosis of ROHHAD syndrome, showing improved responsiveness, reduced hypersomnolence, and a decline in temperature. However, further longitudinal follow-up is warranted to elucidate the therapeutic efficacy of rituximab in this patient.

The overall survival (OS) rate of neuroblastoma patients has demonstrated sustained improvement over recent decades, attributable to multimodal therapeutic approaches encompassing surgical resection, hematopoietic stem cell transplantation, and targeted radiotherapy. Reported 5-year OS rates are 97.5% among low-risk patients, 96.7% among intermediate-risk patients, and 48.9% among high-risk patients (18). ROHHAD syndrome, a rare clinical entity, is characterized by significant morbidity, with a reported mortality rate of 50–60% (4). Harvengt et al. described a cohort of 32 ROHHAD-NET patients, with six fatalities documented. Among these, two deaths were secondary to sudden cardiorespiratory arrest, one resulted from endotracheal tube obstruction during mechanical ventilation, and another was attributable to septic shock complicated by multisystem organ failure (15). However, the OS of ROHHHAD-NET patients remains unclear; more clinical data and long-term follow-up are needed.

Conclusions

Oncologists should suspect ROHHAD in paediatric neuroblastoma patients with rapid-onset obesity, even when there is an absence of features such as hypoventilation or hypothalamic endocrine dysfunction. A multidisciplinary approach enables early recognition/intervention, critically improving patient prognosis and enhancing long-term survival through prompt tumour surveillance.

Supplementary

The article’s supplementary files as

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from each participant’s parents for the publication of this case report and the accompanying images. Copy of the written consents are available for review by the editorial office of this journal.