Neonatal Presentation of Congenital Central Hypoventilation

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Neonatal Presentation of Congenital Central
Hypoventilation Syndrome
Y. K. Abu-Osba, Miqdad H. Mukahhal Neonatal
Intensive Care Unit Jordan Hospital, Amman,
Jordan
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Presentation outline

• Introduction.
• Definition and diagnosis of CCHS.
• Case presentation.
• Summary.
• Conclusions.
• Recommendations.

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Neonatal Presentation of CCHS Background -1

• The appropriate nomenclature for the disorder
  known as Ondine curse is congenital central
  hypoventilation syndrome (CCHS). The literary
  misnomer "Ondine's curse" has been used in prior
  literature.
• In the story of Ondine, a German folk epic, the
  nymph Ondine falls in love with a mortal. When
  the mortal is unfaithful to the nymph, the king
  of the nymphs places a curse on the mortal. The
  king's curse makes the mortal responsible for
  remembering to perform all bodily functions, even
  those that occur automatically, such as
  breathing. When the mortal falls asleep, he
  "forgets" to breathe and dies.
• Because Ondine did not actually curse the mortal
  (it was her king) and the approximately 300
  children worldwide with CCHS do not forget to
  breathe, the term Ondine's curse is a misnomer
  and should be avoided.

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Neonatal Presentation of CCHS Background -2

• Classic congenital central hypoventilation
  syndrome (CCHS) is characterized by adequate
  ventilation while the affected individual is
  awake and by hypoventilation with normal
  respiratory rates and shallow breathing during
  sleep more severely affected individuals
  hypoventilate when both awake and asleep.
• Children with CCHS often have physiologic and
  anatomic manifestations of a generalized
  autonomic nervous system dysfunction/dysregulation
  (ANSD) a subset have altered development of
  neural crest-derived structures (i.e.,
  Hirschsprung disease) and tumors of neural crest
  origin including neuroblastoma, ganglioneuroma,
  and ganglioneuroblastoma.

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Neonatal Presentation of CCHS Background -3

• Recently, it has been recognized that some
  individuals with nocturnal alveolar
  hypoventilation, features of ANSD, and a
  polyalanine expansion mutation in PHOX2B
  characteristic of CCHS do not present until
  childhood or adulthood.
• Its inherited in an autosomal dominant matter
  with 5 of them having an asymptomatic parent who
  has somatic mosaicism for a PHOX2B mutation.
• Many individuals with CCHS who have been
  successfully ventilated are now in their 20s,
  suggesting the potential for a normal life span.

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Neonatal Presentation of CCHS Background -4

• CCHS is diagnosed in individuals with the
  following
• Hypoventilation with absent or negligible
  ventilatory sensitivity to hypercarbia and absent
  or variable ventilatory sensitivity to hypoxemia
• Generally adequate ventilation while awake, but
  hypoventilation with normal respiratory rate and
  shallow breathing (diminished tidal volume)
  during sleep
• Hypoventilation both while awake and asleep
• Absent perception of asphyxia (i.e., absent
  behavioral awareness of hypercarbia and
  hypoxemia) and absent arousal
• No evidence of primary neuromuscular, lung, or
  cardiac disease or identifiable brain stem lesion
  that might account for the constellation of
  symptoms

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Neonatal Presentation of CCHS Case report
Initial presentation

• Rania and Abdallah were born by C/S after 36
  weeks of pregnancy (IVF-due to paternal history
  of Immotile Cilia Syndrome).
• Their birth weight was 2.44 kg and 2.41 kg ,
  Apgar score was 5/6/7 at 1/5/10 minutes
  respectively.
• Naloxone was given during resuscitation due to
  poor respiratory effort.
• They were sent to nursery and observed closely
  after starting them on O2 by head box due to poor
  respiratory effort. Rest of their physical
  examination was normal.

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Neonatal Presentation of CCHS Case report

• ABGs at one hour of age
• Abd PH 7.004 , PaCO2 74.9 mmHg ,PaO2 107
  mmHg HCO3 18.4 mmol/l,BE-12.8 .
• Ran PH 7.044, PaCO2 69, PaO2 68, HCO3
  18,BE -12.
• They were admitted to NICU with poor respiratory
  effort and hypopnea resulting in cyanosis and CO2
  retention .
• The patients were started on Nasal CPAP trial,
  ABGs after one hour showed
• Abd PH 7.00 , PaCO2 106.2 mmHg,PaO2 51.5
  mmHg , HCO325.6 mmol/l,BE -8.6.

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Neonatal Presentation of CCHS Case report

• Ran PH 7.08,PaCO2 86,PaO2 87,HCO3
  25,BE-5.
• The patients were intubated started on
  mechanical ventilation (SIPPV), VBGs after one
  hour of ventilation
• Abd PH 7.24 , PaCO2 36.3mmHg, PaO2
  40.5mmHg , HCO3 15.2mmol/l, BE -11.
• Ran PH 7.44, PaCO2 20, PaO2 89, HCO3 13,
  BE-11.
• Several trials of CPAP ventilation failed due to
  hypoponea prolonged apnea, blood gases were
  done as needed.
• Aminophylline intravenously was given at maximum
  doses it was stopped when caffeine was given on
  the request of the family.
• They received Intravenous Antibiotics for 5 days,
  which were discontinued after ruling out sepsis.

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Neonatal Presentation of CCHS Case report

• Investigations
• Chest X ray No signs of RDS, normal lung fields.
  
• Cranial ultrasonography normal. No evidence of
  ICH.
• Abdominal Ultrasound normal.
• Echocardiogram normal cardiac structure,
  dextroposition of the heart with normal axis , no
  evidence of pulmonary hypertension.
• Blood and urine cultures negative.
• CBC normal for age.
• Kidney Function Test normal
• Serum immunoglobulin levels normal for age.

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Neonatal Presentation of CCHS Case report

• Metabolic Screen urine serum Amino acids
  unremarkable.
• Serum ammonia lactate normal levels
• Carnitin blood level was low, Subsequent levels
  were normal.
• Brain CT scan revealed assymetry in the lateral
  ventricles in the girl only which was interpreted
  by neurosurgeons as normal variation.

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Neonatal Presentation of CCHS Case report

• Presentation and clinical course is not
  consistent with surfactant deficiency, pneumonia,
  sepsis, metabolic disorder, ICH, or PPHN, which
  had been ruled out by laboratory, and
  radiological investigation and clinical course.
• Our differential diagnosis was either CCHS or a
  new presentation for Primary Immotile cilia
  syndrome / dyskinesia.

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Neonatal Presentation of CCHS Hospital Course

• During their stay in NICU,the twin were started
  on N/G feeding and increased gradually which was
  tolerated without any problems.
• Cardiology evaluation normal echocardiography
  and normal 24 hr holter monitoring without any
  arrythmias.
• Neurology evaluation no clinical neurological
  abnormalities detected.

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Neonatal Presentation of CCHS Hospital Course

• Ophthalmology consultation bilateral retinal
  examination showed immature retina Zone II III
  with no retinal pigmentation. No ROP. Follow up
  exams were normal.
• Infectious dis. consultant was following them
  during their hospitalization with routine
  cultures and appropriate antibiotics when
  indicated.
• Consultations with centers abroad( England and
  USA) for definite diagnosis.

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Neonatal Presentation of CCHS Hospital Course

• Recurrent trials of VERY slow weaning from
  mechanical ventilation failed with acidosis and
  hypercarbia.
• Recurrent reintubation became difficult and done
  by expert anesthetists with time.
• Muscle biopsies were taken from both babies at
  the age of 3 months and blood samples from
  parents were all sent to Rush University and
  Medical Center . Results confirmed the diagnosis
  of CCHS in the twin ( Positive for PHOX2B
  gene-20/27).
• The father had a CCHS polyalanine repeat
  expansion mutation(20/27) suggesting somatic
  mosaicism without clinical symptoms.
• By that time the family started to accept the
  idea of tracheostomy and home ventilators for the
  twin.

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Neonatal Presentation of CCHS Hospital Course

• Treatment Modalities
• Tracheostomy.
• Gastrostomy.
• Home ventilation.
• Diaphragmatic pacing.

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Neonatal Presentation of CCHS Hospital Course

• At the age of 4 months, tracheostomy was done
  for them by pediatric surgeon. Postoperatively
  tracheostomy tubes were out and they
  were reintubated again. During this attack,
  Abdullah suffered from asphyxia that lead to
  recurrent seizures and eventually declared brain
  dead by flat EEG record and abscent brainstem
  reflexes.
• Abdullah died on 30/7/2007 at the age of five
  months.
• Rania was put on mechanical ventilator by ETT
  and did well afterwards.
• Rania was transferred to another hospital for
  long term management. Currently shes 9 months
  old on tracheostomy tube and mechanical
  ventilator and feeding by gastrostomy.

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Neonatal Presentation of CCHS Summary

• To our knowledge we report for the first time the
  clinical presentation of a dizygotic twin with
  PHOX2B Positive CCHS. Symptoms were severe since
  birth and persisted during awakeness and sleep
  and didnt improve with age.
• They didnt have any manifestation of ANSD.
• The father had the gene which is known to be
  autosomal dominant without any clinical
  manifestations apart from his disease( PCDS).

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Neonatal Presentation of CCHS Conclusions

• CCHS is underestimated to be affecting only 300
  children in the world.
• High index of suspicion is the most important
  factor to give these babies the best survival
  with less morbidity.
• Early diagnosis minimize health care cost and
  exposure to asphyxia.
• Mortality is mainly due to acute or chronic
  asphyxia and their sequale ( neurological and
  pulmonary).

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Neonatal Presentation of CCHS Recommendations

• Establishing referral centers for long term
  followup for such patients is important.
• Prenatal diagnosis is possible if mutation is
  identified.
• Increase awareness of CCHS since rarity of the
  disease makes it difficult for practitionors to
  see cases and diagnose them easily.
• Collaboration with the Arab pediatricians to
  increase awareness to rare diseases through
  U.A.P.

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