Child and Chest Health Care Delhi NCR

• Anaphylaxis a potential life threatening condition.
• It is defined as a medical condition,which is rapid in onset(minutes to hours),allergic in nature and may culminate into death if left untreated.
• It is charachterised by acute onset urticaria,pruritus,edema of the face,lips,uvula,larynx with respiratory,cardiovascular,and gastrointesninal symptoms.
• It is very difficult to recognise the symptoms of anaphylaxix in infants as few symptoms like excessive cry with sudden calmness,excessive fussiness and excessive swaeting may be observed in infants not suffering from anaphylaxix.Moreover,infants can not express their symptoms.
• Majority of anaphylaxis have been observed in children rather than adults,all over the world.
• Most common allergen leading to anaphylaxis in children is food allergen.
• Most common food allergens are peanut,treenut,shellfish,egg and milk.
• Food preservatives,additives,coloring agents,and spices are potential allergens
• Galactose which is found in meat may be an allergen and the allergic manifestations due to it, may take 4-6 hours to appear.
• Some food allergens cause allergic reactions only after exercise ,when exercise is performed within 3-4 hours after taking meals.
• Some children are allergic to latex being used to manufacture gloves used for various procedure in hospital.
• Allergic reactions may be mediated through IgE or non IgE like IgG mediated in case of high molecular weight dextran use and direct release of mediators from cells after exercise.
• The incidence of anaphylaxis has increased enormously all over the world in last 2 decades.

DIAGNOSTIC CRITERIA:Any one of the following three ,makes it a diagnosis of anphylaxis-

1.Onset within minutes to hours(ACUTE) of generalised  itching,hives,swelling of lips,uvula,tounge and flushing(INVOLVEMENT OF SKIN AND/OR MUCOSAL TISSUES)  and one of the following two-

a.breathlessness,wheeze,bronchospasm,stridor.hypoxemia,reduced PEF(RESPIRATORY COMPROMISE)

b.Low blood pressure for the age or symptoms of end organ dysfunction in the form of collapse,hypotonia,incontinence or syncope.(HYPOTENSION)

2.Two or more of the following four:

a.Generalised involvement of skin and/or mucosal tissues

b.Respiratory compromise

c.Reduced blood pressure for the age or symptoms of end organ failure

d.Crampy abdominal pain,vomiting which is persistent(PERSISTENT GASTROINTESTINAL SYMPTOMS)

3.Low blood pressure

a. For infants one month to 12 months, systolic BP less than 70mm of Hg and  for children 1 year to 10 years Systolic BP less than 70+age in years OR >30% drop in systolic BP

b.For adults ,systolic BP <90mm of Hg OR >30% drop in systolic BP

ESSENTIAL CRITERIA IS ,THE ABOVE FEATURES SHUOLD BE INTERPRETED ONLY AFTER EXPOSURE TO KNOWN OR LIKELY ALLERGEN.

 

Triggers of anaphylaxis:Foods,medicines,vaccines,immunotherapy,insect venoms,latex,cold exposure and exercise.

IT MAY BE IDIOPATHIC

WHAT HAPPENS IN THE BODY(Pathogenesis): The main process is the release of mediators like histamine and  tryptase and cytokines from the cells like mast cell and basophils and possibly from macrophages. These mediators and cytokines produce allergic symptoms in whole body.

The release of these chemicals may be  IgE dependent or non IgE dependent.In case of IgE dependent, the child  must be exposed previously to an allergen which produces allergen specific antibody(IgE) which gets bound to mast cells. Upon reexposure these mast cells which are bound to IgE start releasing histamines and tryptase which is responsible for the symptoms.

Anaphylaxis may also be caused by release of mediators by the process than IgE mediated like direct release by medication like morphine,by physical factors like cold and exercise,disturbance of leukotriene metabolism like after use of aspirin and non steroidal anti inflammatory drugs,immune aggregates and complement activations like after ithe use of blood products,probably by complement activation like after the use of radiocontrast dyes and IgG mediated reactions like arter the use of humanised monoclonal antibodies and chimeric.

Pathological features are: airway obstruction,pulmonary edema  alveolar hemorrhage,visceral congestion ,laryngeal edema and angioedema. Vasomotor dilataton and/or cardiac dysrhythmia is responsible for hypotension (low BP)

INVESTGATIONS: It is a clinical diagnosis.No investgation is reliable,although serum tryptase level may be raised for several hours but not in food allergy.

TREATMENT:The mainstay of treatment is epinephrine(adrenaline).

 

It comes in the market in injectable form in 1ml ampoule of 1:1000 strength.It shuold be kept at around the temeratue of 25dC.It should be injected undiluted intramuscularly in lateral thigh in the dose of 0.01ml/kg upto a maximum of 0.5ml(1ml=1mg).It can be repeated at an interval of 5 to 15 minutes twice if symptoms persist and intravenous line has not been established.In case of persistent symptoms i.v line should be established and adrenaline drip should be started.For i.v. use the injection must be diluted to 1:10000 strength. In case of non establishment of i.v. line ,it can be given through endotracheal or intraosseous route.

Patient should be kept in supine position with leg end raised in case of hemodynamic compromise.

In case of non response,oxygen inhalation should be started after estalishing airway,N/S or R/L should be given in the dose of 30ml/kg over one hour if BP is low and salbutamol nebulisation should be given if there is bronchspasm.

In case of non responders specially in the users of beta blockres, glucagon should be used and for bronchodilation ipratropium should be used. Some patients may require vasopressin and in case of asystole and pulseless electrical activity atropine should be used.

Other drugs being used are: HI blocker-cetrizine in the dose of 0.25mg/kg upto a maximum of 10 mg  orally or Diphenhydramine in the dose of 1.25mg/kg upto a maximum of 50 mg orally or IM,H2blocker-ranitidine and corticosteroids

Crticosteroid-The dose of methyleprednisolone is 1-2mg /kg i.v upto a maximum dose of 125mg.(SOLUMEDROL)

Inramuscular dose is 1mg/kg upto a maximum of 80mg(DEPOMEDROL)

CAUTION:1. Rapid i.v. infusion or incorrect strength during i.v. use of adrenaline may cause pulmonary edema,hypertension and myocardial infarction

2.Rapid i.v. infusion of ranitidine may cause hypotension

Some patients may experience biphasic anaphylaxis. In this phenomenon,the features of anaphylaxix reappears after clinical resolution. In more than 90% of cases,it happens within 4 hours. So patients must be observed for at least 4 hours before discharge.

MANAGEMENT AFTER DEALING WITH EMERGRNCY:Antihistamine should be given for 3 days and it is optional to prescribe 3 days of oral corticosteroid.

REFERENCES:

Sampson, HA, Muñoz-Furlong, A, Campbell, RL. J Allergy Clin Immunol. vol. 117. 2006. pp. 391-7.

(A summary of the second international conference to develop a universally accepted definition of anaphylaxis, establish clinical criteria that would accurately identify cases of anaphylaxis with high precision, and review the evidence on the most appropriate management of anaphylaxis.)
Simons, FE. “Pharmacologic treatment of anaphylaxis: can the evidence base be strengthened”. Curr Opin Allergy Clin Immunol. vol. 10. 2010. pp. 384-93.

Sheikh, A, Shehata, YA, Brown, SG, Simons, FE. “Adrenaline for the treatment of anaphylaxis: Cochrane systematic review”. Allergy. vol. 64. 2009. pp. 204-12.

Sheikh, A, Ten Broek, V, Brown, SG, Simons, FE. “H1-antihistamines for the treatment of anaphylaxis: Cochrane systematic review”. Allergy. vol. 62. 2007. pp. 830-7.

Choo, KJ, Simons, FE, Sheikh, A. “Glucocorticoids for the treatment of anaphylaxis”. Cochrane Database Syst Rev. 2010 Mar 17. pp. CD007596.

Pumphrey, RS. “Lessons for management of anaphylaxis from a study of fatal reactions”. Clin Exp Allergy. vol. 30. 2000. pp. 1144-50.

Cox, L, Nelson, H, Lockey, R. “Allergen immunotherapy: a practice parameter third update”. J Allergy Clin Immunol. vol. 127. 2011. pp. S1-55.

Bock, SA, Muñoz-Furlong, A, Sampson, HA. “Fatalities due to anaphylactic reactions to foods”. J Allergy Clin Immunol. vol. 107. 2001. pp. 191-3.

Bock, SA, Muñoz-Furlong, A, Sampson, HA. “Further fatalities caused by anaphylactic reactions to food, 2001-2006”. J Allergy Clin Immunol. vol. 119. 2007. pp. 1016-8.

Pumphrey, RS, Gowland, MH. “Further fatal allergic reactions to food in the United Kingdom, 1999-2006”. J Allergy Clin Immunol. vol. 119. 2007. pp. 1018-9.

Greenberger, PA, Rotskoff, BD, Lifschultz, B. “Fatal anaphylaxis: postmortem findings and associated comorbid diseases”. Ann Allergy Asthma Immunol. vol. 98. 2007. pp. 252-7.

Simons, FE, Ardusso, LR, Bilò, MB. “International consensus on (ICON) anaphylaxis”. World Allergy Organ J. vol. 7. 2014. pp. 9.

Muraro, A, Roberts, G, Worm, M. “EAACI Food Allergy and Anaphylaxis Guidelines Group. Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology”. Allergy. vol. 69. 2014. pp. 1026-45.

Wood, RA, Camargo, CA, Lieberman, P. “Anaphylaxis in America: the prevalence and characteristics of anaphylaxis in the United States”. J Allergy Clin Immunol. vol. 133. 2014. pp. 461-7.

Lieberman, P, Nicklas, RA, Randolph, C. “Anaphylaxis–a practice parameter update 2015”. Ann Allergy Asthma Immunol. vol. 115. 2015 Nov. pp. 341-84.

(This practice parameter provides updated guidelines for the diagnosis and management of anaphylaxis using evidence from recent medical literature.)
Simons, FE, Ebisawa, M, Sanchez-Borges, M. “2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines”. World Allergy Organ J. vol. 8. 2015 Oct 28. pp. 32.

(This provides updated evidence supporting recommendations for the diagnosis and management of anaphylaxis.)
Lee, S, Hess, EP, Lohse, C. “Trends, characteristics, and incidence of anaphylaxis in 2001-2010: A population-based study”. J Allergy Clin Immunol. 2016 Jun 4. pp. S0091-6749.

(These data show an increase in the rate of anaphylaxis between 2001-2010 and describe differences in triggers affecting different age groups.)

Hereditary angioedema is a potential life threatening condition.

It requires earliest possible diagnosis and immediate treatment to save the life in certain cases.

It is caused by either deficiency of C1  inhibitor(Type 1) or dysfunction (Type 2).

It is an autosomal dominant disorder.

In a randomised control trial ,published in JAMA,Lanadelumab,a monoclonal human antibody against Kallikrein was proved to be very effective in reducing the frequency of attacks as well as reducing the severity of individual attack.The level of evidence is level 1,means excellent.

The study was conducted at 41 places in Canada,Jordan,Europe and United states. All the subjects included were previously diagnosed cases of Hereditary angioedema and all were more than 12 years of age.

84 patients were given Lanadelumab and 41 were given placebo.There was a run in period of 4 weeks preceded by 2 weeks of wash out period for any prophylactic treatment being used by patients knowingly or unknowingly. Patients were followed up for a period of 26 weeks for occurence of any episode of angioedema its severity, or any adverse effect of interventional medication.Patients were randomised 2:1 to receive Lanadelumab and placebo. The Lanadelumab receiving patients were divided into 3 groups, and the treatment period was of 26 weeks. The first group received Lanadelumab suncutaneously 150 mg every 4 weeks,second group received 300mg every 4 weeks and the third group 300mg every 2 weeks. The number of episode of angioedema and its severity was observed through a study period of 26 weeks. Adverse events were also observed.

In the group receiving 150mg Lanadelumab subcutaneously every 4 weeks,mean number of attack was 0.48(CI₉₅ 0.31-0.73) in comparision to mean number of attack 1.97 in the placebo group(CI₉₅ 1.64-2.36) ).In the group receiving 300mg of Lanadelumab every 4 weeks .the mean number of attack was 0.5((CI₉₅ 0.36-0.77) ) and for those receiving 300mg of Lanadelumab every 2 weeks the mean number of attack was 0.26(CI₉₅ 0.14-0.46) )

Patients receiving Lanadelumab had improved quality of life with reduced number of attacks(p<0.001),less use of anti C1 inhibitor medications( an20.2% vs 65.9%; p < 0.001) and less episode of moderate to severe attacks(p<0.001)

Adverse effects were seen in 98.5% cases and they were mild to moderate, including headace(7.1%),pain at the site of injection(41.7%),erythma at the site of injection(9.5%) and bruising at the site of injection(6%)

REFERENCES:

Pulmonology Advisor > Trial Tracker > Lanadelumab may be an effective prophylactic treatment for hereditary angioedema

Asthma is the most common chronic respiratory disorders in children.

Worldwide,the incidence of asthma has increased over the past few decades.

Mortality from asthma is still high even in this era of sophisticated diagnostic facilities and availabilities of advanced treatment modalities.

If the risk of getting asthmatic is predicted in children,the preventive measures can be applied to some extent.

Hperbilirubinemia is the most common clinical signs warranting treatment in neonates.

The level of serum bilirubin is an indicator of starting phototherapy.

In most of the cases,rise in serum bilirubin is physiological in newborns requiring only reassurance to the parents.

In some newborns,the rise in bilirubin may go unnoticed.

Now,there has been a retrospetive study of asthmatic children,relating the diseases to the level of serum bilirubin during neonatal period.

The study was conducted on 109,212 infants born at or after 35 weeks of gestation. The study centre was Kaiser Permanente Northern California Hospital.Total serum bilirubin was measured over all infants universally at the time of discharge and again at the age of one month.Other covariables were also included in the study like,age,race,ethnicity of mothers and sex,birth weight,gestational age and 5 minutes apgar scores of newborn.

The incidence of asthma,which was the main interest of study was defined as 2 or more visits to OPD with a physician diagnosed asthma and 2 or more asthma medications within a period of one year separeted by a period of one month after the child crosses the age of 2 years..

Among the infants in study group,the highest level of serum bilirubin was 18mg or more in 4.7% and 15mg or more in 16.7%.In 11.5% infants, phototherapy had to be given.

When compared with infants having serum bilirubin between 3-5.9gm/dl,the asthma risk was greater in infants having serum bilirubin level of 9-11.9mg/dl(hazard ratio [HR] 1.22; 95% CI, 1.11-1.34; P <.001),12-14.9mg/dl((HR, 1.18; 95% CI, 1.08-1.29; P <.001) and 15 to 17.9mg/dl(HR, 1.30; 95% CI 1.18-1.43; P <.001)

Interestingly the total serum bilirubin level at or more than 18 mg/dl did not show any correlation with incidence of asthma(HR, 1.04; 95% CI, 0.90-1.20; P =.9)

Induction of phototherapy did not increase the risk of asthma(HR, 1.07; 95% CI, 0.96-1.20).

The causal relationship between asthma and level of serum bilirubin could not be eastablished as the study was limited by its retrospective nature.

REFERENCES:

Kuzniewicz MW, Niki H, Walsh EM, McCulloch CE, Newman TB. Hyperbilirubinemia, phototherapy, and childhood asthma. Pediatrics. 2018;142(4):e20180662.

 

Congenital hypoventilation syndrome(CCHS) is a rare disorder.

It has myriad clinical presentations,affecting various systems.

It may present at birth or in adulthood depending on mutations.

If it presents in neonatal period,the person becomes ventilator dependent but lator on,may require ventilator only during sleep.

If it presents in adulthood,the person remains asymtomatic during entire childhood period.

Some affected individual becomes symptomatic only during respiratory infections,sedations or during anesthesia due to other surgical reasons.

Some individuals get detected only when there is great difficulties in weaning from ventilator due to any cause.

Some children get detected when they have abnormally high capacity to hold breath for a prolonged period.

Some adults and adolescents have been diagnosed only after they showed abnormally high capacity for a prolonged period to swim underwater.

Some affected individuals may have excessive episodic perspirations(sweating).

Affected individuals may be less sensitive to pain or less anxious in situations where normal individuals have symptoms of anxiety.

There is no sign of respiratory distress even when they are severly hypoxic or hypercapneic.

Following are the clinical manifestations from different systems/Organs:

RESPIRATORY SYSTEM; Alveolar hypoventilation,decreased perception of dyspnea

CARDIOVASCULAR SYSTEM:Increased sinus pause(more than 3 seconds),low day time blood pressure

orthostatic hypotension,bradycardia,less increase in BP after exercise,syncope

NERVOUS SYSTEM:less perception of pain,less anxiety,neurocognitive defect,sizure

GASTROINTESTINAL:Oesophageal dismotility,constipation,in 20%cases may Hirschprungs disease

ENDOCRINE:Hyperglycemia,hypoglycemia,hyperinsulinism

SKIN:Sporadic excessive swaeting

TUMOURS:Neuroblastoma,ganglioneuroma

OTHERS:Low baseline body temperature,heat tolerance may be poor.

CLINICAL PRESENTATIONS:In most of the cases it presents in neonatal period with apnea,hypoventilation of central origin with hypoxemia,hypercapnea and cyanosis.They require assisted ventilation,invasive or non invasive to survive.Once put on ventilator,they are unable to be weaned off from ventilator.As they grow and mature,some require assisted ventilation only during sleep.

Children and adults present with unexplained apnea,respiratory failure during respiratory infections or sedation requiring assisted ventilation.There is no sign of respiratory distress even they are severly hypoxemic or hypercapneic.They may present with unexplained seizure due to undetected hypoxemiaand/or hypercapnea for a prolonged period.

They may show unusual capacity to hold breath for a long time and unusually high capacity for underwater swimming. They may present with features of right heart failure confusing with congenital heart disease.

Older children and adults may present with features of pulmonary hypertension,or cor pulmonale

CAUSES:  Respiration is initiated by peripheral chemreceptors located in aortic and carotid bodies, which mainly sense changes in Po2 and to a lesser extent Pco2 and PH ,and central chemreceptors located in medulla, which sense changes in Pc02 and PH.Respiration is controlled by the centre located in medulla and pons which integrate the inputs from chemoreceptors and send signal to the respiratory muscles to perform the process of breathing.

PHOX2B gene, located on chromosome 4p12, is a protein comprising  314 amino acids with two short and stable polyalanine repeats of 9 and 20 residues in the C terminus. It encodes for highly conserved homeodomain transcription factor that is essential in the development of Respiratory control NEURONS and ANS.

CCHS is a result of mutational defect in PHOX2B gene.Normal PHOX2B gene has 20 alanine repeats (20/20 genotype). The majority of CCHS patients have polyalanine repeat mutations(PARM).

Variable clinical manifestations are the results of variable mutations.

DIAGNOSIS: After ruling out other cause of hypoventilations,by approriate investigations,all suspected cases should be confirmed by gene mutatin analysis for PHOX2B gene.There 3 methods available currently.

1.PHOX2B targeted mutation analysis

2.PHOX2B sequence analysis

3. Deletion/duplication test

MANAGEMENT: Goal of management is to provide adequate ventilatory support during both sleep and awake states to maintain pco2 at near to 35mmhg and aeterial saturation above 95%.For asymptomatic patients,it is important to remember that they may go intrespiratory decompensation while in stress,infections or sedations.

As these patients are unable to sense hypoxia as well as hypercarbia,spo2 monitoring and tco2 monitoring particularly during sleep is important.

MODES OF VENTILATORY SUPPORT:Invasive positive pressure ventilation through tracheostomy

Non invasive positive pressure ventilation

Diaphragmatic pacing

GENETIC COUNCELLING:PHOX2B gene mutation has autosomal pattern of inheritance with variable penetrance.

Genetic counseling is important as there is 50% chance of recurrence with each

child.So if a parent is affected,there is 50% chance for  siblings to get

affected

It is important to test parents of affected child even if they are asymptomatic.

 

 

 

References
1. Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Keens TG,
Loghmanee DA, Trang H. An official ATS clinical policy statement:
Congenital central hypoventilation syndrome: genetic basis, diagnosis,
and management. Am J Respir Crit Care Med. 2010;181(6):626–644.
2. Fleming PJ, Cade D, Bryan MH, Bryan AC. Congenital central
hypoventilation and sleep state. Pediatrics. 1980;66(3):425–428.
3. Huang J, Colrain IM, Panitch HB, et al. Effect of sleep stage on
breathing in children with central hypoventilation. J Appl Physiol.
2008;105(1):44–53.
4. Chen ML, Keens TG. Congenital central hypoventilation syndrome:
not just another rare disorder. Paediatr Respir Rev. 2004;5(3):182–189.
5. Weese-Mayer DE, Shannon DC, Keens TG, Silvestri JM. Idiopathic
congenital central hypoventilation syndrome: diagnosis and management.
American Thoracic Society. Am J Respir Crit Care Med.
1999;160(1):368–373.
6. Trang H, Dehan M, Beaufils F, Zaccaria I, Amiel J, Gaultier C. The
French Congenital Central Hypoventilation Syndrome Registry:
general data, phenotype, and genotype. Chest. 2005;127(1):72–79.
7. Shimokaze T, Sasaki A, Meguro T, et al. Genotype–phenotype relationship
in Japanese patients with congenital central hypoventilation
syndrome. J Hum Genet. 2015;60(9):473–477.
8. 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.
9. Weese-Mayer DE, Berry-Kravis EM, Zhou L, et al. Idiopathic
congenital central hypoventilation syndrome: Analysis of genes
pertinent to early autonomic nervous system embryologic development
and identification of mutations in PHOX2b. Am J Med Genet.
2003;123A(3):267–278.
10. Hasegawa H, Kawasaki K, Inoue H, Umehara M, Takase M. Japanese
Society of Pediatric Pulmonology Working Group (JSPPWG). Epidemiologic
survey of patients with congenital central hypoventilation
syndrome in Japan. Pediatr Int. 2012;54(1):123–126.
11. Kasi A, Perez I, Kun S, Keens T. Congenital central hypoventilation
syndrome: Diagnostic and management challenges. Pediatr Heal Med
Ther. 2016;7:99–107.
12. Maloney MA, Kun SS, Keens TG, Perez IA. Congenital central
hypoventilation syndrome: diagnosis and management. Expert Rev
Respir Med. 2018;12(4):283–292.
13. Kasi AS, Jurgensen TJ, Yen S, et al. Three-Generation Family
With Congenital Central Hypoventilation Syndrome and Novel
PHOX2B Gene Non-Polyalanine Repeat Mutation. J Clin Sleep Med.
2017;13(07):925–927.
14. Vanderlaan M, Holbrook CR, Wang M, Tuell A, Gozal D. Epidemiologic
survey of 196 patients with congenital central hypoventilation
syndrome. Pediatr Pulmonol. 2004;37(3):217–229.
15. Magalhães J, Madureira N, Medeiros R, et al. Late-onset congenital
central hypoventilation syndrome and a rare PHOX2B gene mutation.
Sleep Breath. 2015;19(1):55–60.
16. Doherty LS, Kiely JL, Deegan PC, et al. Late-onset central hypoventilation
syndrome: a family genetic study. Eur Respir J. 2007;29(2):312–316.
17. Barratt S, Kendrick AH, Buchanan F, Whittle AT. Central hypoventilation
with PHOX2B expansion mutation presenting in adulthood.
Thorax. 2007;62(10):919–920.
18. Trang H, Laudier B, Trochet D, et al. PHOX2B gene mutation in a
patient with late-onset central hypoventilation. Pediatr Pulmonol.
2004;38(4):349–351.
19. Mahmoud M, Bryan Y, Gunter J, Kreeger RN, Sadhasivam S. Anesthetic
implications of undiagnosed late onset central hypoventilation
syndrome in a child: from elective tonsillectomy to tracheostomy.
Pediatric Anesthesia. 2007;17(10):1001–1005.
20. Mahfouz AK, Rashid M, Khan MS, Reddy P. Late onset congenital
central hypoventilation syndrome after exposure to general anesthesia.
Can J Anaesth. 2011;58(12):1105–1109.
21. Antic NA, Malow BA, Lange N, et al. PHOX2B mutation-confirmed
congenital central hypoventilation syndrome: Presentation in adulthood.
Am J Respir Crit Care Med. 2006;174(8):923–927.
22. Repetto GM, Corrales RJ, Abara SG, et al. Later-onset congenital
central hypoventilation syndrome due to a heterozygous 24-polyalanine
repeat expansion mutation in the PHOX2B gene. Acta Paediatr.
2009;98(1):192–195.
23. Paton JY, Swaminathan S, Sargent CW, Keens TG. Hypoxic and
hypercapnic ventilatory responses in awake children with congenital
central hypoventilation syndrome. Am Rev Respir Dis.
1989;140(2):368–372.
24. Shea SA, Andres LP, Paydarfar D, Banzett RB, Shannon DC. Effect
of mental activity on breathing in congenital central hypoventilation
syndrome. Respir Physiol. 1993;94(3):251–263.
25. Diedrich A, Malow BA, Antic NA, et al. Vagal and sympathetic heart
rate and blood pressure control in adult onset PHOX2B mutationconfirmed
congenital central hypoventilation syndrome. Clin Auton
Res. 2007;17(3):177–185.
26. Rita Azeredo Bittencourt L, Pedrazzoli M, Yagihara F, et al. Lateonset,
insidious course and invasive treatment of congenital central
hypoventilation syndrome in a case with the Phox2B mutation: case
report. Sleep Breathe. 2012;16:951–955.
27. Antic N, Mcevoy RD. Primary alveolar hypoventilation and
response to the respiratory stimulant almitrine. Intern Med J.
2002;32(12):622–624.
28. F-G MR, Manna S, Durward A. Cor pulmonale due to congenital
central hypoventilation syndrome presenting in adolescence. Pediatr
Crit Care Med. 2009;10(4):e41-2 1p.
29. Chuen-Im P, Marwan S, Carter J, Kemp J, Rivera-Spoljaric K.
Heterozygous 24-polyalanine repeats in the PHOX2B gene with
different manifestations across three generations. Pediatr Pulmonol.
2014;49(2):E13–E16.
30. Swaminathan S, Gilsanz V, Atkinson J, Thomas GK, Keens TG. Congenital
central hypoventilation syndrome associated with multiple
ganglioneuromas. Chest. 1989;96(2):423–424.
31. Jennings LJ, Yu M, Rand CM, et al. Variable human phenotype associated
with novel deletions of the PHOX2B gene. Pediatr Pulmonol.
2012;47(2):153–161.

32. Trochet D, O’Brien LM, Gozal D, et al. PHOX2B genotype allows
for prediction of tumor risk in congenital central hypoventilation
syndrome. Am J Hum Genet. 2005;76(3):421–426.
33. Faure C, Viarme F, Cargill G, Navarro J, Gaultier C, Trang H. Abnormal
esophageal motility in children with congenital central hypoventilation
syndrome. Gastroenterology. 2002;122(5):1258–1263.
34. Rohrer T, Trachsel D, Engelcke G, Hammer J, Hammer J. Congenital
central hypoventilation syndrome associated with Hirschsprung’s disease
and neuroblastoma: case of multiple neurocristopathies. Pediatr
Pulmonol. 2002;33(1):71–76.
35. Woo MS, Woo MA, Gozal D, Jansen MT, Keens TG, Harper RM.
Heart rate variability in congenital central hypoventilation syndrome.
Pediatr Res. 1992;31(3):291–296.
36. Silvestri JM, Hanna BD, Volgman AS, Jones PJ, Barnes SD, Weese-
Mayer DE. Cardiac rhythm disturbances among children with idiopathic
congenital central hypoventilation syndrome. Pediatr Pulmonol.
2000;29(5):351–358.
37. Gronli JO, Santucci BA, Leurgans SE, Berry-Kravis EM, Weese-
Mayer DE. Congenital central hypoventilation syndrome:PHOX2B
genotype determines risk for sudden death. Pediatr Pulmonol.
2008;43(1):77–86.
38. Trang H, Girard A, Laude D, Elghozi JL. Short-term blood pressure and
heart rate variability in congenital central hypoventilation syndrome
(Ondine’s curse). Clin Sci. 2005;108(3):225–230.
39. Trang H, Boureghda S, Denjoy I, Alia M, Kabaker M. 24-hour BP
in children with congenital central hypoventilation syndrome. Chest.
2003;124(4):1393–1399.
40. Goldberg DS, Ludwig IH. Congenital central hypoventilation syndrome:
ocular findings in 37 children. J Pediatr Ophthalmol Strabismus.
1996;33(3):175–180.
41. Basu AP, Bellis P, Whittaker RG, Mckean MC, Devlin AM. Teaching
NeuroImages: Alternating ptosis and Marcus Gunn jaw-winking
phenomenon with PHOX2B mutation. Neurology. 2012;79(17):e153.
42. Patwari PP, Stewart TM, Rand CM, et al. Pupillometry in congenital
central hypoventilation syndrome (CCHS): quantitative
evidence of autonomic nervous system dysregulation. Pediatr Res.
2012;71(3):280–285.
43. Boulanger-Scemama E, Fardeau C, Straus C, et al. Ophthalmologic
impairment during adulthood in central congenital hypoventilation
syndrome: a longitudinal cohort analysis of nine patients. Ophthalmic
Genet. 2014;35(4):229–234.
44. Hennewig U, Hadzik B, Vogel M, et al. Congenital central hypoventilation
syndrome with hyperinsulinism in a preterm infant. J Hum Genet.
2008;53(6):573–577.
45. Farina MI, Scarani R, Po’ C, Agosto C, Ottonello G, Benini F. Congenital
central hypoventilation syndrome and hypoglycaemia. Acta
Paediatr. 2012;101(2):e92–e96.
46. Marics G, Amiel J, Vatai B, Lódi C, Mikos B, Tóth-Heyn P. Autonomic
dysfunction of glucose homoeostasis in congenital central hypoventilation
syndrome. Acta Paediatr. 2013;102(4):e178–e180.
47. Gelwane G, Trang H, Carel J-C, Dauger S, Léger J. Intermittent
hyperglycemia due to autonomic nervous system dysfunction: a new
feature in patients with congenital central hypoventilation syndrome.
J Pediatr. 2013;162(1):171–176.
48. Hopkins E, Stark J, Mosquera RA. Central Congenital Hypoventilation
Syndrome associated with hypoglycemia and seizure. Respir Med Case
Rep. 2017;20:75–76.
49. Saiyed R, Rand CM, Carroll MS, et al. Congenital central hypoventilation
syndrome (CCHS): Circadian temperature variation. Pediatr
Pulmonol. 2016;51(3):300–307.
50. Weese-Mayer DE, Rand CM, Zhou A, Carroll MS, Hunt CE. Congenital
central hypoventilation syndrome: a bedside-to-bench success story
for advancing early diagnosis and treatment and improved survival and
quality of life. Pediatr Res. 2017;81(1-2):192–201.
51. Pattyn A, Morin X, Cremer H, Goridis C, Brunet J-F. The homeobox
gene Phox2b is essential for the development of autonomic neural
crest derivatives. Nature. 1999;399(6734):366–370.
52. Pattyn A, Morin X, Cremer H, Goridis C, Brunet J-F. Expression and interactions
of the two closely related homeobox genes Phox2a and Phox2b
during neurogenesis. Development. 1997;1249374403(20):4065-4075.
53. Marcus CL, Bautista DB, Amihyia A, Ward SL, Keens TG. Hypercapneic
arousal responses in children with congenital central hypoventilation
syndrome. Pediatrics. 1991;88(5):993–998.
54. Gozal D, Marcus CL, Shoseyov D, Keens TG. Peripheral chemoreceptor
function in children with the congenital central hypoventilation
syndrome. J Appl Physiol. 1993;74(1):379–387.
55. Stornetta RL, Moreira TS, Takakura AC, et al. Expression of Phox2b
by brainstem neurons involved in chemosensory integration in the
adult rat. J Neurosci. 2006;26(40):10305–10314.
56. Takakura AC, Barna BF, Cruz JC, Colombari E, Moreira TS. Phox2bexpressing
retrotrapezoid neurons and the integration of central and
peripheral chemosensory control of breathing in conscious rats. Exp
Physiol. 2014;99(3):571–585.
57. Dauger S. Phox2b controls the development of peripheral chemoreceptors
and afferent visceral pathways. Development.
2003;130(26):6635–6642.
58. Moreira TS, Takakura AC, Czeisler C, Otero JJ. Respiratory and autonomic
dysfunction in congenital central hypoventilation syndrome. J
Neurophysiol. 2016;116(2):742–752.
59. Guyenet PG, Stornetta RL, Abbott SBG, Depuy SD, Kanbar R. The
retrotrapezoid nucleus and breathing. In: Advances in Experimental
Medicine and Biology. Vol. 2012;758:115–122.
60. Dubreuil V, Barhanin J, Goridis C, Brunet J-F. Breathing with Phox2b.
Philosophical Transactions of the Royal Society B: Biological Sciences.
2009;364(1529):2477–2483.
61. Dubreuil V, Ramanantsoa N, Trochet D, et al. A human mutation in
Phox2b causes lack of CO2 chemosensitivity, fatal central apnea,
and specific loss of parafacial neurons. Proc Natl Acad Sci U S A.
2008;105(3):1067–1072.
62. Rudzinski E, Kapur RP. PHOX2B immunolocalization of the
candidate human retrotrapezoid nucleus. Pediatr Dev Pathol.
2010;13(4):291–299.
63. Pattyn A, Goridis C, Brunet JF. Specification of the central noradrenergic
phenotype by the homeobox gene Phox2b. Mol Cell Neurosci.
2000;15(3):235–243.
64. Nobuta H, Cilio MR, Danhaive O, et al. Dysregulation of locus coeruleus
development in congenital central hypoventilation syndrome.
Acta Neuropathol. 2015;130(2):171–183.
65. Tomycz ND, Haynes RL, Schmidt EF, Ackerson K, Kinney HC. Novel
neuropathologic findings in the Haddad syndrome. Acta Neuropathol.
2010;119(2):261–269.
66. Ogren JA, Macey PM, Kumar R, Woo MA, Harper RM. Central
autonomic regulation in congenital central hypoventilation syndrome.
Neuroscience. 2010;167(4):1249–1256.
67. Weese-Mayer DE, Marazita ML, Rand CM, Berry-Kravis EM.
Congenital Central Hypoventilation Syndrome. Seattle: University
of Washington; 2014. Available from: http://www.ncbi.nlm.nih.gov/
pubmed/20301600. Accessed July 25, 2018.
68. Jennings LJ, Yu M, Zhou L, Rand CM, Berry-Kravis EM, Weese-
Mayer DE. Comparison of PHOX2B testing methods in the diagnosis
of congenital central hypoventilation syndrome and mosaic carriers.
Diagn Mol Pathol. 2010;19(4):224–231.
69. Bachetti T, Parodi S, di Duca M, Santamaria G, Ravazzolo R, Ceccherini
I. Low amounts of PHOX2B expanded alleles in asymptomatic
parents suggest unsuspected recurrence risk in congenital central
hypoventilation syndrome. J Mol Med. 2011;89(5):505–513.
70. Barrett PM, Komatireddy R, Haaser S, et al. Comparison of 24-hour
Holter Monitoring with 14-day Novel Adhesive Patch Electrocardiographic
Monitoring. Am J Med. 2014;127(1):95.e11-95.e17–95.
71. Walsh JA, Topol EJ, Steinhubl SR. Novel Wireless Devices for Cardiac
Monitoring. Circulation. 2014;130(7):573–581.
72. Zelko FA, Nelson MN, Leurgans SE, Berry-Kravis EM, Weese-Mayer
DE. Congenital central hypoventilation syndrome: Neurocognitive functioning
in school age children. Pediatr Pulmonol. 2010;45(1):92–98.

73. Charnay AJ, Antisdel-Lomaglio JE, Zelko FA, et al. Congenital Central
Hypoventilation Syndrome: Neurocognition Already Reduced in
Preschool-Age Children. Chest. 2015.
74. Silvestri JM, Weese-Mayer DE, Nelson MN. Neuropsychologic abnormalities
in children with congenital central hypoventilation syndrome.
J Pediatr. 1992;120(3):388–393.
75. Zelko FA, Stewart TM, Brogadir CD, Rand CM, Weese-Mayer DE.
Congenital central hypoventilation syndrome: Broader cognitive deficits
revealed by parent controls. Pediatr Pulmonol. 2018;53(4):492–497.
76. Marcus CL, Jansen MT, Poulsen MK, et al. Medical and psychosocial
outcome of children with congenital central hypoventilation syndrome.
J Pediatr. 1991;119(6):888–895.
77. Diep B, Wang A, Kun S, et al. Diaphragm Pacing without Tracheostomy
in Congenital Central Hypoventilation Syndrome Patients. Respiration.
2015;89(6):534–538.
78. Matera Iet al. PHOX2B mutations and polyalanine expansions correlate
with the severity of the respiratory phenotype and associated
symptoms in both congenital and late onset Central Hypoventilation
syndrome. J Med Genet. 2004;41(5):373–380.
79. Trochet D, Hong SJ, Lim JK, et al. Molecular consequences of PHOX2B
missense, frameshift and alanine expansion mutations leading to autonomic
dysfunction. Hum Mol Genet. 2005;14(23):3697–3708.
80. Bachetti T, Matera I, Borghini S, Duca MD, Ravazzolo R, Ceccherini
I. Distinct pathogenetic mechanisms for PHOX2B associated polyalanine
expansions and frameshift mutations in congenital central
hypoventilation syndrome. Hum Mol Genet. 2005;14(13):1815–1824.
81. di Lascio S, Bachetti T, Saba E, Ceccherini I, Benfante R, Fornasari
D. Transcriptional dysregulation and impairment of PHOX2B autoregulatory
mechanism induced by polyalanine expansion mutations
associated with congenital central hypoventilation syndrome. Neurobiol
Dis. 2013;50:187–200.
82. H-T W, Y-N S, Hung C-C, Hsieh W-S, K-J W. Interaction between
PHOX2B and CREBBP mediates synergistic activation: mechanistic
implications of PHOX2B mutants. Hum Mutat. 2009;30(4):655–660.
83. Low KJ, Turnbull AR, Smith KR, et al. A case of congenital central hypoventilation
syndrome in a three-generation family with non-polyalanine repeat
PHOX2B mutation. Pediatr Pulmonol. 2014;49(10):E140–E143.
84. Cain JT, Kim DI, Quast M, et al. Nonsense pathogenic variants in exon
1 of PHOX2B lead to translational reinitiation in congenital central
hypoventilation syndrome. Am J Med Genet A. 2017;173(5):1200–1207.
85. Lombardo RC, Kramer E, Cnota JF, Sawnani H, Hopkin RJ. Variable
phenotype in a novel mutation in PHOX2B. Am J Med Genet A.
2017;173(6):1705–1709.
86. di Lascio S, Benfante R, di Zanni E, et al. Structural and functional
differences in PHOX2B frameshift mutations underlie isolated or
syndromic congenital central hypoventilation syndrome. Hum Mutat.
2018;39(2):219–236.
87. Berry-Kravis EM, Zhou L, Rand CM, Weese-Mayer DE. Congenital
central hypoventilation syndrome: PHOX2B mutations and phenotype.
Am J Respir Crit Care Med. 2006;174(10):1139–1144.
88. Kwon M-J, Lee G-H, Lee M-K, et al. PHOX2B mutations in patients
with Ondine–Hirschsprung disease and a review of the literature. Eur
J Pediatr. 2011;170(10):1267–1271.
89. Trang H, Brunet J-F, Rohrer H, et al. Proceedings of the fourth international
conference on central hypoventilation. Orphanet J Rare Dis.
2014;9(1):194.
90. Beckerman R. Home positive pressure ventilation in congenital central
hypoventilation syndrome: more than twenty years of experience.
Pediatr Pulmonol. 1997;23:154–155.
91. Perez IA, Keens TG, Davidson Ward SL. Noninvasive positive pressure
ventilation in the treatment of hypoventilation in children. Sleep Med
Clin. 2010;5(3):471–484.
92. Kerbl R, Litscher H, Grubbauer HM, et al. Congenital central
hypoventilation syndrome (Ondine’s curse syndrome) in two siblings:
Delayed diagnosis and successful noninvasive treatment. Eur J Pediatr.
1996;155(11):977–980.
93. Migliori C, Cavazza A, Motta M, Bottino R, Chirico G. Early use of
Nasal-BiPAP in two infants with Congenital Central Hypoventilation
syndrome. Acta Paediatr. 2003;92(7):823–826.
94. Vagiakis E, Koutsourelakis I, Perraki E, et al. Average volume-assured
pressure support in a 16-year-old girl with congenital central hypoventilation
syndrome. J Clin Sleep Med. 2010;6(6):609–612.
95. Kam K, Bjornson C, Mitchell I. Congenital central hypoventilation
syndrome; Safety of early transition to non-invasive ventilation. Pediatr
Pulmonol. 2014;49(4):410–413.
96. Khayat A, Medin D, Syed F, et al. Intelligent volume-assured pressured
support (iVAPS) for the treatment of congenital central hypoventilation
syndrome. Sleep Breath. 2017;21(2):513–519.
97. Weese-Mayer DE, Hunt CE, Brouillette RT, Silvestri JM. Diaphragm
pacing in infants and children. J Pediatr. 1992;120(1):1–8.
98. Chen ML, Tablizo MA, Kun S, Keens TG. Diaphragm pacers as a
treatment for congenital central hypoventilation syndrome. Expert
Rev Med Devices. 2005;2(5):577–585.
99. Hartmann H, Jawad MH, Noyes J, Samuels MP, Southall DP. Negative
extrathoracic pressure ventilation in central hypoventilation syndrome.
Arch Dis Child. 1994;70(5):418–423.
100. Tibballs J, Henning RD. Noninvasive ventilatory strategies in
the management of a newborn infant and three children with
congenital central hypoventilation syndrome. Pediatr Pulmonol.
2003;36(6):544–548.
101. Shaul DB, Danielson PD, Mccomb JG, Keens TG. Thoracoscopic
placement of phrenic nerve electrodes for diaphragmatic pacing in
children. J Pediatr Surg. 2002;37(7):974–978.
102. Nicholson KJ, Nosanov LB, Bowen KA, et al. Thoracoscopic placement
of phrenic nerve pacers for diaphragm pacing in congenital central
hypoventilation syndrome. J Pediatr Surg. 2015;50(1):78–81.
103. Wang A, Kun S, Diep B, Davidson Ward SL, Keens TG, Perez
IA. Obstructive Sleep Apnea in Patients With Congenital Central
Hypoventilation Syndrome Ventilated by Diaphragm Pacing Without
Tracheostomy. J Clin Sleep Med. 2018;14(2):261–264.
104. Sritippayawan S, Hamutcu R, Kun SS, Ner Z, Ponce M, Keens TG.
Mother-daughter transmission of congenital central hypoventilation
syndrome. Am J Respir Crit Care Med. 2002;166(3):367–369.
105. Rajendran GP, Kessler MS, Manning FA. Congenital Central Hypoventilation
syndrome (Ondine’s curse): prenatal diagnosis and fetal breathing
characteristics. J Perinatol. 2009;29(10):712–713