Congenital Central Hypoventilation Syndrome

Yakov SivanDept. of Pediatric Pulmonology, Critical Care and Sleep Medicine

Dana Children’s Hospital, Tel Aviv Medical Center

23/12/2015, תל אביב

Case presentation

Dan & Yonathan – monozygotic bi-chorionic twins were born after 34 weeks gestation.

Post natal course: had apneas & bradycardias – considered as A&B of prematurity. Y required non-invasive ventilation started via nasal prongs most of the time.

At age 1.5 months - PHOX2B showed 25/20 phenylalanine repeat mutation.

Transferred to our PICU.

Tracheostomy was addressed. Parents were reluctant.

Mellins RB. Failure of automatic control of ventilation (Ondine’s curse). Report of an infant born with this syndrome. Medicine 1970.

CCHS is a rare (1:200,000 births), lifelong condition of primary failure of autonomic

control of breathing causing alveolar hypoventilation typically during sleep.

Historical milestones

Association with

Hirschprung dis (20%)

Neural crest tumors (2-5%) [neuroblastoma,

ganglioneuroma,

ganglioneuroblastoma].

Haddad G et al. Medicine 1978

Genetics discoveredGene - PHOX2b

Amiel J et al. Nat Genet 2003

Weese-Mayer DE et al. Am J Med Genet 2003

"every waking breath would be a testimony of my love"

"You swore faithfulness to me with every waking breath, and I accepted your oath. So be it. As long as you are awake, you shall have your breath, but should you ever fall asleep, then that breath will be taken from you and you will die!"

Ondine, a water nymph, fell in love with a knight and married him

She bore his child. In doing so, she lost her eternal youth and immortality. Catching her husband in bed with another women, she placed a curse on him:

Pathphysiology - Effect of sleep state

Hypoventilation is more pronounced during quiet or NREM than REM sleep –the tonic excitatory inputs to the respiratory system that exists during REM and wakefulness decline during NREM sleep and is insufficient to maintain ventilation in NREM sleep.

Normally,During sleep ventilatory chemoreception ensures effective regulation of ABG.

During wakefulnessadditional non-chemoreceptive inputs (behavioral and arousal-related influences) affect ventilatory control.

ventral medulla respiratory column

Also in: nodose ganglion which contains the neurons responsible for the pulmonary stretch or Herring-Breuer reflex

carotid body which contains O2 and CO2 sensors

petrosal ganglion that innervates the carotid body

PHOX2B is expressed and required in the development of:

Ventilatory responsiveness to CO2 during both

wakefulness and sleep and arousal response

to CO2 is blunted.

Unable to appropriately adapt her/his

ventilation to environmental demands.

Altered or absent perception of shortness

of breath when awake.

When faced with respiratory challenges

(infection or life-threatening

hypoventilation) during sleep, are unable to

augment ventilation to meet demands or

arouse.

CCHS

More severely affected patients

hypoventilate also during wakefulness.

chemoreceptor neuron

fMRI data

Fig. 2. T2-relaxometry procedures, which quantify free water content, indicate

neural injury or failed development of neurons in CCHS children

fMRI responses to 5% CO2 in CCHS subjects, compared to age- and gender-matched control adolescents.

Signals increase in CCHS subjects, in the dorsal medulla, cerebellum, and amygdala. In the parabrachial

pons/locus coeruleus, midbrain and hippocampus, signals decline. The warm colors represent an increase in

signal responses in CCHS cases compared to controls, the cool colors represent a greater decline in CCHS over

values in controls. Harper et al. (2005)

thalamus

medial midbrain

dorsolateral pons

These structures serve many functions including:

• the ability to respond to hypercapnia (cerebellum)

• mediate the sensation (and thus, drive to breathe) from shortness of breath (cingulate, insular cortex)

• responsible for switching from inspiration to expiration

responses to 5% CO2 in CCHS subjects relative to control adolescents, demonstrating other

significant clusters of enhanced signals. In CCHS subjects, signal increases appear unilaterally in

the insula and cerebellar cortex. Arrows indicate response differences in globus pallidus, putamen,

and thalamus (1, 2, 3), caudate (4), and hippocampus (5) (Harper et al. (2005).

Structural injury and functional deficits appear in cerebellum, lateral medulla, and a

region of tissue extending from the posterior thalamus through the midbrain [Harper et

al. (2005), Kumar et al. (2008), and Macey et al. (2005)].

structural

functional

Esther Leshinsky-Silver

Molecular genetic lab

Dorit Lev

Genetic Institute

Wolfson Medical Center

Congenital Central Hypoventilation Syndrome; a polyalanine repeat disorder-

Amiel J et al. Nat Genet 2003Weese-Mayer DE et al. Am J Med Genet 2003

• found heterozygous de novo mutations in PHOX2B in 18 of 29 individuals with CCHS.

• Most mutations consisted of 5-9 alanine expansions within a 20-residue polyalanine tract probably resulting from non-homologous recombination.

Polyalanine repeat expansions

Polyalanine repeat expansions • All these genes (excluding

PABPN1) are transcription factors that play important roles during development.

• Recent in vitro and in vivo findings indicate that expansions of polyalanine tracts beyond a certain threshold result in protein misfolding, aggregation and subsequent degradation.

PHOX2B

• PHOX2B maps to chromosome 4p12 and encodes a highly conserved homeoboxtranscription factor of 314 amino acids with two short and stable polyalanine repeats of 9 and 20 residues, respectively.

• The length of the polyalanine tracts is conserved in mice and humans.

Bristol Genetics Laboratory 2010

• Paired-Like Homeobox

• 4p12, 3 exons, 314 amino acids

• Highly conserved homeodomain transcription factor

• 2 polyalanine repeat tracts (9 and 20 Ala)

– Imperfect repeats; can expand by unequal allelic recombination

The PHOX2B Gene

5’ 3’1 2 3

NH2 COOH

PHOX2B structure

PHOX2B transcript

Adapted : Amiel et al. (2003) Nature Genetics 33(4), 459-461

Ala repeats

Bristol Genetics Laboratory 2010

Polyalanine Expansion Analysis

•All expansions are confirmed by sequencing of PHOX2B exon 3 (fragment B)

Normal control +6 Ala expansion Parent mosaic for +6 Ala

PHOX2B Testing Strategy; WMC- molecular lab

Diagnostic referrals from:Neonatology, Respiratory Medicine, General Paediatrics, Neurology, Clinical Genetics.

Wolfson Medical Center

• 63 referrals from Ichilov , Schnieder, Assaf Harofeh, Hadassah, Aline, Meir, Naharia, Mukased, MayameiHayeshua.

• 49 had normal polyalanine repeats(usually 20)

• 14 (25%) had expansion(20/27)-two were identical twins

• Two prenatal diagnosis to exclude mosaicism

Genetic Counseling

• Germline Mosaicism of PHOX2B Mutation Accounts for Familial Recurrence of Congenital Central Hypoventilation Syndrome (CCHS) Casey M. Rand,1Min Yu,2 Lawrence J. Jennings,2Kelvin Panesar,1 Elizabeth M. Berry-Kravis,3 Lili Zhou,3 and Debra E. Weese-Mayer1 * Am J Med Genet A. 2012

• Recurrence of CCHS associated PHOX2B poly-alanine expansion mutation due to maternal mosaicism. Bachetti

T, Di Duca M, Della Monica M, Grappone L, Scarano G, Ceccherini I.. Pediatr Pulmonol. 2014

• These cases suggest that up to 25% are inherited from asymptomatic parents with somatic mosaicism for these mutations

Prenatal diagnosis for affected patients

אבחון גנטי טרום השרשה

Preimplantation Genetic

Diagnosis (PGD

Clinical presentation

o Most present immediately after birth as cyanosis or cyanotic spells.

o Some present in the first few months of life with ALTE.

o Absence of hyperventilation in response to hypercapneic challenge.

Lethal soon after birth

Late onset

Genotype – phenotype relationships

o In alanine expansions > +6, the ventilatory phenotype is fully penetrant.

o A higher number of repeats is associated with a greater severity of the respiratory phenotype. Genotypes from 20/27 to 20/33 usually require ventilatory support also during wakefulness, while those with the 20/25 genotype usually require only nocturnal ventilation.

o Later onset cases with milder hypoventilation have been documented with 20/24 or 20/25 genotypes.

o Individuals with the +6 ala expansions genotype have a moderate risk and those with > +7 are at greatest risk for Hirschsprung’s.

o Neuroblastoma occurs in NPARMs mutations.

o Ganglioneuroma, ganglioneuroblastoma develop in a small subset of those with the longest PARMs.

+5 ala expansion – mildest form

o incomplete penetrance for the ventilatory phenotype

o milder forms – apneas and desaturations after birth, may improve over weeks/months

o some do not require ventilatory support

o late onset

o at risk for acute ventilatory decompensation during anesthesia, respiratory infections

o no hirschsprung's disease or neuroblastoma

Why some patients with +5 genotype have a mild course while other are ventilator dependent?

The most common genotypes are 20/25, 20/26, and 20/27. Because the phenotype of

the cases with 20/24 and 20/25 is relatively mild, it is anticipated that these cases are

underrepresented at the present time.

Over 1,000 PHOX2B mutation-confirmed cases of CCHS have been reported

Alanine contractions (−5, −7 and −13 alanines) in the 20-alanine stretch can be observed with no phenotypic consequences reported to date.

In most case the mutation arise de novo. However, 15 to 20% of unaffected parents show somatic mosaicism for the mutation identified in the child.

As a germ line mosaicism cannot be ruled out, parents with no somatic mosaicism detected are counseled at 1% recurrence risk in siblings.

temperature instability (low basal body temp)

excessive sweating

decreased perception of discomfort and anxiety

decreased HRV, extreme BHS, vasovagal syncope, cardiac arrhythmia, including life-threatening bradycardia (may need cardiac pacemaker (asystoles can occur in adults with LO-CCHS [not reported in children])

blood pressure does not fall during sleep

ophthalmologic disorders (sluggish pupils, altered lacrimation, anisocoria)

characteristic facial features (increase with the length of the PHOX2Balanine repeat expansion)

Associated autonomic dysfunctions

Initial investigations

Severity assessment

Hb / Hct - polycythemia

ABG - respiratory acidosis, compensation, bicarb.

ECG, cardiac echo – pulmonary hypertension

PSG – respiratory physiology and gas exchange during sleep (including ETCO2 / TcCO2)

PHOX2B testing confirmation is now required for a diagnosis of CCHS (ATS statement on CCHS 2010).

30 sec. epoch120 sec. epoch

Other investigation – for consideration

• R/O Hirschsprung’s disease, Barium enema or rectal biopsy should be performed for patients with constipation or abdominal distension.

• In patients without cardiac abnormalities, 24-72-hour Holter ECG monitoring is recommended once a year to estimate heart rhythm and exclude bradyarrhythmias and asystoles.

• Chest and abdominal imaging if there is any possibility of a neural crest tumor, particularly in patients with the corresponding mutations.

• A comprehensive ophthalmologic examination to identify eye involvement for early intervention to avoid interference with learning.

• Neurocognitive testing if there is developmental delay or learning disability.

Management

The goal of treatment for CCHS is to ensure adequate oxygenation and ventilation during both wakefulness and sleep.

Oxygen administration alone will improve spO2 levels and reduce cyanosis but will not prevent hypoventilation and the ensuing complications.

All patients require some form of assisted ventilation in the home setting for life.

Keeping paCO2 at 30-35 mmHg allows for better spontaneous ventilation during the day.

PPV via tracheostomy NIPPV

Diaphragmaticpacing

Medications

It is vital that objective measurements of adequate ventilation, including pulse oximetry levels, are monitored consistently in the home.

8 of the 19 cases (42%) with 25 PARM were complicated by mental retardationShimokaze et al. Journal of Human Genetics 6.2015

children with CCHS already demonstrate reduced neurocognitive performance.Do deviations in neurocognitive performance are intrinsic to the CCHS genotype or due to diffuse central nervous system insult (e.g, hypoxia).

Are LO-CCHS children at greater risk for ND deficiencies due to unrecognized sleep hypoxemia?

Shimokaze et al. Journal of Human Genetics 6.2015

Non-invasive positive pressure ventilation:

no surgical procedure

an unstable ventilator-child interface especially in young children

difficulty triggering machines in young children

inconvenience

potential for severe facial malformation/deformation

potential for neurocognitive impairment because of unstable ventilator

support.

in the event of increased respiratory load such as an intercurrent illness,

response may be inadequate and patients will need to be intubated for

(likely) several days/weeks/for life.

Desogestrel: facts and hope

Response to CO2 was restored in two female patients with CCHS taking desogestrelas a contraceptive pill.

Respir Physiol Neurobiol 2010

Desogestrel - a potent progesterone receptor agonist induces changes in respiratory control by activating autonomic CO2 chemosensitive regions that are unaffected by PHOX2B mutations, such as chemoreceptors in the hypothalamus and the peripheral nervous system.

Progress in studies identifying candidate drug treatments that modulate the expression of the PHOX2B gene. Several in vitro studies have investigated drugs that promote the clearance of mutant proteins.

Long-term prognosis

Mortality = 10-38%, causes – cor pulmonale, aspirations, pneumoniacommon age – small infants

QOL – most = good. Home settings, treatment, resources and support – crucial

Most maintain regular schools. many of these patients now live full adult lives with careers and families.

The first generation of children with CCHS is now surviving to adulthood. Since most current cases of CCHS represent de novo mutations in the PHOX2B gene familial cases of CCHS are likely to increase.

Back to our twin patients

Parents refused tracheostomy

Babies sustain non-assisted breathing during sleep for 3 d.

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