Spinal anesthesia and postoperative epidural analgesia in a patient with congenital central hypoventilation syndrome: a case report / 대한마취과학회지

BACKGROUND: Congenital central hypoventilation syndrome (CCHS) is a rare disorder characterized by alveolar hypoventilation and autonomic dysregulation. Patients with CCHS have adequate ventilation while awake but exhibit hypoventilation while asleep. More severely affected patients exhibit hypoventilation both when awake and when asleep. CASE: Here, we report a case of successful spinal anesthesia and postoperative epidural analgesia in a patient with CCHS who underwent orthostatic surgery. CONCLUSIONS: In patients with CCHS, anesthesia is used with the goal of minimizing respiratory depression to avoid prolonged mechanical ventilation. Regional anesthesia should be considered where appropriate. Continuous oxygen saturation and end-tidal carbon dioxide monitoring must be available.

Congenital central hypoventilation syndrome: a report of four cases / 中国新生儿科杂志

Objective To study the molecular genetic mechanism of congenital central hypoventilation syndrome ( CCHS).Method The clinical data and molecular genetics results of CCHS diagnosed in neonatology department from 2014 to 2016 were analyzed retrospectively.The relationship between genotypes and clinical phenotypes in patients of CCHS was analyzed , and the diagnostic thinkings , follow－up and prognosis were summarized.Result A total of 4 infants with CCHS were included in this study.Among them, 2 were boys and the other 2 were girls.They were all full－term neonates without asphyxia at birth , but they soon sufferd from dyspnea and cyanosis , required assisted ventilation.One case had difficult defecation. All 4 cases had difficulty in weaning.The respiratory rhythm became weak developed apnea and carbon dioxide retention was detected in blood gas analysis.All the 4 cases died after withdrawal of treatment.The results of molecular genetic testing were as follows.There was a 38bp heterozygous deletion mutation in exon 3 of gene PHOX2B ( e.756＿776 del21bp).Three cases were found small fragment insertion in exon 3 of gene PHOX2B, which attributed to polyalanine repeat expansion mutations (PARMs).One case belonged to type 20/27 and another 2 cases belonged to type 20/26.Conclusion The main manifestation of CCHS in the neonatal period is ventilator dependant , which can combined with megacolon and atypical autonomic nerve disorder.According to the literature, more than 95%of CCHS are caused by the PHOX2B mutation. The symptom is severe when it got a non－PARMs mutation.It′s useful to make a definite diagnosis with genetic diagnosis results , which could be helpful for treating and predicting.Only effective respiratory support and standardized follow－up system can improve the quality of life in patients of CCHS.

Progress of diagnosis and treatment of congenital central hypoventilation syndrome / 中华实用儿科临床杂志

Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder characterized by ventilatory insensitivity to hypercapnia and hypoxemia during sleep and/or wakefulness presenting in infancy,childhood or adulthood.Paired-like homeobox 2B (PHOX2B) is the disease-defining gene for CCHS,which includes 2 mutation types,polyalanine repeat expansion mutation(PARM) and non-PARM.The CCHS-phenotype is associated with PHOX2B genotype.Children with CCHS typically have normal breathing when awake,while have progressive shallow breathing,cyanosis,hypercapnia and hypoxemia when asleep,but they don't response with respiratory effort.CCHS patients mainly present at birth,some may present in adult years.CCHS is also associated with generalized dysfunction of the autonomic nervous system,and Hirschsprung disease and tumors of neural crest origin are associated with the disease.Non-invasive ventilation is an effective treatment and it can increase the quality of life for CCHS patient.

Congenital central hypoventilation syndrome diagnosis and treatment / 国际儿科学杂志

Congenital central hypoventilation syndrome (CCHS)is a rare disorder characterized by hypoventilation during sleep and blunted ventilatory responses to hypercapnia and hypoxemia.It is normally found in neonatal and infant.Late-onset cases have been reported recently.The paired-like homeobox gene PHOX2B is the disease-defining gene for CCHS;a mutation in the PHOX2B gene is requisite to the diagnosis of CCHS.As a lifelong disease,the key treatment is ensuring adequate ventilation and oxygenation,effective modalities include positive pressure ventilation,negative pressure ventilation and diaphragmatic pacing.The strategy of anti-mutant protein and the use of progestin open up clinical perspectives to enhance ventilation in CCHS patients.

Haddad Syndrome: A case report in a Filipino infant

@#Haddad syndrome is a rare congenital disorder in which congenital central hypoventilation syndrome (CCHS) occurs with Hirschsprung’s disease. It is extremely rare with only more than 60 cases reported in the worldwide literature. We report on a Filipino newborn male infant who presented with signs and symptoms of progressive abdominal enlargement, bowel obstruction, and recurrent hypoventilation. The diagnosis of Haddad syndrome was made clinically and confirmed by sequence analysis of the PHOX2B gene which showed a 27repeat heterozygous expansion of the polyalanine-coding region. All CCHS patients require assisted ventilation especially during sleep to prevent lung atelectasis and other complications. An early diagnosis and confirmation by genetic testing is vital for proper management of affected patients.

Congenital central hypoventilation syndrome associated with Hirschsprung's Disease: case report and literature review / Síndrome de hipoventilação central congênita associada à doença de Hirschsprung: relato de caso e revisão de literatura

Abstract Objective: To report the case of a newborn with recurrent episodes of apnea, diagnosed with Congenital Central hypoventilation syndrome (CCHS) associated with Hirschsprung's disease (HD), configuring Haddad syndrome. Case description: Third child born at full-term to a non-consanguineous couple through normal delivery without complications, with appropriate weight and length for gestational age. Soon after birth he started to show bradypnea, bradycardia and cyanosis, being submitted to tracheal intubation and started empiric antibiotic therapy for suspected early neonatal sepsis. During hospitalization in the NICU, he showed difficulty to undergo extubation due to episodes of desaturation during sleep and wakefulness. He had recurrent episodes of hypoglycemia, hyperglycemia, metabolic acidosis, abdominal distension, leukocytosis, increase in C-reactive protein levels, with negative blood cultures and suspected inborn error of metabolism. At 2 months of age he was diagnosed with long-segment Hirschsprung's disease and was submitted to segment resection and colostomy through Hartmann's procedure. A genetic research was performed by polymerase chain reaction for CCHS screening, which showed the mutated allele of PHOX2B gene, confirming the diagnosis. Comments: This is a rare genetic, autosomal dominant disease, caused by mutation in PHOX2B gene, located in chromosome band 4p12, which results in autonomic nervous system dysfunction. CCHS can also occur with Hirschsprung's disease and tumors derived from the neural crest. There is a correlation between phenotype and genotype, as well as high intrafamilial phenotypic variability. In the neonatal period it can simulate cases of sepsis and inborn errors of metabolism.

Resumo Objetivo: Relatar caso de neonato com episódios de apneias recorrentes, diagnosticado com síndrome de hipoventilação central congênita (SHCC) associada à doença de Hirschsprung (DH), o que configurou síndrome de Haddad. Descrição do caso: Terceiro filho de casal não consanguíneo, nascido a termo, parto normal sem intercorrências, peso e comprimento adequados para idade gestacional. Logo após o nascimento apresentou bradipneia, bradicardia e cianose, foi submetido à intubação orotraqueal e iniciada antibioticoterapia empírica devido à suspeita de sepse neonatal precoce. Durante internação em UTI neonatal evoluiu com dificuldade de extubação devido a episódios de dessaturação durante sono e vigília. Apresentou quadros recorrentes de hipoglicemia, hiperglicemia, acidose metabólica, distensão abdominal, leucocitose, aumento de proteína C reativa, com hemoculturas negativas e suspeita de erro inato do metabolismo. Aos dois meses foi diagnosticada doença de Hirschsprung de segmento longo, foi submetido à ressecção do segmento e colostomia à Hartmann. Feita pesquisa genética por reação em cadeia da polimerase para pesquisa de SHCC, que evidenciou alelo mutado do gene PHOX2B e confirmou o diagnóstico. Comentários: Trata-se de doença genética rara, de herança autossômica dominante, causada por mutação no gene PHOX2B, localizado na banda cromossômica 4p12, que resulta em disfunção do sistema nervoso autônomo. A SHCC também pode cursar com doença de Hirschsprung e tumores derivados da crista neural. Há correlação entre fenótipo e genótipo, além de grande variabilidade fenotípica intrafamiliar. No período neonatal pode simular quadros de sepse e erros inatos do metabolismo.

The research development of congenital central hypoventilation syndrome / 中国小儿急救医学

Congenital central hypoventilation syndrome,also known as “Ondine′s curse”,is charac-terized by hypoventilation during sleep and impaired ventilatory responses to hypercapnia and hypoxemia. This disorder is associated with a malfunction of the nerves that control involuntary body functions and abnor-mal development of early embryonic cells that form the spinal cord. This review summarized the latest pro-gression in the pathogenesis,clinical symptoms,diagnosis,treatment and prognosis.

Haddad Syndrome with a Germ-Line Mutation in the PHOX2B Gene in a Korean Neonate

Congenital central hypoventilation syndrome (CCHS) is a life-threatening disease that primarily manifests as sleep-associated respiratory insufficiency and a markedly impaired ventilatory response to hypercarbia and hypoxemia. Paired-like homeobox 2b (PHOX2B) gene mutations are known to cause CCHS. Almost all patients with CCHS are heterozygous for a poly-alanine expansion in PHOX2B. However, some patients have other germ-line abnormalities, including missense, nonsense and frame shift mutations. CCHS combined with Hirschsprung disease (Haddad syndrome) is extremely rare. Here, we report the case of a 1-day-old male neonate with recurrent apnea and bowel distension. Genetic analysis showed that he was heterozygous for a germ-line mutation in the PHOX2B gene. Only three cases of CCHS including two with Haddad syndrome confirmed by PHOX2B gene mutations have been reported in Korea. All of these cases have been heterozygous for a poly-alanine expansion mutation. This is the first report describing Haddad syndrome with a germ-line mutation in the PHOX2B gene in a Korean neonate.

Molecular genetics of congenital central hypoventilation syndrome and Haddad syndrome

Congenital central hypoventilation syndrome (CCHS) is a disorder of the autonomic nervous system characterized by a decreased response to hypercarbia. CCHS is frequently associated with congenital megacolon; the combination is called Haddad syndrome. CCHS is associated with dysfunction in respiratory features of the autonomic nervous system and with other disorders, including facial deformities, cardiovascular symptoms, and tumors. Patients with CCHS frequently have a mutation in the homeobox protein 2b (PHOX2B) gene. Most mutations involve heterozygous expansion of alanine repeats (GCN). Interestingly, a higher polyalanine repeat number is associated with a more severe clinical phenotype. To clarify the role of PHOX2B in disease pathogenesis, we introduce and review the clinical and molecular features of CCHS and Haddad syndrome.

Clinical study of congenital central hypoventilation syndrome in four cases / 中国小儿急救医学

Objective This study aimed to explore the clinical characteristics and treatment of congenital central hypoventilation syndrome(CCHS),to raise awareness on the CCHS for early diagnosis and treatment.Methods The clinical data of 4 babies with CCHS were analyzed,all of the babies were repeated bruising,hypercapnia,and difficult-to-wean.After the relevant checks,we precluded the primary diseases of heart,lung and neuromuscular dysfunction that lead to low ventilation,and detected the major pathogenic genes,Phox2b of CCHS,refer to literature and diagnostic criteria of CCHS.Results Four babies all had typical clinical features of CCHS:enough ventilation when awake.But when they were asleep,their respiratory rate slowed down,hypoventilation,cyanosis and hypercapnia appeared,and they can not be awaked by hypercapnia and hypoxemia caused by hypoventilation.Genetic testing confirmed the presence of Phox2b mutations.Two infants were supported by non-invasive biphasic positive airway pressure(BiPAP),an infant was discharged home at 3 months of age with non-invasive BiPAP,and an infant was discharged home at 1 month of age.Both of them were monitored and treated at home,and showed normal development.Conclusion For babies who were repeated bruising,hypercapnia,and difficult-to-wean,but no primary diseases of heart,lung and neuromuscular dysfunction that lead to low ventilation,CCHS must be considered.Genetic testing of Phox2b can be used as an important diagnostic tool,and non-invasive BiPAP is one of the efficacious methods in the treatment of CCHS.

Haddad Syndrome with PHOX2B Gene Mutation in a Korean Infant

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.

Haddad Syndrome with 27 Polyalanine Repeats in PHOX2B Gene in a Korean Infant / 대한주산의학회잡지

Haddad syndrome is an extremely rare disorder which combines congenital central hypoventilation syndrome (CCHS) and Hirschsprung's disease. Several reports have demonstrated that CCHS was related to mutation of the PHOX2B gene. We report here a newborn male infant with apnea and bowel obstruction. He has been diagnosed with combined congenital central hypoventilation syndrome and Hirschsprung's disease, and had 27 polyalanine repeats in the PHOX2B gene. Two cases of Haddad syndrome with identified PHOX2B gene mutation have been recently reported in Korea. Both of them had extended alleles containing 26 polyalanine repeats. It is known that increased number of polyalanine repeat mutations is associated with a more severe clinical phenotype. The baby reported here had 27 alanine repeats (i.e. one more than the previously reported cases in Korea) and ganglion cells could be found only in the distal 70 cm of his small bowel.

A Case of Congenital Central Hypoventilation Syndrome with PHOX2B Gene Mutation in a Korean Neonate

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.

A Case of Haddad Syndrome / 대한소아소화기영양학회지

The combination of Congenital central hypoventilation syndrome with Hirschsprung's disease, also known as Haddad syndrome, belongs to the family of diseases now designated as Neurocristopathies. We have experienced a case of Haddad syndrome in a male infant who presented with repetitive abdominal distension, bilious vomiting, and sleep apnea. Following colon study and rectal biopsy disclosed the absence of the ganglion cell. And the infant could not be weaned from mechanical ventilation since birth because of the absence of effective, spontaneous respiration during sleep. As he was diagnosed as Haddad syndrome, tracheostomy and ileostomy were performed consecutively. At the age of 4 months, he was relatively healthy but remained ventilator-dependent. We report the first Korean case of Haddad syndrome with a brief review of the related literature.

The Neurocristopathy in a Newborn with Congenital Central Hypoventilation Syndrome, Hirschsprung's Disease and Ganglioneuroblastoma

Neurocristopathy is characterized as having a common origin in aberrant neural crest development. Congenital central hypoventilation syndrome (Ondine's curse) is characterized by marked depression of respiratory drive during sleep and normal ventilation while awake because of no response to both hypercapnea and hypoxia. The girl was full-term, weighing 3020 grams. The girl had poor respiratory effort at birth, but improved with oxygen supply and stimulation. abdominal distention and calcification were noted. During laparotomy transitional zone was found at distal jejunum; a jejunostomy was constructed. Numerous attempts at extubation failed because of apnea. The results of an apnea work-up, including brain sonography, echocardiogram, were normal. The girl died of sepsis at 37 days of age. para-aortic ganglioneuroblastoma was found on autopsy. We experienced a newborn with congenital central hypoventilation syndrome, Hirschsprung's disease and congenital ganglioneuroblastoma representative of neurocristopathy.