OBJECTIVE: To study the trinucleotide repeats of GCN (GCA, GCT, GCC, GCG) encoding Alanine in exon 3 of the PHOX2B gene among healthy individuals from southwest China and two patients with Congenital central hypoventilation syndrome (CCHS). METHODS: The number and sequence of the GCN repeats of the PHOX2B gene were analyzed by capillary electrophoresis, Sanger sequencing and cloning sequencing of 518 healthy individuals and two newborns with CCHS, respectively. RESULTS: Among the 1036 alleles of the 518 healthy individuals, five alleles were identified, including (GCN)₇, (GCN)₁₃, (GCN)₁₄, (GCN)₁₅ and (GCN)₂₀. The frequency of the (GCN)₂₀ allele was the highest (94.79%). And five genotypes were identified, which included (GCN)₇/(GCN)₂₀, (GCN)_13/(GCN)₂₀, (GCN)₁₄/(GCN)₂₀, (GCN)₁₅/(GCN)₂₀, (GCN)₂₀/(GCN)₂₀. The homozygous genotypes were all (GCN)₂₀/(GCN)₂₀, and the carrier rate was 89.58%. Four GCN sequences of the (GCN)₂₀ homozygous genotypes were identified among the 464 healthy individuals. The GCN repeat numbers in the exon 3 of the PHOX2B gene showed no significant difference between the expected and observed values, and had fulfilled the,Hardy-Weinberg equilibrium. The genotypes of the two CCHS patients were (GCN)₂₀/(GCN)₂₅ and (GCN)₂₀/(GCN)₃₀, respectively. CONCLUSION It is important to determine the GCN repeats and genotypic data of the exon 3 of the PHOX2B gene among the healthy individuals. The number of GCN repeats in 518 healthy individuals was all below 20. The selection of appropriate methods can accurately detect the polyalanine repeat mutations (PARMs) of the PHOX2B gene, which is conducive to the early diagnosis, intervention and treatment of CCHS.
Humans ; Infant, Newborn ; Homeodomain Proteins/genetics* ; Hypoventilation/congenital* ; Mutation ; Sleep Apnea, Central/genetics* ; Transcription Factors/genetics*

OBJECTIVE To report on the phenotype of an infant with central hypoventilation syndrome (CCHS) and result of PHOX2B gene mutation analysis for the purpose of genetic counseling and prenatal diagnosis. METHODS Clinical data of an infant with CCHS was collected and analyzed. Potential mutation of PHOX2B gene was analyzed by amplified fragment length polymorphism (amp-FLP) and DNA sequencing. RESULTS The patient had typical clinical features of CCHS including frequent hypoventilation during sleeping, hypoxemia and hypercapnia which could be corrected by continuous ventilatory support. She also had repeated bruising and was difficult-to-wean, but without any cardiac, pulmonary, neuromuscular or brainstem lesions. DNA sequencing and amp-FLP of the PHOX2B gene showed that the patient has carried a polyalanine expansion repeat mutation (PARM) in exon 3. A 27 bp duplication was confirmed in the repeat sequence of 20 alanines by cloned and sequenced. This has led to an expansion of the repeat tract to 29 alanines. The genotype was therefore 20/29. CONCLUSION A patient with CCHS has been described. Mutation screening of PHOX2B gene can be used as an important support for diagnosis and genetic counseling for such patients.
Female ; Homeodomain Proteins ; genetics ; Humans ; Hypoventilation ; congenital ; genetics ; Infant, Newborn ; Mutation ; Sleep Apnea, Central ; genetics ; Transcription Factors ; genetics

Congenital central hypoventilation syndrome (CCHS) is a life-threatening disorder with apnea and cyanosis during sleep requiring immediate endotracheal intubation during the first day of life. The PHOX2B gene has been identified as the major gene involved in CCHS. This is the first report of a Korean neonate with CCHS confirmed to have a PHOX2B mutation with expanded alleles containing 20 polyalanine repeats that is a relatively small number compared to previous cases. The patient required intermittent ventilator support during sleep only and did not suffer from any other disorders of the autonomic nerve system. He consistently needs ventilator support during sleep and remains alive. Analysis of PHOX2B gene is useful for diagnosis and appropriate therapeutic intervention of CCHS patients.
Alleles ; Asian Continental Ancestry Group/*genetics ; Genotype ; Homeodomain Proteins/*genetics ; Humans ; Hypoventilation/congenital/*genetics ; Infant, Newborn ; Male ; Mutation ; Peptides/genetics ; Republic of Korea ; Sequence Analysis, DNA ; Transcription Factors/*genetics ; Ventilators, Mechanical

Congenital central hypoventilation syndrome with Hirschsprung's disease, also known as Haddad syndrome, is an extremely rare disorder with variable symptoms. Recent studies described that congenital central hypoventilation syndrome had deep relation to the mutation of the PHOX2B gene in its diagnosis and phenotype. We report a newborn male infant with clinical manifestations of recurrent hypoventilation with hypercapnea and bowel obstruction. These clinical manifestations were compatible with congenital central hypoventilation syndrome and Hirschsprung's disease, and polyalanine 26 repeats in the PHOX2B gene supported the diagnosis of congenital central hypoventilation. We described a first case of Haddad syndrome in Korean and its clinical and genetic characteristics were discussed.
Asian Continental Ancestry Group ; Base Sequence ; DNA Mutational Analysis ; Hirschsprung Disease/diagnosis/genetics/pathology ; Homeodomain Proteins/*genetics ; Humans ; Hypoventilation/congenital/diagnosis/genetics ; Infant, Newborn ; Male ; Molecular Sequence Data ; *Mutation ; Sleep Apnea, Central/diagnosis/genetics ; Transcription Factors/*genetics

OBJECTIVETo evaluate clinical characteristics and PHOX2B gene mutations in congenital central hypoventilation syndrome (CCHS) and to facilitate the early diagnosis and management of CCHS and reduce the misdiagnosis.

METHODClinical data of 3 infants with CCHS who had recurrent respiratory failure episodes and dependent on mechanical ventilation support in 3 from March 2008 to April 2012 were analyzed, and blood gas analysis was performed respectively in the awaken and sleeping status. Gene sequencing was used for detection of PHOX2B gene mutation.

RESULTAll the three patients had adequate ventilation during awaken time, but they presented with abnormal frequency and shallow breathing associated with alveolar hypoventilation after falling asleep. Blood gas analysis showed hypercapnia and CO2 partial pressure was consistently over 60 mm Hg (1 mm Hg = 0.133 kPa) after falling asleep, which is in accordance with the clinical features of CCHS. The PHOX2B gene sequencing showed that 6 GCN repeats were inserted at exon3 of PHOX2B in case 1, at same position, 5 GCN repeats were inserted in case 2 and 3.

CONCLUSIONNormal ventilation in awaken status while shallow slow breathing accompanied with hypercapnia in sleep are the main clinical characteristics of CCHS, which requires mechanical ventilation. Acquired mutation in exon 3 of PHOX2B gene encoding repeated GCN sequence seems to be the molecular etiology of these three patients.

Alanine ; genetics ; Blood Gas Analysis ; Carbon Dioxide ; blood ; DNA Mutational Analysis ; Exons ; Female ; Homeodomain Proteins ; genetics ; Humans ; Hypercapnia ; diagnosis ; etiology ; Hypoventilation ; congenital ; diagnosis ; genetics ; therapy ; Infant ; Infant, Newborn ; Male ; Mutation ; Oxygen Inhalation Therapy ; Polymerase Chain Reaction ; Polysomnography ; Respiration, Artificial ; Retrospective Studies ; Sleep Apnea, Central ; diagnosis ; genetics ; therapy ; Transcription Factors ; genetics