congenital central hypoventilation syndrome ( cchs ) is a life - threatening disorder characterized by an idiopathic failure of the automatic control of breathing , particularly during sleep . in cchs , patients breathe with insufficient depth due to impaired sensitivity to hypercapnea and hypoxia . hirschsprung 's disease ( hd ) , also known as congenital aganglionic megacolon , is characterized by the absence of ganglion cells in any part of the bowel wall . the absence of ganglion cells in hirschsprung 's disease inhibits normal peristalsis , resulting in a functional intestinal obstruction . the combination of cchs and hd was reported first by haddad in 1978 and it has been extremely rare with approximately 60 cases reported in the worldwide literature ( 1 , 2 ) . previous studies described that de novo mutation of the phox2b gene was involved in cchs pathogenesis ( 3 , 4 ) . many patients with cchs are heterozygous for a polyalanine expansion mutation in the second polyalanine repeat residue of the phox2b gene , with one allele having 20 repeats and the affected allele having 25 - 33 repeats of the polyalanine sequence ( 3 , 4 ) . some authors reported that a subset of patients had other mutations in the phox2b gene ( 5 , 6 ) . in korean population , only one case has been reported , however , genetic analysis has not been performed ( 7 ) . here , we report a haddad syndrome with the phox2b gene mutation for the first time in a korean . this 41-week - gestation male was born to a 30-yr - old mother with good health by normal spontaneous vaginal delivery in november 2009 . there was neither family history of congenital anomalies nor maternal exposure to drugs during pregnancy . the baby had apgar scores of 7 and 5 at 1 and 5 min , respectively . the baby was immediately transferred to our hospital for further evaluation and management after stabilization . for the next few days , we tried extubation several times , but failed to succeed because the baby suffered from recurrent apnea and hypercarbia leading to the clinical suspicious of cchs . on day 8 of life , a cranial ultrasound study was performed and it did not show evidence of hemorrhage or mass lesions . during the second day of life , it was noted that the patient had distended abdomen and was unable to pass meconium without rectal stimulation . a gastrografin contrast enema study showed multiple meconium plugs in the colon suggesting meconium plug syndrome ( fig . meconium was passed and abdominal distension was relieved after contrast study . on day 6 of life , he showed sustained abdominal distension with poor bowel movement . a barium contrast enema study was needed to rule out other causes of lower gastrointestinal obstruction . he was noted to have long segment hd with a transition zone at mid descending colon . seromuscular biopsies of the bowel taken 3 cm proximal and distal to the transition zone revealed the presence of ganglion cells in the proximal biopsy specimen only . the cytogenetic study was performed clinically in the infant and his parents and their karyotypes were normal . genomic dna of the patient and his parents was isolated from peripheral blood using the wizard genomic dna purification kit according to the manufacturer 's instructions ( promega , madison , wi , usa ) . amplification of the coding sequence of the phox2b gene by polymerase chain reaction ( pcr ) was carried out as previously described with minor modifications ( 4 ) . polymerase chain reaction - single strand conformational polymorphism ( pcr - sscp ) was performed as previously described ( 8) . pcr products in the patient , his parents , and normal controls were electrophoresed through 8 and 10% polyacryamide gels ( fig . a mutant band was found , however , his parents had no mutant band . to determine the sequences of the dna sample showing the mutant band , direct sequencing was performed by macrogen inc , in korea however , the quality of the result was not clear . to get apparent result of sequencing , paisley , united kingdom ) and 10 single colonies were collected for extracting plasmid dna . direct sequencing revealed expanded alleles containing polyalanine 26 repeats in exon 3 of the phox2b gene , further supporting the diagnosis cchs ( fig . importantly , we were able to prove a phox2b gene mutation containing polyalanine 26 repeats in this patient . hirschsprung 's disease often produces intestinal obstruction in the neonate , characterized by abdominal distention , bilious vomiting , and failure to pass meconium within the first 48 hr . cchs is characterized by relatively normal ventilation when the infant is awake and hypoventilation , even apnea , during sleep . haddad syndrome is interpreted not so much as a combination of two diseases but rather as a complicated form of cchs . when hd is associated with cchs , it is different from classical hd , characterized by extensive intestinal aganglionosis ( 9 ) . the incidence of cchs is extremely low in hd cases , however , the incidence of hd in cchs cases varies from 16% to 50% according to previous studies ( 3 , 5 , 6 , 9 ) . additional symptoms are ophthalmic abnormalities , esophageal dysmotility , sensorineural hearing loss , neural crest tumors ( ganglioneuromas , neuroblastomas ) , and dysmorphic facial features ( 3 , 5 , 9 ) . however , additional symptoms were not found in our case . according to previous report in korean , a haddad syndrome patient also had no additional symptoms except congenital ptosis ( 7 ) . ( 3 ) , and its rate was over 90% among cchs patients ( 4 , 6 ) . polyalanine expansions are the most common mutations in patients with cchs , though rare mutations have been reported such as frameshift mutation , nonsense mutation or missense mutation ( 3 - 5 ) . in our case , his parents showed no phox2b gene mutation , suggesting de novo mutation of the phox2b gene in haddad syndrome . interestingly , genotype - phenotype correlation has been described in cchs patients with the phox2b gene mutation ( 4 ) . increasing polyalanine repeat mutation size is associated with a more severe clinical phenotype ( 4 ) . ( 10 ) described that haddad syndrome ( cchs + hd type ) showed usually expansions of + 6 and + 7 alanines , and frameshift or missense phox2b mutations may predispose to neuroblastoma . clinical phenotype of our patient was severe , presenting long segment hd and no capacity to maintain sufficient oxygenation and ventilation for at least 30 - 60 min of sleep after removing mechanical ventilation support ( 4 ) . however , our case with expansion of + 6 alanines had no additional symptoms like neural crest tumors . though the symptoms of cchs and hd were severe , no additional symptom in the patient with this mutation type was in agreement with the hypothesis by trochet et al . this result supports that the assay for phox2b polyalanine repeat mutation represents a highly sensitive and specific technique for confirming the diagnosis of cchs and estimating the prognosis . in summary , this report presents a rare case of haddad syndrome with de novo mutation of the phox2b gene in korean for the first time . considering the difficulty of diagnosis of this syndrome because of overlapped of symptoms and signs in an infant