BioMed Research International
Volume 2018 (2018), Article ID 1250721, 17 pages
https://doi.org/10.1155/2018/1250721

Research Article

Rapid-Onset Obesity with Hypoventilation, Hypothalamic, Autonomic Dysregulation, and Neuroendocrine Tumors (ROHHADNET) Syndrome: A Systematic Review

Jiwon M. Lee,¹ Jaewon Shin,² Sol Kim,³ Heon Yung Gee,⁴ Joon Suk Lee,⁴ Do Hyeon Cha,⁴ John Hoon Rim,⁴ Se-Jin Park,⁵ Ji Hong Kim,² Ahmet Uçar,⁶ Andreas Kronbichler,⁷ Keum Hwa Lee,2,8 and Jae Il Shin2,8,9

¹Department of Pediatrics, Chungnam National University Hospital, Daejeon, Republic of Korea
²Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea
³Yonsei University Wonju College of Medicine, Seoul, Republic of Korea
⁴Department of Pharmacology, Yonsei University College of Medicine, Seoul, Republic of Korea
⁵Department of Pediatrics, Geoje Children’s Hospital, Ajou University School of Medicine, Geoje, Republic of Korea
⁶Department of Pediatric Endocrinology and Diabetes, Health Sciences University, Sisli Hamidiye Etfal Education & Research Hospital, Istanbul, Turkey
⁷Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, Innsbruck, Austria
⁸Division of Pediatric Nephrology, Severance Children’s Hospital, Seoul, Republic of Korea
⁹Institute of Kidney Disease Research, Yonsei University College of Medicine, Seoul, Republic of Korea

Correspondence should be addressed to Jae Il Shin; shinji@yuhs.ac

Received 14 May 2018; Revised 24 September 2018; Accepted 28 October 2018; Published 21 November 2018

Academic Editor: Sheba Mohankumar

Copyright © 2018 Jiwon M. Lee et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Background and Aim. ROHHADNET (rapid-onset obesity with hypoventilation, hypothalamic, autonomic dysregulation, neuroendocrine tumor) syndrome is a rare disease with grave outcome. Although early recognition is essential, prompt diagnosis may be challenging due to its extreme rarity. This study aimed to systematically review its clinical manifestation and to identify genetic causes. Materials and Methods. We firstly conducted a systematic review on ROHHAD/NET. Electronic databases were searched using related terms. We secondly performed whole exome sequencing (WES) and examined copy number variation (CNV) in two patients to identify genetic causes. Results. In total, 46 eligible studies including 158 patients were included. There were 36 case reports available for individual patient data (IPD; 48 patients, 23 ROHHAD, and 25 ROHHADNET) and 10 case series available for aggregate patient data (APD; 110 patients, 71 ROHHAD, and 39 ROHHADNET). The median age at onset calculated from IPD was 4 years. Gender information was available in 100 patients (40 from IPD and 60 from APD) in which 65 females and 35 males were showing female preponderance. Earliest manifestation was rapid obesity, followed by hypothalamic symptoms. Most common types of neuroendocrine tumors were ganglioneuromas. Patients frequently had dysnatremia and hyperprolactinemia. Two patients were available for WES. Rare variants were identified in PIK3R3, SPTBN5, and PCF11 in one patient and SRMS, ZNF83, and KMT2B in another patient, respectively. However, there was no surviving variant shared by the two patients after filtering. Conclusions. This study systematically reviewed the phenotype of ROHHAD/NET aiming to help early recognition and reducing morbidity. The link of variants identified in the present WES requires further investigation.

1. Introduction

Rapid-onset obesity with hypoventilation, hypothalamic, autonomic dysregulation (ROHHAD) syndrome is a rare disorder of respiratory failure and autonomic dysregulation with endocrine abnormalities [1]. The suffix -NET was later added to describe a subset of patients with ROHHAD who were found with neuroendocrine tumors (NET) as ROHHADNET [2].

ROHHAD or ROHHADNET may mimic genetic obesity syndromes and present with hypothalamic-pituitary dysfunctions which are not fully investigated [3]. Since the central respiratory control becomes progressively impaired in the patients, the outcome is often fatal and associated with cardiopulmonary arrest [4]. Prompt diagnosis based on early recognition is essential to provide timely respiratory support and to minimize morbidity and mortality. We thereby sought to systematically review the clinical manifestation, laboratory profiles, and treatment strategies of patients with ROHHAD/NET to help understanding and managing the disease. In addition, we performed whole exome sequencing (WES) in 2 patients with ROHHADNET in the attempt to identify the genetic causes.

2. Methods

2.1. Search Methods

We conducted a systematic review of the medical literature to identify all published cases of ROHHAD and/or -NET using the online databases of MEDLINE/PubMed, EMBASE, and Google Scholar, until July 7th, 2018. There were no language restrictions; non-English language articles were translated and included. The broad search query was designed to include “ROHHADNET” OR “ROHHAD”; OR “obesity” AND two of the following terms; “hypoventilation” OR “hypothalamic” OR “autonomic” OR “tumor” OR “neural crest tumor” OR “neuroendocrine tumor.” We reviewed the titles, abstracts, and full texts adhering to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) individual patient data (IPD) guidelines (Figure 1; Supplementary Table S1) [5].

Figure 1: PRISMA IPD flow diagram.

2.2. Eligibility Criteria

The basic criteria for consideration of the diagnosis of ROHHAD had been published by Ize-Ludlow et al. [6]. The criteria briefly included the following: (1) onset of rapid and extreme weight gain after an age of 1.5 years (typically 2–7 years) in a previously nonobese and seemingly normal child, (2) evidence of hypothalamic dysfunction, (3) alveolar hypoventilation, and (4) features of autonomic dysregulation. We collected published case reports and case series which contained data on clinical manifestations fulfilling the criteria of ROHHAD/NET. Due to the extreme paucity of data, congress abstracts were also included. All cases from the literature were included as applicable.

2.3. Exclusion Criteria

Duplicates, letters, commentaries, or replies were excluded. Original articles not containing patient data, such a review articles, were also excluded.

2.4. Selection of Studies

Two reviewers (J.M.L, and S.K.) working independently considered the potential eligibility of each abstract and title that resulted from the initial search. The full-text versions of the eligible studies were reviewed. Disagreements were harmonized by consensus and, if not possible, through arbitration by a third reviewer (J.I.S.).

2.5. Data Extraction

Data were extracted from all of the case reports and case series which were included in the systematic review. Demographic information included age, gender, and ethnicity. Clinical manifestation included presence of symptoms, such as hypothalamic dysfunction, hypoventilation, autonomic dysregulation, neuroendocrine tumors, and neurologic or other remarkable reports. Data regarding the laboratory findings, management strategy, and clinical outcomes were also examined.

2.6. DNA Preparation, Whole Exome Sequencing, Sequence Alignment, and Variant Calling

This study was approved by the institutional review board of the Severance Hospital, Yonsei University Health System (IRB No.2017-2991-001). There were two patients with ROHHADNET with available samples, Case 1 [7] and Case 2 [8] (Supplementary Table S2). After obtaining informed consent, whole blood (3 ml) was collected from the two individuals with ROHHADNET. Genomic DNA was extracted using RBC Lysis Solution, Cell Lysis Solution, and Protein Precipitation Solution (iNtRon Biotechnology, Inc). Whole exome capture was performed using the Agilent SureSelect V5 enrichment capture kit (Agilent Technologies). The enriched library was then sequenced using the HiSeq 2500 sequencing system (Illumina; 101-base paired-end sequencing). Image analysis and base calling were performed with the Pipeline software (Illumina) using default parameters. Sequence reads were mapped to the human reference genome assembly (GRCh37/hg19) using the CLC Genomic Workbench (version 9.0.1) software (QIAGEN). Mapping was performed using the “Map Reads to Reference” function of the CLC Genomic Workbench software with the following settings: mismatch cost, 2; insertion cost, 3; deletion cost, 3; length fraction, 0.5; similarity fraction, 0.9; and map to nonspecific reads, random. Nonspecific reads were ignored for count and coverage. All variants with a minimum coverage of 2 were called using the “Basic Variant Caller” function of the CLC Genomic Workbench and annotated.

2.7. Filtering and Evaluation of Variants

Whole exome sequencing was analyzed as previously described [9]. Briefly, variants with minor allele frequencies >1% in the single nucleotide polymorphism (dbSNP; version 138) or 1000 genomes (2504 individuals; phase 3 data) databases were excluded. In the second step, variants present in the homozygous or hemizygous state in 59 healthy individuals without ROHHAD syndrome (internal control WES data) were excluded. In step 3, synonymous variants and intronic variants not located within splice site regions were excluded. In step 4, a recessive inheritance pattern was assumed on the basis of the pedigree of affected individuals. Therefore, homozygous and biallelic compound heterozygous variants were retained, while single heterozygous variants were excluded from further evaluation. In Case 1 who was a male, hemizygous variants were also considered. De novo variants could not be evaluated because parental DNAs were not available. In the final step, the remaining variants were ranked based on conservation of the mutated amino acid residue across species and their probable impact on the function of the encoded protein. The remaining variants were confirmed in the original participant DNA samples by Sanger sequencing.

2.8. Copy Number Variant (CNV) Analysis

Analysis of CNV was performed using the paired-end WES data using the EXCAVATOR version 2.2 [10] and ExomeDepth version 1.1.10 tools [11] with default settings. The GRCh37/hg19 database was used as the reference assembly for calculation of GC content. The WES dataset of 11 internal control subjects was compared with that of the study participants. Copy number variations at specific target regions were estimated according to different CNV detection algorithms using the Agilent SureSelect V5 kit.

3. Results

In total, 321 articles were identified using electronic and manual search methods (Figure 1). After serially reviewing the titles, abstracts, and full texts, 46 eligible studies including 158 patients were included. Among them, there were 36 case reports available for individual patient data (IPD; 48 patients, 23 ROHHAD and 25 ROHHADNET) [3, 4, 7, 8, 12–43]. The remaining ten studies were reporting patients in groups or cohorts and were therefore available for aggregate patient data (APD; 110 patients, 71 ROHHAD and 39 ROHHADNET) [6, 44–50].

Data regarding gender were available in 100 patients (40 from IPD and 60 from APD). There were 65 females and 35 males showing female preponderance, and female to male ratio was 1.9 to 1. Aside from gender, most of clinical information was extracted from 36 case reports where IPD were available. Limited information was retrievable from 10 studies with APD. Detailed profiles of the studies and patients’ data are presented in Tables 1 and 2.

Table 1: Summary profiles of individual patient data (IPD) of ROHHADNET syndrome (case-reports).

No.
Patient No.
Authors, year
Age/Sex
Height (cm)/Weight (kg)/BMI
Presenting symptoms
Rapid obesity
Hypothalamic dysfunction
Hypoventilation
Autonomic dysregulation
Behavioral changes
Neurologic findings
Neural crest tumor
Other findings
Na (mmol/L)
Prolactin (ng/mL)
fT4 (ng/dL)
Treatment
Outcome

1
1
Park, 2010 [7]
13/M
161/70.6/28
Pain on both thighs, gait disturbance, general weakness, cold body sensation
No
Yes
Yes
Yes
No
Seizure
Ganglio-
neuroma
Rhabdo-
myolysis
198
35.8 > 13.
0.5 > 0.8
Hydration,
IVIG
Alive

2
2
Thaker,
2015 [12]
2/M
163 (11 yr)/166.3 (11 yr)/62
-
No
No
No
Yes
Yes
No
No
No
Normal
-
1.04
-
Alive

3
3
Gordon,
2015 [13]
4/F
-/-/-
-
No
DI
Sleep apnea
Yes
No
No
Ganglio-
neuroblast
oma
No
-
Hyper-
prolactinemia
Hypo
-
thyroidism
Caffeine
Alive

4
4
Tellingen, 2015 [14]
4/F
-/-/-
Rapid weight gain, growth retardation
Yes
DI
Yes
No
No
No
Ganglio-
neuroma
No
-
-
Hypo
-
thyroidism
-
Alive

5
5
Grudnikoff,
2013 [15]
4/F
-/-/-
Weight gain, growth retardation, irritability, aggression
Yes
Yes
Sleep apnea
No
Yes
No
Ganglio-
neuroma
No
-
-
-
-
Alive

6
6
Patwari, 2011 [16]
8/F
150/45>80/36
-
Yes
Precocious puberty
Sleep apnea
Pupil dilatation
Yes
No
Ganglio-
neuroblast
oma
Pneumonia,
scoliosis
158
56
-
Artificial
ventilation
Alive

7
7
Sartori, 2012 [17]
4/M
-/-/-
-
Yes
Polyuria,
polydipsia
Sleep apnea
Yes
Yes
No
No
No
Normal
Hyper-
prolactinemia
-
IVIG,
artificial
ventilation
Alive

7
8
Sartori,
2012 [17]
5/F
-/-/-
-
Yes
Yes
Yes
No
Yes
No
No
No
-
-
Central
hypo-
thyroidism
-
Alive

8
9
Dhondt,
2013 [18]
3/F
-/-/-
Stagnation of neurodevelopment,
aggression,
hyperphagia
Yes
Precocious puberty
Yes
Yes
Yes
Yes
No
No
-
-
-
Artificial
ventilation
Alive

9
10
Bougnères, 2008 [19]
4/-
-/-22
-
Yes
Yes
Yes
Yes
Mental retardation,
psychosis
No
Ganglio-
neuroma
No
156
19
8.5
-
Alive

9
11
Bougnères,
2008 [19]
3/-
-/-/40
-
Yes
Yes
Sleep apnea
Yes
Mental retardation
No
Ganglio-
neuroma
No
161
39
9.8
-
Alive

9
12
Bougnères,
2008 [19]
3/-
-/-/29
-
Yes
Yes
Yes
Yes
No
No
Ganglio-
neuroma
No
150
14
17.1
-
Alive

9
13
Bougnères,
2008 [19]
3/-
-/-/35
-
Yes
Yes
Sleep apnea
Yes
No
No
Ganglio-
neuroma
No
151
22
16
-
Alive

9
14
Bougnères,
2008 [19]
2/-
-/-/24
-
No
Yes
Yes
Yes
No
No
Ganglio-
neuroma
No
145
31
16
-
Alive

9
15
Bougnères,
2008 [19]
2/-
-/-/44
-
No
Yes
Yes
Yes
No
No
Ganglio-
neuroma
No
149
34
12.4
-
Alive

10
16
Paz-Priel,
2011 [20]
5/F
-/-/17 > 25
-
Yes
Yes
No
Left exotropia
Aggressive
behavior
No
Ganglio-
neuroblast
oma
No
-
76.5
Normal
Cyclophosphamide,
IVIG,
prednisone,
rituximab
Alive

11
17
Chandrakantan,
2012
[21]
5/F
108/29/25
-
Yes
DI
Yes
Pupil dilatation,
pupil response decrease
No
No
Ganglio-
neuroblast
oma
No
Hyper Na
Hyper-
prolactinemia
-
Artificial
ventilation,
tracheostomy
Alive

11
18
Chandrakantan,
2012
[21]
9/F
137/54/29
-
Yes
DI
Yes
Chronic constipation,
neurogenic
bladder
No
Developmental
delay
No
No
Hyper Na
-
-
Noninvasive
mask
Alive

12
19
Kocaay,
2014
[22]
13/F
145/69/32 (10 yrs)
Respiratory distress,
cyanosis
Yes
Hypogonadism,
secondary amenorrhea,
precocious puberty
Yes
No
Social withdrawal
Drowsiness
No
Megaloblastic
anemia,
acanthosis
nigricans,
Raynaud
phenomenon
151
1.044 (10 yrs)
0.88
-
Alive

13
20
Sumanasena,
2012 [23]
10/F
-/35/-
Progressive
respiratory difficulty,
edema
Yes
No
Yes
No
Hallucination
Drowsiness
Ganglio-
neuroma
No
167
Normal
-
-
Alive

14
21
Abaci,
2013 [3]
3/M
92 > 95.8 (9 mo)/20 > 25.7 (9 mo)/24>28
Cyanosis,
recent onset dyspnea
Yes
Polyuria,
polydipsia
Yes
No
Yes
No
Ganglione
Uroblasto
ma
No
143
44.7
0.75
Cyclophosphamide,
IVIG,
dexamethasone,
rituximab
Alive

15
22
Atapattu,
2015
[24]
4/F
-/-/-
Excessive weight gain,
increase food seeking,
daytime somnolence
Yes
No
Yes
No
Yes
No
Ganglione
uroma
Celiac
disease
-
-
-
Hypertension
medication
Alive

16
23
Uçar,
2013
[8]
6/F
-/-/-
Blurring of consciousness,
recurrent fever
No
GH deficiency
Yes
No
No
Yes
Hamartoma
tous
mass
with neural
elements
No
152
89
-
Desmopressin acetate,
ventilatory support
Alive

17
24
Sethi,
2014 [25]
5/F
117/25 > 37/14>28
Behavior outbursts,
poor school performance,
hyperphagia,
fever,
abdominal pain with rectal prolapse
Yes
Yes
No
Bilateral tonic pupils
Yes
No
Ganglione
uroblasto
ma
Metabolic
alkalosis
HypoNa
-
Normal
Endotracheal intubation,
risperidone, benzodiazepines,
antipsychotic medications
Multiorgan failure,
death

18
25
Gallizia,
2012 [26]
3/F
-/-/-
Rapid weight gain,
polyuria,
sleep apnea
Yes
Yes
Sleep apnea
No
No
No
No
No
-
Hyper-
prolactinemia
Normal
-
Alive

18
26
Gallizia,
2012
[26]
3/F
-/-/-
Rapid weight gain, fatigue,
polydipsia,
syncope episodes,
strabismus,
behavioral problems
Yes
Yes
No
Strabismus
Yes
Yes
No
No
-
Hyper-
prolactinemia
Normal
Mechanical
ventilation
Alive

19
27
Baronio,
2013
[27]
1/M
-/-/-
Severe obesity,
hyperreninemic hypertension
Yes
No
No
No
No
No
Ganglione
uroblasto
ma
No
-
-
0.62
Mechanical
ventilation,
brain
hypothermia,
steroid pulse
Alive

19
28
Baronio,
2013
[27]
2/F
-/-/-
Severe obesity,
hyperreninemic hypertension
Yes
GH deficiency
No
No
No
No
Ganglione
uroblasto
ma
No
-
Hyper-
prolactinemia
0.17
Mechanical
ventilation,
brain
hypothermia,
steroid pulse
Alive

20
29
Chow,
2014 [28]
15/M
174/87/29
Fever, headache,
vomiting,
weight gain
Yes
No
No
No
Irritability, lethargy, somnolence
No
No
No
150>123
-
-
Mechanical
ventilation,
IVIG,
methylprednisolone
Alive

21
30
Kot,
2012
[29]
9/M
short stature/-/-
Weight gain,
short stature,
hyperphagia,
hypodipsia,
thermal dysregulation,
excessive perspiration,
cold extremity,
livedo reticularis,
sleep apnea
Yes
Hypodipsia, GH
deficiency
Sleep apnea
Yes
No
No
No
No
161
Hyper-prolactinemia
Normal
GH replacement
Alive

22
31
Cemeroglu,
2015 [30]
5/-
-/-/-
Short stature,
obesity
Yes
DI, GH
deficiency
Sleep apnea
Yes
Flat affect
No
No
Scoliosis
157>153
-
0.9>0.5
GH
replacement,
levothyroxine, desmopressin,
tonsillectomy,
adenoidectomy, CPAP
Alive

23
32
Chew,
2011 [31]
11/M
-/35/26
Fever, drowsiness,
shallow breathing
No
DI,
hypogonadism
Sleep apnea
Thermal dysregulation,
excessive sweating,
right divergent squint
0
Seizure, developmental delay
No
Respiratory
acidosis
192
Hyper-prolactinemia
Normal
Anti-epileptics
Alive

24
33
Petty,
2014 [32]
-/M
-/-/-
Weight gain,
enuresis,
sleep apnea, fever
Yes
No
Yes
Transient visual loss
Hallucination
No
No
Thrombocy
topenia
-
-
-
IVIG,
CPM,
rituximab
Alive

25
34
Maksoud,
2015
[33]
6/F
119/38/27
Abdominal
mass,
rapid onset obesity
Yes
Premature
thelarche, GH
deficiency
Sleep apnea
Urinary incontinence
No
No
Ganglione
uroma
Hepatitis C
156
-
0.79
-
Alive

26
35
Sanklecha,
2016 [34]
2/F
-/-/-
Gait disturbance,
head jerky movement, nystagmus
Yes
DI, polyuria,
polydipsia
Yes
No
Aggressiveness
Seizure
Ganglione
uroblasto
ma
No
189>115
-
-
Chemotherapy,
mechanical ventilation, tracheostomy,
nasal BIPAP,
rituximab, CPM
Cardiac arrest, sudden demise

27
36
Erensoy,
2016 [35]
8/F
-/-/-
Overweight,
recession, fatigue,
decreased school success
Yes
No
No
No
Poor school performance, MDD, ADHD
No
No
No
-
-
-
Fluoxetine,
methylphenidate
Alive

28
37
Al-Harbi,
2016 [36]
8/F
126/45/28
Progressive fatigue,
skin bluish discoloration,
fever
Yes
Breast enlargement
Shortness of breath, sleep apnea
Cold intolerance, excessive sweating,
altered pain sense
Slow mental function, poor school performance, sleepiness
No
No
No
186
Hyper-prolactinemia
Normal
BIPAP
Alive

29
38
Aljabban,
2016 [37]
4/F
110/25/-
Rapid weight gain,
excessive eating
Yes
polyuria,
polydipsia
Sleep apnea
Cold extremity,
GI dysmotility
Mood alteration, anxiety, aggressiveness, recurrent fatigue, social withdrawal, sleepiness
Seizure
Ganglio-
neuroma
No
Normal > 162
-
Normal
Antipsychotics,
mechanical ventilation,
tracheostomy
Cardiac arrest, death

30
39
Bagheri,
2017 [4]
5/F
120/40/-
Cough,
cyanosis
Yes
Central
hypothyroidism
Sleep apnea
Cold extremities, hyperhidrosis, constipation
Mood change
Seizure
Ganglio-
neuroblast
oma
Facial
plethora,
buffalo
neck
125
Hyper-prolactinemia
0.8
Mechanical
ventilation,
tracheostomy
Alive

31
40
Galewicz-zielinska,
2012
[38]
9/-
-/-/-
-
No
No
Mixed sleep
apnea
No
Yes
No
No
Tonsillar
hypertrophy
-
-
-
BIPAP
Alive

32
41
Jacobson,
2016 [39]
2/F
-/-/40
Hyperphagia,
weight gain (16.8 > 35.5 kg)
Yes
Partial
DI
Sleep apnea
Reduced pain perception,
strabismus
Social withdrawal, autism
No
Ganglio-
neuroblast
oma
Papular
rash
-
-
-
Rituximab,
cyclophosphamide
Alive

32
42
Jacobson,
2016 [39]
3/M
-/-/34
Hyperphagia,
weight gain (18 kg for 3 mo)
Yes
Yes
Sleep apnea
excessive sweating,
thermal dysregulation,
enuresis,
altered pain sense,
strabismus
Social withdrawal
No
No
No
-
Hyper-prolactinemia
-
Rituximab,
CPM
Alive

33
43
Lucas-Herald,
2012 [40]
1/F
-/32 (3 yr)/22
Hyperphagia,
food stealing
Yes
Hyper-prolactinemia, GH deficiency, water imbalance
Sleep apnea
Altered pain perception
No
No
No
Renal
failure
184
-
-
BIPAP
Alive

33
44
Lucas-Herald,
2012 [40]
2/M
-/33/29
Obesity
Yes
Hyper-prolactinemia, failed GH
Mixed sleep apnea
No
No
No
No
No
-
-
-
BIPAP
Alive

34
45
Ibanez-Mico,
2017 [41]
2/F
-/-/-
Obesity,
increased appetite
Yes
Hyper-prolactinemia, Central hypothyroidism

Sleep apnea
Yes
Aggression, hyperactivity, impulsivity
Yes
No
Altered
pain sense,
GI
dysmotility
175
166
1.05
IVIG, steroids,
cyclophosphamide
Tracheostomy
Sudden death

35
46
Isasa,
2018 [42]
10/M
136/66.5/34.92
Seizures (hyponatremia)
Yes
Hyper-prolactinemia
Central hypothyroidism
Central hypoventilation
Thermal dysregulation
Polydipsia
Aggressiveness
Yes
No
No
Hyper-/hypo-
-
-
-
Alive

36
47
Siraz,
2018 [43]
7/F
130/61/36.0
obesity
Yes
Central hypothyroidism
DI, MDD, Central precocious puberty
GH deficiency
Hyper-prolactinemia
Secondary adrenal insufficiency
No
Excessive sweating
hypothermia
No
No
No
Pulmonary hyper-tension
IQ 65
156
33
0.7
-
Alive

36
48
Siraz,
2018 [43]
5/F
101/31/30.4
Obesity,
seizure
Yes
Central hypothyroidism
Hyper-prolactinemia
Central
hypoventilation
Yes
Aggressiveness
Yes
No
Central cyanosis
IQ of 3 years of age
164
56
0.8
Tracheostomy
Alive

ADHD, attention deficit hyperactivity disorder; BIPAP, bilevel positive airway pressure; CPAP, continuous positive airway pressure; CPM, cyclophosphamide; DM, diabetes mellitus; DI, diabetes insipidus; IVIG, intravenous immunoglobulin; IQ, intellectual quotient; GH, growth hormone; GI, gastrointestinal; OCD, obsessive-compulsive disorder; SIADH, syndrome of inappropriate antidiuretic hormone secretion.

Table 2: Summary profiles of aggregate patient data of ROHHADNET syndrome (case-series and cohorts).

Author, year
N° patients
Age (yr)
Sex (M/F)
Rapid obesity
Hypothalamic dysfunction (N° patients)
Hypoventilation (N° patients)
Autonomic dysregulation (N° patients)
Behavioral changes (N° patients)
Neurologic symptoms (N° patients)
Neuroendocrine tumors (N° patients)
Other findings (N° patients)
Na (mmol/L) (N° patients)
Treatment (N° patients)
Outcome (N° patients)

Gil, 2012 [44]
5
-
-
Yes
Yes(5), hypothyroidism(1), adrenal insufficiency(1),
precocious puberty(1)
Central apnea(2), transient obstructive apnea(2)
Yes(5)
Yes(2)
No
Ganglio-neuroma
(3)
No
-
-
Death(1)

Reppucci, 2014 [45]
7
8.3
(4.7~10.1)
-
Yes
No
Yes(3), sleep apnea(5)
No
No
No
Yes
No
-
-
Alive

Barclay, 2016 [51]
16
4.3
-
No
Yes(16)
Yes(16),
Yes(16)
No
No
Yes(7)
No
-
Artificial ventilation(16)
Alive

Biancheri, 2013 [46]
6
-
2/4
Yes
Hypothyroidism(5),
adrenal insufficiency(2),
precocious puberty(2)
Central apnea(4)
No
Yes(6)
No
No
No
Electrolyte imbalance (6)
-
Alive

Napoli, 2014 [47]
6
2~4
-
Yes
Hypothyroidism(5),
adrenal insufficiency(3),
precocious puberty(2)
Central apnea(4)
No
Yes(6)
No
No
No
Electrolyte imbalance (6)
Non-invasive ventilation
Alive

Napoli, 2014 [47]
7
-
-
Yes(7)
Hypothyroidism(6),
adrenal insufficiency(4),
precocious puberty(2)
Sleep apnea(7)
No
Yes(7)
No
Ganglio-neuroma
(3)
No
-
-
Alive

Ize-Ludlow, 2007 [6]
15
-
6/9
Yes(8)
Hypothyroidism(5), adrenal insufficiency(4),
precocious puberty(2),
delayed puberty(2), amenorrhea(1), irregular menstruation(1),
premature adrenarche(2), hypogonadism(1),
SIADH(2), polydipsia(8), hypodipsia(4), polyuria(4)
Alveolar hypoventilation
(15). sleep apnea(8), cyanosis(4)
Ophthalmologic manifestations
(13), thermal dysregulation
(11), GI dysmotility(10), Altered pain perception(8),
altered sweating(8), cold extremity(6)
Depression(2),
flat effect(2), psychosis(2), behavioral outbursts(1),
bipolar disorder(1), emotional lability(1),
OCD(1), oppositional-defiant disorder(1),
Tourette’s syndrome(1), hallucination(1)
Syncope(1),
developmental delay(3), regression(3), seizure(5), hypotonia (4)
Yes(5)
Scoliosis(3), type 2 DM(2), enuresis(4), asthma(3), hyper-somnolence(2), pneumonia(2)
HyperNa (7), hypoNa (2)
-
Cardiac arrest(9)

Barclay, 2015 [48]
35
-
14/21
Yes
Yes(35)
Yes(35)
Yes(35)
No
No
Yes(15)
No
-
Artificial ventilation (35)
Alive

Gueorguieva, 2011 [49]
9
0~4
-
No
Hypogonadism(4)
Yes(9)
Yes(9)
Mental retardation(4)
No
Ganglio-neuroma
(6)
No
Mean 150
-
Death (2)

Abel, 2010 [50]
4
-
1/3
Yes
No
Alveolar hypoventilation
Thermal dysregulation, cold extremity, altered pain perception
Emotional lability, behavioral outburst
No
No
No
-
-
Alive

3.1. Individual Patient Data (IPD) from Case Reports

There were 48 patients in the 36 case reports, in which 100% were pediatric cases. The median age at the time of diagnosis was 4.0 years (range, 1-15). Twelve patients (12/40, 30 %) were boys, 28 (28/40, 70%) were girls, and no information could be retrieved in the 8 remainders. Female to male ratio from IPD was 2.3 to 1.

3.1.1. Clinical Presentation

The most common presentation of patients with ROHHAD/NET was rapid obesity and hypothalamic dysfunction found in 40 cases (83%) respectively, followed by hypoventilation reported in 36 cases (75%). Hypothalamic dysfunction presented in various forms of endocrine disorder, such as growth hormone deficiency (25%), diabetes insipidus (19%), and central precocious puberty (15%). Hypoventilation most commonly presented as obstructive sleep apnea (44%). For symptoms of autonomic dysregulation, ophthalmologic abnormality such as blurred vision was most commonly reported (25%), followed by altered pain perception (13%) and gastrointestinal dysmotility (13%). Excessive sweating was noted in 10% of the patients. Behavioral change was a common (60%) form of cognitive dysfunction, and the symptoms included mood changes, fatigue, social withdrawal, poor school performance, and intellectual disability. Other neurologic manifestations majorly included seizures, altered consciousness, sleep disturbance, and developmental delay. The clinical presentations of the patients are summarized in Table 3.

Table 3: Clinical presentations of patients with ROHHADNET syndrome (IPD).

Clinical findings
Total number of patients (n=48)

Number of patients ()

Rapid obesity
40 (83.3)

Hypoventilation
36 (75.0)

    Obstructive sleep apnea
21 (43.8%)

    Respiratory distress
5 (10.4%)

    Cyanotic episodes
4 (8.3%)

Hypothalamic dysfunction
40 (83.3)

    Growth hormone deficiency
13 (25.3%)

    Diabetes insipidus
9 (18.8%)

    Polyuria/polydipsia
8 (16.7%)

    Central precocious puberty
7 (14.6%)

    Hypogonadotropic hypogonadism
2 (4.2%)

    Premature thelarche
2 (4.2%)

Autonomic dysregulation
32 (66.7)

    Ophthalmologic abnormality
12 (25.0%)

    Altered perception of pain
6 (12.5%)

    Gastrointestinal dysmotility
6 (12.5%)

    Cold extremity
4 (8.3%)

    Neurogenic bladder
4 (8.3%)

    Excessive sweating
5 (10.4%)

    Thermal dysregulation
3 (6.3%)

    Syncope
1 (2.1%)

    Urinary incontinence
1 (2.1%)

Behavioral disorders
29 (60.4)

    Irritability & aggression
10 (20.8%)

    Fatigue
4 (8.3%)

    Social withdrawal
4 (8.3%)

    Poor school performance
3 (6.3%)

    Intellectual disability
2 (4.2%)

     Mood change
2 (4.2%)

    Flat affect
2 (4.2%)

    Hallucination
2 (4.2%)

    Major depressive disorder
1(2.1%)

    Attention deficit disorder
1(2.1%)

    Psychosis
1(2.1%)

Neurologic abnormality
16 (33.3)

    Seizure
7 (14.6%)

    Blurring of consciousness
4 (8.3%)

    Sleep disturbance
3 (6.3%)

    Developmental delay
3 (6.3%)

    Gait disturbance
2 (4.2%)

    Nystagmus
1 (2.1%)

    General weakness
1 (2.1%)

Other findings

    Fever
6 (12.5%)

    Papular rash
3 (6.3%)

    Enuresis
2 (4.2%)

    Scoliosis
2 (4.2%)

    Rhabdomyolysis
1 (2.1%)

    Pneumonia
1 (2.1%)

    Headache
1 (2.1%)

    Megaloblastic anemia
1 (2.1%)

    Thrombocytopenia
1 (2.1%)

    Acanthosis nigricans
1 (2.1%)

    Raynaud phenomenon
1 (2.1%)

    Celiac disease
1 (2.1%)

    Metabolic alkalosis
1 (2.1%)

    Hepatitis C
1 (2.1%)

    Buffalo neck
1 (2.1%)

    Tonsillar hypertrophy
1 (2.1%)

    Abdominal mass
1 (2.1%)

    Renal failure
1 (2.1%)

    Edema
1 (2.1%)

    Pulmonary hypertension
1 (2.1%)

    Cough
1 (2.1%)

3.1.2. Laboratory Findings

In 13 patients who had available datasets, all had hypoxemia at initial presentation and hypercapnia was also dominant (14/15, 93%; Table 4). Dysnatremia was accompanied in most of the patients (30/31, 97%): 25 hypernatremia and 5 hyponatremias. Hyperprolactinemia (27/28, 96%), decreased IGF-1 level (12/16, 75%), and hypothyroidism (18/30, 60%) were also common.

Table 4: Laboratory findings of patients with ROHHADNET syndrome (IPD).

Laboratory findings
Total number of patients (n=48)

Number of patients ()

ABGA

    Hypoxemia
13/13(100%)

    Hypercapnia
14/15 (93.3%)

    Normal
0/15 (0%)

    No information
34/48 (70.8%)

Dysnatremia

    Hypernatremia
25/31 (80.6%)

    Hyponatremia
5/31 (16.1%)

    Normal
2/31 (6.5%)

    No information
17/48(35.4%)

Prolactin

    Hyperprolactinemia
27/28 (96.4%)

    Normal
1/28 (3.6%)

    No information
19/48 (39.6%)

Thyroid dysfunction

    Hypothyroidism
18/30 (60.0%)

    Normal
12/30 (40.0%)

    No information
17/48 (35.4%)

IGF-1 level

    Low
12/16 (75.0%)

    Normal
4/16 (25.0%)

    No information
31/48 (64.6%)

ABGA: Arterial blood gas analysis, IGF-1: Insulin-like growth factor-1.

Hypoxemia is defined in terms of reduced partial pressure of oxygen below 80 mmHg or decreased oxygen saturation less than 90%.

Hypercapnia is defined in terms of elevated carbon dioxide above 45 mmHg.

3.1.3. Treatment Strategies and Survival

At the time of diagnosis, high proportion of patients (21/48, 44%) required respiratory support: mechanical ventilation in 20 (42%) cases and tracheostomy in 6 (13%) cases (Table 5). Six of the 44 (14%) patients were treated with steroids, while other immunosuppressive measures including rituximab and/or cyclophosphamide were administered in 7 cases (7/48, 14%). There were 4 deaths (3 sudden cardiac arrests and 1 multiorgan failure after sepsis) out of the 48 cases (Table 1).

Table 5: Treatment of case-reported patients with ROHHADNET syndrome (IPD).

Treatment
Total number of patients (n = 48)

Number of patients ()

Respiratory support
21 (43.8)

    Mechanical ventilation
20 (41.7%)

    BIPAP
7 (14.6%)

    CPAP
1 (2.1%)

    Noninvasive mask
1 (2.1%)

    Tracheostomy
6 (12.5%)

Steroids
7 (14.6)

    Methylprednisolone
2 (4.2%)

    Steroid pulse therapy
2 (4.2%)

    Prednisolone
2 (2.1%)

    Dexamethasone
1 (2.1%)

Fluid resuscitation
4 (8.3)

Intravenous immunoglobulins
7 (14.6)

Immunosuppressive agents
7 (14.6)

    Rituximab
5 (10.4%)

    Cyclophosphamide
6 (12.5%)

Other agents

    Antipsychotics
3 (6.3%)

    Desmopressin acetate
2 (4.2%)

    GH replacement
2 (4.2%)

    Anti-epileptics
2 (4.2%)

    Levothyroxine
4 (8.3%)

    Caffeine
1 (2.1%)

    Hypertensive medication
1 (2.1%)

Procedure
2 (4.2)

    Brain hypothermia
1 (2.1%)

    Tonsillectomy
1 (2.1%)

BIPAP: bilevel positive airway pressure; CPAP: Continuous Positive Airway Pressure; GH: growth hormone.

3.1.4. Tumor Presentation

Out of 48 patients, twenty-five had neuroendocrine tumors (52.1%). The features of the tumors are described in Table 6. The most common type was ganglioneuromas: 15 ganglioneuromas (60%), 9 ganglioneuroblastomas (36%), and 1 hamartoma with neural tissue (2%). Although the lesions usually presented as intra-abdominal mass, 2 cases with mediastinal masses were reported.

Table 6: Tumor presentation of patients with ROHHADNET syndrome (IPD and aggregate data).

Author, year [ref]
Type/histology
Location/size
Associated symptoms/signs
Treatment

Park, 2010 [7]
Ganglioneuroma
Right adrenal
N/A
IVIG

Gordon, 2015 [13]
Ganglioneuroblastoma
Left adrenal
N/A
N/A

Tellingen, 2015 [14]
Ganglioneuroma
N/A
N/A
N/A

Grudnikoff, 2013 [15]
Ganglioneuroma
N/A
N/A
resection

Patwari, 2011 [16]
Ganglioneuroblastoma
Right paraspinal
N/A
N/A

Bougnères, 2008 [19]
Ganglioneuroma (6 patients)
1 mediastinal
2 right adrenal
3 left adrenal
N/A
N/A

Paz-Priel, 2011 [20]
Ganglioneuroblastoma
Retroperitoneal mass
Opsoclonus- myoclonus-ataxia syndrome
resection, cyclophosphamide, IVIG

Chandrakantan, 2012 [21]
Ganglioneuroblastoma
Left adrenal
N/A
resection

Sumanasena, 2012 [23]
Ganglioneuroma
Left adrenal
N/A
resection

Abaci, 2013 [3]
Ganglioneuroma/ intermixed type with favorable histology
Retroperitoneal mass
(6.5 × 3.5 × 2.0 cm)
N/A
Resection, cyclophosphamide, IVIG, dexamethasone

Atapattu, 2015 [24]
Ganglioneuroma
Right adrenal
N/A
resection

Ucar, 2013 [8]
Hamartomatous mass with neural elements of benign nature
Parahilar mass (2.5 cm)
N/A
Resection

Sethi, 2014 [25]
Ganglioneuroblastoma
Right adrenal mass
(4.0 × 3.0 × 4.0 cm)
N/A
N/A

Baronio, 2013 [27]
Ganglioneuroblastoma intermixed
N/A
Hypertension, Cushing syndrome
Resection

Maksoud, 2015 [33]
Ganglioneuroma
Paravertebral mass (8.0 × 3.5cm) compressing the right ureter
Right hydroureteronephrosis
Resection

Sanklecha, 2016 [34]
Ganglioneuroblastoma
Paravertebral mass
Gait disturbance
Resection, chemotherapy (not specified)

Aljabban, 2016 [37]
Ganglioneuroma
Posterior mediastinal mass
(10 × 10 cm)
N/A
resection

Bagheri, 2017 [4]
Ganglioneuroblastoma
Mediastinal mass (1.5 cm)
N/A
N/A

Jacobson, 2016 [39]
Ganglioneuroma
N/A
N/A
resection

IVIG, intravenous immunoglobulin; N/A, not available for information.

3.2. Aggregate Patient Data (APD)

The 10 studies with APD included 110 patients (Figure 1; Table 2). Although limited data were available regarding age, all of the reported were pediatric cases. Sixty patients were available for gender information: 23 males (38%) and 37 females (62%). Female predilection was consistently noted. Rapid-onset obesity was observed in 65% (71/110) of the patients. Hypoventilation was reported in 51/110 (46%) patients, 63% of them (32/51) presented with sleep apnea, supporting the findings from IPD. Autonomic dysfunction was reported in 80/106 (75%) patients and behavioral changes were observed in 40/110 (36%). There were 46/110 (42%) patients who had neuroendocrine tumors and ganglioneuroma was the most common type as in IPD (12/46; the remaining 34 were not available for histology). In line with the IPD results, dysnatremia was the most commonly observed electrolyte imbalance (21/27, 78%). Information regarding treatment strategies was available in 51 patients and 100% of them eventually received artificial ventilation. There were 12 deaths (9 sudden cardiac arrests and 2 not available for cause of death) out of the 110 patients. The frequencies and characteristics of clinical manifestation generally conformed to those from IPD.

3.3. Next Generation Sequencing

We described previously reported human candidate genes [6, 12, 51–54] for ROHHAD/NET in Table 7. None of these, however, have been identified in the patient cases to date. In our study, there were two ROHHADNET patients with available samples for whole exome sequencing: Case 1, a 15-year-old Korean boy [7]; and Case 2, a 5-year-old Turkish girl [8]. Details with regard to these two patients are briefed in Supplementary Table S2. Currently, there is no known genetic cause for ROHHAD or ROHHADNET [55]. To identify genetic variants related to ROHHAD syndrome, we performed WES for Case 1 and Case 2. Since ROHHAD syndrome in these individuals was sporadic and had childhood onset, we assumed the following inheritance patterns: (1) biallelic variants in recessive genes and (2) hemizygous variants in X-chromosome genes in Case 1. Variant filtering reduced the number of candidate genes to five in Case 1 and three in Case 2, respectively, as outlined in Supplementary Table S3. In Case 1, variant filtering was begun with 188,415 variants from the normal reference sequence. This number was reduced to 1,914 upon exclusion of homozygous and hemizygous variants in healthy domestic individuals, common variants (minor allele frequencies >1% in public databases), and synonymous variants. Upon considering only those genes with hemizygous variants or more than two variants in the same gene, the number of variants was further reduced to 50 variants (14 genes). Exclusion of artefacts by direct inspection of sequence alignment and exclusion of variants with minor allele frequencies < 0.005 in public databases left six variants in three candidate genes—PIK3R3, SPTBN5, and PCF11 (Supplementary Table S4). These variants were predicted likelihood to be deleterious for the function of the encoded protein in some prediction tools and PIK3R3, SPTBN5, and PCF11 are not linked to any disease phenotype in human yet. The WES of Case 2 was analyzed in the same manner to identify candidate variants (Supplementary Table S4), but none of them overlapped with variants identified in Case 1; SRMS and ZNF4 were not linked to any disease phenotypes, whereas mutations in KMT2B, which encodes lysine-specific methyltransferase 2B, cause childhood-onset dystonia [56]. All variants were confirmed by Sanger sequencing of the DNA of the affected individuals.

Table 7: Reported human candidate genes for ROHHAD/NET.

Gene
Location
Protein
Function
Reference Number

RAI1
17p11.2
p.R1089X
Craniofacial and nervous system development
Thaker et al. [12]

NTRK2
9q21.33
p.P204H
Tropomyosin receptor kinase B (TrkB),
Neuroendocrine /synaptic plasticity
Ize-Ludlow et al. [6]

NECDIN
15q11–q13
Necdin (p.V318A)
Hypothalamic/respiratory
De Pontual et al.[52]

ASCL1
12q23.2
Human achaete-scute homolog 1 (hASH1)
Neuroendocrine
De Pontual et al. [52]

PHOX2B
4p13,
Paired mesoderm homeobox protein 2B (NBPhox)
Respiratory/autonomic
Ize-Ludlow et al. [6]
De Pontual et al. [52]

BDNF
11p14.1
Brain-derived neurotrophic factor (BDNF)
Neuronal development/synaptic plasticity
Ize-Ludlow et al.[6]
Han et al. [53]

HCRT
17q21.2
Hypocretins
Sleep/wake regulation, energy balance, and the control of breathing
Barclay et al. [51]

HCRTR1
1p35.2
Hypocretin receptor type 1 (HcrtR1),
Sleep/wake regulation, energy balance, and the control of breathing
Barclay et al. [51]

HCRTR2
6p12.1
Hypocretin receptor type 2 (HcrtR2),
Sleep/wake regulation, energy balance, and the control of breathing
Barclay et al. [51]

HTR1A
5q12.3
5-hydroxytryptamine (serotonin) receptor 1A
Appetite control, energy regulation, autonomic response to homeostatic stress
Rand et al. [54]

OTP
5q14.1
Orthopedia (Otp) homeodomain protein
Hypothalamic expression, with an important role in hypothalamic cell specification in the developing hypothalamus
Rand et al. [54]

ADCYAP1
18p11.32
Adenylate Cyclase Activating Polypeptide 1
Maintenance of normal energy homeostasis, respiratory chemosensitivity and preventing neonatal hypoventilation at reduced body temperatures
Rand et al. [54]

In addition, we analyzed CNVs; has been previously abbreviated using WES in Case 1 and Case 2. The CNVs detected by both EXCAVATOR and ExomeDepth tools were 38 in Case 1 and 48 in Case 2, respectively. We specifically focused on deletion or duplication of alleles in an AR pattern; however, there was no surviving CNV upon manual inspection of WES data.

4. Discussion

ROHHAD/NET is a rare disease and differential diagnosis from other obesity syndromes or neuroendocrine disorders requires clinical suspicion based on its phenotype. The genetic basis of this syndrome is still unknown.

The first part of this study is a systematic review on phenotypes of ROHHAD/NET involving 46 studies with 158 patients. Clinical manifestation, laboratory findings, tumor characteristics, and patient courses were reviewed. The results showed that it has a pediatric onset and it is noteworthy that no adult case has been reported to date. There was a female preponderance, with the girls being twice as often affected than the boys, consistently in both IPD and APD. This finding is in contrast to what has been reported on acquired sleep disorders with a 2:1 predominance of males in the reported frequency of obstructive sleep apnea [57]. Rapid obesity may often be the first recognizable sign, since other endocrine dysfunctions are gradually present. The results implicated that common endocrine disorders such as hypothyroidism or precocious puberty may be early signs for recognition. In addition, it has been reported that one of the major effects of hypothyroidism is its influence on the central ventilatory control and that both hypoxic and hypercapnic ventilatory impairment are significantly present in untreated thyroid insufficiency [58]. Such impaired ventilatory responses are thought to be related to the decrease in oxygen consumption associated with hypothyroidism [59]. In that, it is tempting to speculate that disturbance of thyroid function may be in part responsible for respiratory distress in patients with ROHHADNET. Electrolyte imbalance, especially dysnatremia, was present in a majority of the patients, requiring attention. Impaired water balancing condition such as polydipsia or diabetes insipidus due to hypothalamic dysfunction may have caused dysnatremia. Ganglioneuromas were the most common type of accompanied tumor and may presented not only as abdominal but also as mediastinal masses. We therefore suggest that suspected patients take both thoracic and abdominal imaging to screen for tumors. As ROHHAD/NET involves progressive impairment of the respiratory center, we observed that artificial ventilation was commonly initiated from the first place. Cardiac arrest probably due to preceding respiratory arrest was the major cause of deaths in these patients. We noted that all of the patients were already exposed to hypoxemia at the time of diagnosis. We believe that earlier recognition and timely application of pressure supporting devices during sleep may improve the quality of life and prevent sudden death.

The second part of this study was a WES which attempted to identify the genetic basis of ROHHAD/NET. It has been noted that central hypoventilation syndrome (CHS) resulting from PHOX2B mutations is associated with tumors of neural crest origin (neuroblastoma, ganglioneuroblastoma, and ganglioneuroma) in approximately 6% of cases [59]. However, the association of ROHHADNET and PHOX2B mutations has not been identified. Recently, several studies have made progress in investigating genetic basis of ROHHAD/NET (Table 7). Thaker et al.[12] identified a de novo retinoic acid-induced 1 (RAI1) gene mutation in a child with ROHHAD and proposed RAI1 as a candidate gene for children with morbid obesity. Furthermore, there were studies which performed NGS in a set of ROHHAD/NET patients [6, 51, 52, 54]. Rand and colleagues [54] analyzed 5-hydroxytryptamine receptor 1A (HTR1A), orthopedia (OTP), and Adenylate Cyclase Activating Polypeptide 1 (ADCYAP1, formerly PACAP) genes which are involved in the embryologic development of the hypothalamus and autonomic nervous system in a set of 25 ROHHAD patients and 25 matched controls. Although there were no significantly correlating variations, this report provided evidence that variation of the HTR1A, OTP, and ADCYAP1 genes are unlikely responsible for ROHHAD/NET. Barclay et al. [51] analyzed 16 ROHHAD patients using a combination of NGS and Sanger sequencing. They examined mutations in the exons of the genes for hypocretin and accompanying receptors, namely, HCRT, HCRTR1, and HCRTR2, and found no rare or novel mutations. In this study, we also identified rare variants in two ROHHAD/NET patients. However, the causality of these variants remains unclear and demands further investigation. Nevertheless, we believe that accumulation of these attempts would contribute to progress.

There are some limitations in our research. Firstly, we could not analyze the relationship between the treatments and the subsequent outcomes. Secondly, there remains the possibility of existing case reports or series that were not accessible. Thirdly, some studies only had grouped data where IPD were not available. Nevertheless, this study also has its strengths in that it provides a pooled data and combined evidence on a disease of extreme rarity.

ROHHAD/NET is a rare disease, which has pediatric onset and female preponderance. Rapid obesity and hypothalamic dysfunction are earliest detectable signs. Prompt recognition and timely application of respiratory support may prevent grave complications leading to unprepared mortality. WES on 2 ROHHADNET patients identified no significant mutations or copy number variations. Further analyses of patients in prospective studies are required.

Data Availability

The data used to support the findings of this study are included within the main manuscript and the supplementary information file.

Conflicts of Interest

The authors declare no conflicts of interest.

Authors’ Contributions

Jiwon M. Lee, Jaewon Shin, and Sol Kim contributed equally to the work

Acknowledgments

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2015R1D1A1A01056685 to Heon Yung Gee), and by Chungnam National University Hospital Research Fund (2017-CF-023 to Jiwon M. Lee).

Supplementary Materials

Supplementary Table : checklist summarizing compliance with PRISMA guidelines Supplementary Table : clinical details of the two patients included in WES. Supplementary Table : filtering process of whole exome sequencing analysis performed in two patients. Supplementary Table : possible variants identified in individuals with ROHHAD syndrome by WES. (Supplementary Materials)

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