Congenital central hypoventilation syndrome (CCHS) is a rare disorder characterized by failure of automatic control of breathing. Diagnosis is made by exclusion of other causes of hypoventilation. Genetic etiology is strongly suspected. Other autonomic nervous system dysfunctions, tumors of neural crest origin and Hirschsprung's disease are often found in affected children. Association with Hirschsprung's disease is known as Haddad syndrome. We present a newborn with respiratory distress since birth and Hirschprung's disease subsequently diagnosed with Haddad syndrome.
Congenital central hypoventilation syndrome (CCHS) is defined as the failure of automatic control of breathing, present from birth in absence of pulmonary, cardiac, neuromuscular and identifiable brainstem lesion.
Congenital central hypoventilation syndrome (CCHS) is a very rare entity, characterized by adequate ventilation during wakefulness and by hypoventilation during sleep. More severely affected individuals hypoventilate, both when awake and asleep. Genetic etiology is strongly suspected.1, 2 Lifetime ventilation support is required to maintain adequate oxygenation. Other autonomic nervous system dysfunctions, tumors of neural crest origin (such as neuroblastoma, ganglioneuroma and ganglioneuroblastoma) and Hirschsprung's disease are often found in affected children.3, 4, 5, 6 CCHS associated with Hirschsprung's disease is known as the Haddad syndrome. It is named after the author who first described three newborns with absent control of breathing and Hirschsprung's disease.7 We report a newborn admitted with respiratory distress and Hirschsprung's disease who was subsequently diagnosed with Haddad syndrome.
Following an uneventful pregnancy, a full-term, male infant was born by elective C-section to a 31-year old Gravida 2 Para 1 mother. Family history was non-contributory. Apgar scores were 6 and 9 at first and fifth minute, respectively, and birth weight was 3035 g. Shortly after birth, the baby presented with shallow breathing, apnea, duskiness and O2 saturation between 70 and 80%. The rest of the physical exam was normal. Respiratory distress was initially managed with nasal CPAP and oxygen supplement. Antibiotics were started for presumed sepsis. On the second day of life, the baby was placed on mechanical ventilation and started on caffeine. Worsening of respiratory distress presented in the form of apneic spells, which were presumed to be due to abdominal distention. On the third day of life, the baby developed transient lethargy, poor suck and decreased muscle tone. Hematologic profile, blood chemistry and ammonia levels were normal. Blood and cerebrospinal fluid cultures were negative. Chest and abdominal X-ray were normal except for nonspecific dilated intestinal loops. Head CT scan was normal. Over the first 3 days of life the baby had increasing abdominal distension, passed only smears of meconium and developed greenish gastric drainage. The baby was diagnosed with Hirschsprung's disease and underwent surgery with mid-sigmoid colostomy placed during the first week of life. After the surgery the baby remained intubated, on a fentanyl drip, which was tapered down. On the fifth day post-surgery, after an attempt to extubate, the baby developed apnea followed by tonic-clonic seizures. Blood gas revealed significant hypercarbia. Narcotic withdrawal and/or CNS pathology were suspected. The baby was reintubated and placed back on mechanical ventilation. Initial EEG revealed epileptiform activity, which was considered to be a symptomatic event, possibly due to hypoxia. As repeated EEG still showed presence of seizure activity; the baby was started on diphenylhydantoin (Dilatin®). Brain MRI, HUS, BAER test and ophthalmology exams were all normal. Subsequent attempts to extubate resulted again in respiratory failure with hypercapnia and hypoxia. The baby's respiratory rate was mainly correlating with the rate set on ventilator and this phenomenon was observed more during sleep. CXR was normal. Cardiac ECHO revealed mild mitral regurgitation. In the absence of pulmonary and cardiac pathology and neurological disease, CCHS was suspected. Genetic testing confirmed the diagnosis of Haddad syndrome owing to the combination of Hirschsprung's disease, CCHS, and genetic testing consistent with a mutation in PHOX2B. Caffeine administration was ineffective. Nasal SIMV trial for short period of time failed to provide sustained adequate ventilation. Tracheostomy was performed owing to the need for continuous and prolonged mechanical ventilatory support. The baby was fed through an orogastric tube. Before discharge to a Rehabilitation Center, a gastric tube was placed to provide adequate nutrition. He was discharged home, still requiring mechanical ventilatory support at night.
Congenital central hypoventilation syndrome (CCHS) is a very rare respiratory disorder. Although there are only about 300 reported cases worldwide, it is considered that the number is much higher. Disease typically presents in the newborn period. Diagnosis is established clinically by exclusion of other causes of hypoventilation.2, 3 Genetic testing may confirm diagnosis; detection rate is 40–97% in affected individuals.8
CCHS is inherited in autosomal dominant manner. There are several reports of affected siblings and transmission of disease from parent to offspring. The majority of patients are heterozygous for polyalanine repeated expansions mutation in PHOX2B. The mutation is usually new. Some patients have an asymptomatic affected parent who has somatic mosaicism for PHOX2B.Other genes mutations were found, but the relationship to disease or phenotype is not yet clear. Prenatal testing for pregnancies at risk is possible if the expansion mutation has been identified in an affected family member.6, 9
Hypoventilation in CCHS is the result of depressed or absent ventilatory sensitivity and arousal response to hypercarbia and hypoxemia or combination of both. Perception of asphyxia is absent; so affected children do not develop dyspnea in response to increased oxygen demand while exercising or in case of respiratory infection. Autonomic nervous system dysfunctions such as decreased basal body temperature, episodes of profuse sweating, esophageal dysmotility, constipation, lack of heart rate variability, decreased perception of discomfort and anxiety, diminished pupillary light reflex are described in affected children. Tumors of neural crest origin such as neuroblastoma, ganglioneuroma and ganglioneuroblastoma and Hirschprung's disease are other associated conditions.10, 11
CCHS is a lifelong disease and most of these patients require continuous or intermittent ventilatory support to maintain ventilation. Several patients are known to be entering adulthood. It is speculated that if untreated, the disease is compatible with life for 1–2 months owing to severe hypoxic multiorgan damage. A combination of diaphragm pacemaker and night-time ventilatory support may be used for older infants.12, 13
CCHS is a very rare disorder and many practitioners have never seen a case. Early diagnosis is very important in terms of establishing adequate ventilatory management and thus minimizing the consequences of hypoxia. Lifelong ventilatory dependence is a very disabling condition. These children require a lot of supportive care and multidisciplinary approach from the earliest age to improve their quality of life.
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Dejhalla, M., Parton, P. & Golombek, S. Case report of Haddad syndrome in a newborn: congenital central hypoventilation syndrome and Hirschsprung's disease. J Perinatol 26, 259–260 (2006). https://doi.org/10.1038/sj.jp.7211480
- congenital hypoventilation syndrome
- Hirschrprungs's disease
- Haddad syndrome
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