CONFERENCE PRESENTATION SUMMARIES

1. Panel Discussion: Best Clinical Practices in CCHS

Moderator: Dr. Maida Chen, M.D. (US)

CCHS experts from US/International community talk about CCHS and answer patient/family

questions/top concerns/top care issues.

Dr. Piumelli, M.D. (Italy), Dr. Samuels, M.D. (UK), Dr. Sivan, M.D. (Israel), Dr. Keens,

M.D. (US), Dr. Trang, M.D. (France), Dr. Frerick, M.D. (Germany)

CCHS experts discussed the standard of care for CCHS in different countries. Many of the same

challenges are seen across country borders. One of the main challenges is there is a need for

conformity of practice based on evidence, experience and resources.

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2. CCHS and Gastrointestinal Complications

Dr. Jose Garza, M.D., Medical Director Neurogastroenterology and Motility

Children’s Healthcare of Atlanta

One of the most common diseases associated with CCHS is Hirschsprung’s disease (HSCR),

which can also be classified as Haddad syndrome. CCHS and HSCR may also present

simultaneously with neuroblastoma (NB); the three diseases together are manifestations

categorized as “neurocristopathy”. Neurologic abnormalities appear to indicate aberrations

of neural cell growth, migration, or differentiation as the primary defect. CCHS should be

suspected in any newborn with Hirschsprung’s disease who needs assisted ventilation

without major cardiopulmonary anomalies.

Failure of enteric neural crest-derived cells to colonize the entire gut results in

Hirschsprung’s disease, a congenital disorder in which enteric neurons are missing from

variable lengths of the distal bowel. As enteric neurons are essential for propulsive motility,

the affected “aganglionic” region is obstructed leading to an accumulation of gut contents on

the proximal side and the formation of a “megacolon”. The most important source of enteric

neurons is the vagal neural crest, which encompasses the most caudal hindbrain and the most

rostral trunk levels of the neural axis. Hirschsprung's disease always starts in the anal verge,

but the length of the segment without ganglion cells varies: rectosigmoid 75%; long segment

12% ; total colon 10%; small intestine 3%. Mutations in >12 genes have been associated

with Hirschsprung disease.

Clinical presentation in a newborn patient: No meconium passed in first 48 hours, abdominal

distention increasing from birth, poor feeding, emesis (bilious), enterocolitis. Clinical

presentation in an older patient: Chronic “constipation”, frequent impactions, abdominal

distention, failure to thrive, enterocolitis (develops in 15% to 50% of the cases; remains the

main cause of death, mortality rate can reach 20 to 50%).

A barium enema may be used for diagnosis, but it may be less helpful in the newborn

because a visible transition zone is often not present. A final diagnosis needs to be based on

the pathologic demonstration of aganglionosis with the use of rectal biopsies. Because

obtaining biopsies involves risks, other less invasive techniques, such as anorectal

manometry, can be used to select those patients that require a biopsy (but this can be

challenging testing in a child). Following anorectal manometry, if the rectoanal inhibitory

reflex is absent, these patients should be referred for RSB to confirm the diagnosis of HD. If

the rectoanal inhibitory reflex is present, HD could be reasonably excluded.

IF HD is diagnosed, treatment includes the correction of fluid and electrolyte imbalances,

antibiotics if enterocolitis is present and rectal decompression. When the normal

housekeeping function of the colon is altered, stasis of intestinal contents promotes dilation

of the small intestine and bacterial overgrowth, resulting in diarrhea, malabsorption, weight

loss and vitamin deficiencies. The basic principle for the definitive surgical therapy is

resection of the aganglionic segment followed by a pull-through of ganglionic bowel down to

the anus. Even with treatment, HD remains a life-long condition. Many patients experience

persisting bowel dysfunction, predominantly constipation and fecal incontinence, and

psychosocial issues into adulthood. Persistent internal anal sphincter (IAS) dysfunction is

one of the most common causes for obstructive symptoms seen in treated patients. This

dysfunction is sometimes referred as "internal sphincter achalasia”, and is related to specific

abnormalities in the innervation of the IAS. It is possible that the IAS pressure produces a

functional outflow obstruction, that with time leads to colonic dilatation and less efficient

peristalsis to expel stool. The persistent chronic obstruction from the IAS may also lead to

recurrent enterocolitis, or bacterial overgrowth with stasis. The injection of intrasphincteric

botulinum toxin (BoTox) has become the treatment of choice for these patients. Motility

dysfunction can be helped by stimulant laxatives. Rectal therapy, large volume irritation of

the rectum and colon, performed by introducing a catheter (often with a balloon) or a cone

through the anus, may also be a treatment option. This therapy offers predictable

rectosigmoid emptying.

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3. CCHS Network One World Registry: Talk and Q/A Period

Sarah Yang, Ph.D., Vandana Dole, Ph.D., Melinda Riccitelli, Ph.D., CCHS Network

Being rare is hard. Rare diseases present unique challenges for researchers and clinicians working

towards treatments and cures:

• Small Patient populations

• Difficult/delayed diagnosis

• Clinical endpoints that are often unclear • Enrollment and retention challenges for clinical trials

• Because of this, there is a poor understanding of the natural history of rare diseases and their

progression

CCHS is complicated:

• Very rare - CCHS patients are one in 6.3 million

• Multiple mutations, delineated between PARMS and NPARMS

• Varying degrees of affectedness…

The IAMRARE™ Registry Program was started by NORD, with funding from the NIH, to help rare

disease organizations conduct IRB approved longitudinal natural history studies that:

• Aim to fill research gaps to help medical researchers better understand how diseases progress

over time, • Yield vital information that is essential to clinical trial design, such as biomarkers,

demographics, important clinical symptoms, genetic and environmental variables, and patient

perspectives,

• Empowers patients and families to help eliminate some of the ‘I don’t know’ in rare disease

research, making way for progress, and

• The system is easy to use system and allows patients and organizations to inform and shape

medical research and translational science for rare diseases.

Some preliminary data (of those taking surveys):

• 29% of CCHS patients claim they have had adverse reactions to anesthesia.

• 8% of CCHS patients have been diagnosed with ADD/ADHD; 4% with autism spectrum

disorder.

• 17% of CCHS patients have a formal learning disability diagnosis.

• 50% of patients report motor delays; 25% report motor planning delays.

• 62% of CCHS pregnancies were full term; 26% report normal levels of amniotic fluid

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4. Exploring Molecular Drug Targets in CCHS

Dr. Isabella Ceccherini, M.D., UOC Genetica Medica Istituto Giannina Gaslini

Dr. Ceccherini’s lab has focused on understanding genes and signaling pathways regulated by

PHOX2B. She has been studying the effect of geldanamycin, 17-AAG and curcumin on PHOX2B

regulated pathways using neuronal cell lines as an experimental model for CCHS.

What we know:

Polyalanine expansion mutations of PHOX2B cause aggregation of the PHOX2B protein. The

aggregated protein cannot function. The aggregates are also toxic to the cells.

17-AAG, a synthetic derivative of geldanamycin, is FDA approved for cancer treatment and as an

orphan drug for CML (Chronic Myelogenous Leukemia).

17-AAG activates a heat shock protein called Hsp70, reducing levels of mutant PHOX2B in

cytoplasmic and nuclear aggregates, and helping to restore some of the normal functions of

PHOX2B.

Dr. Ceccherini’s lab also compared changes in gene expression associated with PHOX2B poly-alanine

expansion mutations (PARM). They started by analyzing 24,000 genes expressed in neuronal cell line:

10 genes/pathways (gene networks) were identified that have altered expression associated with

PHOX2B PARM mutations. Completing the circle, the lab found that some of these 10 genes regain

normal expression when treated with 17-AGG. They will continue these studies to understand

physiologic effect of 17-AGG for treatment of CCHS.

In addition, Dr. Ceccherini’s lab is also comparing the expression profile of the drugs available in

public databases with that of PHOX2B mutations and 17-AAG treatment. Using this reverse

approach, Dr. Ceccherini’s lab will be able to identify molecules acting either opposite to PHOX2B

mutations or consistent with the 17-AAG effect. These molecules will become new candidates (to be

validated/confirmed) for CCHS treatment.

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5. Molecular Biology of Respiratory Drive: Undoing Ondine

Dr. Douglass Bayliss, Ph.D., Joseph & Frances Larner Professor and Chair of Pharmacology

at the University of Virginia

Dr. Bayliss' laboratory has developed highly sophisticated methods to look at expression patterns of

various genes in a single neuron. This is done by creating genetic reporters and by tagging different

genes to unique colors that can be visualized using high resolution fluorescence microscopy.

Dr. Bayliss' research has focused on understanding diversity of neurons in the RTN (retrotrapezoid

nucleus) in the brain. RTN neurons regulate multiple aspects of breathing, including active expiration,

and automatic breathing during non-REM sleep. In a mouse model of CCHS (polyalanine expansion

in PHOX2b gene / PARM), RTN nucleus fails to develop normally. It is not clear if this is also the

case in CCHS patients.

Dr. Bayliss’ research has elucidated that neurons in the RTN region are not all alike. Many PHOX2b-

expressing neurons in the RTN also express Neuromedin B (Nmb). Most PHOX2b- and Nmb-

containing cells also express GPR4 (a proton activated receptor), and a pH sensitive potassium

channel called TASK-2. The pH sensors allow RTN neurons to respond directly to changes in acidity

and CO2.

Dr Bayliss’ lab is continuing to explore how CO2 levels are detected by these specialized subset of

neurons in the RTN. How do other brain cell connections influence their CO2 sensitivity? and how do

RTN neurons communicate to the other brain circuits that regulate breathing and arousal? Finally, the

Bayliss lab is also trying to understand if similar regions and proton/CO2 detectors might also

function in the human brain to regulate breathing and arousal.

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6. PHOX2B and the Genes It Controls

Dr. Diego Fornasari, M.D., Ph.D., Pharmacologist, Department of Medical, Biotechnology,

and Translational Medicine, University of Milan

Dr. Fornasari’s lab has been trying to determine if other genes besides PHOX2B can be a targeted for

treatment of CCHS.

There are 2 reasons for this approach-

a. PHOX2B regulates many genes and signaling pathways. Since the expression and

functioning of PHOX2B is very complex and not clearly understood, the strategy adopted by

Fornasari lab is not to target PHOX2B directly. Instead, Dr. Fornasari’s lab studies some of

the pathways affected by PHOX2B in the hope of bypassing some of the toxic effects of

mutant PHOX2B protein. The group uses a cell line model and started validation of about 14

candidate genes that are regulated by PHOX2B. Current data points to Potassium channel as a

promising target.

b. The other reason to target genes regulated by PHOX2B (such as, ion channels inhibitors) is

that there might be FDA approved drugs that could potentially be re-purposed for CCHS

treatment.

The group is also trying to understand how Desogestrel symptomatically helps with breathing in some

CCHS patients. Preliminary data suggests Desogestrel regulates potassium channels in neurons. If

confirmed, this will be an interesting correlation.

It is also interesting to note that Dr. Bayliss's laboratory found a Potassium channel in PHOX2B

expressing neurons. It's always very encouraging when findings from two independent laboratories

converge to the same potential target.

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7. What to Expect When you Are Expecting Pacers

Dr. Maida Chen, M.D., Associate Professor of Pediatrics, UW SOM, Division of

Pulmonary and Sleep Medicine, Medical Director, Sleep Disorders Program

Four stages should be thought through when considering Phrenic Nerve Pacing: eligibility,

pacer placement pre-operative assessment, pacer placement intraoperative pathway, and

pacer placement post-operative pathway. When determining eligibility ask WHY pacers are

wanted:

• Replace current sleep ventilatory modality?

• Replace current daytime ventilatory modality?

• Further driven by quality of life, overall health, CCHS-specific health issues, airway

considerations.

Also the patient/family need to have a realistic understanding of potential implications and

possible outcomes (e.g., still needs trach) of acer placement. To assess patient eligibility for

pacers, Seattle has developed an “Eligibility Pathway” protocol:

If patient is eligible, further consultation with surgery, anesthesiology, neurosurgery,

cardiology, pediatric intensive care, respiratory therapy, and social worker is required.

Seattle uses a pre-operative placement check list to plan:

In Seattle, the surgical placement of the pacer is done thoroscopically via “video assisted

thorascopic surgery (VATS)”: Three incision ports are made on each side: two for

instruments, one for camera. Ventilation during surgery is supported with a double lumen

endotracheal tube for single lung ventilation. The surgical procedure involves an electrode

placed on the phrenic nerve amd pacer wire buried in chest and tunneled out to right beneath

skin. The end of the pacer wire is tunneled out to skin with small incision (4th incision per

side) and the wire connected via a male-female connector to the receiver, which is then

placed beneath skin.

Pacers are tried intraoperatively to ensure connectivity, but are NOT USED in the immediate

post operative period to allow for healing. When surgery is concluded patient is extubated to

BiPAP or back on vent (NO O2 alone) and vigilant monitoring, especially CO2, is conducted.

Once transferred to the PICU the patient is on 24h ventilation for few days because of a high

risk for atelectasis and post op pneumonias.The post-operative pathway involves monitoring

sedation/pain control, supporting ventilation, monitoring for bradycardia, wound care

(incisite site is not soaked in bath/swim and is open to air for 7 days) and antibiotics, and

watching GI function. Pacers are actovated 6 weeks post-operatively for use. Settings are

determined by:

• Gas Exchange (amplitude and rate)

• AMPLITUDE = tidal volume

• Bigger amplitude decreases CO2, increases O2Rate

• Higher rates decreases CO2, increases O2

• Comfort (amplitude)

• Pain usually ipsilateral shoulder or chest if too strong

• Upper airway (amplitude)

• No stridor

• No obstructive sleep apnea on sleep study

Reliable use of pacers to support ventilation takes time and a lot of tinkering. The time to

use is done slowly, increase pacer time to build tolerance – this is highly variable in how

quickly tolerated by the patient. Overnight nursing very helpful for nighttime transition.

Awake tolerance/efficacy ≠ Asleep tolerance/efficacy. Monitoring gas exchange via

ambulatory monitoring in clinic or in sleep study is crucial during the transition.

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8. Life Transitions in CCHS (sequential discussions of interest)

Moderator: Sheila Kun, RN, BSN, BA, MS, CPN, FCCP, Nurse Care Manager,

Pediatric Pulmonology CHLA

Transition to Non-Invasive Ventilation: Dr. Iris Perez, M.D., Bethany Jerabek, DNP, and

Rebecca Martine, MSN, RN, PMHCNS, nurse and CCHS mom

Getting Ready for School; 504 Planning and Beyond: Marne Harvich-Chergi and Wendy

Stroup

Am I Ready To Move Out?: Nico Meyering, Mollee Hallett, and Rebecca Martine

Please see video recording of these presentations

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9. Inhibition of HSP90 in Mice: Respiratory Function Recovery

Dr. Namasivayam Ambalavanan, M.D., Professor in the Department of Pediatrics,

Molecular, and Cellular Pathology, and Cell, Developmental, and Integrative Biology at

University of Alabama, Birmingham

Dr. Ambal was awarded a CCHS Foundation grant award to study the potential effects of

hsp90 inhibitors on breathing in mouse models of CCHS. This concept stems from the

findings of Dr. Ceccherini, who showed in cells that inhibition of hsp70 may restore the

function of the PHOX2B protein that is dysfunctional in CCHS. (See synopsis review of

hsp90 above). Dr. Ambal’s laboratory has verified Dr. Ceccherini’s results and also showed

that the hsp90 inhibitor under study has better restoration of PHOX2B function compared to

the hsp inhibitors that was previously used. Importantly, he gave the inhibitor to pregnant

mice to see the effects of the drug on the mom as well as the fetus. Preliminary results

suggested that at high concentrations the hsp90 inhibitor although safe for the mom, did

cause the pregnancy to terminate. They are continuing to optimize the dosage of the drug to

give safely to then test the drug in mouse models of CCHS.

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10. Control of Breathing. Lessons From CCHS Patients and Animal Data.

Dr. Ha Trang, M.D., Associate Professor of Physiology and head of the Pediatric Sleep

Center of the Robert Debré Hospital

Control of breathing is shared by two brain regions: voluntary/behavioral is in the cortical

region of the brain; autonomic/chemical control is subcortical/brain stem. Central

chemoreceptors and peripheral chemo and mechano-receptors monitor CO2, O2, pH, and

chest movement to stimulate breathing. CCHS is marked by Hypoventilation during sleep,

mainly during NREM sleep and abnormal Hypercapnic and Hypoxic ventilatory response

(VR) in all states of vigilance. Despite abnormal chemical VR during wakefulness, most

CCHS patients breathe adequately while awake. A cortical breathing mechanism is likely to

be determinant to maintain ventilation in awake CCHS patients. The “supplemental motor

area” (SMA) has been shown to play an important role in modulating breathing in awake

normal humans and in awake patients with NeuroMuscular Diseases. A study of 7 CCHS

patents (5 female; 20-30 years of age) revealed pre-inspiratory cortical activity in awake

CCHS patients during resting breathing. This provides neurophysiological evidence for SMA

to contribute to the cortical drive to breathe in awake CCHS patients.

One patient was tested for the cerebral cost of breathing: results showed that executive

functioning was better with mechanical ventilation (MV) than with spontaneous breathing

(SB); Default Mode Network (DMN) was restored during MV as compared to SB; functional

connectivity patterns of brain activity differ during MV and SB. These observations suggest

the benefit of MV use while executing cognitive tasks shows the different brain functioning

during MV and SB. But data needs to be obtained from a larger cohort of CCHS patients.

Finally, Dr. Trang reported that two CCHS adult female patients were incidentally found to

have increased RR and lower PetCO2 while using the drug Desogestrel. Progestins may act

via mechanisms involving supramedullary structures to improve respiratory response to

acidosis. Etonogestrel (a progestin medication) is likely to have ventilatory effects via

serotoninergic pathways (where serotonin is the neurotransmitter) and seems to modify the

efficiency of GABAA-mediated (another neurotransmitter found in the brain) modulation

and the efficiency of NMDA-mediated modulation.

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11. Three Generations of Same PHOX2B Mutation But Different Phenotype

Dr. Ajay Kasi, M.D., Pediatric Pulmonologist, Children’s Healthcare of Atlanta

Dr. Ajay Kasi works closely with Dr. Iris Perez and Dr. Thomas Keens to care for CCHS patients.

Dr. Kasi described a case study of a CCHS (NPARM) family. Dr. Kasi's team traced the NPARM

(c.245C > T), mutation in 4 females across 3 generations in this family. The mutation was passed from grandmother (asymptomatic mosaic, 1st generation) to two of her daughters (2nd generation).

One of the daughter carrying NPARM remained asymptomatic until adulthood but her NPARM

positive child (3rd generation) was symptomatic at birth and is ventilator dependent at night. The other

NPARM positive daughter was diagnosed at 4 month of age, and like her niece is ventilator

dependent at night, and also has a cardiac pacemaker.

Dr. Kasi makes following observations:

1. Not all NPARM mutations are severe and result in Hirschsprung disease, full time ventilator-

dependence, or neural crest tumors. NPARM mutations can cause mild symptoms (late onset

diagnosis, or ventilator dependent only during sleep).

2. Asymptomatic or symptomatic family members of CCHS patients should be screened for

PHOX2B gene mutation.

a. Parental tests for PHOX2B mutation of a CCHS patient should be performed in case they

have been undiagnosed due to mosaicism or low penetrance.

b. Family members from same or younger generation of a CCHS patient should be screened

if they have any symptoms.

3. Asymptomatic individuals with documented PHOX2B gene mutation should be monitored

regularly, in case symptoms are expressed later in life.

Dr. Kasi’s study provides insight into the lingering dilemma – why do we see a spectrum of

symptoms in CCHS patients carrying the same mutation (PARM or NPARM)?

In this case study, the grandmother was likely asymptomatic due to mosaicism. Only one third on her

blood cells were found to carry PHOX2B mutation. Her children and grandchildren who inherited the

gene carry mutant PHOX2B gene in 100% of their cells. The second and third generation cases in this

family are asymptomatic, late onset or ventilator dependent from early childhood. Variation in genetic

background is a likely cause of the variation in symptoms in these patients.

Explanation of technical terms and concepts:

Mosaicism: Phox2B mutation can appear spontaneously is some cells of an individual. It’s not

understood why this happens. Since an individual with phox2B mosaicism carries mutation in only

some cells, the symptoms are usually mild or absent.

Inheritance of phox2B from mosaic parent: Mosaicism is a condition in which cells within the same

person have a different genetic makeup. A mosaic mutation is not present in all the cells of an

individual. A child can inherit a PHOX2B mutation from a mosaic parent and develop symptoms of

CCHS if the mutation is carried in the egg/sperm (germline). The child will not be a mosaic as the

mutation will be present in the germline and will be replicated in every cell.

Penetrance: Penetrance refers to the proportion of people with a particular genetic mutation who

exhibit signs and symptoms of a genetic disorder. If some people with the mutation do not develop

features of the disorder, the condition is said to have reduced (or incomplete) penetrance. Reduced

penetrance probably results from a combination of genetic, environmental, and lifestyle factors, many

of which are unknown.

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12. Clinical Practice and Research Agenda in Israel

Dr. Yakov Sivan, M.D., Department of Pediatric Pulmonology, CCHS Center, Safra

Children's Hospital, Sheba Medical Center, Tel Aviv University, Sackler Faculty of

Medicine, Israel

Dr. Sivan presented on the care of CCHS patients in Israel.

Until 12/2017, the evaluation, follow-up, treatment, family support and genetic consultation

for children with CCHS and their families was not standardized in Israel and there was no

dedicated clinical service for CCHS patients. Recently, the 1st CCHS Center in Israel was

started. The goals of this Center are to provide care and form plans for all patients in the

country, lead the mission nationwide, establish guidelines for the insurance agencies and the

Ministry of Health and to educate, consult and support all community physicians caring for

CCHS patients. A registry has been completed that includes 22 cases who were located and

contacted. During 2015-2017, Israel population reached about 8 million inhabitants with an

average of 180,000 births a year. 7 new cases were born (including identical twins). Hence,

the average rate of CCHS over the last 3 years was 1:91,000, which is more than twice the

worldwide reported occurrence of 1:200,000. In addition, 4 asymptomatic PARM and 12

asymptomatic NPARM carriers were found, all are family members of the CCHS patients.

Cases and clinical dilemmas were presented:

Case I – A 3 year old boy is the 1st child to healthy parents. Soon after birth, apneas and

oxygen desaturations were observed, mainly during sleep and bottle feedings. PHOX2B

analysis was performed by The Center for Autonomic Medicine in Pediatrics at the Ann &

Robert H. Lurie Children’s Hospital of Chicago & Rush University Medical Center, Chicago,

IL, USA and found that the infant carried both a NPARM and a 20/24 PARM expansion.

He inherited the PARM allele from his father and NPARM from his mother. Family

investigation showed that the PARM involved 3 generations of the father's family (4 carriers)

and that the NPARM also involved 3 generations of the mother's family (6 carriers). All 10

carriers were completely asymptomatic also as small babies and after general anesthesia.

Case II – 4 year old girl with a novel NPARM. Her father and her paternal grandfather carry

the same NAPRM, but are completely asymptomatic. Two father’s brothers have

Hirschprung disease (HSCR) and a father’s sister died of neuroblastoma.

These two familial case highlight several dilemmas:

Should asymptomatic carriers undergo an extensive evaluation for respiratory

competence, autonomic nervous system and CCHS associated complications?

Should extensive evaluation be completed also in clinically asymptomatic grandparents

(> 60 y.o. and grad-grandparents)?

Once evaluation is complete, should these asymptomatic family members undergo

periodic assessments (72 h. Holter, imaging, eye, CO2 challenge)?

What causes the same mutation to present differently in different family members?

What is the risk for clinical CCHS presentation in a family with 2-3 generations of

asymptomatic carriers?

If amniocentesis is positive for 20/24, should cessation of pregnancy be recommended d/t

the risk of LO-CCHS while all other family members with the same PARM have been

healthy for 2-3 generations?

Case III – a small infant was diagnosed with neuroblastoma. Due to cyanotic episodes,

PHOX2B was studied and a novel NPARM was found.

Case IV – a 6 year old asymptomatic boy with 20/26 PARM underwent a 72 hours cardiac

Holter monitoring showing 20 episodes of sinus pauses, the longest being 4.0 seconds. This

poses a dilemma regarding the criteria for cardiac pacemaker insertion in CCHS patients.

Case V - 3 year old identical twin twins with 2025 PARM are receive only non-invasive

ventilation.

Conclusions

• CCHS center in Israel has just recently started. Clinical protocols are mainly adapted and

applied from leading CCHS centers in the US and Europe.

• NPARM phenotype shows a large variability and may present with mild respiratory

phenotype.

• A 20/30 PHOX2B PARM genotype does not necessarily require 24 h. assisted

ventilation.

• Formal HSCR may be negative in CCHS patients with classic clinical gastrointestinal

symptoms.

• Cardiac criteria for pacing in CCHS are required.

• Neurologic involvement is not infrequent and may present a variety of clinical entities.

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13. Clinical Practice in Japan: Diagnosis and Treatments

Dr. Yosuke Yamada, M.D., Dr. Hisaya Hasegawa, M.D., Tokyo Women's Medical

University, Medical Center East, Division of Neonatal Intensive Care

Dr. Hisaya Hasegawa and Dr. Yosuke Yamada presented on the progress in diagnosis, health

management of CCHS patients in Japan since 2011 when Hasegawa et al reported the first nationwide

survey of CCHS patients.

Japan has around 130 reported cases of CCHS with 6 to 7 new patients diagnosed every year.

Additionally, there are some cases of late-onset-CCHS.

Japan has 23 Institutions that offer medical treatment for CCHS. This is 4.5% of the total institutions

for pediatric training in Japan with about 1.5 cases per institution. Because of the small number of

patients, it was hard for an institute to develop in-depth understanding of CCHS, and establish

consistency in care for CCHS patients. Hence, ‘CCHS respiratory “dock” (comprehensive CCHS

medical check-up) at Tokyo Women’s Medical University Medical Center East, Department of

Neonatology was established in 2013 to provide consistent and comprehensive medical check-up for

CCHS patients.

Patients are invited to stay at the dock for 4 nights and 3 days every 2-3 years, for a series of

comprehensive tests. Laryngo-Bronchoscopy is performed to detect airway lesions that might be

caused by upper airway obstruction, mismatch of the tracheostomy tube, tracheal granuloma,

tracheomalacia, or other reasons. Presence of hypoventilation during wakefulness, confirmation of

ventilatory settings during sleep, and severity of hypoventilation during sleep without ventilation are

assessed using pulmonary functional tests. Based on the data collected, a personalized respiratory

management plan is recommended.

General recommendations based on common findings are also provided for CCHS patients. The

recommendations include the following:

• tracheomalacia should be evaluated in cases of crying apneic spells.

• hypoventilation should be evaluated during wakefulness.

CCHS respiratory dock and the Japanese CCHS Network also engage the Japanese community,

insurance companies and the Japanese Department of health in discussions on long-term management

of the condition, such as, whether medical support for CCHS patients should be provided for young

patients (till 15 or 18-years of age), or also for adult patients. In 2017, insurance coverage in Japan

was extended for the diaphragm pacing system.

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14. Neurocognition in CCHS: Keeping Your Eye on the Prize

Dr. Debra Weese-Mayer, M.D., Pediatric Autonomic Medicine Physician-Scientist at Ann

& Robert H. Lurie Children’s Hospital

Dr. Weese-Mayer presented data on deterioration of ETCO2 and SpO2 patterns in CCHS children

during breath holding spells. She also presented data on reduced cerebral blood flow during cardiac

pauses in CCHS patients. The following recommendations were provided to minimize adverse effects

of hypoventilation:

• Upon diagnosis, allow the baby to remain intubated till a tracheostomy tube can be placed.

• For young children, provide oxygen cushion during crying spells and breath holding spells. A

trained person should observe the child whenever the child is awake and not connected to a

ventilator and monitor. When sleeping, ETCO2 and SpO2 should be monitored and a trained

person should always at bedside to intervene quickly, if needed.

• For adolescents, schedule 72 hour Holter recordings every 6-12 months. Sports should be in

moderation with meticulous attention to hydration and rapid standing. Always set alarms on

oximetry and capnography monitors before sleeping. If you going for a drink, always go with

a trained and alert Buddy who can quickly connect you to a ventilator and monitors when

needed.

Dr. Weese-Mayer has reported previously that preschoolers and school age children with CCHS

diagnosis have lower scores on various cognition tests. However, a large data set is needed to

conclusively evaluate the impact of ventilation and environmental factors on cognition. Dr. Weese-

Mayer’s group has undertaken the NIH Toolbox Cognition Battery (NTCB) program to evaluate

neurocognitive functions in CCHS patients in a longitudinal study. NTCB is a set of 7 tasks

administered via interactive iPad tablet application. Summary scores based on clustering of these

tasks are generated and compared to non-CCHS population. NTCB measures 6 cognitive domains:

executive function, attention, episodic memory, language, processing speed, and working memory.

Data collected from 27 participants (14 females) with a mean age of 12.74 ± 7.97 years was

presented. CCHS patients performed poorer than non-CCHS population in the NTCB cognition tests.

Dr. Weese-Mayer’s team plans to recruit more patients in the study and evaluate if better ventilator

management, enrichment of educational environment and other modifiable factors can potentially

improve cognition.

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15. CCHS and Cardiac Pauses

Dr. Sabrina Tsao, M.D., Cardiologist at Ann & Robert H. Lurie Children's Hospital

Dr. Sabrina Tsao from Division of Pediatric Cardiology, Childeren’s Hospital of Chicago discussed

cardiac pacing options for CCHS patients.

CCHS patients may have profound, abrupt sinus pauses that may result in cardiac arrest or remain

asymptomatic. Cardiac pacing is highly recommended if there is an increase in sinus pauses >3

seconds on serial Holters, symptomatic bradycardia, unexplained syncope or history of prolonged

pauses. Cardiac pacing prevents sudden death from cardiac pauses and may also improve

neurocognitive outcome. Currently, ~26% patients seen at Lurie Children’s Pediatric Autonomic

Medicine Program have cardiac pacemaker.

Post-implantation of a cardiac pacer, follow ups are recommended at 72h, 2-12 weeks, every 3-12

months, and thereafter annually.

Currently, the common cardiac pacing options are Epicardial pacing or Transvenous pacing.

Epicardial pacing:

• Epicardial pacing is recommended for patients <25kg (~50 lbs) or patients without venous access,

Epicardial pacing leads are sutured onto the surface of the heart at the most desirable site.

Pacemaker generator is usually placed under the muscle of the abdomen and outside of the organ

cavity. Epicardial pacer with Unipolar Epicardial lead needs suturing of 1 Epicardial lead, and

Bipolar Epicardial lead needs suturing of 2 Epicardial leads on the heart.

• Unipolar Epicardial pacing in not recommended for patients with diaphragmatic pacing as they

are more likely to have inaccurate sensing and may falsely be inhibited by diaphragmatic pacing.

Unipolar Epicardial pacer can stop pacing when the generator for diaphragmatic pacer is removed

from pocket during generator change.

• Bipolar Epicardial leads require suturing of 2 electrodes, but they have excellent sensing and are

unlikely to be inhibited by diaphragmatic pacing, and will continue pacing when the generator for

diaphragmatic pacer is removed from pocket during generator change.

• Epicardial leads are NOT MRI-compatible.

• If there is a fracture of Epicardial lead an open chest procedure needs to be performed again.

Transvenous pacing:

• Transvenous pacing leads are inserted through a vein into the heart. The procedure requires larger

vein size, hence is not recommended for young patients.

• Pacemaker generator is usually implanted in the shoulder area below the clavicle. For this reason,

the transvenous lead are more susceptible to damage by contact sports or repetitive arm

movement.

• Transvenous pacing is usually implanted with bipolar leads.

• The fMRI-compatible Transvenous pacing systems are available.

• Transvenous pacing is not an open chest procedure.

• Leadless pacers

• Micra Transcatheter pacing System (TPS) (Medtronic) and Nanostim LCP (St. Jude Medical) are

leadless pacemakers. A Leadless pacer can only be implanted in adolescent/ adult patients (>30

kg/ 65 lbs) with adequate venous access. Leadless cardiac pacing device is moved through a vein

in the leg to the heart. There is a risk of vascular injury, perforation, device embolization

associated with the currently available leadless pacemakers.

Hopefully technical advancements would provide us a safer, long lasting, Leadless pacer in the near

future.

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16. CCHS Patient Panel – Loud and Proud: Hear from the Real Experts About CCHS

Moderator: Dr. Iris Perez, M.D. Division of Pediatric Pulmonology, Children’s Hospital

Los Angeles

Please see video recording of this presentation

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17. Pregnancy and CCHS

Dr. Thomas Keens, M.D. Professor of Pediatrics, Physiology and Biophysics, Keck School

of Medicine of the University of Southern California. Division of Pediatric Pulmonology,

Children’s Hospital Los Angeles

A CCHS parent has a 50% chance of passing CCHS onto offspring. For CCHS moms an

enlarging uterus interferes with breathing and a CCHS mom may not be able to adequately

compensate (CCHS mom cannot increase respiratory drive to compensate because of the

CCHS related defects in respiratory drive). CHLA has observed that pregnant CCHS

mothers have decreased breathing and increased PCO2 compared to when not pregnant. A

CCHS mom should be monitored for adequacy of ventilatory support periodically.

Delivery and labor can be challenging for a CCHS mom:

• CCHS mothers may need ventilatory support during labor.

• Especially if labor is long.

• Especially if she gets drowsy or sleeps.

• Should plan in advance.

• Diaphragm pacing may not work as well during labor.

Post-partum issues unique to CCHS may arise:

• CCHS mother will likely be drowsy and sleep.

• Preparations should be made to provide ventilatory support.

• Diaphragm pacing works after a normal vaginal delivery.

• Diaphragm pacing will be very painful after Caesarian birth, so NIPPV should be

arranged.

What about the baby?

• CCHs is caused by mutations in the PHOX2B gene. While most CCHS is due to

sporadic mutations a CCHS parents have a 50% chance of passing on CCHS with

each pregnancy.

• Therefore, CCHS mothers should deliver in a high risk perinatal center with NICU.

• Prenatal testing is available to determine CCHS status in fetus. Even if families do

not want to use information to terminate a pregnancy, the knowledge of whether or

not the child is affected permits planning how best to care for the infant at birth.

• Chronic villus sampling at 9-14 weeks or amniocentesis at 14-18 weeks are methods

used to determine the genetic status of the fetus. There is a risk of miscarriage with

both of these procedures (amniocentesis = 0.8%; CVS = 2.18%).

Using preimplantation procedures a CCHS parent can avoid having a CCHS child:

• For a father with CCHS: artificial insemination with donor sperm prevents the child

from inheriting CCHS.

• For a mother with CCHS: in vitro fertilization of a non-CCHS egg donor and non-

CCHS father’s sperm and pre-implantation genetic testing for CCHS. A transfer of

only unaffected embryos are implanted into CCHS mother.

In conclusion, genetic procedures in the 21st century allow for a CCHS parent to not have a

CCHS child. These procedures do not come cheap. If pregnancy arises naturally the CCHS

family should prepare for birth by doing genetic testing on fetus. If baby has CCHS then

delivery should be planned for at a high risk perinatal center with NICU. If mom has CCHS,

ventilation should be periodically assessed during pregnancy and support adjusted as needed.

Additional ventilatory support may be needed during delivery and post-partum.

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