Neonatal Presentation of Congenital Central Hypoventilation Syndrome

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

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

4. Neonatal Presentation of CCHSBackground -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.

5. Neonatal Presentation of CCHSBackground -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.

6. Neonatal Presentation of CCHSBackground -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. It’s 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.

7. Neonatal Presentation of CCHSBackground -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

8. Neonatal Presentation of CCHSCase 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.

9. Neonatal Presentation of CCHSCase 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 , HCO3:25.6 mmol/l,BE: -8.6.

10. Neonatal Presentation of CCHSCase 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.

12. Neonatal Presentation of CCHSCase 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.

13. Neonatal Presentation of CCHSCase 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.

14. Neonatal Presentation of CCHSCase 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.

17. Neonatal Presentation of CCHSHospital 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.

18. Neonatal Presentation of CCHSHospital 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.

19. Neonatal Presentation of CCHSHospital 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.

23. Neonatal Presentation of CCHSHospital Course • Treatment Modalities: • Tracheostomy. • Gastrostomy. • Home ventilation. • Diaphragmatic pacing.

24. Neonatal Presentation of CCHSHospital 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 she’s 9 months old on tracheostomy tube and mechanical ventilator and feeding by gastrostomy.

26. Neonatal Presentation of CCHSSummary • 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 didn’t improve with age. • They didn’t 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).

27. Neonatal Presentation of CCHSConclusions • 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).

28. Neonatal Presentation of CCHSRecommendations • 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.