The role of MYCN and PHOX2B gene combined with plasma cell-free DNA detection in risk stratification and predicting the prognosis of high-risk neuroblastoma / 中华实用儿科临床杂志

Objective:To explore the clinical significance of the MYCN gene, PHOX2B gene and plasma cell-free DNA (cfDNA) in risk stratification and predicting the prognosis of high-risk neuroblastoma (NB). Methods:This was a prospective study involving 94 high-risk NB children admitted to Beijing Children′s Hospital, Capital Medical University from August 2017 to December 2018.Relative levels of MYCN and PHOX2B and cfDNA at diagnosis, and 4 and 6 cycles of chemotherapy were detected, and their differences were compared by the Chi- square test.Kaplan-Meier survival analysis was performed to explore their prognostic potential in high-risk NB. Results:Among the 94 high-risk NB children, 14 cases (14.9%) had MYCN amplification, 76 cases (80.8%) had positive expression of PHOX2B and 56 cases (59.6%) had cfDNA level higher than 100 μg/L.The proportion of high lactate dehydrogenase (LDH, ≥1 500 U/L) level in the MYCN gene amplification group (6/14 cases) was higher than that in the normal group (9/80 cases) ( P=0.009). The proportion of multi-site metastasis (54/76 cases) and high neuron specific enolase (NSE) level (NSE≥370 μg/L, 37/76 cases) in PHOX2B positive group were significantly higher than those in the negative group (5/14 cases, 2/14 cases) ( P=0.015, 0.020). The proportion of high LDH and high NSE in high cfDNA concentration (≥229.6 μg/L)group (13/37 cases, 28/37 cases) were significantly higher than those in low cfDNA concentration group (2/48 cases, 10/48 cases) (all P<0.001). With the decreased tumor burden during the treatment, the copy number of PHOX2B gene and cfDNA level were significantly lower than those at the initial diagnosis [0 (0-719.6) copies vs.1 723.5 (0-186 000.0) copies; 19.0 (1.1-225.5) μg/L vs.200.6 (8.0-5 247.4) μg/L, all P<0.001]. The 2-year event-free survival (EFS) rate of the MYCN gene amplification group was significantly lower than that of the normal group[(33.3±13.1)% vs.(58.5±7.1)%, P=0.020]. The 2-year EFS rate of PHOX2B positive group was significantly lower than that of the negative group[(47.9±7.1)% vs.(79.1±11.1)%, P=0.043]. EFS rate in high cfDNA concentration group was significantly lower than that in cfDNA low concentration group[(38.6±9.8)% vs.( 71.7±8.2)%, P=0.001]. After 6 cycles of chemotherapy, EFS rate in the PHOX2B positive group was significantly lower than that in the negative group [(16.7±14.4)% vs.( 60.6±6.6)%, P=0.014]; which was significantly lower in the Metaiodobenzylguanidine (MIBG) positive group than that of the negative group[(35.2±11.7)% vs.(65.8±7.1)%, P=0.037]. The MYCN gene and cfDNA concentration were not correlated with the prognosis of high-risk NB.Survival analysis of the combination of PHOX2B and MYCN gene ( PHOX2B+ /MIBG + , PHOX2B+ or MIBG + , PHOX2B-/MIBG -) showed a significant difference in the survival among three groups[0 vs.(53.6±1.2)% vs.(65.5±7.4)%, P=0.003]. Conclusions:The MYCN and PHOX2B gene and cfDNA concentration are of significance in risk stratification and predicting the prognosis of high-risk NB.Compared with the MYCN gene and cfDNA concentration, the PHOX2B gene is more suitable for monitoring the curative effect of chemotherapy on high-risk NB.A combined analysis of PHOX2B gene and MIBG before treatment can be more accurate in evaluating the treatment effect and residual lesions.

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.

Síndrome de hipoventilación alveolar central congénita / Congenital central alveolar hypoventilation syndrome

ResumenIntroducción: El síndrome de hipoventilación alveolar central congénita (SHACC) es un raro trastorno respiratorio del dormir, aunque cada vez más frecuentemente diagnosticado en clínicas de sueño y servicios de neumología pediátrica. Si bien se desconoce su epidemiología, en la literatura médica existen cerca de 300 casos reportados, y su incidencia es de 1 caso por cada 200,000 recién nacidos vivos. Se caracteriza por hipoventilación alveolar que se presenta o empeora durante el sueño. Es secundario a la disminución/ausencia de la respuesta ventilatoria a la hipercapnia o hipoxemia, y en el 90% de los casos es debido a una mutación tipo PARM del gen PHOX2B. Su tratamiento incluye ventilación mecánica y marcapasos diafragmático. Si la terapéutica no se inicia en forma temprana, el paciente desarrollará insuficiencia respiratoria crónica, hipertensión arterial pulmonar, cor pulmonale y la muerte.Casos clínicos: Se presentan tres casos de SHACC diagnosticados, tratados y en seguimiento en la Clínica de Trastornos Respiratorios del Dormir del Instituto Nacional de Enfermedades Respiratorias.Conclusiones: El diagnóstico temprano es importante para el inicio del soporte ventilatorio, y para prevenir el desarrollo de complicaciones y reducir la mortalidad.

AbstractBackground: Congenital central alveolar hypoventilation syndrome (CCAHS) is a rare sleep-related breathing disorder. Although increasingly frequently diagnosed in sleep clinics and pediatric pulmonology services, its epidemiology is not known. There are about 300 reported cases reported in the literature with an incidence of 1 case per 200,000 live births. CCAHS is characterized by alveolar hypoventilation that occurs or worsens during sleep and is secondary to a reduction/absence of the ventilatory response to hypercapnia and/or hypoxemia. In 90% of the cases it is due to a PARM-type mutation of the PHOX2B gene. Treatment includes mechanical ventilation and diaphragmatic pacemaker. If therapy is not initiated promptly the patient can evolve to chronic respiratory failure, pulmonary hypertension, cor pulmonale and death.Case reports: In this paper we present three cases of CCAHS diagnosed, treated and followed up at the Sleep Disorders Clinic of the National Institute of Respiratory Diseases in Mexico.Conclusions: Early diagnosis is important to initiate ventilatory support so as to prevent any complications and to reduce mortality.

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.

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.